Hepatol Int (2016) 10:1–98

DOI 10.1007/s12072-015-9675-4


Asian-Pacific clinical practice guidelines on the management
of hepatitis B: a 2015 update
S. K. Sarin1 • M. Kumar1 • G. K. Lau2,27 • Z. Abbas3 • H. L. Y. Chan4 •
C. J. Chen5 • D. S. Chen6 • H. L. Chen7 • P. J. Chen8 • R. N. Chien9 •
A. K. Dokmeci10 • Ed Gane11 • J. L. Hou12 • W. Jafri13 • J. Jia14 • J. H. Kim15 •

C. L. Lai16 • H. C. Lee17 • S. G. Lim18 • C. J. Liu7 • S. Locarnini19 •
M. Al Mahtab20 • R. Mohamed21 • M. Omata22 • J. Park23 • T. Piratvisuth24 •
B. C. Sharma25 • J. Sollano26 • F. S. Wang28 • L. Wei29 • M. F. Yuen30 •
S. S. Zheng31 • J. H. Kao32

Received: 20 May 2015 / Accepted: 14 September 2015 / Published online: 13 November 2015 
The Author(s) 2015. This article is published with open access at Springerlink.com

Abstract Worldwide, some 240 million people have update the recommendations for the optimal management
chronic hepatitis B virus (HBV), with the highest rates of of chronic HBV infection. The 2015 guidelines were
infection in Africa and Asia. Our understanding of the developed by a panel of Asian experts chosen by the
natural history of HBV infection and the potential for APASL. The clinical practice guidelines are based on
therapy of the resultant disease is continuously improving. evidence from existing publications or, if evidence was
New data have become available since the previous unavailable, on the experts’ personal experience and
APASL guidelines for management of HBV infection were opinion after deliberations. Manuscripts and abstracts of
published in 2012. The objective of this manuscript is to important meetings published through January 2015 have

& S. K. Sarin 12
Department of Infectious Diseases and Hepatology Unit,
shivsarin@gmail.com Nanfang Hospital, Guangzhou, China
1 Department of Medicine, Aga Khan University, Karachi,
Department of Hepatology, Institute of Liver and Biliary
Sciences, New Delhi, India
2 Beijing Friendship Hospital, Capital Medical University,
Division of Gastroenterology and Hepatology, Humanity and
Beijing, China
Health Medical Centre, Hong Kong SAR, China
3 Seoul, Korea
Department of Hepatogastroenterlogy, Sindh Institute of
Urology and Transplantation, Karachi, Pakistan Department of Medicine, University of Hong Kong,
4 Hong Kong, China
Institute of Digestive Disease, The Chinese University of
Hong Kong, Hong Kong, China Internal Medicine Asan Medical Center, Seoul, Korea
5 18
Genomics Research Center, Academia Sinica, National Division of Gastroenterology and Hepatology, National
Taiwan University, Taipei, Taiwan University Health System, Singapore, Singapore
6 19
Department of Internal Medicine, National Taiwan Research and Molecular Development, Victorian Infectious
University College of Medicine, Taipei, Taiwan Diseases Reference Laboratory, Melbourne, Australia
7 20
Graduate Institute of Clinical Medicine, National Taiwan Bangabandhu Sheikh Mujib Medical University, Dhaka,
University College of Medicine, Taipei, Taiwan Bangladesh
8 21
Department of Internal Medicine, National Taiwan Department of Medicine, Faculty of Medicine, University
University Hospital, Taipei, Taiwan Malaya, Kuala Lumpur, Malaysia
9 22
Liver Research Unit, Chang Gung Memorial Hospital and Yamanashi Hospitals (Central and Kita) Organization, 1-1-1
University, Chilung, Taiwan Fujimi, Kofu-shi, Yamanashi 400-8506, Japan
10 23
Department of Gastroenterology, Ankara University School Department of Internal Medicine, Institute of
of Medicine, Ankara, Turkey Gastroenterology, Yonsei University College of Medicine,
11 Seoul, Korea
New Zealand Liver Transplant Unit, Auckland City Hospital,
Auckland, New Zealand


2 Hepatol Int (2016) 10:1–98

been evaluated. This guideline covers the full spectrum of according to the Grading of Recommendations Assessment
care of patients infected with hepatitis B, including new Development and Evaluation (GRADE) system (Table 1).
terminology, natural history, screening, vaccination, The strength of recommendations reflects the quality of the
counseling, diagnosis, assessment of the stage of liver underlying evidence, which has been classified into one of
disease, the indications, timing, choice and duration of three levels, according to the GRADE system: high (A),
single or combination of antiviral drugs, screening for moderate (B) or low (C). The GRADE system offers two
HCC, management in special situations like childhood, grades of recommendation: strong (1) and weak (2) [1, 2]
pregnancy, coinfections, renal impairment and pre- and (Table 1). Thus, the higher the quality of evidence, the more
post-liver transplant, and policy guidelines. However, areas likely a strong recommendation is warranted; the greater the
of uncertainty still exist, and clinicians, patients, and public variability in values and preferences, or the greater the
health authorities must therefore continue to make choices uncertainty, the more likely a weaker recommendation is
on the basis of the evolving evidence. The final clinical warranted. Grades are not provided for definitions.
practice guidelines and recommendations are presented
here, along with the relevant background information.
1 Introduction
Keywords HBV  Guidelines  Acute hepatitis
An estimated 240 million persons worldwide are chroni-
cally infected with hepatitis B virus (HBV) [3], placing
Methodology of guideline development them at increased risk of developing cirrhosis, hepatic
decompensation, and hepatocellular carcinoma (HCC).
These APASL clinical practice guidelines represent an Although most chronically HBV-infected subjects will not
update of the last APASL guidelines published in 2012. develop hepatic complications, 15–40 % will develop
The 2015 guidelines were developed by a panel of Asian serious sequelae during their lifetime.
experts chosen by the APASL. The clinical practice
guidelines are based on evidence from existing publica- Why this update was needed?
tions or, if evidence was unavailable, on the experts’ per-
sonal experience and opinion after deliberations. New data have become available since the previous
Manuscripts and abstracts of important meetings published APASL guidelines for management of HBV infection were
through January 2015 have been evaluated. The evidence published in 2012. These new data and information relate
and recommendations in these guidelines have been graded to new terminology, natural history of hepatitis B, diag-
nosis, assessment of the stage of liver disease using inva-
sive and noninvasive methods, and the indications, timing,
NKC Institute of Gastroenterology and Hepatology, Prince of choice and duration of treatments in noncirrhotic and cir-
Songkla University, Songkhla, Thailand rhotic patients and in special situations like childhood,
Department of Gastroenterology, G.B. Pant Hospital, pregnancy, coinfections, renal impairment and pre- and
New Delhi, India post-liver transplant. In the current guidelines, policy rec-
Department of Medicine, University of Santo Tomas, Manila, ommendations for support and directions for HBV pre-
Philippines vention and eradication in Asian countries have also been
The Institute of Translational Hepatology, Beijing, China provided. The 2015 guidelines are an update to the 2012
Treatment and Research Center for Infectious Diseases, APASL guidelines, and reflect new knowledge and evi-
Beijing 302 Hospital, Beijing, China dence regarding HBV infection.
Peking University Hepatology Institute, Beijing, China
Division of Gastroenterology and Hepatology, Department of
Medicine, University of Hong Kong, Pofulam, Hong Kong 2 Context of guidelines
Department of Hepatobiliary and Pancreatic Surgery,
Collaborative Innovation Center for Diagnosis and Treatment 2.1 Epidemiology and public health burden
of Infectious Diseases, Key Laboratory of Combined Multi- of chronic HBV infection in Asia Pacific
organ Transplantation, Ministry of Public Health, First
Affiliated Hospital, Zhejiang University School of Medicine,
Hangzhou 310003, Zhejiang Province, China HBV infection is a serious global public health problem. It
is estimated that at least two billion people, or one-third of
Graduate Institute of Clinical Medicine and Hepatitis
Research Center, National Taiwan University College of
the world’s population, have been infected with HBV.
Medicine, National Taiwan University Hospital, Taipei, Approximately 240 million people, or about 6 % of the
Taiwan world’s population, are chronically infected with HBV [3].


Hepatol Int (2016) 10:1–98 3

Table 1 Grading of evidence and recommendations (adapted from the GRADE system) [1, 2]
Notes Symbol

Grading of evidence
High quality Meta-analysis or randomized trials without important limitations or double-upgraded observational A
studiesa. Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality Downgraded randomized trials; upgraded observational studiesa. Further research is likely to have an B
important impact on our confidence in the estimate of effect and may change the estimate
Low Double-downgraded randomized trials; observational studiesa C
Very low quality Triple-downgraded randomized trials; downgraded observational studies; case series/case reportsa
Further research is very likely to have an important impact on our confidence in the estimate of effect and
is likely to change the estimate. Any estimate of effect is uncertain
Grading of recommendation
Strong recommendation Factors influencing the strength of the recommendation included the quality of the evidence, presumed 1
warranted patient-important outcomes, and cost
Weaker Variability in preferences and values or greater uncertainty: more likely a weak recommendation is 2
recommendation warranted. Recommendation is made with less certainty; higher cost or resource consumption
Cohort, cross sectional, and case–control studies are collectively referred to as observational studies. Limitations that reduce the quality of
evidence of randomized controlled studies include study limitations (such as lack of allocation concealment, lack of blinding, large losses to
follow-up, failure to adhere to an intention-to-treat analysis, stopping early for benefit, or failure to report outcomes), inconsistent results,
indirectness of evidence, imprecision, and publication bias. Factors that can increase the quality of evidence of observational studies include
large magnitude of effect, plausible confounding that would reduce a demonstrated effect, and dose–response gradient

The prevalence of HBV infection is highly heterogeneous 0.5 % in 2004 [9]. This has also resulted in a marked
throughout the world, with an intermediate to high preva- decline in the incidence of infant fulminant hepatitis,
lence in the Asia-Pacific region, representing three-quarters mortality associated with chronic liver disease and HCC in
of chronic HBV-positive subjects worldwide [4]. In addi- those born since advocacy of HBV vaccination began [10].
tion, the Western Pacific region (defined by the World In mainland China, a national survey of HBV seroepi-
Health Organization as 37 countries including China, demiology has already shown a decrease in the general
Japan, South Korea, Philippines, and Vietnam) accounts prevalence of HBsAg, from 9.75 % in 1992 to 7.18 % in
for nearly 50 % of all chronic HBV infection globally, 2006, and a decrease in children years of age, from
although it has less than one-third of the world’s population 9.67 % in 1992 to 0.96 % in 2006 [11].
[5]. In Korea, the prevalence rates of chronic HBsAg posi-
Prior to implementation of the HBV vaccination pro- tive subjects were 4.61 % in 1998 and 2.98 % in 2010;
gram, the Asian-Pacific region was divided into three cat- among teenagers (10–19 years), it decreased from 2.2 % in
egories in terms of HBsAg prevalence [6]. High-prevalence 1998 to 0.12 % in 2010 [12].
([8 %) regions included mainland China, the Hong Kong A study conducted in Taiwan showed relative risk of
special administrative region (SAR), Taiwan, Korea, HCC of 9.6 % for males who were positive for HBsAg
Mongolia, Philippines, Thailand, Vietnam, and the South alone, but the risk increased to 60.2 % in males who were
Pacific island nations. Intermediate-prevalence (2–8 %) both HBsAg- and HBeAg-positive [13]. It is estimated that
regions included central Asia, the Indian subcontinent, approximately one-third liver cirrhosis cases and more than
Indonesia, Malaysia, and Singapore. Low-prevalence half of the HCC cases in the Asian region are attributable to
( %) regions included Australia and New Zealand, HBV [14]. Indeed, chronic HBV infection is the dominant
although prevalence has increased in recent years due to risk factor for HCC in most areas of Asia-Pacific. More
immigrants from high-prevalence countries [7, 8]. than 700,000 new HCC cases were diagnosed in 2008, with
Universal HBV vaccination in newborns has dramati- an age-adjusted incidence of 10.8 per 100,000 worldwide
cally changed the epidemiology of chronic HBV infection. [15]. Most HCC cases ([80 %) occur in eastern Asia and
A systematic review published by WHO experts in 2012 sub-Saharan Africa, where the incidence is [20 per
showed a decrease in prevalence of chronic HBV infection 100,000 individuals [16], and is higher in males than
from 1990 to 2005 in most regions of the world [3]. females. For example, in Korea, the age-standardized
For example, in Taiwan, where universal vaccination of incidence rate of HCC is 47.1 per 100,000 persons for
newborns was started in 1983–1985, HBsAg prevalence in males and 11.4 per 100,000 persons for females. In Thai-
children younger than 15 years of age decreased from land, the annual incidence is 38.6/100,000 persons for
9.8 % in 1984 to 0.7 % in 1999, and was further reduced to males and 17.2/100,000 persons for females, and in China


sub-group.4 Hepatol Int (2016) 10:1–98 it is 37. This phase is also infection in infected subjects. staging of the disease. value of 98 % in diagnosing reactivation of reacti- while to have the lower ALT values for early vation of HBV [23]. or detection of HBV DNA with and as raised ALT if [29 ULN [19]. Chronic hepatitis B is defined as chronic necroin- flammatory disease of the liver caused by persistent 1. as HBV infection is a dynamic interaction between the host Various clinical terms relating to HBV infection have been and the virus. Occult HBV infection infection with a current state of HBsAg(-) and anti- HBs(?) Terminologies related to HBV infection 6.000 and 14. identification of liver injury and treatment of 8. Although and detection of anti-HBe in a person who was there is data to suggest that patients with ALT previously HBeAg positive and anti-HBe negative. values [0.5 and 19 the upper limit of laboratory HBV replication (C2 log increase from baseline reference (ULN).7 % incidence of 2.5 times the upper limit of normal but 10. Acute exacerbation or flare of hepatitis in chronic HBV-infected patient is defined as intermittent 1. women revealed a prevalence of around 1. Alanine aminotransferase (ALT) level Determina. Reactivation of hepatitis B Reactivation of HBV level is termed as high normal serum ALT if it is replication should be defined as a marked increase in between 0. different time points and gives the individual an natural history.000 for males and females. HBeAg reversion is defined as reappearance of . where a large study in 1987 of approximately and females. The precise 3. 11. HBV DNA ULN for an ALT level of 30 U/l for male and level of [20. as low normal serum ALT if the levels or a new appearance of HBV DNA to a level level is B0. and the inactive state could change at adopted worldwide for diagnosis.2 Terminology in chronic HBV infection ‘‘inactive carrier’’ should be avoided. as it explains the state of HBV infection. Resolved hepatitis B is defined as previous HBV 5. Serum ALT 7. Some authors a level C20. at present. there is HBeAg in a person who was previously HBeAg little data to show that patients belonging to such a negative and anti-HBe positive. These can be undue false sense of security. a conventional ALT level of 40 IU/ml rather than respectively [16]. Related to resistance to nucleo(s)tide analogues (NAs) 5. respond to antiviral therapy.1 %. HBeAg seroconversion is defined as loss of HBeAg 40 IU/ml as the upper limit of normal. 8575 pregnant women had shown a 3. respectively (Table 2). the liver dsyfunction as indicated by raised serum APASL guidelines committee suggested the use of bilirubin (more than 2. Related to response to antiviral therapy atitis B (CHB).0 of ULN still have liver disease [21]. a recent study of 20. patients with chronic HBV infection. undetectable levels. The term 2. 4. as minimally raised serum of C100 IU/ml) in a person with previously stable or ALT if between ULN and 29 ULN of ALT level. the majority of countries in Asia are using ALT of 9. classified into five categories: 4. Chronic HBV infection is defined as HBsAg HBV infection [17].104 pregnant seropositive status at 6 months or beyond. elevations of serum aminotransferase level to more tion of serum ALT level is important for starting than five times the upper limit of normal and more antiviral treatment as well as for follow-up of than twice the baseline value [22]. A large number of past known as ‘‘inactive carrier’’ and ‘‘inactive chronic studies have shown a reduction in the prevalence of HBV HBV infection.000 IU/ml in a person with no baseline have suggested lower values be used to define the HBV DNA [22. In one earlier study. and treatment strategies.2/100. HBeAg clearance is defined as loss of HBeAg in a patients chronically infected with HBV.9/100. the lowered values of 30 and 19 IU/ml for males In India. 23]. if treated. Related to natural history of chronic HBV infection HBeAg-positive and HBeAg-negative chronic hep- 3. Hepatic decompensation is defined as significant Due to these reasons.’’ However.5 times the upper limit of 123 . Related to HBV infection infection with HBV. after due deliberations. person who was previously HBeAg positive.59 ULN. tive chronic HBV infection’ term is preferred. the use of ‘low replica- infection in the Indian subcontinent. It can be subdivided into 2. Low replicative chronic HBV infection is defined as reasons for the decreased incidence of HBV infection could HBsAg(?) anti-HBe(?) with persistent normal be the introduction of the HBV vaccination [18] and the serum ALT (PNALT) and HBV DNA 000 IU/ wide availability of antiviral drugs to treat the primary ml and no evidence of liver injury.000 IU/ml had a positive predictive 19 U/l for female [20]. While it would be worth.

or occurrence of complications agents such as nucleoside/nucleotide analogues (Table 3). and at the end and assay. Since ALT activity often fluctuates over time.Hepatol Int (2016) 10:1–98 5 Table 2 Terminologies related to HBV infection Terminology Definition ALT level High normal Serum ALT between 0.5 or occurrence of complications such as ascites and hepatic encepahalopathy Undetectable serum HBV DNA Serum HBV DNA below detection limit of a PCR-based assay normal) and prolonged prothrombin time (prolonged pegylated interferon alpha (IFN or PEG-IFN). after the end of therapy. as tran- Please refer to the section on natural history below. The rates of sustained off-treatment biochemical responses may sometimes be difficult to evaluate. 12. Two different types of drugs can be used in the treatment of Serological response for HBeAg Serological response for CHB: immune modulators such as conventional or HBeAg applies only to patients with HBeAg-positive CHB 123 . and hence needs to be worked up Chronic hepatitis B Chronic necroinflammatory disease of liver caused by persistent infection with hepatitis B virus. least 2 years after ALT elevation seems to be reasonable in virological and histological responses. anti-HBe positive Hepatic decompensation Defined as significant liver dysfunction as indicated by raised serum bilirubin (more than 2. additional close ALT follow-up of at Responses can be divided into biochemical. the timing (on or after therapy) and type of therapy. subject (IDAHS) Such a subject could have different levels of HBV DNA and could have no evidence of liver disease to varied stages of liver disease. HBV DNA 000 IU/ ml and no evidence of liver injury Incidentally detected HBsAg positive An asymptomatic individual who has been found to be HBsAg positive on routine blood screening.5 and 19 upper limit of laboratory reference (ULN) Low normal Serum ALT B0. sient (usually months duration) ALT elevations before long-term biochemical remission may occur in some CHB Terminologies related to response to antiviral therapy patients within the first year after treatment discontinua- tion. All responses can be order to confirm sustained off-therapy biochemical remis- estimated at several time points during and after therapy. but now HBsAg(-) and anti-HBs(?) Acute exacerbation or flare of hepatitis Intermittent elevations of aminotransferase to more than 5 times the upper limit of normal and more B than twice the baseline value Reactivation of hepatitis B Reappearance of active necroinflammatory disease of liver in a patient known to have the inactive chronic HBV infection state or resolved hepatitis B infection HBeAg clearance Loss of HBeAg in a person who was previously HBeAg positive HBeAg seroconversion Loss of HBeAg and detection of anti-HBe in a person who was previously HBeAg positive and anti- HBe negative HBeAg reversion Reappearance of HBeAg in a person who was previously HBeAg negative. Undetectable serum HBV DNA is defined as a serum Biochemical response (B) Biochemical response is HBV DNA level below the detection limit (2 IU/ defined as normalization of ALT levels. In such cases. HBeAg(-) anti-HBe(?) status with persistent normal serum ALT. However. It can be subdivided into HBeAg-positive and HBeAg-negative chronic hepatitis B Resolved hepatitis B infection Previous HBV infection.5 times the upper limit of normal) and prolonged prothrombin time (prolonged by more than 3 s). such as ascites and hepatic encephalopathy [24]. and antiviral by more than 3 s). a minimum follow-up of at least 1 year post- treatment with ALT determinations at least every 3 months Terminologies related to natural history of chronic HBV is required to confirm sustained off-treatment biochemical infection response.59 ULN Minimally raised Serum ALT between ULN and 29 ULN Raised Serum ALT 29 ULN Chronic HBV infection HBsAg seropositive status beyond 6 months Low replicative chronic HBV infection HBsAg(?). or INR[1. sion [25]. serological. It can be evaluated ml) of a sensitive validated quantitative PCR-based at several time points during therapy. biochemical responses may not cor- The definitions of virological responses vary according to relate with DNA responses.

depending on the Virological response is defined as an HBV DNA con. ALT levels. but Virological responses on IFN/PEG-IFN therapy with HBV DNA detectable after at least 6 months of therapy in compliant patients. as well as at 6 and increase in HBV DNA level of more than 1 log10 IU/ml 12 months after the end of therapy. Responses to Peg-IFN therapy are defined differently than Virological response is defined as undetectable HBV responses to NA therapy. compared to the nadir (lowest value) HBV DNA level on Sustained off-treatment virological response is defined therapy (as confirmed 1 month later). associated with genotypic resistance Cross resistance Mutation selected by one antiviral agent that also confers resistance to other antiviral agents and is defined as HBeAg loss and seroconversion to anti. as confirmed 1 month later Secondary treatment failure Viral breakthrough in an adherent patient (due to drug resistance) Sustained off-treatment No clinical relapse during follow-up after stopping therapy virological response Complete response Sustained virological response with HBsAg seroclearance Viral relapse Serum HBV DNA [2000 IU/ml after stopping treatment in patients with virological response Clinical relapse Viral relapse along with ALT [29 ALT Histological response Decrease in histology activity index by at least two points and no worsening of fibrosis score compared to pre-treatment liver biopsy or fibrosis reduction by at least one point by Metavir staging Drug resistance Genotypic resistance Detection of mutations in the HBV genome that are known to confer resistance and develop during antiviral therapy Phenotypic resistance Decreased susceptibility (in vitro testing) to inhibition by antiviral drugs. it may precede a as HBV DNA levels below 2000 IU/ml for at least biochemical breakthrough. severity of liver disease and the type of NA. It is usually evaluated at Virological breakthrough is defined as a confirmed 6 months and at the end of therapy. Virological responses on NA therapy HBe. HBsAg loss and development of anti-HBs (any titers). centration of 000 IU/ml. Primary non-response is defined as log 10 IU/ml Serological response for HBsAg Serological response for decrease in HBV DNA level from baseline at 3 months of HBsAg applies to all CHB patients and is defined as therapy. DNA by a sensitive PCR assay. every 3–6 months during therapy.6 Hepatol Int (2016) 10:1–98 Table 3 Terminologies related to response to antiviral therapy and resistance to NAs Terminology Definition Biochemical response Normalization of serum ALT level Serological response For HBeAg HBeAg loss and seroconversion to anti-HBe in patients with HBeAg-positive chronic HBV infection For HBsAg HBsAg loss and seroconversion to anti-HBs Virological response on IFN/Peg-IFN therapy Virological response HBV DNA levels below 2000 IU/ml Sustained virological response HBV DNA levels below 2000 IU/ml for at least 12 months after the end of therapy Virological response on NA therapy Primary nonresponse Reduction of serum HBV DNA log IU/ml at 12 weeks of oral antiviral therapy in an adherent patient Suboptimal or partial virological Reduction of serum HBV DNA [1 log IU/ml but still detectable at 24 weeks of oral antiviral therapy in an response adherent patient Virological response Undetectable serum HBV DNA during therapy Virological breakthrough Increase of serum HBV DNA [1 log IU/ml from nadir of initial response during therapy. The main causes of virological breakthrough 123 . characterized by an increase in 12 months after the end of therapy. Suboptimal or partial virological response is defined as a decrease in HBV DNA of more than 1 log10 IU/ml. It is usually evaluated Primary non-response has not been well established.

which may last 1–4 decades in different populations and individuals. The disease typically becomes quiescent after the HBV resistance to NA(s) is characterized by selection of immune-clearance phase. its subsequent course largely consists diagnosis of immune tolerance and immune clearance of four phases of the underlying liver disease. persistently normal serum ALT levels. overall natural course of the infection. ening of fibrosis score compared to pre-treatment liver By contrast.e. despite Cross resistance is defined as mutation selected for by evidence of active HBV replication denoted by the pres- one antiviral agent that also confers resistance to other ence of HBeAg and HBV DNA in serum. the majority (75 %) of cir- Complete response is defined as sustained off-treatment rhosis complications and HCC occur in this population of virological response. spontaneous and treatment-induced 2. or because it is of although this still remains controversial. All phases have been pathogeneti. characterized by HBeAg sero- HBV variants with amino acid substitutions that confer conversion to anti-HBe and HBV DNA that remains at a reduced susceptibility to the administered NA(s). often continues [26]. phase. However. An Histological response is defined as a decrease in his. tance may result in primary non-response or virological breakthrough on therapy. erant phase is defined as persistence of HBeAg-positive HBV infection without significant ongoing necroinflam- Importance of age of acquisition of the virus matory disease of the liver. ALT levels. About Viral relapse is defined as serum HBV DNA [2000 IU/ 70–85 % of HBeAg seroconverters remain in sustained ml after stopping treatment in patients with virological remission. Phases of chronic HBV infection following vertical Genotypic resistance is defined as detection in the HBV transmission genome of mutations that are known to confer resistance and develop during antiviral therapy. patients who acquire the virus after early biopsy. some have proposed lowering the upper limit of normal either because it may not be an obligatory step in the (ULN) to 30 IU/l for male and 19 IU/l for female [29]. During this antiviral agents.3 Natural history of chronic HBV infection HBeAg seroconversion is infrequent ( %/year). HBeAg-negative. Some authors have suggested that the immune-tolerant phase can be defined as having Patients who acquire HBV infection either at birth or HBeAg positivity. relatively low level or becomes undetectable. either ‘‘vertical’’ or and serum HBV DNA [2 9 107 IU/ml. has been strength and targets of the host immune reactivity against reported to be significantly associated with risk of liver- the replicating HBV. chronicity to the next is not recognizable in all patients. chronic HBV-infected people [27]. the first phase (immune tolerance) bility (in vitro testing) to inhibition by antiviral drugs is characterized by the absence of biochemical symptoms associated with genotypic resistance. Immune-tolerant phase In patients with perinatally Phenotypic resistance is defined as decreased suscepti- acquired HBV infection. within the first 1–2 years of life (i. but HBeAg-negative hepatitis occurs in the response. Therefore. In fact.e. immune-tolerance phase. even though it is within the normal range. reflecting the dynamic interaction between the virus and the human host immune system.. remaining HBeAg seroconverters. the latter is a critically Clinical relapse is defined as viral relapse along with important subgroup in which progression of liver disease ALT [29 ALT. These individuals be discontinued in some patients. Resis. or fibrosis reduction by at least one point by childhood generally do not experience the immune-tolerant Metavir staging. majority of the world’s HBV-infected population. a slightly increased serum ALT cally linked to the level of HBV replication and the level.Hepatol Int (2016) 10:1–98 7 on NA therapy are poor adherence to therapy and/or ‘‘horizontal’’ transmission) typically have a prolonged selection of drug-resistant HBV variants (resistance). Transition from one phase of related mortality in the general population [28].. The immune tol- very short duration. Liver biopsy during immune tolerance often reveals an absence A number of phases of chronic HBV infection are recog- of inflammation and scarring. nized. phase. patients who do not develop cirrhosis. followed by an often equally Sustained off-treatment virological response NA(s) may prolonged immune-clearance phase. Sustained off-treatment include nearly all Asian and African patients and some virological response may be defined as no clinical relapse from the Mediterranean countries. with liver biopsy 123 . of liver disease (i. accounting for a during follow-up after stopping therapy. together with loss of HBsAg. elevated transaminase levels). additional complexity is that HBV can cause HCC even in tology activity index by at least two points and no wors. Once HBV infection Diagnosis of immune-tolerant phase The differential has become chronic. of variable depends mainly on sequential determinations of serum duration and outcome.

The annual rate of spontaneous HBeAg More important than defining the immune-tolerant phase clearance in this phase ranges from 3 to 12 %. and active inflammation on liver biopsy. The median (range) of fibrosis scores pression of serum HBV DNA levels and accelerated among HBeAg-positive patients with persistently normal clearance of HBeAg with seroconversion to anti-HBe ALT was comparable between patients with HBV DNA positivity. but many with fibrosis from without any fibrosis on liver biopsy was flares only result in transient decreases in serum HBV 0. in an Indian study of 73 HBeAg. symp- histology [34]. These quency and severity of the flares. high or fluctuating serum HBV DNA levels. However.0 (0. Also. 31]. Recurrent flares occur more patients who are in the immune-tolerant phase. 28 % of HBeAg-positive patients with nor. and continues despite HBeAg loss and the development of anti- found that only 5 % progressed to cirrhosis and none to HBe antibodies. This phase is characterized by the presence of levels C2 9 106 IU/ml [1. indicating that HBV DNA is a poor surrogate for DNA levels without loss of HBeAg. HBV replication mean age 27. 33]. it The duration of the immune-tolerant phase is variable. levels of 9 106 IU/ml [1. However. The persistent or intermittent elevation in serum aminotrans- area under ROC curve (AUROC) to determine whether ferases. D. although the [35]. 23 had HBV DNA flare in aminotransferase levels.001) [40]. correlates with the risk of findings indicate that prognosis is generally favorable for cirrhosis and HCC [42]. showed only mild disease in all. HBV genotype C [ B. Recent studies have found an association between seroconversion include older age.0–3. More typically. HBs. 44]. it appears to be very short and is hardly This phase may end not only in HBeAg seroconversion. in a Immune-reactive phase During the immune-reactive Korean study. D [ A. Increased immune pres- levels of C2 9 106 IU/ml and 50 had HBV DNA levels of sure on the virus during this phase is reflected by sup- 9 106 IU/ml. recognizable. the time of seroconversion [41]. and some flares may fibrosis on liver biopsy [21. toms of liver disease may appear for the first time. such as in horizontal HBV spread (p \ 0. commonly in males and may explain why HBV-related Transition from immune tolerance to immune clearance cirrhosis and HCC are more common in males than in phase Spontaneous HBeAg seroconversion generally females. D) under other conditions. based on ALT and (Asians [ non-Asians). and patients who progress phase. p = 0. 35]. Two important questions are: (1) What should the phase is related to such factors as age of infection cutoff HBV DNA levels be for considering the patients to (younger [ older). B. especially in Asian patients who acquire the virus early in Genotype C is also associated with more liver injury at life [36]. liver biopsy sent [ absent) [30]. as well as being higher in HBeAg(?) than in to the immune-clearance phase often face disease HBeAg(-) patients [43. as the positive patients with persistently normal ALT.0)] and HBV DNA HBeAg.5 years [26]. and HBV genotypes (A. among children. and the fre- HCC during a follow-up period of 10. was found that after losing HBeAg. 40]. but also in HBsAg clearance and seroconversion to anti- A study from Taiwan followed 240 patients (54 % male.8 Hepatol Int (2016) 10:1–98 examination showing only minimal histological changes progression [33]. associated liver injury may not regress and fibrosis can result [38]. The duration of the immune tolerance [30. These there is a HBV DNA level that could differentiate patients flares may precede HBeAg seroconversion.649]. Factors is to identify patients with histological evidence of liver associated with higher rates of spontaneous HBeAg disease. while state as compared to those with other genotypes (A.6 years) who presented in this phase. occurs before 40 years of age in more than 90 % of HBsAg HBsAg titer has been found to be higher during the positive patients [37].0–4.0 (0. B [ C) [39. F. loss of immune tolerance immune tolerance phase than during the immune clearance occurs at a rate of 10–15 %/year. ethnicity predict histology without liver biopsy. and ALT flare during follow-up (pre- ml. including 57 and 40 Asian patients. Of these patients. However. mode of infection (vertical [ horizon- be in the immunotolerant phase of infection. higher aminotransferase even low levels of HBV DNA and CHB complications. in a number of patients. levels. HBV DNA levels? In two studies on HBeAg-positive baseline biochemical and histological activity (high- patients with normal ALT and HBV DNA [2 9 106 IU/ er [ lower). Thus. it may last for more than three decades. liver fibrosis cannot lead to hepatic decompensation. The duration of this phase. In a study from Alaska. the flare be predicted based on HBVDNA levels and ALT alone subsides after a variable period of time. and (2) how to tal).0). 123 . 40 % had host immune response leads to hepatocyte lysis with a significant fibrosis. immune status (suppressed [ competent). and no patient had a histological fibrosis score of [1 [32.424. B. phase (also known as immune active/immune clearance/ mal ALT and HBV DNA [2 9 104 IU/ml had significant HBeAg-positive CHB/HBeAg clearance phase). those with genotypes In vertical HBV transmission from HBeAg-positive C and F were more likely to revert to the HBeAg-positive mothers.

presence of anti-HBe. and 2. The median change in an erroneous label for a fair proportion of patients.0 outcomes. Among confidence interval) was 4. ALT activity can fluctuate with long eight (29 %) had a one-point change.5–U/l9 ULN than for the group with ALT [21]. 1932 HBsAg-seropositive and with active liver disease on histology.1 %) had a four-point change. 123 . However. fibrosis score was 1. Eight (29 %) that the potential for further disease flares exists and other subjects had no change in fibrosis score and 20 (71 %) had complications such as HCC can supervene. 52]. Other studies have also found that 30–40 % of patients who HBV DNA levels in HBeAg-negative patients with normal exhibited normal serum ALT for more than 6 months had ALT It has traditionally been believed that patients who significant histological findings [51. and distribution necroinflammation and fibrosis to cirrhosis and even to of fibrosis stages (0/1/2/3/4) were 35/46/19/0/0 %. so that cumulative seroconversion. in (range 0–4). HBV DNA ( 9 104 IU/ml) and 18. Spontaneous ALT flares patients with infection acquired at an early age. persistently normal ease [histological activity index (HAI) C3 and/or fibrosis aminotransferase levels. Liver biopsy usually shows mild hepatitis and biopsy. and low or undetectable serum stage C2].6 (2.Hepatol Int (2016) 10:1–98 9 Low replicative phase Although the previous phase of significant fibrosis (F C2). fibrosis score was 1.0 (0.0–2. 50].1–4. most cases of cirrhosis and HCC occurred in patients with low–normal ALT (###BOT_TEXT###. it largely terminates respectively. development of HCC and death.3 %/year among patients who were HBeAg majority of complications occur after HBeAg negative with persistently normal ALT. 28 underwent repeat liver biopsy after median minimal fibrosis. HAI was 3. Many initial studies showed that among patients with seronegative and anti-HCV-seronegative participants were chronic HBV infection with normal ALT. The multivariate-adjusted hazard ratio (95 % higher prevalence of liver injury in such patients. This phase has also been point change. recent studies have shown that this Long-term prognosis of HBeAg-negative patients with may not always be true. In another followed for 4 years. and two referred to as the ‘‘inactive HBsAg carrier’’ state. In a report from ALT Elevated ALT has been considered to be associated REVEAL study group.0). Indeed. Six (21 %) subjects had no change in HAI.0 replicative chronic HBV infection compared to controls (1.5–6 U/l times the ULN) was at highest risk of C2 9 106 IU/ml. rate of liver disease progression was associated with higher mal serum ALT levels. Recent studies have described study entry. Among 414 HBeAg-negative normal ALT Many studies have shown that although the Taiwanese CHBV-infected patients with persistently nor. but this is (7. about 50–90 % compared. Of the 58 patients who had baseline initial liver HBV DNA.1 (1. Twenty-one percent of HBeAg-negative sooner or later in HBeAg clearance and transition to a low patients with persistently normal ALT (PNALT) and HBV replicative phase. for a one-point change [21. the occurred at 4.0–81).0–3. 45–65 % of cases. compared to CHBV-infected ALT levels. those with patients with ALT 5 U/l [53–55]. However.0 (0. Even when the recently updated ULN complications of cirrhosis and HCC. 35 % of HBeAg-negative patients with values that were one to two times the ULN (range of persistently normal ALT for at least 1 year had HBV DNA comparison 0. are HBeAg negative with normal ALT have low HBV DNA levels. This phase is characterized by absence of DNA 9 104 IU/ml had histologically active liver dis- HBeAg. six (21 %) had a two- periods of normal ALT levels. with progression of the underlying liver (1. but inactive cirrhosis may be observed in 50 months (range 36–68). given fibrosis score from initial biopsy was 1 (0–1). the risk of values (30 IU/l for male and 19 IU/l for female) were used. In another study of high-normal ALT (0. In patients with persistently immune reactivity against HBV may have unfavorable normal ALT as defined by updated criteria.137 HBsAg- ogy. More than two-thirds of the patients who experienced complications were already HBeAg negative Histology in HBeAg-negative patients with normal when the complications occurred [27]. ###BOT_TEXT###. All of them had serum ALT levels 5 U/l and had either minimal or mild changes (chronic persistent no HCC or cirrhosis diagnosed before or within 1 year after hepatitis) on biopsy [46–48].1) for liver-related death for those with low mal ALT who were biopsied. cirrhosis and HCC was greater for the group of patients 42 % of such patients had HBV DNA C2 9 106 IU/ml with ALT [0. However.5–19 ULN) had a greater frequency 3233 Chinese patients with chronic HBV infection who of serum HBV DNA levels [2000 IU/ml and a higher were grouped on the basis of ALT at presentation and prevalence of core promoter mutations [45].3) for HCC incidence 58 Indian HBeAg-negative patients with persistently nor.5 U/l9 ULN. The median change in the patients who had accrued severe liver injury during the Hepatic Activity Index (HAI) from initial biopsy was 2.0) and 14 % had [36].0).59 ULN).0–10.0 preceding ‘‘immune clearance’’ phase. while normal ALT HBeAg seronegative participants with low serum levels of has been considered to be associated with inactive histol. six (21 %) had a three-point change. median (range) HAI was 3. it was found that the group with ALT study from India. 49.5–8. probability for ALT flare was 47 % at 10 years [50].

5–1 %/year in patients with chronic C1000 IU/ml could be used to identify patients with high HBV infection [64]. or older age at the time of HBsAg and the development of HCC is not observed if HBsAg seroclearance [66]. 100 %] [66]. ‘‘HBeAg-negative/anti-HBe positive chronic hepatitis B’’ A recent study found that reactivation of hepatitis B [54]. replicative phase for a long period of time and may also Several investigators have attempted to define cutoff HBV lose HBsAg (around 2 %/year).003). ALT version. the risk being higher in C40 years (p = 0. Whereas most patients reach this phase after a log10 IU/ml/year identifies patients with high probability variable duration of low replicative state. With time. African and Middle East countries of the gories of patients has been based on a HBV DNA cutoff of Mediterranean Basin. significant HBV replication and progressive negative chronic hepatitis from inactive carriers. and 24 % had HBeAg-negative CHB.10 Hepatol Int (2016) 10:1–98 Reactivation phase The previous anti-HBe-positive low course. tors of HBsAg loss [positive predictive value (PPV) elevated aminotransferases. it has been shown that HBsAg occur at a rate of 0. Differentiation between these two cate. normal- that in patients with HBV DNA 000 IU/ml. Cirrhosis phase (p = 0.3 mation. It is therefore HBsAg levels are important in predicting HBsAg loss worthwhile to reconsider whether terminologies such as during follow-up. 95 % and a PPV of 85 % [58]. but has now been reported in all It is important to differentiate patients in the low parts of the world. In a recent study. HBeAg-negative CHB rep- replicative phase from patients who remain at risk of pro. as this rep. with genotype C (p = 0. Although many patients remain in the low 44 % whose ALT levels were intermittently normal [61]. 2000 IU/ml [56. These mutations. negative chronic hepatitis. positive anti-HBe. HBV DNA is above 2000 IU/ml [59]. This is followed by a quiescent HBeAg transcription. but in liver damage [18. 25].6 years after spontaneous HBeAg serocon. male sex (p = 0. In one study of 283 Taiwanese patients followed for a following HBeAg seroconversion correlated significantly median of 8. One Asian study found that in inactive HBV carrier are appropriate or should be HBeAg(-) patients with persistently normal ALT. 4 % had HBeAg levels [59 upper normal limit during the HBeAg-positive reversion. The hallmark of this phase is its fluctuating appear to suffer little morbidity after HBeAg 123 . or able than a single test [62]. replication often HBV genome that prevents the formation of HBeAg.02). transmission tion. Patients in this phase are usually older and have more advanced liver disease. 67 % had sustained remission. serial testing is more reli- damage was first referred to as the reactivation phase. diminishes and host immune pressure results in HBeAg/ whereas the basal core promoter (BCP) mutation affects anti-HBe seroconversion. The necroinflammatory activity in the early months and years precore mutation produces a stop codon in a region of the of chronic HBV infection. Mediterranean countries. Phases of chronic HBV infection following horizontal resents a later phase in the course of chronic HBV infec. The high levels of serum Horizontally acquired disease also evolves through a HBV DNA result from a spontaneous mutation in the core number of phases with active replication and hepatic or core promoter region of the viral genome [60].03). Also. and improved liver histol- level below 1000 IU/ml was associated with a 2 % inci. In one Asian study. This state of HBV-induced liver view of the fluctuating course. a HBsAg ization of liver biochemistries. 57]. including liver damage. particularly in gressive disease. and age at HBeAg seroconversion developed in 8 % and HCC in 2 %. 64 % had fluctuating ALT levels. a abandoned. Certain patients HBeAg. resents the most common type of CHB. HBsAg seroclearance is generally risk of reactivation [58]. Currently. which increased to 8 % with an percent of patients. either singly or in phase of infection with lessened liver injury and evolution combination. European. this level remains contro.002) [63]. 19. a threshold of HBsAg decline C0. In a study of 164 anti-HBe-positive patients who replicative phase is not always equivalent to a permanent were monitored at monthly intervals for a median period of termination of replication and of HBV-induced chronic 21 months. HCC has been reported in a small dence of HCC at 20 years. permit HBV replication in the absence of into an inactive HBV infection state. However. HCV coinfection. others retain or redevelop. Spontaneous HBsAg seroclearance has been reported to versial. This association between cirrhosis. ogy [65]. detectable HBV DNA. those who had active hepatitis after HBeAg seroconversion HBeAg-negative CHB was originally reported in [55]. and continued necroinflam. the risk being higher in those with HBsAg level above 1000 IU/ml. but may be high. it was reported accompanied by undetectable serum HBV DNA. some progress of HBsAg loss with a negative predictive value (NPV) of directly from HBeAg-positive chronic hepatitis to HBeAg. decline C1 log10 IU/ml during a 2-year time period or a The reactivation phase is characterized by negative or single measurement below 200 IU/ml are the best predic- positive HBeAg. DNA levels that would differentiate patients with HBeAg- over time. However. Serum HBV DNA levels are lower than in HBeAg- positive patients.

Genotype A is highly prevalent in sub. HBeAg seroconversion and a lengthier period of active gression to cirrhosis: habitual alcohol intake. respectively [70]. HBV genotype B has a higher response rate to IFN-a fection with HCV. cirrhosis. regardless of HBeAg status. the Mediterranean region and India. infection [76]. ther. the persistence of HBV infection The higher rate of cirrhosis among HBeAg-negative after acute hepatitis B was higher in patients with genotype A patients is related to older age and more advanced liver (23 %) than in those with genotype B (11 %) or C (7 %) disease at presentation. Similarly. Northern Europe. Collectively.1). Genotype C mainly initially identified when they were rejected as blood exists in East and Southeast Asia. tion was significantly higher in genotype C patients than in genotype B patients. Italian patients in the inactive infection state. diabetes. as well as obesity.5–13.3 (95 % CI 6. with genotype A infection [83]. Geno- appreciable increase in liver-related morbidity over many type E is restricted to West Africa. Genotype G has been reported in seroconversion following adult acquisition of HBV. This observation reflects the benefit of HBeAg Central and South America. genotype D-infected patients replication (with accompanying hepatitis) increase the risk who had more progressive liver disease had a higher of cirrhosis. Genotype F is found in years [64]. (C [ B) [67. Genotype D is prevalent in donors. particularly in children and 4–8 % for subtypes. Among HBeAg-positive patients. at least ten HBV genotypes (A–J) and several The impact of vaccination has been profound in reducing subtypes have been identified: [8 % for genotypes and the global burden of HBV. remained HBeAg positive during follow-up.3 (95 % CI 1. HBV genotype may correlate with the modes of transmis- sion. showed that these individuals experienced no Africa. France.6–3. a family history of HCC [71]. and the United States. With these infection with hepatitis C virus (HCV) or human immun. Additional HBV genotype C patients may experience delayed factors have been identified to be associated with pro. 68] and a higher proportion ([45 %) of BCP Compared with genotypes C and D patients. risk of cirrhosis for patients with baseline serum HBV DNA Genotype C infections conferred a higher frequency of [104 and [106 copies/ml was 2. 82]. alcohol intake. HBeAg-positive and 8–10 % for HBeAg-negative patients. high levels of HBV replication. studies of HBsAg-positive Saharan Africa. that is. Europe.4 Clinical significance of HBV genotypes 3 Guidelines and common mutants 3.1 Screening for chronic HBV infection Based on the extent of divergence in the entire HBV genomic sequence. genotype C patients are more prone odeficiency virus (HIV).5) and BCP A1762T/G1764A mutation than genotype B. who were Genotypes B and C are common in Asia. the adjusted relative seroclearance [81. young adults. high levels of HBV replication HBV There is no significant association between HBV geno- genotype C [ B) [72]. and core promoter mutations [73]. HBV viral load was higher in genotype C than in genotype these data suggest that persistent high levels of HBV B patients [72]. genotypes B and C are prevalent in highly Predictors of disease progression in chronic HBV infection endemic areas where perinatal or vertical transmission plays an important role in the viral spreading. In a study from Japan. to develop advanced fibrosis. India and Western Africa. concurrent HBV replication than genotype B patients. remaining genotypes are frequently found in areas where dence of cirrhosis has been estimated to be 2–6 % for horizontal transmission is the main mode of transmission. Germany. type and response to nucleos(t)ide analogues [85]. and even HCC than and patients who had HBeAg reversion. The rate of chronicity after acute genotype D the rate of cirrhosis development is higher in those who infection has also been reported to be relatively high [77]. and smoking [74]. Frequency of pre-S dele- infected subject (0 years old) is unclear. but millions of chronic HBV-infected 123 . of HCC has been estimated to be % for noncirrhotic HBV genotype A has better responses to IFN-a treatment chronic HBV-infected patients and 2–3 % for patients with than genotype D patients. habitual treatment than genotype C in HBeAg-positive patients [85]. genotype A mutataion [69]. and B patients had a higher rate of spontaneous HBsAg infected subjects aged 30–65 years. For example. In one study of 3774 HBsAg chronic HBV. whereas the Chronic HBV infection and cirrhosis The annual inci. Geographic distribution of activity and liver damage. Additional risk factors for HCC include coin. but the prognostic significance of a high serum prevalence of BCP A1762T/G1764A mutation than those HBV DNA level at a single time point in a young HBV. 2. Genotype H is this event typically leads to a durable decrease in viral found in Central America [75]. HBV genotype genotype B patients [78–80]. and 9. Fur- cirrhosis. For instance. and pre-S deletion is associated with Chronic HBV infection and HCC The annual incidence higher risk for HCC development [84].Hepatol Int (2016) 10:1–98 11 seroconversion. unfavorable features.

the logistic chain of screening begins health screening [94]. safe. There should be a plan for managing and monitoring Hepatitis Network and a Framework for Action. Screening should be directed towards an important to undergo testing. prevention of new infections. and medical Principles of screening management of infected people. quate information about benefits and disadvantages of estimates of such a hidden burden of disease are poorly participation documented. and of these.2 % of the estimated (% of patients who agree to take the test). In tiatives: increased disease surveillance. the WHO has launched a medical care as a whole number of initiatives [87]. and approaches ment of viral hepatitis services. which include the Global 7. It is estimated that 45 % of people hepatitis services should encompass five core elements in a living with CHB remain undiagnosed. Treatment started at an early stage should be of more of China.12 Hepatol Int (2016) 10:1–98 patients remain. In a US-based insurance cohort study. The prevalence of HBV in this population was poor. It is recognized that one of the major assurance standards obstacles to action remains the large burden of undiagnosed 8. However. In particular. testing itself. They found that the US periodic health examination.2 % in 2006 after vaccination. There should be evidence that the screening test is these optimistic trends do indicate an eventual eradication effective in reducing mortality and morbidity of the virus. The Institute of Medicine recommenda- Japanese study on HBV and HCV prevalence examined tions [95]. a representative case was that 3. European estimates indi- Consequently. precise and validated performed and show that chronic HBV infection continues screening test to be a major health problem. as otherwise newly diag- nosed patients will be lost and will not receive the benefit In a key article published over 40 years ago. a linkage to care. the World of potential therapy that may be lifesaving. and integration and enhance- under-diagnosis of chronic HBV infection. how chronic HBV infection population) were actually chroni- many were referred and evaluated as requiring therapy. Case finding should be a continuing process and not a hepatitis B amongst Asian Americans in San Francisco once-and-for-all project (n = 3163). A good 123 . the viral that can resolve the issue. the difference in the proportion of patients who tested positive Screening and linkage to care for HBsAg compared to the expected number estimated from the NHANES study was 21 % [89].8 % benefit than treatment initiated later and was reduced to 7. diagnostic chronically infected with HBV that can reduce liver-related procedures and treatment outcomes [86]. can be broadly applied patients. With the World Health Organization (WHO) be economically balanced in relation to expenditure on resolution on viral hepatitis. there should be 20.438 chronically HBsAg seropositive. there are few studies that examine this issue of and community education.63 % or 68. In a large cross sectional study screening for 9. although HBsAg clearance is still not a 6. Potential screening participants should receive ade- cases of chronic HBV infection around the globe. improved provider general. screening to detect those with CHB infection had never been tested before or had not been previously is a justifiable exercise. and then evaluation. A study from Italy A large number of studies of epidemiology of chronic HBV showed that based on HBV prevalence data of 1. identification of infected people. In 5. In Asia. social and peer support. such as first time blood donors and those having a to many other countries as well.792 persons [92]. this would appear to be many decades away. awareness. diagnosed [88]. where the seroprevalence rate in 1992 was 9. screening to detect seropositive patients is cate that three-quarters of those infected with chronic HBV insufficient as a management strategy. and broadly recommended three important ini- was estimated to be 0. but little is known of screening uptake infected patients. There should be a simple. cally infected on follow-up [90]. Health Organization established several principles for Consequently. followed by agreement 1. In this article. Seroprevalence studies have been widely 2. resulting in poor coordinated and comprehensive manner—outreach and health outcomes and risk of transmission [93]. the criteria were: with information and education. The benefit of screening should outweigh the physical the interim. in order to the screening program and an agreed set of quality tackle these issues. who were unaware of their infrastructure for management of chronic viral hepatitis hepatitis status. 65 % of those who tested HBsAg positive were Chronic HBV infection clearly falls into this category. The opportunity cost of the screening program should realistic goal. While 4. while specific to the US. unaware they had had chronic HBV infection—either they consequently. without proper infection are unaware of their infection [91]. but only 445 (2. it health problem ends with treatment in those who need it. there is good established treatment for patients and psychological harm caused by the test.29 % from infection only examine those who are detected to be the Ligurian region.

based on evidence that negatives extremely low. In an excellent systematic review of community gram reached 11. These studies excluded screening conducted by state and local public show that screening does pick up significant cases of health departments. screening reduces mortality or complications of disease. Most remember to initiate the process. a significant difference in Population-based screening is where a test is offered outcome (e. This involves would seem that such studies are unlikely. the second ing tests on the same occasion. the BFreeNYC pro. screening itself is a and HBeAg seroconversion [102]. and a further 365 cases Opportunistic screening is less organized and generally were discovered during follow-up [99]. during the initial screening. screening versus no screening. and to inform about the testing process rather. monitoring and evaluation. ing programs can have potentially harmful consequences due to nonspecificity of tests (leading to anxiety and Evidence for screening unnecessary testing). 436 and proportion who require treatment. to provide information screening studies did not examine clinical outcomes. a screening strategy needs to sensitivity and specificity [103]. While cancer screen- major exercise. with treatment of those multiphasic health screening involves a battery of screen- screened and found to be suitable for therapy. Consequently.. par. the NYC Department of Health and Mental Treatment for chronic HBV infection has reduced out- Hygiene. and it management. In the REVEAL study [53]. and community-based organizations [96]. cirrhosis or mortality) then systematically to all individuals in the defined target group favors the screening arm. have the best outcomes in terms of proportion of patients 164 cases of HCC were detected during follow-up. Such interventions have criteria. but and education. treatment.g. In taking up screening. since the lead considerable infrastructure and protocols. effort. Consequently. In addition. the number of patients screened and the number and consequences if tested positive. proportion of patients that test positive evaluation of cirrhosis. all of which involve considerable time and comprehensive screening program. However. protocols. this does not appear to be the case with screening for hepatitis B. Types of screening ment or investigation [98]. cases of cirrhosis were found. false negative or positive results. However. and opportunistic screening is where all participate in screening and those with refers to screening offered to patients who attend a health positive test results are randomized to treatment or no practitioner for some other reason. many stakeholders need to come together infection for those without cirrhosis has shown to and coordinate efforts and resources in order for this improve surrogate markers such as LFTs. is the Hepatitis Outreach Network. social issues. including discrimination and stigmatization of the Some screening strategies are potentially harmful. if patients fulfill treatment in which the strategy is delivered. liver cancer. While models: 123 . advanced liver disease. as it relies on the healthcare worker to significant increase in liver-related mortality [100].000. liver histology strategy to be effective. need to be addressed adequately before ticularly in the case of cancer screening. HBsAg has a high level of for chronic HBV infection. Robotin people.Hepatol Int (2016) 10:1–98 13 example of the approach to screening and linkage to care screening may potentially detect such complications. Establishment of of not treating if there is a positive result may be ethi. reviewed strategies that specifically and 22 of end-stage liver failure [101]. A comes in patients with significant liver fibrosis or similar study was undertaken in Sheffield in the UK [97]. As the largest and most therapy. the second screening strategy chronic HBV infection in most countries. patients. Such a time to development of such complications would take scheme does not appear to have been established for many decades. Unfortunately. making false positives or have evidence of efficacy. which combines the whether screening followed by treatment would prevent expertise and resources of the Mount Sinai School of such complications has not yet been demonstrated. In both scenarios. screened approximately 9000 screening strategies for chronic HBV infection. no such studies within a framework of agreed policy. when there are embarking on screening programs. They categorized programs into four advanced liver disease and their complications. in the While it seems sensible and rational to perform screening screening test for hepatitis B. and diagnosed and managed six cases of HCC and George [104]. and options for of positive HBsAg cases found. Secondly. adverse events of labeling or early diagnosis and adverse effects of treat. proof of effi- cacy relies on randomized control trials of screening There are several types of screening: mass screening or using one of two designs [98]—the first is randomized to population screening involves screening a large population. quality have been performed in chronic HBV infection. There was also a less effective. a screening strategy then requires deliberation on the mode cally difficult to carry out. evidence for screening is largely to be tested in randomized control trials to determine which based on observational data. and treatment of chronic HBV Consequently. Medicine.

. injection-drug use. not just screening alone. The overall evaluation was that these screening programs In countries with high endemicity. which contains beneficial for persons already chronically infected and elements of (B) and (C). Aids such as flyers. health fairs) and potentially treatable stage. • Family members. No data on the proportion of patients HBsAg positivity of C8. A key aspect of this is perinatal. household contacts and sex partner of liver failure. while the community outreach model (B) had ferent countries of the Asia Pacific region. it is worth doing screening leaflets. HBsAg prevalence of target communities. while in most successful programs achieved significant buy-in from countries of low endemicity (i. Counseling is crucial to educate and inform patients about Screening of the general population may be cost effec- chronic HBV infection. consid. implementation need to be established. %). So there are areas of high. the majority of new infections occur among ado- cational initiatives and offering comprehensive care pack. as vaccination is not (D) Outreach and partnership model. sexually transmitted infection chronic infection leads to the development of cirrhosis. socioeconomic status. tion [7.e. but many programs had high medium. sexual. trained counselors and trusted community of ‘high-risk groups’ irrespective of prevalence and contacts can be used to help patients understand this better. and the consent and information to be provided to the patient. • Persons who have received unsafe injections (used geted screening for HBV infection in high-risk individuals syringes or needles) because the infection remains asymptomatic in a vast • Men who have sex with men (MSM) majority of infected individuals. • vaccinate unprotected individuals. where screening is • take measures to reduce risk of transmission to others. The authors felt that the the result of perinatal or household transmission. the logistics of endemicity. the consequences and sequelae of tive in finding new cases in countries with high prevalence. which involves screen. volunteers providing logistic support • counsel to avoid excessive alcohol use. health-care related.. (B) Community outreach model. where screening occurs in is unnecessary for persons already immune (either community setting with a community organization through prior vaccination or a previous resolved acute that has direct links to the target community infection. household. chronic infection and the treatment options available. or HCC. use exposures. delivering culturally appropriate edu. 107–110]: • Persons with liver disease Risk factor screening • Persons needing immunosuppressive or cancer chemotherapy Certain groups are at higher risk of acquisition of HBV and • Injection drug users (IDU) of becoming chronically infected. but it is not in regions with low prevalence. (C) Partnership and contract model. it would depend upon the linkage to care need to be established. • permit ultrasound surveillance to detect HCC at a ing in community settings (e. multiple modes of transmission operate. based on risk factors and doctors provide counseling • plan antiviral therapy which can delay or reverse the and testing referrals progression of liver disease. Screening is of liver damage. i. outsourced to a general health screening company • avoid unnecessary vaccination. The prevalence less uptake.e. Successful linkage to care was China to % in Australia [6]. The systematic review found that screening uptake was highest for programs using an outreach and partnership The prevalence of HBV varies markedly between dif- model (C).g.14 Hepatol Int (2016) 10:1–98 (A) Community clinic model with screening integrated • detect and evaluate stage of the liver disease and extent into routine primary care services. websites. lescents and adults as a result of sexual and injection-drug ages. infections occurred among infants and young children as ering the global burden of disease. and low endemicity based on a prevalence of dropout rates. In countries advice on what is to be done if the test is positive and the with intermediate prevalence. There is a need for tar. In countries of intermediate HBV Whichever screening strategy is employed. Also. 105]: • Inmates of correctional facilities 123 . However. offered by some programs. especially those who • Persons with multiple sexual partners or history of acquire infection at birth or during childhood. 2–7. Proper clinical studies are needed to test whether such The following groups should be tested for HBV infec- methods are useful in increasing screening uptake. Moreover. Identification of a HBV-infected a person with hepatitis B person is helpful to [7. and screenings offered by clinical experts had of chronic infection ranges from 10 % of the population in low uptakes (1–2 %). [90 % of new had at best screened modest numbers of patients. socioeconomic status. [106].. respectively requiring treatment or referral for treatment was provided. and %.

there infected with HBV and should be tested for are few audits of blood safety measures in developing chronic HBV infection include (B1): countries. but anti-HBc posi- • Blood or organ donors tive individuals should be further tested for both HBsAg • Health care workers and anti-HBs to differentiate infection from immunity. sex partners of a person infected and cost effective in populations at higher prevalence. or the presence of less HCV. In such a case. household contacts. both HBsAg and ant-HBs may be negative. Saharan Africa testing at least 95 % of donations for HBV 3:1:5 Strategies to enhance screening acceptance increased from 76 to 94 %.e. Tests used for screening Screening tests are inexpensive infants. In Asia. i. as with hepatitis B cost per case identified decreases. 244 facilities were 3:1:2 There is insufficient evidence to recommend assessed with 71. 123 . STDs if your patient is protected against HBV.874 live any specific screening strategy for CHB and births in 2009.Hepatol Int (2016) 10:1–98 15 • Dialysis patients The total hepatitis B core antibody (total anti-HBc) test • HCV. as new during the window phase of acute hepatitis B. Anti-HBc antibody is also positive practice [111]. Persons with liver disease Family members. Inmates of correctional facilities body can be produced in response to vaccination. 113]. The anti-HBs test will tell with multiple sexual partners. Central and Western regions of China. the impact of the GAVI project on reducing perinatal infection). evidence-based standard of immune response. However. HBV infection was evaluated. cancer chemotherapy tality [117]. Anti-HBs anti. [112. This included a proportion of 3:1:1 Screening for hepatitis B infection is an pregnant females screened for HBV.694 live births in 2002 and 125. patients with immunity show anamnestic Screening in special populations response after one dose of HBV vaccine. Morbidity and Mortality Weekly Report (MMWR) [115] 3:1:4 Screening in high-risk populations should indicates that the number of countries in Africa and sub- continue to be a high priority (A1). there is still room for (C1). This has become even more important. diagnose chronic HBV infection. this is clearly an 3:1:3 Existing screening strategies in antenatal care important area to ensure high compliance. However. nucleos(t)ide analogues in the last trimester of pregnancy Individuals with past HBV infection (anti-HBc reactive) haves been established through randomized control trials should not donate blood even if they have recovered. while patients with occult infection do not [120]. • Infants born to females with chronic HBV This test can be utilized for screening. recovery Dialysis patients from an acute hepatitis B infection.or HIV-infected individuals common pre-S mutants [118]. Patients with false-posi- identify newborns who require prophylaxis against perinatal tive results will need a full course of vaccine to have an infection is a well-established. using a cluster sampling methodology in Eastern. widely available in the developing world [116]. In a large prospective study 3:1 Recommendations (screening for chronic HBV [114]. The HBV screening rate increased from 64 % further research is needed in this crucial area in 2002 to 85 % in 2009. it is unclear to what extent is blood safety is established. • Pregnant female (preferably during the first trimester to The test by itself does not indicate whether immunity or vaccinate unprotected mothers) chronic infection has developed as a result of exposure. and they have the Persons needing immunosuppressive or potential to reduce HBV-associated morbidity and mor. With regard to blood safety. consequently. Consequently.or HIV-infected individuals tells if a person has been previously exposed to HBV [119]. improvement. Nucleic acid testing (NAT) is not and uptake should be undertaken (C1). and is now 3:1:6 High-risk persons who are most likely to be considered a standard of care in blood safety. after the strategies to even further reduce perinatal transmission using disappearance of HBsAg and before the anti-HBs develop. the effectiveness of such screening programs in real life is not ideal. syringes or needles) The HBsAg test is the primary way to definitively Persons who have sex with males (MSM). Between 2002 and important tool to discover new cases of 2009. A recent report in and blood supply should be strengthened (A1). The individuals found to be negative during Injection drug users (IDU) the screening should be vaccinated.. chronic infection (A1). and cases identified Persons who receive unsafe injections (used should be counseled and treated. This test may be false- Antenatal screening for hepatitis B in pregnant females to positive in low prevalence areas.

as well as the importance of lifelong monitoring. to vaccinate unprotected mothers) donor organs are used for HBV seronegative recipients. However. universal vaccination. organs or sperm Can participate in all activities including contact sports Children should not be excluded from daycare or school participation and should not be isolated from other children Can share food. or kiss others 123 . life- HBc (B2). where willingness to pay is moderate. 3:2 Recommendations: counseling and prevention of The risk of infection after blood transfusion and trans- transmission of hepatitis B from individuals with plantation of nonhepatic solid organs (kidneys.2 Counseling and prevention of transmission and concurrent hepatitis B vaccine have been shown to be of hepatitis B from individuals with chronic HBV 95 % efficacious in the prevention of perinatal transmis- infection sion of HBV. In a recent analysis comparing the cost-effectiveness regarding lifestyle modifications and prevention of trans. it was any effect on the progression of CHB. universal vaccination alone is increased risk of HBV infection and therefore should be optimal [127]. immune globulin (HBIG) and hepatitis B vaccine can be made for their newborn immediately after delivery. If anti-HBc-positive trimester. counseling and referral for further care includ- HBsAg-positive female who are pregnant should be ing clinical evaluation. utensils. The risk of infection after transplantation of liver 3:2:1 Chronic HBV-infected persons should be from HBsAg-negative. barrier pro. anti-HBs (B2) and total anti- non-hepatic solid organs. Health care workers antiviral therapy should be administered to prevent de novo Blood or organ donors HBV infection. heavy concluded that HBIG treatment for neonates of HBsAg use of alcohol ([20 g/day in female and [30 g/day in positive mothers is likely to be a cost-effective addition to male) may be a risk factor for the development of cir. the efficacy is lower for mothers with very high serum HBV DNA levels ([7–8 log10 IU/ml) [125. of HBV control strategies combining universal vaccination mission. Targeting HBIG to neonates of Persons chronically infected with HBV should be higher risk. such 3:1:7 Testing should include a serological assay for as 6–12 months. chronic HBV infection: heart) from persons with isolated anti-HBc is low: 0–13 % [122]. vaccinated if they test negative for HBV serological Transmission of HBV from infected health care workers markers. HBIG 3. a limited duration.16 Hepatol Int (2016) 10:1–98 Pregnant females (preferably during the first immune status of the recipients [123]. For sex partners who have not been tested or have to patients may occur in rare instances (see ‘‘3. particularly in settings with adequate rhosis [121]. HBeAg-positive mothers may be preferred counseled regarding transmission to others (Table 4). with hepatitis B immunoglobulin (HBIG) treatment for No specific dietary measures have been shown to have neonates of chronically HBV-infected mothers. While the optimal duration of prophylactic therapy has not been determined. health care infrastructure. but whether HBIG 3:1:8 Screening should be linked to appropriate is necessary is unclear [124].13. Table 4 Recommendations for infected persons regarding prevention of transmission of HBV to others Have sexual contacts vaccinated Use barrier protection during sexual intercourse if partner not vaccinated or naturally immune Do not share toothbrushes or razors Cover open cuts and scratches Clean blood spills with detergent or bleach Do not donate blood.4 Health not completed the full immunization series. For transplantation of livers. need for treatment and counseled to make sure they inform their providers so that vaccination (if found to be negative for HBV appropriate decisions regarding administering hepatitis B infection) (C1). may be sufficient for transplantation of HBsAg (A1). in very Household members and steady sexual partners are at resource-limited settings. However. Patients with chronic HBV infection should be counseled 126]. lungs. long antiviral therapy is recommended. tection methods should be employed. care workers’’ section). anti-HBc-positive donors has been counseled regarding prevention of transmis- reported to be as high as 75 % and is related to the HBV sion of HBV (Table 4) (A1).

the latter an obvious need to develop and use noninvasive. there is antibodies and Hepatitis B DNA measurement. These include serum to get tested for HBV serological markers (HBsAg. and procedure-re- phosphatase. family history of disease. markers or radiographic techniques have been introduced. for elasticity imaging. rise in bilirubin and prolongation of the pro- (A1). being the best marker of viral replication [130]. pneumothorax. biochemical tests. anti-HBs) and to be vaccinated. Comorbidities. Usually.and inter-observer variability in histological prognosis. stage of fibrosis in chronic HBV infection with no clear Other causes of chronic liver disease should be sys. and single measurements of 3:2:4 Chronic HBV-infected subjects should not be ALT and AST do not indicate disease stage. even if it is generally serological and virological markers of HBV. Hepascore. noninvasive tests are helpful in assessing the serum HBV DNA levels [131. the age-spleen- In subjects with chronic HBV infection. but with in their work place (A1). if they are negative aminotransferase (AST) to ALT. The diagnostic accuracy of liver biopsy decreases examination focuses on identifying presence of cirrhosis because it is often subject not only to sampling error. it is invasive and can be ultrasound should be part of the initial evaluation. as it has an impact on also to intra. Knowl- HBV seromarkers should receive hepatitis B edge of the underlying histology can help guide therapeutic vaccination (A1). the AST to platelet ratio index (APRI). the AST/ALT ratio may be 3:2:5 HBV-infected children should not be isolated reversed. biochemical tests include ALT.Hepatol Int (2016) 10:1–98 17 3:2:2 Sexual and household contacts of chronic choosing therapeutic strategies and for monitoring the HBV-infected persons who are negative for responses to anti-viral or anti-fibrotic treatment. A progressive decline in serum albumin con- in the educational and social environment centrations. and the Hui index. Thus. AST. and reproducible tests for detecting liver injury. treatment. However. low-up assessment of the stage of fibrosis during or after HCV and/or HIV. anti-HBe role for liver biopsy among chronic HBV infection. the discriminated and stigmatized in the society or ALT concentrations are higher than those of AST. but or decompensated liver disease. Liver biopsy is considered the tion should include a detailed history and physical reference standard for the histological evaluation of liver examination. diabetes mellitus and metabolic syndrome even in the best possible scenario. interpretation [134]. The associated with rare but potentially serious complications. an area under the should be assessed. should be part of the history taking. levels may fluctuate with time. Comorbidities such taking into account a range of accuracies of the biopsy. 132]. decisions when patients do not meet the clinical practice 3:2:3 Abstinence of alcohol is recommended in guidelines and treatment may be helpful. Aminotransferase chronic HBV-infected subjects (A1). including coinfections with HDV.3 Assessment of persons with chronic HBV the stage of fibrosis and/or the grade of activity in patients infection with a high viral load and high-normal or minimally raised ALT levels and in those older than 30 years without clin- The initial evaluation of an individual with HBV infec. Hepatic steatosis in individuals with receiver operating characteristic (AUROC) [0. a liver biopsy is usually recommended to determine 3. including alcoholic. such as the ratio of aspartate HBc. ical evidence of cirrhosis. magnetic 123 . 4). The physical [133].90 cannot CHB is related to co-existent metabolic factors rather be achieved even for a perfect marker of liver disease than being virally induced [128. or in those who require fol- tematically looked for. biochemical parameters. and hepatic accepted to be a safe procedure. The lated mortality. and determine the likely mode of HBV acquisition and that liver injury is typically irregularly distributed in the possible superinfection with other hepatitis virus(es) liver. In addition. liver biopsy is an imperfect reference standard. the enhanced severity of necroinflammatory activity is essential for liver fibrosis test and. indication for a liver biopsy. autoimmune. the Forns index. as obesity. alkaline including hemorrhage. For time PCR quantification assay should be used to measure example. all first-degree relatives and sexual partners and they are being increasingly used to assess the severity of patients with chronic HBV infection should be advised of liver disease in clinical practice. Alcohol consumption. Thus. Moreover. thrombin time are characteristically observed as decompensated cirrhosis develops. and metabolic liver disease with steatosis or Several noninvasive tests based on serum fibrosis steatohepatitis should be assessed. serum albumin and prothrombin time. 129]. GGT. disease progression to cirrhosis. Spe- assessment of the extent of hepatic fibrosis and/or the cialized tests include Fibrotest.000 of the entire liver. the fibrosis score-4 (FIB- for these markers. and assessment of risk factors to biopsy represents just *1/50. it is important to remember that a liver HBV and HCC. A complete blood count. In chronic HBV infec- tion. accurate platelet index. A real. although there is still an important virological assessment consists of HBeAg. accurate. anti.

Several significant fibrosis and cirrhosis.. and a low cutoff with high sensitivity (i. monitoring the treatment response during long-term. PPV and tice. However. pres- although TE has displayed reliable diagnostic accuracy in ence of hepatic inflammation/fibrosis. and taken into account in therapeutic decision-making. Some persons will fall in advantage of noninvasive tests is that they allow repeated the indeterminate range of test results (i.e. A major of a particular stage of fibrosis. Asian-Pacific and sub-Saharan African regions.e.0–13. to improve the overall and 1. all of the available clinical and biological data must be 70–80.5 treatment strategies.0 and 2. Most commonly reported the severity of liver fibrosis. 19–34 and 91–94 % for APRI high cutoff utilization of noninvasive tests for assessing liver his- [137]. as the use of a single cutoff would result in sub. age. 147].98. which elevated risk of HCC development [13. their score will serial measurements of liver fibrosis. Although. shortened survival. the identification and triage of patients who are ranges of 6. Following vigorous validations in challenge.18 Hepatol Int (2016) 10:1–98 resonance (MR) elastography and transient elastography frequently presents as fluctuating patterns associated with (TE) [135. and can be performed in an outpatient setting. such as acoustic radiation force a complementary tool in the management of chronic impulse imaging and diffusion-weighted MR imaging HBV-infected patients.. fol- fewer false-negative results) is used to rule out the presence low-up longitudinal assessments [141. VIR CF2) were 71–84. recent evaluations of noninvasive tests optimal sensitivity and specificity. respectively. and specific HBV genotypes (e. does not require particular expertise in inter. family history of HCC. In recent years. 0. the role of be between the low and the high cutoff) and will need noninvasive tests is no longer confined to the detection of future re-testing and evaluation. have been developed as well. necroinflammatory activity. and regardless of specific methodological advances. and 28–45. A high cutoff with high have focused on their ability to predict the risk of disease specificity is used to diagnose persons with a particular progression or liver-related death. 50–69. the global number of individuals infected extensive accumulated experience. These 123 . tests can be used to screen patients for early HCC treat- Pacific countries have been evaluated by TE. low and high diagnostic performance. These approaches make up for the weak points in the liver biopsy by improving the Use of risk calculators histology results. 136]. HCC causes poor quality of life and first developed in 2003 and is the most extensively evalu. positivity.3–7. 142]. patients. NPV for diagnosing cirrhosis (METAVIR F4) were 55–73. especially in endemic areas such as TE in diagnosing significant fibrosis (CF2 stage) and cir. Beyond the cross- stages. Chronic HBV infection remains an important cause of Liver stiffness measurement using TE (Fibroscan) was HCC development. such as gender. The 22–49. Indeed. resulting in an overestimation of TE values. Sensitivity. only a rhosis (F4 stage) are good.9 and 9. low and high cutoffs for APRI are 0. Sensitivity. and for cirrhosis (METAVIR F4). Furthermore. and surveillance with surrogate for liver biopsy in assessing the severity of liver abdominal ultrasonography and serum alpha-fetoprotein fibrosis [138–140]. factors. is bilirubin must be considered as a potential confounder inexpensive. sectional studies. and on their use in stage of fibrosis. 90–95. [143–145]..5. but not completely Emerging technologies utilizing ultrasound and MR replace. the advantages of combining TE cutoffs for APRI are 1. but they also reduce the need for liver biopsy. 52–61 and 76–84 % for Neither noninvasive testing nor liver biopsy alone is APRI low cutoff. 81–94. and is thus regarded as a major health ated method of this type. the need for liver biopsy and should be seen as imaging platforms. food intake. but further validation is still required. Because of the have been identified to be independently associated with complex natural history of chronic HBV infection. hepatitis Be antigen (HBeAg) necroinflammation.g. 67. APRI uses two cutoff points for diagnosing specific fibrosis Liver fibrosis is a dynamic process. it can be influenced by factors such as tion. with AUROC of 0. alcohol consump- this setting. 68–81 and 65–72 % sufficient to make a definitive decision in clinical prac- for APRI high cutoff. edema. and serum markers have been established in several studies PPV and NPV for diagnosing significant fibrosis (META. specificity. respectively.8–0. resulting in ment. Most studies report estimated cutoff Therefore. serum levels of ALT and The APRI is a simple test that is readily available. when interpreting the TE values of chronic HBV-infected pretation. tology can significantly reduce. rather. elevated viral load. genotype C). specificity. TE was shown to be a reliable and accurate reduced by antiviral therapy [146].0. noninvasive approa- cutoff values for APRI for the detection of significant ches provide a surveillance tool that predicts clinical out- fibrosis and cirrhosis are as follows: For significant fibrosis come and long-term prognosis. The risk of CHB progressing to HCC may be many studies. thus helping to determine (METAVIR CF2). many patients in Asia. 18–28 and 93–97 % for APRI low cutoff. and cholestasis.95 and small number of patients develop end-stage liver diseases.8 kPa for the diagnosis of at high risk of HCC development is important.81–0. The performances of with CHB is extensive.

cirrhosis. this study also provided a pre- to reveal the future risk of HCC progression in patients diction model for predicting the long-term development of with viral hepatitis so that preventive measures can be cirrhosis. This upgraded HCC risk infected patients. Based on patient’s personalized HCC risks. family history of HCC. surveillance patterns. AUC Although the derivation and validation cohorts were quite 0.61–1.907) and older (C45 years. especially in ity of life and prolonged survival. This study derived seronegative patients.664). quantitative serum HBsAg level. The area risk of HCC. HCV infection.816). and 15-year HCC risk for each score was pre-calcu- clinical variables to estimate HCC risk for chronic HBV. HBeAg and HBV the 2012 Asian Pacific Association for the Study of the genotype) [152]. older (C40 years) HBeAg-seropositive patients was poor rhosis. The potential cutoff risk 123 . levels) [149]. mainly because and the corresponding 95 % CI were 0. HBV DNA levels. a the lack of external validation. (ALT) concentration. ranging from 0. core expensive compared to all other risk predictors in the risk promoter mutations and cirrhosis) [150]. established prediction models that incorporated several 10-. In this study. the minimal REACH-B score should be 7 and 6. All these groups then col. excluded from the validation cohort [153]. Additionally.78 cohort (REVEALHBV). lated and depicted in a nomogram. with an adjusted OR (95 % CI) of 1. chronic hepatitis.790–0. In this study. The risk prediction model for HCC included age. These included IPM from Korea (hospital calculator was internally validated using a third of the based using gender. their follow-up intervals. the risk score developed from the derivation cohort (AUC 0. In HBeAg-seropositive patients. tive patients. and validated its use in a com. This risk score could predict HCC with a wide observed.769 (0.Hepatol Int (2016) 10:1–98 19 factors.4 % at 5 years. age. serum HBV DNA levels. AFP population from which the model was derived. family history of HCC. this posite hospital-based cohort (n = 1505) from Hong Kong same score-dependent eligibility of treatment was not and Korea. HBeAg seronegative patients.0 to 81.903) and in both young (5 years. the original REVEAL nomograms were upgraded by patients with chronic HBV infection.0 to 23. frequent blood tests during follow-up.4 % of HBeAg- accurately and reliably estimated the HCC risk at 3.775–0.and 10-year HCC risk. serum alanine transaminase ment. HBV infection.6 % at 10 years for eligibility for young (0 years) HBeAg-seropositive patients with the lowest through the highest scores. and 0. and serum HBV DNA respectively. bilirubin.883) HBeAg- different in their distributions of sex. viral. a risk calculator might be generated in which scoring system from Hong-Kong (hospital based using age. sex. the REACH-B score could predict treatment rhosis-free CHB patients in a community-based Taiwanese eligibility.796 (0. From the individu. total of 904 noncirrhotic CHB patients were enrolled. as estimated by a REACH score C11. serum HBV DNA and Risk calculators for HCC in chronic HBV-infected patients ALT levels.0 to REACH-B score was excellent in discriminating treatment 47. HBV DNA levels and cirrhosis) [151]. in HBeAg-seronega- a 17-point risk model from 3584 treatment-free and cir.6 % at 3 years. and environmental factors.747–0. patients (AUC 0. incorporating qHBsAg into the HCC risk prediction model alized medicine point of view. age. the authors also showed that the range of risks. age. 5 and seropositive patients older than 40 years of age with high 10 years of follow-up in the validation cohort. their ALT levels never exceeded 29 ULN. and HBV without antiviral treatment Many Asian study groups genotype as the predicting parameters. but the discriminatory capability for serostatus. timely antiviral therapy in HBsAg levels (which are reproducible and low cost) in high-HCC-risk patients may lead to improvement in qual- providing additional predictability of HCC. applied to those at high risk [148]. and showed levels. and cir. anti-viral treatment eligibility of CHB patients according to alcohol consumption. and a combined variable encompassing HBeAg serostatus. age. quantitative serum HBsAg levels can be used in lieu of albumin. The projected 5-. AUC 0. would under the receiver operating characteristic curve (AUROC) be erroneously excluded from treatment. CUHK clinical calculator. (1. HBV DNA levels. and referral With recent studies showing utility of quantitative serum strategies can be tailored. respec. including patient. HBeAg status. tively. 0. GAG-HCC risk score from Hong-Kong Since serum HBV DNA measurement is relatively (hospital based using gender. in predicting 3-. The performance of the decisions during clinical management of chronic HBV-in- risk score was improved when cirrhotic patients were fected patients.98). and REVEAL nomograms from Taiwan (community based The REACH-B scoring system has been used to classify using gender. HBV DNA level. ALT levels. They also found that 46. and it laborated to develop a HCC risk score (REACH-B) showed that for patients to be eligible for anti-viral treat- incorporating gender.811 (0. The most important issue with these was Liver (APASL) treatment guidelines [156]. ALT concentration. these factors should be used [155]. and 0. patients with low levels of HBV DNA (000 IU/ml) interact with one another and lead to HCC development in [154].790). alcohol use and ALT excellent prediction accuracy and discriminatory ability. In addition to HCC. 5. Also. even after 0.831). for HBeAg-seropositive and HBeAg- level as the predicting parameters [153]. however. indicating These risk calculators can be used for evidence-based a fair discriminatory capability.

decompensated cirrhosis. and The ultimate goal is global eradication of HBV infection by serum albumin and globulins. degree of inflammation tal factors such as aflatoxin and alcohol (B1). and the presence and stage of liver disease. Then. 3:3:10 Specific risk calculators need to be developed 3:3 Recommendations (assessment of persons with and validated in patients of different ethnic- chronic HBV infection) ities. and prothrom- various strategies. make decisions to manage such patients (B2). metabolic liver disease with steatosis HBV infection cannot be completely eradicated due to the or steatohepatitis should be assessed (A1). 123 . lessens the risk of cirrhosis and decreases the risk of HCC. although these risk calculators have been also a significant liver disease. the inference of predicted risks under circum. and HBV DNA. fibrosis score) and above 11 raises suspicion Besides HCC. for whom different risk scores are required [158]. This goal can be achieved if HBV repli- 3:3:3 Other causes of chronic liver disease should cation can be suppressed in a sustained manner. including coinfections with accompanying reduction in histological activity of CHB HDV. Because surveillance strategies the stage of fibrosis and/or the grade of derived from a Taiwanese population might not apply activity in patients with a high viral load and globally. the be looked for. patients. above 8 indicates used for predicting HCC risk among patients on anti-virals significant fibrosis (F C2 by METAVIR [159]. and and population variations (A1). 3:3:8 Transient elastography is especially useful in Since current HCC risk prediction tools were generated the assessment of liver fibrosis in patients from a natural history cohort without history of antiviral with normal ALT and bilirubin levels (AI). end-stage liver ment and subsequent monitoring of infected disease. HCV and/or HIV (A1). HBsAg. 3:3:7 Noninvasive tests such as transient elastog- bidities. These cutoffs may have regional milestones of chronic HBV infection. making for treatment and monitoring clinical oped in Asians are poor or modest in Caucasian CHB outcome (BI). HBV genotypes. ages at infection. and for decision- applicability and predictability of HCCrisk scores devel. HBV infection is to improve quality of life and survival of 3:3:2 Measurement of HBV DNA is essential for the infected person by preventing progression of the dis- the diagnosis. several pre. assessment for initiating treat- ease to cirrhosis. A detailed history to investigate the possible 3. and exposures to environmental factors such as raphy can be a useful. liver-related mortality. stiffness measurement generally excludes propriate. autoim- particularly in noncirrhotic patients. Although the risk calculators are easy-to-use and the but also to identify patients who require REACH-B predictive score was externally validated to be antiviral treatment (AI). as well as infection physical examination. a patient infected with hepatitis B. comor. bilirubin.20 Hepatol Int (2016) 10:1–98 and corresponding management strategies still remain an 3:3:5 Accurate assessment of the degree of fibrosis issue. 3:3:6 A liver biopsy is recommended to determine cautions are warranted. It has been shown that the tool for the diagnosis. including alcoholic. further validation is still needed in patients of high-normal or minimally raised ALT levels different ethnicities. and prevention of transmission of subjects (A1). geographical areas. In therapy. 3:3:1 The initial evaluation of an individual with genetic backgrounds. can also be suitable for risk in chronic HBV-infected patients and the development of risk prediction tools. is essential not only to determine prognosis. biochemical tests [in- cluding aspartate aminotransferase (AST) Goal of therapy and ALT. a liver stances of antiviral therapy should theoretically be inap. as well as the seroclearance of 3:3:9 Risk calculators may be used to assess HCC HBeAg. including vaccination. HBV to others. an applicable tool for HCC risk estimation. without clinical evidence of cirrhosis (AI). such as cirrhosis. genetic background. reliable and practical aflatoxin and alcohol [157]. several other clinical outcomes and of cirrhosis. 3:3:4 Comorbidities. treatment and bin time]. HCC and death. gamma-glutamyl transpeptidase (GGT). HBV genotypes or species. ages at infection.4 Goals and endpoints of therapy in chronic HBV source of HBV transmission. complete blood count and hepatic prevention of transmission. and exposures to environmen- the level of viremia. The goal of therapy for chronic ultrasound should be performed (A1). HBV infection should include assessment of comorbidities. alkaline phosphatase. chronic mune. geographical areas. However.

In order to The indications for treatment are generally based mainly on improve HRQOL of CHB patients. and also.5 Indications of therapy in chronic HBV infection period. Even though some antiviral medications decrease HRQOL during the acute treatment 3. version) and HBeAg-negative patients is a satisfactory 3:4:4 Induction of sustained off-therapy virological endpoint. This endpoint. improvement and prevention of complications. the effect of comprehensive intervention on health-related health status. end-stage liver disease. Significant clinical improvement can be standardized medical care. treatment and prevention of trans- that will lead to biochemical remission. decom- a complete and definitive remission of the activity of CHB pensated cirrhosis. 165]. A more realistic endpoint is the induction 3:4:3 The ideal endpoint in both HBeAg-positive of sustained or maintained virological remission [25]. genome integrates into the host genome and might favour 3:4 Recommendations: goals and endpoints of therapy in oncogenesis and the development of HCC [160]. with or person by preventing development of disease. and HBeAg-negative patients is sustained off- Induction of sustained off-therapy virological response in therapy HBsAg loss.05) [163]. is infrequently achievable with the currently available mission of HBV to others (A1). and community involvement. antiviral therapy may not be sufficient to rescue with the Short Form 36 and HBV-specific health surveys. proper treatments [162]. the HBV (p \ 0. without seroconversion to anti-HBs. The ideal 3:4:2 The goal of therapy for CHB is to improve endpoint in both HBeAg-positive and HBeAg-negative quality of life and survival of the infected patients is sustained off-therapy HBsAg loss. Comprehensive interven- Patients with decompensated cirrhosis and tion included government support. and an improved long-term outcome. how. liver biopsy or noninvasive methods). all decompensated patients and they should be considered After comprehensive intervention. anti-HBV agents. HCC and death. the HRQOL in patients for liver transplantation at the same time (Fig. social functioning. negative patients is a satisfactory endpoint detectable HBVDNA by a sensitive PCR assay) under (A1). then a maintained virological remission HBeAg-negative patients is the next most desirable (undetectable HBV DNA by a sensitive PCR endpoint. chronic HBV infection Endpoints of therapy 3:4:1 The overall goal is global eradication of HBV infection by various strategies including vac- Therapy must ensure a degree of virological suppression cination. version to anti-HBs (A1). and by prevention of trans- ever. attention should be paid the combination of three criteria: serum HBV DNA levels. technical guidance from detectable HBV DNA require urgent antiviral treatment the Chinese Center for Disease Control and Prevention. particularly in those with more anti-HBe seroconversion. assay) under long-term antiviral therapy in Health-related quality of life (HRQOL) is significantly HBeAg-positive patients who do not achieve affected in CHBV patients. with NA(s). with or without serocon- both HBeAg-positive (with sustained anti-HBe serocon. certainly improve HRQOL. family history of HCC or cirrhosis and quality of life and provided guidance on improving extrahepatic manifestations (Table 5).Hepatol Int (2016) 10:1–98 21 persistence of covalently closed circular DNA (cccDNA) in support increased. ative patients. is the next most desirable gression with early treatment or liver transplantation can endpoint (A1). the HRQOL of CHBV patients improves after completion of antiviral treatment [161]. histological mission (A1). HRQOL before and 1 year after intervention was measured However. This is associated with progression of the disease to cirrhosis. A recent Chinese study evaluated Indications for treatment should also take into account age. Prevention of disease pro. to the reduction of patients’ treatment cost burden and the serum ALT levels and severity of liver disease (assessed by provision of early health education accompanied with clinical evaluation. Patients with compensated cirrhosis and HBV DNA vitality. and financial concerns decreased the nucleus of infected hepatocytes. and in HBeAg-neg- severe forms of the disease. 1). and mental as well as physical [2000 IU/ml should also be considered for treatment even and mental component score (p \ 0. If sustained off-therapy response not tained anti-HBe seroconversion) and HBeAg- achievable. because it has been shown to be associated with response in both HBeAg-positive (with sus- improved prognosis. HRQOL for patients with CHB.05). long-term antiviral therapy in HBeAg-positive patients 3:4:5 If sustained off-therapy response is not achiev- who do not achieve anti-HBe seroconversion and in able. Family and social 123 . associated with control of viral replication [164. then a maintained virological remission (un. with CHB showed significant improvements in body pain.

Treat if moderate to severe inflammation or significant fibrosisa Persistently normal Assess Fibrosis noninvasively. Assess Fibrosis noninvasively. positive chronic Treat. Treat. Treat if moderate to severe inflammation or significant fibrosisa 000 [ULN Rule out other causes of elevated ALT. Treat if moderate to severe inflammation or significant fibrosisa 2000–20. Biopsy. Treat if moderate to severe inflammation or significant fibrosisa Persistently normal (age Assess fibrosis noninvasively. Biopsy if noninvasive tests suggest evidence of significant fibrosis. age [35 years or with family h/o HCC or cirrhosis. Histology should be obtained or assessed noninvasivelya hepatitis B 1–29 ULN Assess fibrosis noninvasively. Treat if moderate to severe inflammation or significant fibrosisa Noncirrhotic HBeAg. Cirrhosis by noninvasive markers means liver stiffness C11 kPa (by Fibroscan) or APRI C2. Monitor every 3 months. or there is a phase) family h/o HCC or cirrhosis. Biopsy if noninvasive tests suggest evidence of significant fibrosis. Biopsy if noninvasive tests suggest evidence of significant fibrosis. age [35 years.000 Any ALT Rule out other causes of elevated ALT. significant fibrosis means F C2 by METAVIR fibrosis score or Ishak fibrosis stage C3. Histology should be obtained or assess fibrosis noninvasively hepatitis B 1–29 ULN Rule out other causes of elevated ALT. noninvasive tests suggest evidence of significant fibrosis. ALT becomes elevated.000 [29 ULN Observation for 3 months if no hepatic decompensation concerns. Significant fibrosis by noninvasive markers means liver stiffness C8 kPa (by Fibroscan) or APRI C1. age [35 years. Biopsy if ALT becomes elevated. Consider LT of no stabilization cirrhosis Compensated cirrhosis [2000 Any Treat. Biopsy if noninvasive tests suggest evidence of significant fibrosis.5. Histology should be obtained or assess fibrosis noninvasivelya Severe reactivation of Detectable Elevated Treat immediately chronic HBV Noncirrhotic HBeAg. negative chronic Treat.Assess fibrosis noninvasively. [20. age [35 years or with family h/o HCC or cirrhosis. or there is a family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosisa 000 \ULN Assess fibrosis noninvasively. Assess fibrosis noninvasively. Monitor every 3 months. Monitor every 3 months. if noninvasive tests suggest evidence of significant fibrosis. Treat if moderate to severe inflammation or significant fibrosis [ULN Rule out other causes of elevated ALT. age [35 years or with family h/o HCC or cirrhosis. Histology not needed. age [35 years or with family h/o HCC or cirrhosis. age [35 years or family h/o HCC or cirrhosis. Monitor every 3 months. Monitor ALT every 3–6 months and/or DNA every 6–12 months. or there is a family h/o HCC or cirrhosis.0 123 . ALT is persistently elevated. [2000 [29 ULN Observation for 3 months if no hepatic decompensation concerns. Biopsy if noninvasive tests suggest evidence of significant fibrosis. ALT is persistently elevated. Monitor every 3 months. ALT is persistently elevated. Monitor every 3 months.22 Hepatol Int (2016) 10:1–98 Table 5 Treatment indications for chronic HBV-infected patients HBsAg positive patient HBV DNA ALT Treatment (IU/ml) Decompensated Detectable Any Treat. Biopsy if ALT becomes elevated. ALT is persistently elevated. Monitor every 3 months. noninvasive tests suggest evidence of significant fibrosis. if moderate to severe inflammation or significant fibrosisa Persistently normal Assess fibrosis noninvasively. Treat if moderate to severe inflammation or significant fibrosisa a Moderate to severe inflammation on liver biopsy means either hepatic activity index by Ishak activity score[3/18 or METAVIR activity score A2 or A3. Monitor every 3 months.Assess fibrosis noninvasively. Biopsy if 0) (immune tolerant noninvasive tests suggest evidence of significant fibrosis. ALT is persistently elevated. age [35 years or with family h/o HCC or cirrhosis.

Therefore. or minimally raised ALT levels (1–2 times the ULN) These group of patients are not uncommon and the experts respond poorly. it is reason- but noninvasive assessment of fibrosis is another option able to delay treatment for an observation period of (Fig. 3 months. infected patients if they have persistently elevated ALT Patients with severe reactivation of chronic HBV levels [2 times the upper limit of normal (ULN) (at least infection [reactivation with the presence of coagulopathy 1 month between observations) and HBV DNA with prolonged prothrombin time (prolonged by more than [20. liver biopsy may pro. One recent meta-analysis showed that nearly half may also precede spontaneous HBeAg seroconversion. A nonin. and (48 %) of the 683 CHB patients with minimally increased 123 . decompensation. ommended for this group of patients unless they have thrombin time measurement. HBV DNA Detectable • HBV DNA detectable if elevated ALT • Treat • Treat Treat • Histology not needed • Histology should be immediately • Consider LT of no obtained or assess stabilizaon fibrosis noninvasively. 1). serial noninvasive monotherapy and the combination of TDF and emtric- assessment of fibrosis and bio-chemical assessment of itabine are effective in the suppression of HBV DNA in inflammation and disease severity should be done. protocol. or are under a larly in patients with declining serum HBV DNA level.0 if ALT levels are normal. and even severe hepatitis or 192 weeks of therapy with combination of TDF and hepatic decompensation. no drug treatment is rec- with weekly or biweekly serum ALT. particu. may be followed by disease remission. They should be monitored closely emtricitabine [166]. A recent article unanimously agreed that these patients do merit antiviral evaluating the effects of tenofovir disoproxil fumarate therapy. when deliberated on the treatment options for them. patients with normal ALT and high viral load. in the sub-groups of patients where there is significant Available information suggests that patients with per- fibrosis. 1 Treatment indications for chronic HBV-infected patients with cirrhosis or Chronic HBV Infected Paent reactivation of chronic HBV infection Severe reacvaon of Decompensated Cirrhosis Compensated Cirrhosis* Chronic HBV • HBV DNA > 2000 IU/ml if normal ALT. cirrhosis. The authors demonstrated that both TDF regression of fibrosis.* * Cirrhosis by non-invasive markers means Liver sffness ≥ 11 kPa (by Fibroscan) or APRI ≥2.000 IU/ml if HBeAg positive and [2000 IU/ml if 3 s) or INR increased to [1. In such patients. In addition. Such exacerbations. hepatic decompensation should be treated immediately vide additional useful information.Hepatol Int (2016) 10:1–98 23 Fig. Liver biopsy is recommended. including those developing acute on chronic liver failure’’ There is lack of sufficient data to start antiviral therapy section) (Fig. sistently normal alanine aminotransferase levels (PNALT) vated or the DNA levels are below the defined limits. Patients with a rising trend in ALT or bilirubin may be only 5 % of patients achieved HBeAg seroconversion after developing an exacerbation. if there is no concern about hepatic Treatment may be started in pre-cirrhotic chronic HBV.5] with impending or overt HBeAg negative. rioration of hepatic decompensation (see ‘‘Treatment of vasive method for the estimation of the extent of fibrosis is patients with reactivation of chronic HBV infection useful in patients who start treatment without liver biopsy. It was treated with currently available drugs. ALT and high levels of HBV DNA in a double-blinded therapy might help in stabilizing their disease or even way was reported. in order to prevent further progression of fibrosis (TDF) in HBeAg-positive patients with normal levels of and other complications of liver disease. 1). and pro. In these cases. Thus. However. bilirubin. in terms of HBeAg seroconversion. especially in those with with antiviral agents to prevent the development or dete- doubtful causes of hepatic necroinflammation. but the ALT levels are normal or minimally ele. evidence of significant fibrosis.

ALT persistently elevated. Age >35 yr.0 indicates cirrhosis Fig.000 IU/mL ALT Any Any ALT1-2x ULN or N ALT>2x ULN • If elevated ALT. exclude • If elevated ALT. Liver sffness ≥ 11 kPa (by Fibroscan) or APRI ≥2.0 indicates cirrhosis Fig. other causes exclude other causes • Observe for 3 months. Age >35 yr.24 Hepatol Int (2016) 10:1–98 Non-cirrhoc HBeAg posive Chronic HBV infected paent VIRAL HBV DNA HBV DNA HBV DNA LOAD <2000IU/mL 2000 -20.$ significant fibrosis. $ significant fibrosis. ALT persistently elevated.$ invasively.$ or significant fibrosis.000IU/mL >20.5 indicates significant fibrosis. or family h/o HCC or cirrhosis. if no • Assess fibrosis • Monitor ALT 3-6 • Individualize liver concerns of hepac noninvasively monthly and DNA 6-12 biopsy@ decompensaon • Monitor 3 monthly monthly • Treat if moderate to • Treat if no • Individualize liver • Individualize liver severe inflammaon seroconversion biopsy@ biopsy@ or significant fibrosis* • Obtain histology or • Treat if moderate to • Treat if moderate to assess fibrosis non- severe inflammaon or severe inflammaon or invasively. • Assess fibrosis • Assess fibrosis • Assess fibrosis if no concerns of noninvasively noninvasively noninvasively hepac Fibrosis • Monitor 3 monthly • Monitor 3 monthly • Monitor 3 monthly decompensaon • Individualize liver • Individualize liver • Individualize liver • Treat if no biopsy@ biopsy@ biopsy@ seroconversion • Treat if moderate to • Treat if moderate to • Treat if moderate to • Obtain histology or severe inflammaon or severe inflammaon or severe inflammaon assess fibrosis non- significant fibrosis.5 indicates significant fibrosis. 3 Treatment indications for noncirrhotic HBeAg-negative chronic HBV-infected patients 123 .$ @ Biopsy if non-invasive tests suggest evidence of significant fibrosis. $ • Moderate to severe inflammaon on liver biopsy means either Hepac acvity index by Ishak acvity score >3/18 or METAVIR acvity score A2 or A3 • Significant fibrosis on liver biopsy means F≥2 by METAVIR fibrosis score or Ishak fibrosis stage ≥ 3 • Liver sffness ≥ 8 kPa ( by Fibroscan) or APRI ≥1. $ • Moderate to severe inflammaon on liver biopsy means either Hepac acvity index by Ishak acvity score >3/18 or METAVIR acvity score A2 or A3 • Significant fibrosis on liver biopsy means F≥2 by METAVIR fibrosis score or Ishak fibrosis stage ≥ 3 • Liver sffness ≥ 8 kPa ( by Fibroscan) or APRI ≥1. Liver sffness ≥ 11 kPa (by Fibroscan) or APRI ≥2.$ @ Biopsy if non-invasive tests suggest evidence of significant fibrosis. or family h/o HCC or cirrhosis.$ significant fibrosis. 2 Treatment indications for noncirrhotic HBeAg-positive chronic HBV-infected patients Non-cirrhoc HBeAg negave Chronic HBV infected paent VIRAL LOAD HBV DNA <2000IU/mL HBV DNA>2000 IU/mL ALT ALT > ULN Persistently normal ALT1-2x ULN or N ALT>2x ULN • If elevated ALT. exclude • Assess fibrosis • Assess fibrosis • Observe for 3 Fibrosis other causes noninvasively noninvasively months.

sonography and/or HBV DNA every 6–12 months is A subgroup of HBeAg-positive and HBeAg-negative needed (Fig. 2). A liver biopsy should be considered if nificant fibrosis. A suspicion of significant assessment of fibrosis noninvasively. without [2000 IU/ml if HBeAg negative) but ALT any evidence of liver disease and without a family history 9 ULN should obtain assessment of fibro- of HCC or cirrhosis.5] of chronic HBV infection should be [2000 IU/ml) and minimally elevated (1–29 ULN) or started on antiviral therapy immediately after persistently normal ALT should have liver fibrosis asses. 3:5:2 Patients with compensated cirrhosis and HBV If patients are not considered for treatment. noninvasive assessment of liver [20. sending tests for quantitative HBV DNA. with serum HBV DNA [20. Another study tried to explore HBV infection the hepatic histological changes after long-term antiviral therapy in CHB patients with persistently normal ALT 3:5:1 HBsAg positive patients with decompensated levels and advanced hepatic fibrosis [168]. A liver biopsy should treated irrespective of the ALT and HBV DNA be considered in viremic patients older than 35–40 years. Liver biopsy may be needed before therapy to assess without waiting for the results (B1). Evaluation of the severity of fibrosis 0. median duration of 44. treatment in CHB and normal ALT levels. if age is [35 years or there is family of HCC or cirrhosis. 3:5:4 Treatment may be started in pre-cirrhotic and exclude other possible causes of raised ALT levels as a chronic HBV-infected patients if they have guide for consideration of antiviral treatment. and fibrosis should help identify patients for liver biopsy. especially those with high normal or minimally raised ALT 3:5:3 Patients with suspected severe reactivation levels or family history of HCC or cirrhosis. 3). limited data using such an algorithmic should be considered if noninvasive tests approach in CHB. but sed. They should be consid- HBeAg-negative patients with persistently normal ered for treatment if biopsy shows moderate to ALT levels (ALT determinations every 3 months for at severe inflammation or significant fibrosis least 1 year) and HBV DNA levels below 2000 IU/ml. Immunotolerant patients need special attention. [2000 IU/ml if HBeAg negative (B1). they should DNA [2000 IU/ml should be considered for be followed up every 3–6 months. 82. suggest evidence of significant fibrosis. HBeAg-positive patients treatment even if ALT levels are normal (A1). levels (C2). HBeAg.4 % Liver transplantation should be considered if of patients had a baseline fibrosis score of 4 by Scheuer patients do not stabilize with medical man- scoring system and this was reduced to 17. noninvasive assessment of liver every 3 months. (B1). Follow-up with ALT and alpha. do not require 3:5:6 HBeAg-positive patients with HBV DNA immediate therapy. ALT becomes persistently significant fibrosis is suspected or if there is family history elevated. and should be monitored therapy. should obtain screening test in such cases. longed by more than 3 s) or INR increased to Patients with active HBV replication (HBV DNA [1. 3:5:5 Patients with high HBV DNA levels positive patients under 30 years of age with persistently ([20. with intent to [reactivation with the presence of coagulopa- identify the group of patients with significant fibrosis thy with prolonged prothrombin time (pro- requiring treatment (Fig. Biopsy should be considered fibrosis should be done. ALT 123 . without any evidence of liver disease.6 % after a agement (A1). h/o HCC or cirrhosis. The authors cirrhosis and detectable HBV DNA require compared paired liver biopsies before and after lamivudine immediate antiviral treatment with NA(s). If liver between observations) and HBV DNA biopsy is not feasible.000 IU/ml and PNALT should Patients with compensated cirrhosis should be also be followed up every 3 months. should be evaluated for other by a noninvasive method might be useful as the first causes if ALT is elevated. Biopsy There is however.000 IU/ml. 47 %. In these cases. Follow-up should be done at least if noninvasive tests suggest evidence of sig- every 3–6 months. patients showed similar rates of fibrosis (41 vs.000 IU/ml if HBeAg positive and normal ALT levels and a high HBV DNA level.Hepatol Int (2016) 10:1–98 25 ALT levels (levels 1–2 times the ULN) from nine recruited fetoprotein determinations every 3–6 months and ultra- studies had stage 2 or higher fibrosis (95 % CI 36–61 %). generally do not require immediate sis noninvasively. determine the fibrotic stage.000 IU/ml if HBeAg positive and fibrosis should be considered as an alternative. Treatment persistently elevated ALT levels [2 times should be instituted if moderate to severe hepatic upper limit of normal (ULN) (at least 1 month necroinflammation or significant fibrosis is found. the necroinflammatory grade. should be monitored every 3 months. Of them. 3:5 Recommendations: indications of therapy in chronic p = nonsignificant) [167].5 months of therapy.

telbivudine and (19 of 24 patients. in contrast to long-term data using antiviral therapy is 61. In another study including 101 patients from Taiwan 3:5:8 Noninvasive methods for the estimation of the and Hong Kong. 3:5:7 HBeAg-negative patients with HBV DNA HBeAg seroconversion was achieved in approximately 000 IU/ml. but in general. patients who stopped LAM after a minimum of 24 months 3:5:9 Patients who are not considered for treatment of treatment with at least three results of undetectable HBV should be followed up regularly by measure- DNA 6 months apart showed a post-treatment relapse ment of ALT levels. studies among Chinese follow-up (B1). if HBsAg level 00 IU/ml at the end of lamivudine treat- biopsy shows moderate to severe inflammation ment could predict HBsAg seroclearance after stopping or significant fibrosis (C1) (Table 5). the HBsAg decline was slow remains persistently elevated.4 % with consolidation sive markers [mean liver stiffness C8 kPa (by therapy for 2. [171].3 %) at a median of Asia Pacific countries. lamivudine (LAM) trial and a multi-center trial in China. More data is needed for the use ing to undergo liver biopsy may be considered of HBsAg level to guide treatment cessation.1 Results of and predictors of response to nucleos(t)ide including 107 HBeAg-negative patients treated by LAM analogues for 93 ± 35 months showed that end of treatment HBsAg 20 and 00 IU/ml were associated with HBsAg loss Lamivudine. while its development has been [35 years or there is family h/o HCC or stopped in others countries due to myopathy. More 12-month consolidation was 8. 47 ± 35 months showed that end-of-treatment HBsAg predictors of response to therapy. suggest evidence of significant fibrosis.9 % in those with consolidation therapy 2 months needed for these groups of patients.2 %) and sustained response (HBV tenofovir disoproxil fumarate have been approved in most DNA 000 IU/ml.6. adefovir dipivoxil. if age is Korea and the Philippines.5] should be consid- [172].6. longer consolidation of lamivudine was extent of fibrosis are useful in selecting associated with a higher combined response (HBeAg patients for liver biopsy.5 %) at a median with suspected significant fibrosis but unwill- follow-up of 4 years [173]. 79. should obtain follow-up study among 95 CHB patients (43 HBeAg-pos- assessment of fibrosis noninvasively. 93. 175]. HBV DNA. A study among 83 Taiwanese patients found that ered for liver biopsy followed by treatment. respectively Fibroscan) or APRI C1. 28 of 30. 25. In a long-term causes if ALT is elevated. AFP. They should be considered for seroconversion and discontinued lamivudine. ultra- (HBV DNA C104 copies/ml) rate of 37–50 % at 1 year sonography and fibrosis assessment (Table 5) [174. 123 . and itive) on lamivudine for at least 10 years with maintained should be monitored every 3 months if ALT viral suppression (HBV DNA 000 IU/ml). ALT respectively). if age is at 0. Another Taiwanese study 3. cirrhosis. They should be considered for treatment if biopsy shows moderate to severe L-Nucleoside analogues Lamivudine In the Asian inflammation or significant fibrosis (B1). Biopsy [0. entecavir. Patients lamivudine (five of nine patients.6 Results of currently available therapies.000 copies/ml) rate after inflammation or significant fibrosis (C1). should be evaluated for other 44–47 % after 4–5 years of therapy [169].26 Hepatol Int (2016) 10:1–98 becomes persistently elevated. [35 years or there is family h/o HCC or In a Korean study including 178 patients with HBeAg cirrhosis. the relapse treatment if biopsy shows moderate to severe (defined as HBV DNA [140.1 and 97. for treatment (C2) or should be kept on regular In HBeAg-negative patients.7 % in 5 years.0 and 71. A study from Hong Kong including 53 HBeAg- (B1). follow-up B100 IU/ml plus reduction by [1 log from baseline could and stopping rules during therapy in chronic HBV predict sustained response (HBV DNA B200 IU/ml) of infection 100 % (five of five patients) at 12 months and HBsAg loss at 5 years post-treatment [176]. monitoring patients had HBsAg seroclearance.8 %. seven (10 %) is elevated (if ALT is normal. negative patients treated with LAM for a mean of 34 (12–76) months and stopped LAM therapy for 3.166 log IU/ml were optimal cutoffs to predict HBsAg should be considered if noninvasive tests seroclearance (negative predictive values 98. Clevudine has been approved in 4 years post-treatment [177].104 log IU/ml/year [170]. 55. Patients with the seroconversion and undetectable HBV DNA) 6 months suggestion of significant fibrosis by noninva- post-treatment. Baseline HBsAg should be done with ALT every 3–6 months 000 IU/ml and on-treatment reduction of HBsAg and with DNA every 6–12 months). 39. 12–18 and [18 months.

LdT is generally well tolerated. HBeAg seroconversion can be had drug resistance at year 2 in the GLOBE study. 48. HBeAg seroconversion in regression after 240-week treatment with ADV [191].001]. 183].7 %) compared it is still a commonly used therapy in many Asian countries to the continued LdT group at week 104 [185]. be found. seroconversion. Compensatory 18. patients (myopathy and myositis in 0. con. among the 25 patients who had one recent multicenter study on 838 patients. and 21.0 % for codon substitutions that increase viral replication may also HBeAg-negative patients [184]. 53 % of HBeAg-positive patients.5. such as rtL80V/I.5 %) had HBsAg loss [184].749. age [odds ratio (OR) 0.Hepatol Int (2016) 10:1–98 27 LAM is well tolerated. such as telbivudine and entecavir. rtV173L. respectively (p \ 0. The was 25.001) were independent factors for HBeAg serocon- studies including compensated and decompensated version.7 vs. The cumulative HBeAg seroconversion rate at improvement in eGFR was confirmed in another Korean 6 years for the high. 61.974. but needs further 10. (6. as Patients were classified into high ([50 %). 67 % of tectable HBV DNA in 76 % of HBeAg-positive and 86 % patients had HBV DNA 00 IU/ml and 75 % had fibrosis of HBeAg-negative patients.014).1 % of validation [181]. 190]. The key ml (14 patients had undetectable HBV DNA). The In a multi-centered Chinese study among HBeAg-posi- incidence of rtM204V/I substitution increased from 24 % tive patients on LdT. The add-on adefovir group had a higher chance of patients.9/10.6 % for HBeAg-positive and 15. an IPM was established. resistance at year 2 and received LdT up to year 4.8 %) and comparable associated with the emergence of LAM-resistant mutations. even in patients with decom. Among patients who received model may allow screening of LAM responders prior to the LdT for 4 years. intermediate. Among the 61 patients who had increase in serum creatinine of more than 0. patients with decompensated liver cirrhosis [178].0. an individual detectable HBV DNA but 000 IU/ml after 6–12 months prediction model for lamivudine treatment response in of telbivudine. In HBeAg-negative patients. Based on the predictors.6 %) [187]. 00 copies/ml). alytic domain of the HBV polymerase gene (rtM204I/V/S). Another LAM resistant mutation. rtL180M. intermediate measured by calculated eGFR after 24 weeks of therapy. 28 (46 %) had HBV DNA log copies/ pensated cirrhosis or in pediatric patients [178]. This therapy for 24 weeks [188]. The 2-year risk of LdT resistance nucleoside group. creatine kinase increase was reported in commencement of antiviral treatment. The most common LdT resistant substitution is rtM204I. In the subgroup that had no genotypic entecavir.6 % in HBeAg- placebo in patients with compensated CHB.5 mg/dl) was reported in up to 3 % of patients and HBV DNA log copies/ml (98 % had HBV DNA when the therapy is extended to 5 years [191]. 25.8 % in compensatory mutation. Telbivudine Telbivudine (LdT) 600 mg daily has been shown to have more potent HBV DNA suppression than Acyclic nucleotide phosphonates Adefovir dipivoxil In LAM and ADV [182. rate of HBeAg seroconversion (23. Undetectable HBV DNA at copies/ml at week 24 were randomized to add-on adefovir week 24 was associated with 9 and 5 % of LAM resistance treatment versus continuation of telbivudine until week at 2 years among HBeAg-positive and HBeAg-negative 104.7 vs.001). Based p = 0. In the mul- DNA after switching to entecavir for a median follow-up of tivariate analysis. cumulative virological breakthrough/resistance rate was and has partial resistance to tenofovir. achieved in 30–37 % after 3–5 years of adefovir (ADV) tinuation of LdT until year 4 was associated with unde. (30–50 %). and four LAM resistant mutant is at the YMDD locus in the cat.8/10.7 vs. which may confer cross-resistance to other drugs in the L- and rtA181T/V [179]. treatment [189. In a real-life because of its established long-term safety and low cost. 2 years [186].001. The IPM. patients who had HBV DNA C300 in 1 year to 70 % in 5 years. on the databases of the GLOBE study as well as other p \ 0. Reversible negative patients [184]. LdT was found to improve renal function. 50 (82 %) had sustained HBeAg 123 . In cohort in Hong Kong. rtT184S/G [179]. patients. HBV DNA 00 copies/ml (76.1 % of patients and muscle symptoms in 6. a lower risk Although prolonged lamivudine (LAM) therapy is of genotypic resistance (2. respectively [180]. and HBsAg loss in The safety profile of 10 mg ADV daily was similar to 1. which is lower than that of with rtM204V/S and will reduce the susceptibility to lamivudine [180]. or low (B30 %) response groups based on their and this benefit was seen among patient who were aged probability of HBeAg seroconversion according to the [50 years and those with eGFR B90 at baseline [187]. the may confer cross-resistance to adefovir and telbivudine.8 %. rtA181T/V.5 mg/dl telbivudine stopped because of HBeAg loss for [6 months (maximum 1.2 %).9 % of HBeAg-positive patients and 0. 24 (96 %) could achieve undetectable HBV HBeAg-positive CHB patients was suggested. including in baseline alanine aminotransferase level (OR 1. is frequently associated HBeAg-negative patients. 22.1 % in HBeAg-positive patients and 10. and baseline HBV DNA level (OR 0. p \ 0. and low response groups study with 43 patients on LdT and adefovir combination was 66. After excluding patients who HBeAg-positive patients.

The substitution resolved with cessation of tenofovir have been reported rtN236T has partial cross-resistance to tenofovir. and reverse transcription func- 4 years. Approximately 1 % of patients developed 66. In a 5-year follow-up of rtM204V/I ± rtL180M HBV variants. Another European multi- ml in 65 % of HBeAg-positive and 83 % of HBeAg-neg- center study showed that TDF monotherapy and TDF/ ative patients. mutant rtA181V/T ? rtN236T had low level. presence of the double tectable HBV DNA at 3–5 years on continuous ADV add. Rare cases of Fanconi syndrome that readily therapy in HBeAg-negative patients [191]. respectively) among ADV refractory patients. Reduction of seroconversion and % of patients had HBsAg sero- creatinine clearance to 0 ml/min is extremely uncom. but the overall rate of HBeAg seroconversion Entecavir Entecavir (ETV) is a cyclopentyl guanosine was only 5 % (all in patients on combination therapy) analogue with potent selective inhibition of the priming. fumarate (TDF) is an acyclic adenine nucleotide analogue patients with rtN236T showed a similar decline in HBV effective for both HBV and HIV. Among HBeAg-positive patients with high viral load ([108 123 . tibility to TDF. No TDF resistance has been reported up to 7 years ADV is effective in suppressing HBV DNA in patients [200]. HBeAg seroconversion in 40 % and HBsAg emtricitabine combination were equally effective in sup- loss in 10 % (all but one were HBeAg-positive.4 %) and hip (-1. Among immune-tolerant patients undetectable HBV DNA (0 IU/ml) in 90 % of patients (HBeAg-positive. Patients who had high series of 57 patients who failed to achieve complete HBV viral load ([9 log copies/ml) took a longer time to reach DNA suppression by antiviral drugs including entecavir or HBV DNA 00 copies/ml than those with lower baseline TDF due to the presence of multi-drug resistant HBV. including in patients undetectable HBV DNA.9 % of patients who combination of TDF and entecavir (0. but overall. a combination of tenofovir with emtricitabine was associated with a higher rate of undetectable HBV DNA D-Cyclopentanes than tenofovir monotherapy (76 vs.2 % of patients [192]. 87 % of the 348 patients had histological and there was no difference in the response with regard to improvement and 74 % of the 96 cirrhotic patients had the baseline LAM/ADV resistance profile [197]. In vitro tectable HBV DNA at month 6 is the best predictor of studies showed that a single mutation of the ADV resistant maintained HBV DNA suppression. 194]. 55 %) after treatment for 4 years. 26–49 % patients had HBeAg with decompensated liver disease [165]. 5 years. Among 222 mon among patients with normal baseline renal function treatment-naı¨ve patients treated with entecavir in Hong ( %) after 3–5 years of continuous TDF treatment [197. 97. treatment rate of HBsAg decline is approximately 0. reduced on therapy [193. In a multi.125 log IU/ml/ interruption or phosphate supplementation. 96. In a case regression of liver cirrhosis [195]. 205]. Unde.8 %) at week 96 of treatment genotypic resistance to ADV was 29 % after 5 years of [198].28 Hepatol Int (2016) 10:1–98 The primary drug resistance mutations against ADV are there was a small decline in the bone mineral density of the rtA181V/T and rtN236T. emtricitabine (n = 139) in lamivudine-resistant CHB.65 mmol/l). ALT). In Asian cohorts treated with 4 weeks and one patient had an ALT flare within 24 weeks. but it is [199]. and most of achieved HBsAg seroclearance after 5 years [206]. normal after treatment for a median of 21 months [203]. clearance at year 3 of treatment [204. Among the 52 patients who stopped treatment after DNA-dependent synthesis. susceptibility to TDF [201]. add-on ADV therapy on TDF versus 86. On the other hand. ETV 0. The cumulative incidence of spine (-1. sensitive to LAM.7 9 107 IU/ml. 89. approximately 83–92 % patients had TDF is generally well tolerated.3 % patients on a combination of TDF resulted in undetectable HBV DNA in 74 % and genotypic and emtricitabine achieved undetectable HBV DNA ADV resistance in 10. The them resolved without dosage modification. 198]. Tenofovir monotherapy is sufficient in the treatment with rtM204I/V HBV substitution. 51 of them had rapid increase in HBV DNA within tions of HBV polymerase. had little reduced suscep- with undetectable HBV DNA at month 6 had unde.4 % patients cohort of 165 LAM-resistant patients. HBV DNA [1. LdT and entecavir [179]. which explains the need for long-term therapy and centered study comparing TDF (n = 141) with TDF and low rate of HBsAg clearance in ETV-treated patients [206]. (9 IU/ml) after 96 weeks of treatment [198]. 87–100 % of patients mutations. On paired liver biopsy at and 84 %. [166]. In a post hoc analysis of a multi-center study comparing TDF versus TDF and Tenofovir disoproxil fumarate Tenofovir disoproxil emtricitabine combination among ADV refractory patients. Five-year continuous DNA as of those with wild-type HBV in the initial TDF therapy was associated with HBV DNA 00 copies/ 24 weeks by either regime [202].5 mg for naı¨ve or completed 240 weeks of therapy could achieve HBV DNA 1 mg for LAM experienced patients daily) could achieve 69 copies/ml [196].1 % patients had undetectable HBV DNA. a HBV DNA levels. year. 96 % HBV pressing the HBV DNA to 00 copies in 168 weeks (82 genotype A and D) patients [195].5 mg daily.9 % had HBeAg seroconversion and only one patient hypophosphatemia ( mg/dl or 0. Kong. A181T/V or N236T.

rtS202I/G and/or failed to achieve undetectable HBV DNA were exposed to rtM250V [179]. international trial on HBeAg-positive and HBeAg-negative switching or add-on tenofovir was associated with patients and in a long-term follow-up study in Hong Kong. 214]. Reports of cases have also been observed in patients primary non-responders could achieve undetectable HBV treated with ETV. 62. the 11 patients treated with ETV before liver transplant for cumulative rate of virological response (undetectable HBV acute flares of CHB with decompensation. In the long-term follow-up of the to have complete HBV DNA suppression with entecavir. Patients who achieved organ failure. Over 97 % of treatment-naı¨ve resistance requires at least three codon substitutions. 227]. same stop treatment criteria. and not the Child–Pugh score was correlated with the plete HBV DNA suppression and higher risk of virological development of lactic acidosis. entecavir 1 mg daily and ADV could achieve unde- In another prospective study from Hong Kong. rtM204I/V. Switching to ETV monotherapy (1 mg daily) in undetectable HBV DNA had been documented on three LAM resistant patients is associated with a [50 % cumu- occasions. a combination of were retreated by ETV with good HBV DNA suppression. viro.4 % at oside pyrimidine analogue with potent antiviral activity 6 months and 91. fulfilling the 42 % in 2 years [225]. This highlights the impor- 5. and Hong Kong demonstrated reduction in mortality. On the other function and high model for end-stage liver disease hand. while most patients who of the following amino acids: rtT184S/G. In a retrospective Taiwanese study among 95 HBeAg. found to be consistently predictive of post-treatment Virological breakthrough occurs in approximately 25 % of relapse after stopping ETV. 25. Long-term cohort studies among entecavir-treated Although it is likely to be a rare event. For some of these patients. 97–100 % undetectable HBV DNA after 12 months [215.Hepatol Int (2016) 10:1–98 29 IU/ml). suggesting that renal breakthrough.8 % of patients had against HBV. Drug prognosis [213. Nine patients vudine resistant patients who had HBV DNA[2000 IU/ml had spontaneous remission while the remaining 34 patients on LAM and ADV combination therapy. each 6 months apart. Among lami- [2000 IU/ml) was 45. none had evi- DNA) at year 3 is 45–58 % and virological breakthrough is dence of lactic acidosis [223].3 % in 1 year [217]. Among patients who failed resistance is very rare.2 % 216].1–6. With clevudine 30 mg daily. However. and for those with impaired liver function and multi- with liver cirrhosis [210–212]. EASL ( log reduction in HBV DNA at month 3).3 % [205. ETV was tectable HBV DNA (0 IU/ml) in 29 % in 1 year and stopped in 184 HBeAg-negative patients. Interestingly. when they were used in combination with other antiretro- ment-naı¨ve patients had primary nonresponse as defined by viral agents in HIV-infected patients. the reports of lactic acidosis for LAM and TDF have been In a Korean study. only the MELD month 12) was predictive of a lower probability of com. the cumulative probability of ETV resistance was 1. but all 220]. Isolated cases have AASLD ( log reduction in HBV DNA at month 6) or been reported for TEL and ADV in HBV patients [219. Most of monotherapy arm for comparison. undetectable HBV DNA during treatment had better ETV has a high genetic barrier to resistance. after 5 years of ETV treatment [218]. tance of appropriate dose adjustment of NAs according to logical breakthrough might be related to poor drug the calculated CrCl. as rtM204I/V and rtL180M reduce the relapse (ALT[2 time upper limit of normal and HBV DNA genetic barrier of resistance to ETV [224]. clinical vigilance patients compared with historic untreated controls in Japan must be adopted for this potentially fatal complication. among Asian patients with decompensated cirrhosis [164].0 %. ETV is effective in the treatment of ADV resistance negative patients who discontinued ETV therapy after [179]. Lactic acidosis is rarely reported adherence. Among treatment-naı¨ve patients. The US Food and Drug Admin- achieve a higher rate of undetectable HBV DNA than istration (FDA) requires all approved NAs to carry the entecavir monotherapy at week 96 (78. especially among patients apy.8 vs. Approximately 18–26 % of treatment-naı¨ve impairment may be an important contributor. The cumulative rate of viro- Other direct antiviral agents Clevudine is an L-nucle- logical relapse (HBV DNA [2000 IU/ml) was 72. a combination of tenofovir and entecavir could ETV is well tolerated. liver. in particular those with impaired liver DNA after 54 months of treatment [208]. 222]. 123 . ‘‘black box’’ warning for the potential development of respectively) [207].2 % at 1 year. plus a substitution at one on entecavir after 2–3 years. patients could achieve maintained HBV DNA suppression including rtL180M. ETV previous antiviral agents [214]. especially for those who are receiving combination ther- related complication and HCC. 209]. No baseline or on-treatment factors were seroconversion is 23–31 % after 2–3 years [226. the cumulative clinical lative risk of ETV. In a series of patients had partial virological response on entecavir. partial virological response (detectable HBV DNA at (MELD) score [221. approximately 14–16 % of treat. this study lacks the tenofovir lactic acidosis as a result of mitochondrial toxicity. the cumulative elevated ALT level before ETV retreatment was recom- rate of undetectable HBV DNA is 67–83 % and HBeAg menced [218].

multicenter study among 114 treatment- trial.0 vs. noncirrhotic. 95 % CI (1. Combining tel. findings can only be considered exploratory and have to be Tenofovir alafenamide fumarate (TAF) is a nucleotide confirmed in another study focusing on patients with high reverse transcriptase inhibitor and a novel prodrug of viral load.30 Hepatol Int (2016) 10:1–98 patients. open-label. Virological response at 6 months of lamivudine hepatitis B clinical development [229]. HBV DNA level should be abolish.00. Serum ALT and HBeAg and anti- suggests that NAs with the same resistance pattern should HBe (in patients with HBeAg-positive CHB) should be not be combined. Primary non-response.23).01] and HBeAg seroconversion [RR vudine was terminated in 2009 because of case reports of 2. Efficacy and safety of NA therapy should be monitored antiviral response. Myopathy was reported in up to 13 % of patients response rates compared to the ETV group (90. although this reduces. telbivudine).02. This entecavir or tenofovir. is rare with NA therapy [233]. reduced serum L-carnitine.01). At week 96. and HBeAg seroconversion was found in 11. No viral resistance occurred in combination Besifovir (LB80380) is an acyclic nucleotide phospho- therapy and six patients in the ETV group were experi- nate with chemistry similar to ADV and TDF.9 %. 237]. or telbivudine therapy and at 12 months of adefovir ther- Combination of NAs De novo combination of lamivudine apy is associated with the risk of emergence of drug and adefovir does not improve viral suppression over resistance and virological and serological response with lamivudine alone. Furthermore.18. 25. but the L-carnitine levels because the subgroup analysis was not planned a priori. The efficacy of tenofovir monotherapy and tenofovir. 95 % stopping clevudine [226]. such as even increase the risk of telbivudine resistance [230]. 328 patients). the combination group had superior virological mutants.9 monotherapy arm and 83 % in the combination arm had and 58. In a phase enced with viral breakthrough [231]. 235]. and no significant serious myopathy related to myonecrosis.3 %. besi- receive entecavir monotherapy (n = 186) or entecavir plus fovir 150 mg daily and entecavir 0. but may treated with a high genetic barrier to resistance.3–23. declines in HBV DNA were similar to therapy. and provides efficient delivery of active drug to hepato- cytes at reduced systemic tenofovir exposures. LAM ? ADV was more 9. it has combination therapy can be recommended for this group of greater plasma stability than tenofovir disoproxil fumarate. difference was found in the virological response (p = 0. monitored every 3 months. undetectable HBV DNA was found in 63. compliance is recommended in patients with primary non- Tenofovir alafenamide 25 mg has been selected for further response.26. p = 0. p = 0. CI (1. 3. treatment-naı¨ve subjects with CHB in chronic HBV-infected patients treated with nucleos(t)ide were randomized (1:1:1:1:1) to receive tenofovir alafe- analogues namide 8. it was found that at adefovir or tenofovir therapy [236. 1. defined as log10 IU/ml off-treatment for 4 weeks. and pharmacokinetics. after being treated for a mean of 14 (range 78. Checking compliance and testing for genotypic resis- In one meta-analysis evaluating the effectiveness and tance should be done in patients with virological break- resistance of de novo combination of lamivudine and through during NA therapy. In a post hoc 15 and 9.5) months. Closely related to the commonly used reverse- higher dose entecavir (1. and every 6 months in patients tion in HBV DNA than telbivudine monotherapy.11. Adefo. monitoring serum creatinine and serum for nucleos(t)ide-naive patients with chronic HBV infec- phosphate levels should be done every 3 months during tion (five studies. In a recent clinical IIb. (lam. but does not long-term therapy [234. The global development of cle.5 mg daily for tenofovir (n = 198) [232]. However. In a recent Monitoring treatment and guidance for stopping therapy study. HBV DNA below 50 IU/ml (p = 0.5 %.21). lamivudine resistance. Muscle symptoms 123 . No drug resistance or subgroup analysis. 40.0 mg) has to be evaluated before transcriptase inhibitor tenofovir disoproxil fumarate. the returned to normal with supplement.1. or 120 mg. respectively [228]. Tenofovir alafenamide was safe decline in HBV DNA level from baseline at month 3 of and well tolerated. patients.088). and is primarily related to rtM204I ± rtL180M 48 weeks. 3–6 months if agents with low genetic barrier are used bivudine and lamivudine does not achieve greater reduc. Due to potential adefovir dipivoxil compared with entecavir monotherapy nephrotoxicity. 379 treatment-naı¨ve patients were randomized to naı¨ve patients randomized to besifovir 90 mg daily. but it was resolved spontaneously after effective than ETV in ALT normalization [RR 1. By week 96. 76 % in the 48 weeks.003)]. Ninety-four percent of patients on besifovir had and baseline HBV DNA over 8 log IU/ml. p = 0. 62. Checking patient’s tenofovir disoproxil fumarate at all doses evaluated. combination therapy was superior to elevated serum creatinine was found among patients on entecavir monotherapy in patients with positive HBeAg besifovir.6. or tenofovir disoproxil fumarate 300 mg for 28 days and were assessed for safety. followed up by regularly. adefovir measured at month 3 and 6 of therapy and then every resistance was not reported in this study.

95 % CI 1. or retreatment after an initial HBV DNA elevation. at the end of treatment are associated with a lower relapse 3:6:1 Recommendations (results of currently available rate at 1–2 years post-treatment discontinuation (15 vs. However. The cumulative relapse rate Hepatitis relapse with hepatic decompensation and death was 33 % at 6 months. more data is needed to con. and patients were moni- HBsAg level during therapy may predict HBeAg or HBsAg tored with serum ALT and HBV DNA monthly in the first loss with long-term telbivudine. anti-HBe (in with a total of 1732 HBeAg-negative patients (median patients with HBeAg-positive) and ALT duration of therapy. Off-therapy severe flares were but all were HBeAg-negative and had undetectable HBV rare and hepatic decompensation was reported in only one DNA (00 IU/ml) at the time of discontinuation. cessation of [2000 IU/ml measured twice 6 months apart within long-term nucleos(t)ide analogue therapy prior to HBsAg 1 year. HBsAg levels of log10 IU/ml with cirrhosis [246]. A decline of and 6–80 months.5 mg and were followed for 44 (12–117) months thereafter. should be used as first-line therapy (A1). Con. ADV 10 mg daily (A2).Hepatol Int (2016) 10:1–98 31 or muscle weakness should be monitored during tel. and 0 % of the rates depend on the duration of consolidation therapy patients received re-treatment. 123 . the 1-year off-therapy ‘virological relapse’ (HBV firm the results before making a recommendation. The disadvantages are the risk of (n = 20) (p = 0. treatment until HBsAg loss is generally recom. studies). 27 (5 %) out of 520 CHB patients who received 3:6:1:1 Treatment-naı¨ve patients can be treated NA for prolonged periods ultimately lost serum HBsAg with TDF 300 mg daily (A1). The advantages of stopping NA therapy therapy (n = 37) had a 1-year relapse rate of 23. and 55. DNA [2000 IU/ml)and ‘clinical relapse’ (HBV DNA In HBeAg-positive CHB patients who achieve HBeAg [2000 IU/ml ? ALT elevation) occurred in 0 % and seroconversion with undetectable HBV DNA. follow-up ranged from 6 months to 8 years. and 59 were HBeAg-negative. the relapse 0 % of the patients. possibly be desirable.2 % for 1–3 years of consolidation therapy and retention in care. LdT was concluded that patients reaching the therapeutic end.3-fold more likely to lose therapy. and minimization of (n = 32). resulting in an unpredictable worsening of disease HBsAg (hazard ratio 1. For each additional year of consol. pensation after an exacerbation. 600 mg daily (A2) or LAM 100 mg daily point of HBsAg clearance can be safely withdrawn from (A2).7 % at 1 year. Consoli. Thus. respectively. cirrhotics. Relapse was defined as HBV DNA rule and a proper off-therapy monitoring plan. with an appropriate stopping continuation. one recent meta- continuation in patients with HBeAg-negative chronic analysis suggested that NAs withdrawel is safe even in hepatitis. HBsAg levels may be a potential marker to hepatic decompensation was rarely observed in patients guide treatment cessation. However.2 % are a finite duration of treatment.5 % for year of consolidation therapy renal and bone toxicity. Cirrhotics have much [243]. 238]. predictors of response to therapy.02–1. and possible development of fulminant hepatitis and acute- dation therapy of at least 3 years decreased the rate of on-chronic liver failure. ETV 0. as well as the risk of developing relapse and increased the rate of HBsAg loss significantly resistance with ‘‘stop–start’’ therapy. that off-therapy severe flares were rare and that mended [218]. One recent study described 94 patients who stopped patients with shorter treatment. Patients with at least 3 years of consolidation cirrhotic patients.002). entecavir or tenofovir 1–3 months and every 3–6 months thereafter in most therapy [239–241].4 % at is an important issue after cessation of NAs therapy in 5 years. 42. NA following either anti-HBs seroconversion or at least 3:6:1:2 TDF or ETV are the preferred NAs and 12 months of a post-clearance consolidation period [245]. 4–96 weeks bivudine or clevudine therapy [180. and 64. These rates were higher in [242]. nucleos(t)ide analogues. with improved adherence compared to 57.75).34. respectively. 35 patients were HBeAg-positive native to indefinite treatment [246]. reduced costs. However. In one recent study to assess the outcome with chronic HBV infection) of patients withdrawing from NA therapy after HBsAg clearance. consolidation therapy and off-therapy should be monitored every 3 months (A1). reactivation of suppressed disease with discontinuation of idation therapy. in one recent meta-analysis including 22 studies 3:6:1:3 During NA therapy. It daily (A1). patient with cirrhosis. less hepatic reserve for life-threatening hepatic decom- Due to the high relapse rate after NA treatment dis. Patients could be apy ( years) and those treated with less potent HBeAg-positive or HBeAg-negative at the start of therapy. HBeAg. therapies. shorter consolidation ther- NA after at least 1 year of therapy. patients were 1. Biochemical relapse reflecting solidation therapy was defined as treatment duration enhanced immune-mediated hepatocyte killing may lead to between the first undetectable HBV DNA (in case of a higher chance for off-therapy HBsAg seroclearance and HBeAg-positive patients after HBeAg loss) and NA dis. seroclearance in HBeAg-negative CHB is a feasible alter- At the start of therapy. follow- 85 % in those with HBsAg level [2 log10 IU/ml at end of up and stopping rules during NA therapy in patients treatment) [244].

and the therapy can 4–6 months achieved higher HBeAg loss (33 vs. however. entecavir. 3–6 months if agents with a low genetic Immunomodulatory agents include conventional inter- barrier are used (lamivudine. compensated cirrhosis patients treated with IFN had com- Thymosin a1 has also been licensed in some Asian parable or even better response and a similar side effect 123 . considered in cirrhotic patients with a careful off-therapy monitoring plan (A1). Asian 3:6:1:8 The optimal duration of NA therapy is patients with elevated baseline ALT have IFN response unknown in patients with HBeAg-negative rates comparable to Western patients. delayed HBeAg seroconversion could occur in 10–15 % at 6 months apart (B1). Re-treatment of patients who failed previous HBsAg loss following either anti-HBs IFN therapy could achieve HBeAg loss in 20–40 % of seroconversion or at least 12 months of a cases. includ- adefovir. 17 %) and ALT normal- preferably after 3 years (C1) of additional ization than untreated controls with a risk difference of therapy after HBeAg seroconversion with around 25 % for each parameter. clevudine was only approved in Korea at month 3 and 6 of therapy and then every and the Philippines.6.32 Hepatol Int (2016) 10:1–98 3:6:1:4 The HBV DNA level should be measured countries. Peg-IFN-2b has been approved for the Compensated cirrhosis Previous studies showed that treatment of chronic HBV infection in a few countries. as relapse (A2). In addition. viral control).6 %. treatment in children with elevated ALT was also similar to the treatment can be withdrawn (1) after that in adults. 1. monitored at least every 3 months if TDF or ADV is used (A1). and every 6 months in mosin a1. patients should be cumulative incidence of 75 % HBeAg seroconversion (vs. telbivudine. positive patients showed a higher sustained response than iod (B1). A study of tailored regimen of IFN in 247 HBeAg- post-HBsAg clearance consolidation per. especially among responders 3:6:1:10 The stopping of NA therapy may also be [19]. and thy- telbivudine). Conventional interferon 3:6:1:6 Muscle symptoms and muscle weakness should be monitored during telbivudine or HBeAg-positive chronic hepatitis B Meta-analyses of clevudine therapy (A1). be stopped after at least 1 year (A1). However. antiviral action.2 Results of and predictors of response response rate was only 22 %. controlled trials in HBeAg-positive patients showed that 3:6:1:7 For HBeAg-positive patients without liver treatment with conventional interferon-alfa (IFN) at a dose cirrhosis. Table 1 shows the comparison response [19]. adefovir. 1–2 years post-therapy. tenofovir and pegylated ing reduction of HCC and survival and hepatic interferona2a (Peg-IFN-2a) have been approved for the complication-free survival in patients with sustained treatment of CHB globally. 2 years with undetectable HBV DNA HBeAg seroconversion is durable in over 90 % and documented on three separate occasions. or (2) after treatment for at least fixed 6-month treatment (40. IFN-treated patients have a and then every 3–6 months thereafter for lower likelihood of cirrhosis and HCC development. Extending IFN treatment for to therapy with interferons 24 months in Italian patients induced sustained response in 30 % and HBsAg clearance in 18 % at 6 years post-ther- Currently. such as entecavir or teno. sustained 3. monitored monthly for the initial 3 months 52 % in control). These agents have dual actions: enhancing host patients treated with a high genetic barrier immunity to mount a defense against HBV and modest to resistance. The rate of HBsAg undetectable HBV DNA by PCR and seroclearance was also higher (7. lamivudine. Over the past two decades. therapy has been the mainstay of CHB treatment 3:6:1:5 Renal function and bone profile should be worldwide. 12 %).8 %) in IFN- persistently normal ALT levels.013).8 vs. p = 0. IFN treatment improved long-term outcomes. feron-a (IFN). pegylated interferon (Peg-IFN). conventional interferon-alfa (IFN).3 %. the optimal duration of NA of 5 MU daily or 10 MU three times weekly for therapy is unknown. with a risk difference of 5. The efficacy of IFN CHB.5 vs. treated patients. between these two treatment strategies (immune control vs. apy. 28. but HBV DNA suppression (37 vs. and there was up to a 15-year 3:6:1:9 After stopping of NAs. HBeAg-negative chronic hepatitis B A 12-month IFN therapy showed the end-of-treatment biochemical and virological response rates in 60–90 %. well as better overall survival. IFN-based fovir (A1). In patients without liver cirrhosis.

respectively. HBV DNA suppression to 00 HBeAg-positive patients with well-compensated cirrhosis copies/ml was only obtained in 14 % of patients with Peg. HBsAg seroconversion was achieved in 3–5 % and HBV DNA 0. which is the ultimate goal of 11 %. sustained negativity of HBV therapy. the currently recommended treatment increased HBsAg seroclearance over time in dose and duration of Peg-IFN a-2a therapy is 180 lg/week patients with HBeAg loss.Hepatol Int (2016) 10:1–98 33 profile as those without cirrhosis. relapse is common during post HBeAg and HBsAg was observed in 81 and 30 % of 64 NA therapy follow-up. HCC and prolonged survival in compared the treatment response of different doses and responders. the two studies using HBeAg-positive patients. A recent study on a-2b [249]. long-term (mean follow-up of 3 years) sustained negativity of HBeAg and HBsAg in 172 European HBeAg. 3 years of follow-up. However. the combined sustained viral Peg-IFN a-2a therapy also found that Peg-IFN–based response (SVR) (HBeAg loss. 22 %. HBV DNA suppression. respectively.8 % [257]. The virological response based on HBV DNA suppression was found to be Chronic hepatitis B with cirrhosis A prior study on 24 modest with Peg-IFN. treated with 52 weeks of Peg-IFN a-2b with or without IFN a-2a and 7 % with Peg-IFN a-2b. starting with Peg-IFN followed by addition of NA. A previous study of 24-week All three studies showed that the therapeutic efficacy was Peg-IFN a-2b in Chinese HBeAg-positive patients also comparable between Peg-IFN monotherapy and combina- confirmed a higher HBeAg loss rate than conventional IFN tion therapy of Peg-IFN plus lamivudine. which allows weekly injection.7 % [256]. In an early phase 2 study on Asian increased to 8. In addition. Furthermore.8 to 28. Furthermore. lamivudine showed a higher rate of HBeAg serconversion However.000 copies/ml at 26 weeks post-ther- of patients at 6 months post-therapy [250. Two meta-analysis studies have for 48 weeks. most CHB patients fail to positive patients treated with Peg-IFN a-2b was 37 and obtain HBsAg seroclearance. 38 % of the patients who advanced fibrosis. 12 %. With current antiviral agents. 24 weeks post-therapy [248]. 251]. with reduced risk of A recent prospective study with mostly Asian patients hepatic decompensation. had HBV DNA 000 IU/ml.5 lg/kg/week for 48 weeks. In addition. The side effects 6 months post-therapy had sustained seroconversion at were comparable between patients with and without 12 months. and HBsAg clearance rate IFN a-2b (12 KD). improvement of liver fibrosis was found Asian HBeAg-positive patients treated with Peg-IFN a-2a more frequently in patients with advanced fibrosis than in for 48 weeks who achieved HBeAg seroconversion at those without (66 vs. The recommended dose of Peg-IFN a-2b confirmed these long-term benefits of IFN treatment in therapy is 1. In an apy than those without cirrhosis (30 vs. HBeAg-negative chronic hepatitis B With 1 year of Peg- IFN a-2a therapy.02) analysis of the long-term effects of Peg-IFN. There are ativity at 26 weeks post-therapy) [253]. 14 %. and therapy was superior to lamivudine alone in inducing ALT normalization) of Peg-IFN a-2a was twice that with HBeAg seroconversion in HBeAg-positive patients and in conventional IFN a-2a (24 vs. 000 IU/ml occurred in 43 % of patients and HBsAg loss a (Peg-IFN) improves its pharmacokinetic and prolongs its was reported in 4 % at 6 months post-therapy [255]. respectively. and the results showed that trials on HBeAg-positive patients showed that 1 year of extending treatment duration to 96 weeks increased Peg-IFN a-2a and Peg-IFN a-2b monotherapy resulted in response rate (HBV DNA level 000 IU/ml at 1 year HBeAg seroconversion in 32 % and 29 % of patients at post-therapy) from 11. After half-life.001). IFN is contraindicated in patients durations of Peg-IFN a-2a in HBeAg-positive patients with overt decompensated cirrhosis because it can precip.036) at suppressing viral replication in HBeAg-negative patients. resulting in fatal complica. Two types of Peg. Long-term follow-up studies showed that IFN tion or lower dose. combination therapy patients with an initial serological response (HBeAg neg. Therefore. Of note. p \ 0. reducing liver disease progression to cirrhosis and HCC [247]. achieved HBeAg seroconversion at 12 months post-ther- apy had serum HBV DNA levels 00 copies/ml [252]. the data revealed that HBV DNA Pegylated interferon alfa alone Pegylation of interferon. p = 0. 6 months post-therapy. NA. 28 % of HBeAg-negative patients IFN have been developed: Peg-IFN a-2a (40 KD) and Peg. Therefore. 83 % of 150 [258]. most of three approaches for administering combination therapy: the patients who cleared HBsAg were infected by HBV NA followed by addition of Peg-IFN and continuation of genotype A. In particular. for 48 weeks was superior to regimens with shorter dura- tions [19]. 120 Caucasian HBeAg-negative patients with genotype D infection explored whether longer treatment duration could HBeAg-positive chronic hepatitis B Two large phase 3 lead to a better response. Combination therapy of IFN and NAs Moreover. [254]. The data showed that 180 lg/week of Peg-IFN a-2a itate hepatic decompensation. p = 0. could be considered the ideal treatment for CHB. or 123 .

Response was combination therapy with Peg-IFNa-2a ? adefovir dip. All domized to Peg-IFNa-2a monotherapy or to individualized patients were followed until week 96. Peg-IFN add-on led to significantly more loss [262].004). 255].8.095). the Peg-IFN add-on was significantly and seroconversion rates were higher in those patients associated with response (OR 4. treated with the combination therapy.046). At the end of follow-up improved results compared to monotherapy with either (week 72). 160 HBeAg-positive patients were ran. At week 96. HBsAg clearance than 100 patients who continued ETV tectable HBV DNA and HBeAg losses 50 vs. Add-on therapy resulted in more viral decline and appeared Combination of Peg-IFN with telbivudine A study in 159 to prevent relapse after stopping ETV. treated with the combination than in those treated with Peg. The three approaches LdT for 24 weeks (Peg-IFN first). 123 . myalgia [264]. 39 vs.. versus HBeAg-negative patients showed a similar sustained 2/90 (2 %) of patients treated with monotherapy virological response (i.001). Response was Combination of Peg-IFN with adefovir In a multicenter defined as HBeAg loss with HBV DNA 00 IU/ml at prospective study. Another global randomized trial (the ARES study) was However.75). another study found no difference in efficacy conducted in European and Chinese HBeAg-positive between32-week Peg-IFN started simultaneously with patients. However. only one patient dropped out because of both HBeAg-positive and HBeAg-negative subjects. 15 %. therapy (180 lg/week) from week 24 to 48 (n = 85). decline in HBsAg. In this open-label. most investigators have used the first approach and scien. as a high risk of to provide a more profound treatment effect on viral sup. Sequential treatment with Peg-IFN followed or preceded by 24 weeks Combination of Peg-IFN with lamivudine However. DNA 000 IU/ml (47 vs. 251. LAM and that started 8 weeks before LAM or 8 weeks HBeAg-positive CHB patients with compensated liver after commencement of LAM.e.05. p = 0. or to continue ETV monotherapy (n = 90). (p = 0. p = 0.036). 20 %. Adjusted for HBV DNA levels prior to ran- ization and undetectable HBV DNA). which was 79 % (11/14) versus 25 % (2/8) of 24 weeks) after the EOT among those treated with a those who discontinued ETV (p = 0. Responders discontinued ETV at week 72. leading to an early ment response.34 Hepatol Int (2016) 10:1–98 simultaneous administration of NA and Peg-IFN. 22 48-week combination of Peg-IFNa-2a ? ADV or Peg. p = 0. An Italian multicenter study in 60 achieved disease remission after ETV cessation. 13 %. respectively) [259]. At week 96. 95 % CI 1. (26 %) patients assigned add-on versus 12 (13 %) assigned IFNa-2a alone (23 vs. A study on 36 treatment-naive HBeAg-positive patients Combination of Peg-IFN with entecavir One recent study who received LAM 100 mg per day for 4 weeks before (the OSST study) reported on 100 Chinese HBeAg-positive adding Peg-IFN for the following 24 weeks showed that patients with maintained virological response on ETV who they achieved higher sustained (6 months after end of switched to a finite course of Peg-IFN a-2a and achieved treatment) virological responses compared with the 27 significantly higher rates of HBeAg seroconversion and patients who received Peg-IFN from the start (unde. domized therapy. [265]. week 48. multicenter randomized trial. achieved in 16/85 (19 %) patients allocated to the add-on ivoxil (ADV) based on the baseline features and treatment arm versus 9/90 (10 %) in the monotherapy arm response.6–14. with only one monotherapy achieved HBeAg seroconversion patient (3 %) in the combination group achieving HBsAg (p = 0.007). HBeAg and HBV DNA (all p \ 0. However.014). p = 0. There is undetectable HBV viral load and greater reductions in lack of data to recommend one over the other. compared with Peg-IFN monotherapy [250. combined response (ALT normal. Another study compared the efficacy and safety of two tifically prefer the basis of viral load reduction followed by sequential regimens: Peg-IFN for 24 weeks followed by immune modulation as a logical step. HBeAg and HBsAg levels than either drug alone [263].028. HBeAg clearance.5 mg/day) and therapy. have been used with different NAs and Peg-IFN with in 30 HBeAg-negative patients. p = 0. 24 weeks after the end of disease started on ETV monotherapy (0. severe polyneuropathy development was reported in those pression without superior sustained virological off-treat. Eleven (13 %) of add-on treated patients IFNa-2a alone [261]. Hence Peg-IFN add- HBeAg-positive patients reported that a combination of on therapy may facilitate the discontinuation of nucleos(- Peg-IFNa-2a and telbivudine (LdT) led to a higher rate of t)ide analogues [266]. presently the combinations of simultaneous commencement of Peg-IFN and LAM tends Peg-IFN with LdT should be avoided. more patients treated with LdT first had HBV group of drugs. in of LdT was safe. HBV DNA 000 IU/ml (p = 0. or vice versa (LdT first). 15 %. All patients received lamivudine until week 104 were randomized in a 1:1 ratio to either Peg-IFN add-on [260].0. discontinuation of one study [263].

to 18 % in the NA monotherapy group (p = 0. Ninety-six percent of patients log10). or 48 weeks of continued NA continuing on Tenofovir alone through week 48. At Response.6 %). was 48 weeks. p = 0. study) conducted in Europe and China.005).1 treatment follow-up until week 96.14 and 0. A total of seven patients experienced HBsAg IFN add-on group compared to 0 % in the NA seroreversion. followed by randomization to tenofovir plus (nine HBeAg-negative) having undetectable HBV DNA peg-interferon a2b 1. HBsAg levels declined most in the consolidation treatment (week 72).15).8. or reappearance after loss (four in the monotherapy group (p = 0. Patients were randomized to 48 weeks of 48 weeks. p = 0.0185)] [271]. 23. with an average age of 33 years.001)]. compared to the tenofovir monotherapy group. a total of 740 tive patients with compensated liver disease were treated CHB patients (60 % positive for HBeAg) without for at least 12 months with entecavir (ETV) or tenofovir advanced bridging fibrosis or cirrhosis were randomly (TDF) with subsequent HBV DNA 000 IU/ml at ran- assigned to receive tenofovir ? pegylated interferon for domization. however.02).3 %) decades to achieve undetectable levels. 3. One patient who 48-week combination arm and three in the 16-week received Peg-IFN add-on had clearance of HBsAg at combination arm) [268].3 log10). withdrew from treatment after a mean of 16 weeks due to Two patients on sequential therapy had HBsAg loss by a suboptimal HBsAg response (decline of 0. simultaneous combination of Peg-IFN randomized controlled phase III trial ANRS-HB06 plus tenofovir or sequential combination therapy using PEGAN study presented at AASLD 2014 suggested that entecavir first followed by Peg-IFN shows promising addition of a 48-week course of Peg-IFN alfa-2a to oral results.43 ± 2. undetectable serum HBV DNA for at least 1 year results in a low rate of HBsAg clearance (6. Taken together. Peg-IFN early due to side effects. In one randomized controlled trial (PEGON [267]. to HBsAg levels of 0.0 % in the 48-week tenofovir plus pegylated at week 48 (0. on compared to 5 % of patients who continued NA Response rates were substantially lower in the 16-week monotherapy (p = 0. Because it has been observed that during effective NAs may increase HBsAg clearance rate [history of HBeAg therapy. Peg- enced HBsAg loss. Peg-IFN addition. HBsAg interferon group. 0.9 log10 and 4.3 % of patients taking the 48-week tenofovir achieved in 17 % of patients who received Peg-IFN add- plus pegylated interferon regimen showed HBsAg loss. while remaining the same in the other decline [1 log IU/ml was achieved in 19 % of the Peg- three arms. a rapid decline of HBsAg occurred in two (p = 0. log10) and tenofovir monotherapy (-0. None taking tenofovir alone experi. 4. HBsAg decline is very slow and may require seroconversion prior to randomization (23. 82 HBeAg-posi- In a recent open-label study (Study 149).1 presented at AASLD 2014. At the Responders will discontinue treatment after 24 weeks end of treatment.5 mcg/kg/weekly for 24 weeks (se.70 ± 1. Week 48 results were log10). and HBeAg seroconversion (53. ETV = 7. the 16-week tenofovir combination regimen (-0. At 48 weeks.44 log10 2.028).3 vs. 7.017).02 IU/ml at week higher HBV DNA loss (80 vs.25 log10).64 vs. as well as HBeAg seroconversion alone. raised ALT (48–200 IU/ml) Peg-IFN to NAs responders to accelerate the HBsAg patients. and that low Peg-IFN add-on treatment in NAs responders baseline HBs Ag titers and a history of HBeAg sero- conversion.3 %.5 vs. week 48 [270]. and who additionally received Peg- HBsAg loss.09 log10 48 weeks compared with none in tenofovir monotherapy only) [269]. all patients received tenofovir (300 mg/day for decline. the rate of HBsAg loss IFN add-on resulted in significantly more HBsAg decline rose to 9. tenofovir monotherapy.Hepatol Int (2016) 10:1–98 35 Combination of Peg-IFN with tenofovir In one study on of Peg-IFN in chronic HBV-infected patients is to add on HBeAg-positive CHB. either spontaneously or under HBV therapy. Three patients discontinued (p \ 0. Daily tenofovir was continued thereafter until ETV ? TDF = 2). followed by interferon monotherapy (-0. HBeAg loss was achieved in tenofovir combination arm and interferon monotherapy 33 % of patients who received Peg-IFN add-on compared arm (both 2. After add-on of group and 30 % in tenofovir monotherapy had normal ALT PegIFN. with subsequent off- 48-week tenofovir plus pegylated interferon arm (-1. 123 . tenofovir ? pegylated interferon for 16 weeks. (16 copies/ml) for more than 6 months on NAs quential therapy. By 72 weeks. an alternative use (p = 0. 60 % in the sequential therapy IFN as an individualized therapy. mean 48.021). respectively (corresponding to a maximal reduction of HBV DNA reduction [6. Preliminary results of the multicenter.8 %). Patients receiving sequential therapy had patients.29 log IU/ml. Response (HBeAg seroconversion with monotherapy for 120 weeks (continuous monotherapy) or HBV DNA 00 IU/ml) was assessed at week 48. 53 %. LAM ? ADV = 2. One study reported HBsAg kinetics in 12 patients 12 weeks).14).5 were of Asian ethnicity. future large studies are needed to confirm anti-HBV therapy in HBeAg-negative CHB patients with these results. (n = 30). pegylated interferon monotherapy for 48 weeks. n = 30) or tenofovir monotherapy (LAM = 1.59 vs. whereas seven patients p = 0.

A recent study quantified the proportion response was better in genotype B infection compared to of precore (PC) and BCP mutants at baseline and during genotype C infection [273. mutants were qualitatively and quantitatively associated group analysis from the clinical trial using Peg-IFN a-2b with a higher response rate to IFN or Peg-IFN therapy in Table 6 Baseline predictors and stopping rules of 48-week pegylated interferon therapy in Asian and Caucasian chronic hepatitis B patients HBeAg-positive HBeAg-negative Asian Caucasian Asian Caucasian Lower HBV DNA level Better response Better response Not clear Not clear Higher ALT level Better response Better response Not clear Not clear Genotype B and C are A is better than D B and C are comparable Not clear comparable Precore stop codon (PC) and Mutant better Wild type better Not clear Not clear basal core promoter (BCP) than wild type than mutant mutants IL28b SNP No predictive Controversial Not clear Controversial value Lower level HBeAg Better response Better response Not applied Not applied Stopping rule at 12-weeks No decline of HBsAg level No rule could achieve Only in genotype D patients: without HBsAg level at [20. the HBeAg IFN or Peg-IFN treatment in 203 HBeAg-positive patients. For HBeAg-negative patients. 276]. higher ALT level were both associated with a higher treatment response to Peg-IFN-based therapy [256]. seroconversion rate is similar between genotypes B and C and found a dose response relationship between the pro- after 12-month Peg-IFN-based treatment. Two Asian studies similar responses. HBeAg- copies/ml) and an elevated ALT level ([2 times of upper positive patients infected with genotype A have the best limit of normal) were associated with a higher sustained response. 274]. the data comparing the sustained response among Lower serum HBV DNA level and elevated ALT levels In patients receiving Peg-IFN a-2a ± lamivudine showed that CHB patients receiving IFN or Peg-IFN treatment. For HBeAg-negative patients. These results highlight that further with genotype A rather than genotype D infection. a lower HBV DNA level and a the role of HBV genotype may be minimal. These results lend support to the recom. followed by genotypes B and C. sub. while those infected with genotype D 000 IU/ml at 6 months post-therapy) [272]. it is concluded analysis showed that a lower level of HBV DNA ( log10 that with a standard 12-month Peg-IFN treatment. HBeAg-negative patients.36 Hepatol Int (2016) 10:1–98 Baseline and on-treatment predictors of response to Peg. Asian studies HBeAg-associated factors in HBeAg-positive patients with reported that in a shorter 6-month Peg-IFN treatment. followed by genotypes B and C. showed that genotype A had the highest rate of HBsAg loss IFN (Table 6) compared to other genotypes [272]. a pooled Taking these lines of evidence together. Peg-IFN therapy. which had concentrations in clinical practice. itive patients receiving Peg-IFN-based treatment. When HBsAg clearance is defined rate [277]. lower there was no difference between genotypes A and D or HBV DNA level and higher ALT level are known as genotypes B and C after a long-term follow-up of 3 years baseline predictors for a better response. HBeAg level. while those with genotype D had the indicated that pre-therapy BCP mutations could increase worst response. thus far. For HBeAg-pos.000 IU/ml 95 % of negative HBsAg decline and with log HBV week 12 at week 12 predictive value DNA decline 123 . In studies are needed to confirm the predictive value of patients with genotype B or C infection. Buster et al. However. [256]. For have the lowest response. However. precore and basal core promoter mutants A retrospective analysis on 271 HBeAg-positive patients who HBV genotype In a pooled analysis on two large clinical received 48-week Peg-IFN a-2a ± lamivudine showed that trials with HBeAg-positive patients who received HBeAg seroconverters have a lower baseline and on- 12-month Peg-IFN-based therapy. which is the portion of PC/BCP mutants and HBeAg seroconversion current standard of care. there that patients with genotype A infection had the best is no commercial assay available for measuring HBeAg response. These data suggested that both PC and BCP as treatment endpoint in HBeAg-positive patients. HBeAg clearance rate in patients receiving Peg-IFN mendation that Peg-IFN therapy is suitable for patients treatment [273. who have a response rate (HBeAg loss and HBV-DNA level similar response. [272] found treatment levels of HBeAg [275].

In a retrospective Quantitative serum HBsAg level Since serum HBsAg cohort study consisting of 231 and 560 patients enrolled in level varies depending on the balance between viral two phase IV. the role of HBsAg may serve as a biomarker to predict treatment quantitative serum anti-HBc level in predicting HBeAg response to Peg-IFN. (SNPs). a multicenter study. However. which may be anti-HBc level has been reported to reflect host immune attributable to different HBV genotypes. For HBeAg-negative patients results [287]. randomized. several cohorts. Whether the IL-28B SNPs could also predict 6 months post-therapy as the treatment endpoint. the Peg-IFN-based treatment response in CHB has been stopping rule of no HBsAg decline plus log HBV DNA actively investigated.178. only 3 % of than treatment strategy. yielded contradictory HBeAg-positive patients.001).9 %) and 137 (24.000 IU/ml for genotype B and C patients. rule.1 % these findings. and there was no corre- has been shown to predict treatment response at 1-year lation noted between IL28B SNPs and treatment response post-therapy (47. status and hepatitis activity. baseline anti-HBc C4. are associated with a higher genotype D infection. and it was concluded that if treatment level and treatment response of IFN-based therapy has response was defined as sustained response.Hepatol Int (2016) 10:1–98 37 Asian HBeAg-positive patients. then the been explored in 45 HBeAg-positive patients. In summary. 11 %) [278]. To investigate which stopping rule was more universally applicable across Quantitative hepatic HBsAg level In addition to serum HBV genotypes. For patients controversial. In pooled analysis.4 % for HBsAg decline C10 vs. presence of mutant: 34 vs.000 IU/ml at week 12. respectively) [284]. respectively.8 % (50/76) and 37. the baseline anti-HBc level was the patients without decline of HBsAg level at week 12 could best independent predictor for HBeAg seroconversion (OR achieve sustained response [negative predictive value 2. However. which enrolled 205 0 %.577–3. its clinical signifi- cance in CHB therapy remains limited. (NPV) of 97 %]. From then on.4 log10 IU/ml and baseline HBV further prospective studies are still required to validate DNA log10 copies/ml had 65. A French study first reported that a seroconversion was evaluated.4 log10 retrospective studies proposed the role of HBsAg level as a IU/ml was the optimal cutoff value to predict HBeAg ‘‘stopping rule’’ at week 12 of Peg-IFN treatment in both seroconversion for both Peg-IFN and NA. PC and BCP mutant may play different Quantitative serum anti-HBc level Quantitative serum roles in Asians and Caucasians. Patients with HBeAg-positive and HBeAg-negative patients.5 log10 IU/ml at week end of trials. However. patients. In contrast. controlled trials replication and host immunity. a European with genotype D infection. HBsAg [20. it is hypothesized that treated with Peg-IFN or NA-based therapy. the relationship between hepatic HBsAg were pooled. Taken together. The first study enrolled 115 patients receiv- with non-genotype D infections. Nevertheless. a stopping rule HBeAg-positive patients receiving Peg-IFN ± lamivudine for Peg-IFN therapy at week 12 or 24 is clinically useful in from 11 European and Asian centers. In this study. multicenter. [20.000 IU/ml at 24 week could be applied to all Interleukin-28B genotype Several interleukin-28B patients as the 24 week stopping rule. and there 12-week stopping rule can be defined as no decline of was a positive correlation between baseline serum HBsAg HBsAg level for genotype A and D. 95 % CI 1. this was not validated well in baseline anti-HBc titer may serve as a useful predictor of another study with 399 HBeAg-positive Asian patients Peg-IFN and NA therapy efficacy in HBeAg-positive CHB with genotype B or C infection (NPV of 82 %) [281]. which could be used for optimizing the antiviral Instead. around 65 % of the patients 123 . more studies are or BCP mutants lowered the rate of sustained response warranted. HBsAg decline of 10 % ing 6-month Peg-IFN treatment. [273]. However. Baseline anti-HBc level of 4. 99 (42. When using HBV DNA level response rate in Peg-IFN-based treatment for chronic 000 IU/ml combined with normal ALT level at hepatitis C. but HBsAg level level and hepatic HBsAg level [286].009. a week 12 stopping rule is also study with 214 HBeAg-positive patients receiving Peg-IFN clinically applicable. (wild-type vs. while HBsAg [20. The data showed that at the decline in serum HBsAg level of 0. irrespective of HBV (IL28B)-associated single nucleotide polymorphisms genotype [282]. However. the Asian study proposed an alternate stopping therapy of CHB [285]. respectively.5 %) patients 12 could differentiate sustained responders from relapser in achieved HBeAg seroconversion in the Peg-IFN and NA HBeAg-negative patients [279]. other patients with genotype A or D infection [280]. the results remain decline at week 12 had NPV of 100 % [283]. (52/140) rates of HBeAg seroconversion in the Peg-IFN In a study enrolling 202 HBeAg-positive Caucasian and NA cohorts. for HBeAg-negative a-2b ± lamivudine showed that the presence of either PC patients with non-genotype D infection.2 and 16. p \ 0. Therefore. data from three large-scale clinical trials HBsAg level. including CC genotype of rs12979860 and TT Most data regarding HBeAg-negative patients included genotype of rs8099917.

HBsAg should be checked at 12-month intervals if HBV Currently. however. except in patients with cirrhosis or immunosup. Peg-IFN is more appropriate for showing a positive correlation in HBeAg-positive patients. serum HBV DNA levels due to patient’s intolerability has been reported in 2–8 % of should be checked at 6 and 12 months of therapy and at 6 patients treated with Peg-IFN. included 101 Caucasian patients receiving IFN or Peg-IFN which is defined by the genotype-specific HBsAg stopping for 24 months and were followed for a median of 11 years rule. However. Peg-IFN could be stopped at week 12 or only one retrospective study has been reported. In Caucasian patients. pression. A sustained virological response with HBV DNA 000 IU/ml post-therapy is Therapy with pegylated interferon: overall conclusions generally associated with the remission of disease activity. Thus. these encouraging data ml post-therapy is the desired therapeutic endpoint. HBeAg. and 12 months post-therapy. they are well tolerated. HBsAg should be checked at 12-month intervals after HBeAg seroconversion The most frequently reported side effects of IFN-based if HBV DNA is undetectable. Although both were retro. Neu. still suggested that the role of HLA-DP SNPs in Peg-IFN HBeAg-positive patients who develop HBeAg serocon- therapy are worthy of further studies. neu. this is the only study chiatric contraindications. They found that the CC is not recommended for patients who have hepatic genotype of rs12979860 was highly associated with decompensation. fatigue. In patients receiving spontaneous HBsAg clearance in patients with chronic Peg-IFN therapy. anti-HBe anti- response to Peg-IFN. as the rate of HBsAg loss therapy are flu-like symptoms. a low likelihood of HBeAg seroconversion [274]. effects. full blood cell counts and serum ALT HBV infection. it seems reasonable to investigate the be monitored for safety through 12 months of treatment. those who can better tolerate side effects Most of the subsequent studies failed to confirm these and those who are reluctant to receive indefinite treatment. However. The authors 24 if the patients are found to be primary non-responders. association between the HLA-DP SNPs and the treatment In HBeAg-positive patients. Patients Peg-IFN have myelosuppressive effects. HBeAg-positive patients treated with Peg-IFN tropenia and thrombocytopenia induced by IFN or Peg-IFN who fail to achieve serum HBsAg levels below 20. Finally. further investigations are with interferons needed. findings [288]. young patients. it has been shown that rs3077 bodies and serum HBV DNA levels should be checked at 6 GG genotype was associated with a better treatment and 12 months of therapy and at 6 and 12 months post- response in HBeAg-positive patients receiving Peg-IFN therapy. useful and reliable viral and host factors [289]. They found that the CC genotype of rs12979860 was predictive of treatment outcomes need further exploration associated with higher rates of SVR (HBV DNA level to guide individualized Peg-IFN therapy in the future. and local reaction at the injection site.000/ HBV DNA and/or HBsAg levels through 3 or 6 months of mm3 are not common unless patients already have cirrhosis therapy have an increased likelihood of treatment response. Patients recommended as the first-line therapy. Premature discontinuation In HBeAg-negative patients. The currently recommended dose and duration of Peg-IFN SNPs near HLA-DP region Two SNPs near HLA-DP a-2a therapy for both HBeA-positive and HBeA-negative regions rs3077 and rs9277535 were shown to play a role in CHB is 180 lg/week for 48 weeks. Although IFN and Peg-IFN have many side cessation of Peg-IFN therapy may be considered. With regard to HBeAg-negative patients.000 IU/ do not significantly increase the risk of infection and ml or any decline in serum HBsAg levels by month 3 have bleeding. IFN and clearance should be tested for anti-HBs antibodies. Since spontaneous clearance of HBsAg is a levels should be monitored monthly and thyroid function result of host immune activity. In fact. During treatment. ALT normalization and serum HBV DNA below 2000 IU/ spective and small-scale studies. All patients should Peg-IFN treatment. headache. Peg-IFN who become HBsAg seroclearance should be tested for 123 . immunosuppression or medical or psy- HBeAg seroconversion. monotherapy with a potent NA or Peg-IFN is DNA remains undetectable during the follow-up. 000 IU/ml) and HBsAg clearance. increases over time. version with Peg-IFN therapy require long-term follow-up because of the possibility of HBeAg seroreversion or Side effects of IFN-based therapy progression to HBeAg-negative CHB. which could be enhanced by should be monitored every 3 months.38 Hepatol Int (2016) 10:1–98 were of Asian descendants. most studies involving Asian patients failed to identify IL28B Monitoring treatment and guidance for stopping genotype as a possible predictor for HBV treatment therapy in chronic HBV-infected patients treated response. myalgia. treated with Peg-IFN who achieve significant decline of tropenia 000/mm3 and thrombocytopenia 00. In summary. In contrast. Sustained HBeAg seroconversion together with therapy in Asian studies [290]. Patients who become HBsAg sero- alopecia. or low cell counts prior to IFN-based treatment.

ated control of HBV infection with an opportunity to obtain 3:6:2:5 In HBeAg-positive patients. and thus potential of finite of treatment and at 6 and 12 months post- treatment duration.7 Treatment strategies for first-line therapy in pre- 3:6:2:3 In patients treated with Peg-IFN. Thus. Peg-IFN therapy.5 lg/kg weekly (A1). Nil pregnancy. 291. who fail chronic HBV infection to achieve any decline in serum HBsAg 3:6:2:1 Treatment-naı¨ve patients can be treated with levels and a [2 log10 IU/ml decline in Peg-IFN-a2a 180 lg weekly or Peg-IFN-a2b serum HBV DNA levels by month 3 of 1–1. HBsAg levels should be checked every 3 months 3:6:2 Recommendations: results of currently available (A1). HBeAg and a sustained virological response off-treatment. discontinuation of Peg-IFN 3:6:2:2 For Peg-IFN. Peg-IFN-induced HBeAg seroconver- treatment (A1). 3. serum HBV therapy. 12 months post-treatment (A1). decline in serum HBV DNA levels by month 3 of Peg-IFN 3:6:2:7 In HBeAg-negative patients.000 IU/ml (genotype B and Table 7 Comparison of two treatment strategies for chronic hepatitis B Pegylated interferon Nucleos(t)ide analogues Strategy Sustained off-therapy response (immune control) Maintained on-treatment response (viral control) Goal Low HBV DNA level (000 IU/ml) and normal ALT Undetectable HBV DNA level and normal ALT level level Duration Finite Prolonged or indefinite Effectiveness Sustained response in *30 % of patients after Successful suppression of viral replication with continued 48 weeks of therapy treatment. who fail to achieve any infection). NAs] and immune-based therapies 3:6:2:4 In regions endemic for HBV genotype A and (IFN-a or pegylated-IFN-a) (Table 7). 48 weeks for both HBeAg-positive and– negative patients (A1). HBeAg-negative patients who C infection). therapies. 292]. Hepatol Int (2016) 10:1–98 39 anti-HBs antibodies. immunosuppression. stopping Peg-IFN therapy should decline in serum HBsAg levels and a [2 log10 IU/ml be considered (B2). the recommended duration is therapy should be considered (B2).000 IU/ml by week 24 (genotype A–D those with genotype D infection. HBeAg-negative patients. follow- 3:6:2:8 For HBeAg-negative patients. All patients The two therapeutic approaches available for the suppres- should be monitored for safety through sion of HBV replication include antiviral agents [nu- 12 months of treatment (A1). (PEG-) IFN is contraindicated in patients with levels below 20. predictors of response to therapy. seroconversion. cleos(t)ide analogues. HBsAg levels should be sion might be more durable than NA-induced HBeAg checked every 3 months (A1). especially 20. and a anti-HBe antibodies and serum HBV DNA chance of HBsAg loss in patients who achieve and main- levels should be checked at 6 and 12 months tain undetectable HBV DNA. D infection. psychiatric or medical contraindications 123 . or any decline in serum HBsAg achieve sustained response at 12 months post-therapy still levels (genotype A and D infection) by week require long-term follow-up because of the risk of future 12 and serum HBsAg levels below disease reactivation. HBV genotyping should be done The main theoretical advantages of Peg-IFN are the among patients being considered for IFN absence of resistance and the potential for immune-medi- therapy (A1). but high relapse rate after stopping the treatment Contraindication Hepatic decompensation. full blood cirrhotic chronic hepatitis B: nucleos(t)ide counts and serum ALT levels should be analogues or interferons or a combination monitored monthly and TSH should be monitored every 3 months. especially up and stopping rules during interferon therapy in those with genotype D infection. Frequent side effects and subcutaneous 3:6:2:6 For HBeAg-positive patients treated with injection are the main disadvantages of (PEG-) IFN treat- Peg-IFN who fail to achieve serum HBsAg ment. have a very low likelihood of treatment response DNA levels should be measured at 6 and [274. cessation of Peg-IFN therapy should 12 months of treatment and at 6 and be considered.

to IFN versus NAs should be provided. approaches need to be confirmed in larger studies before 3:7:3 Despite the tolerability and the higher rates they are recommended. patients. i. which sustained off-treatment virological response and require necessitates long-term or even life-long treatment. Current extended therapy. events and inconveniences of Peg-IFN versus NAs 3:7:2 A 48-week course of Peg-IFN is mainly (Table 7) should be provided so the patient can participate recommended for HBeAg-positive patients in the decision. of off-therapy response compared to NAs. but additional 3 years to try to achieve a durable off-treatment safety needs to be confirmed in larger studies response. It can also be used for HBeAg- to be safe with promising results. Full information about the advantages. HBeAg seroconversion may minimizing the adverse events. especially with raised anti-HBe on treatment.e. Orally Long-term treatment with NA(s) This strategy is neces- administered NAs are well tolerated. treatment duration is ALT and low to moderate levels of serum unpredictable prior to therapy. if available. Consolidation therapy of at least 3 years before recommendation (B2). However. 3:7:4 Full information about the advantages. Simultaneous combinations of Peg-IFN with the best chance of HBeAg seroconver- with NAs such as entecavir and tenofovir have been shown sion (B1). a careful not be durable after NAs discontinuation. psychosis. It appropriate first-line treatment strategy when can also be used for HBeAg-negative patients. as it is practically the only therapies using viral load reduction followed by addition of option that may offer a chance for sustained Peg-IFN have been found to be safe with improved sero. The most potent drugs with the of achieving sustained off-therapy response. tenofovir or entecavir. mostly due to its easier applica- logues or interferons or a combination bility (once weekly administration). avoid breakthroughs due to HBV resistance.e. i.. novo combination treatment with NAs in NA naive patients Finite-duration treatment with (PEG-) IFN This strategy receiving either entecavir or tenofovir. irrespective of HBeAg status or anti-HBe sero- are planning to have babies and patients with a high chance conversion on treatment. has replaced standard IFN therapy in pre-cirrhotic CHB: nucleos(t)ide ana- in the treatment of CHB. in patients with uncontrolled severe depression or HBsAg loss significantly [243]. This strategy is also recommended in patients with Peg-IFN should be highly considered in young people who cirrhosis. To increase the rates of patients of HBeAg seroconversion and the treatment continuation who may benefit from this treatment while post-HBeAg seroconversion. Therefore. as it depends on the timing HBV DNA. so that the rapidly reduce levels of viremia to undetectable levels and patient can participate in the decision (A1). and in female patients during pregnancy. treatment NAs such as lamivudine. entecavir and should be prolonged for at least 1 year and preferably an tenofovir have been shown to be safe. the Finite-duration treatment with a NA This strategy can be benefits of Peg-IFN are restricted to a is feasible for HBeAg-positive patients who seroconvert to subgroup of patients. such as optimal resistance profile. These of therapy (B2). off-treatment response after a finite duration conversion rates compared to monotherapies. for HBeAg-positive patients who do data show that long-term ETV or TDF therapy is relatively not develop HBeAg seroconversion and HBeAg-negative safe and has minimal risk of drug resistance. is intended to achieve a sustained off-treatment virological 3:7 Recommendations: treatment strategies for first-line response.. cessation. but the rate of viral sary for patients who are not expected to or fail to achieve a relapse is common once the treatment is ceased. genotype A infection or those with more favorable There are as yet no data to indicate an advantage of de predictors. levels. An attempt for finite NA treatment should use the most adverse events and inconveniences of Peg- potent agents with the highest barrier to resistance. 123 . adverse term administration (B2). decreases the rate of relapse and increases the rate of ease. as it is the purpose of treatment is to achieve a practically the only option that may offer a chance for sustained response after a defined treatment sustained off-treatment response after a finite duration of course compared with NAs requiring long- therapy. in a substantial proportion of these patients decisions to achieve treatment optimization requiring close virological monitoring after treatment are required (A1). Once HBeAg 3:7:5 Simultaneous combinations of Peg-IFN with seroconversion occurs during NA administration. A 48-week course of Peg-IFN is mainly recommended for HBeAg-positive 3:7:1 A course of Peg-IFN may be the most patients with the best chance of HBeAg seroconversion. HBeAg-positive patients who have high pre-treatment ALT should be used as first-line monotherapies.40 Hepatol Int (2016) 10:1–98 decompensated HBV-related cirrhosis or autoimmune dis. at least with less patient selection and individualized treatment potent agents. Sequential combination negative patients. Peg-IFN.

has been halted because of risk of approved therapies for HBV. 3:7:10 As of yet. which is approved in Korea but devel- cavir. barrier of that antiviral agent to resistance. Primary virological failure amino acid substitutions within the reverse transcriptase may be either primary nonresponse or partial (suboptimal) domain can significantly reduce NA binding and antiviral 123 . fovir therapy due to suboptimal efficacy of this agent.. Factors that may impact the risk of infected with hepatitis B and reducing the long-term risk of selecting resistant HBV variants during antiviral therapy liver-related complications such as HCC. there are no data to indicate an Viral breakthrough is either due to noncompliance or the advantage of de novo combination treatment emergence of drug resistance. this ‘‘Roadmap Approach’’ really only necessary for patients who are not expected pertains to patients receiving lamivudine or telbivudine to or fail to achieve a sustained off-treatment (drugs with a low genetic barrier to resistance). In the absence of noncompliance. Partial virological response is achievable for HBeAg-positive patients who defined as detectable HBV DNA in plasma after 24 weeks seroconvert to anti-HBe on treatment. and five There are five NAs approved for clinical use. monotherapy with detectable HBV DNA after 24 weeks. thereby reducing replicating in the presence of selection pressure provided the risk of disease progression in patients chronically by the antiviral therapy. two immunomodulators. i. for HBeAg-positive patients with more potent drugs with a high genetic barrier to who do not develop HBeAg seroconversion resistance. lamivudine. given resistance profile.e. Because antiviral therapy with two NAs in NA-naive patients receiving with NA does not completely inhibit the replication of the either entecavir or tenofovir (C2). as it depends on the timing of high baseline viraemia. To date. interferon alpha and pegylated interferon.e. Like HIV. especially in those patients with to therapy.. decompensation include the baseline viral load and diversity. and a sixth nucleos(t)ide analogues (NA). Single secondary viral breakthrough. clevudine. normalize serum species at any one time is the ‘‘fittest’’ virus. tenofovir in treatment- 3:7:7 Finite-duration treatment with a NA is experienced patients). the steady rise in rates of virological response over time should be used as first-line long-term and the very low risk of resistance with both of these agents monotherapies (A1). These approaches need to be appropriate action is to switch to a more potent drug (en- confirmed in larger studies. and should virological response and require extended become obsolete with the shift towards primary therapy therapy. treatment duration is unpredictable prior with all available NAs. 3:7:9 The most potent drugs with the optimal continuation of the same treatment is recommended.Hepatol Int (2016) 10:1–98 41 3:7:6 Sequential combination therapies using viral virological response. log reduction in plasma HBV DNA levels after 24 weeks IFN or add-on Peg-IFN after response to NAs of therapy. Treat- potent antiviral activity. In patients receiving entecavir or tenofovir and HBeAg-negative patients (A1). tecavir in treatment-naı¨ve patients. The dominant permanently suppress viral replication.8 Treatment failure to therapy and its which allows for viral mutations to occur spontaneously management in chronic HBV infection during viral replication. with between 4 and 6 log IU ment failure may be either primary virological failure or reduction in HBV DNA levels over 12 weeks. myopathy. Partial virological response may be encountered ever. The apies (B2). the HBV reverse transcriptase lacks a proofreading function. tenofovir or entecavir. 3. more potent drug without (A1). adefovir. ente- agent. which is the genetic therapeutic options. the emergence of HBV drug resistance is almost inevitable with long-term monotherapy. All NAs target the active site of the HBV The long term efficacy of NAs is determined by the reverse transcriptase of the HBV polymerase and have ability to achieve and maintain viral suppression. In recent years. cross-resistance) if HBV DNA remained detectable after 3:7:8 Strategy of long-term treatment with NA(s) is 24 weeks. capable of ALT levels and improve liver histology. the replicative and death. virus. Primary nonresponse is defined as load reduction followed by addition of Peg. i. How. are opment elsewhere. of therapy. [213]. primary have been found to be safe with improved nonresponse is rare and is now only observed during ade- seroconversion rates compared to monother. The previous APASL HBV Man- HBeAg seroconversion and the treatment agement Guidelines recommended that treatment be mod- continuation post anti-HBe seroconversion ified (switch or add a second. the treatment of chronic hep- fitness of variants and the number of specific mutations that atitis has greatly improved with the development of new are required to confer resistance. However. This results in a pool of viral quasi-species that coexist in different proportions depend- The goals of hepatitis B treatment are to eliminate or ing on their relative replicative fitness. telbivudine and tenofovir (not all countries).

resulting in altered HBsAg antigenicity. 4). Lamivudine has potent antiviral efficacy. but antiviral therapy. 5 Cumulative incidence of Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 8 antiviral resistance in long-term studies of NA therapy 72 Weeks LAM1 23% 46% 55% 71% 80% - ADVǂ1 0% 3% 11% 18% 29% - LdTƚ2. whilst preserving replication capacity. Although all five currently available NAs target the vations with occasional hepatitis flares and clinical same active site of the reverse transcriptase. F__V__LLAQ_YMDD I(G) II(F) A B C D E L-Nucleoside Resistance LMV rtA181T/V rtM204V/I L-dT rtA181T/V rtM204I Acyclic Phosphonate Resistance ADV/TFV rtA181T/V rtN236T D-Cyclopentane Resistance ETV rtL180M plus rtM204V/I rtI169 rtT184 rtS202 rtM250 Fig.2% 1. associated increased risk of HBV recurrence following Viral breakthrough due to drug resistance is defined as liver transplantation. an increase in HBV DNA levels (C19 log10 IU/ml) in Primary resistance mutations have been identified for patients who initially responded to antiviral therapy and are five out of the six currently approved NAs (Fig. 4 Reverse transcriptase mutations associated with drug resistance Terminal Spacer POL/RT RNaseH Protein 1 183 349 (rt1) 692 (rt 344) 845 a. 5). compliant with therapy [293]. NA resistance include changes to the overlapping envelope term benefit of these agents is lost following the selection region. resulting in viral breakthrough surface escape mutants.2% 1.2% 1. reduced binding to HBIG and and subsequent treatment failure.42 Hepatol Int (2016) 10:1–98 Fig. possible of these resistant mutants. with reduced HBeAg seroconversion and also has the lowest barrier to resistance. The long. - TDF§4 0% 0%§ 0%§ 0% 0% 0% 0% ETV*5 <1% <1% 1. Occasionally. in patients with minimal liver disease. The cumulative histological progression. Antiviral resistance Lamivudine: L-nucleoside analogue The first approved is also associated with loss of long-term efficacy of NA for HBV.a. they exhibit decompensation. Other potential consequences of rate of emergence of lamivudine resistance is 15–20 %/ 123 . This will lead to ALT ele.3 25% 5% 29% 35% . even term follow-up studies of each (Fig.2%6 efficacy. the emergence of drug very different genetic barriers to resistance rates in long- resistance may result in acute liver failure and death.

the less expensive resistance—only 1 % over 5 years in treatment-naı¨ve NAs with low barrier to resistance have remained as first- patients. In a large Phase IIb study. The primary mutations associ. Slower rate of drug emergence [198]. The best first-line strategy will always be selection of an directed mutagenesis. This is increased to almost 10 % Because all the NAs share the same target (HBV poly- per annum in patients with prior lamivudine resistance (i. individual differ. respectively. the dose-limiting nephrotoxicity of this 168 weeks [197]. secondary Combining two or more of these older NAs with low mutations are needed to confer resistance to entecavir. Therefore. resistance was observed in 21. This is the only approved NA without any Summary associated clinical resistance. The than LAM. adding emtricitabine did not agent has resulted in suboptimal dosing (10 mg) with improve efficacy. for which there are very limited salvage options available. around 10 % per annum. around 3–5 % per annum. addition. complete viral suppression on tenofovir ± emtricitabine. Again. so entecavir monotherapy can drug (e. LAM plus ADV) [294]. all of who achieved and maintained confer cross-resistance with telbivudine. Both treatments were safe and well tolerated. 105 patients with documented approved NA for the rescue of lamivudine resistance. In the Globe study. monotherapy or to tenofovir plus emtricitabine for Unfortunately.. dine resistance—L180M ? m204I/V. treatment will be with an NA with high antiviral potency Entecavir: deoxyguanosine analogue 100-fold more and a high barrier to resistance. the optimal first-line The latter also confers cross resistance to lamivudine. However. However. In baseline viral load. cross resistance is a major issue (Table 8). dose combination of tenofovir plus emtricitabine (an L- Telbivudine: L-nucleoside analogue Tenfold more nucleoside analogue similar to lamivudine) for 96 weeks potent than lamivudine. Much higher rates of resistance in LAM-experi. particular. The primary mutations are those associated with lamivu. group. therefore the emergence of resistance may limit future ated with adefovir resistance are rt N236T ± rtA181V/T. HBeAg positivity and immunosup. in many potent than LAM and has a very high genetic barrier to countries within the Asia-Pacific region. The primary mutations associated with tel. patients with documented resistance to lamivudine were tance are the rtM204I and rtM204V mutations randomized to either tenofovir monotherapy or the fixed- (±rtL180M). Therefore. multi- difference reflects the pathway to resistance for entecavir. merase). no primary mutations associated agent with both a high barrier to resistance (requires mul- with tenofovir resistance have been detected in any patient tiple mutations before emergence of resistance) and high 123 .e. more potent than adefovir and has a very high barrier to resistance. It has no or prevent the emergence of antiviral resistance to each cross resistance to adefovir. cavir or adefovir was documented at baseline in 12 % and tions. Higher receiving up to 8 years continuous tenofovir therapy. the rate of adefovir resistance is on long-term treatment response. typic resistance mutations did not predict response—in ences in ADV metabolism and prior lamivudine resistance. HBeAg-positive patients and 8. tenofovir salvage therapy. 280 The primary mutations associated with lamivudine resis. Around below LOQ in 84 % of the combination group and 82 % of 20 % of patients have primary treatment failure to this the monotherapy group maintaining HBV DNA levels agent. at the DNA levels were suppressed below LOQ in 86 % of the end of 2 years. whilst HBV genotype and fibrosis stage are not.. Although reduced suscepti- bility to tenofovir has been produced in vitro with site. The baseline geno- include the inadequate dose of 10 mg. It is resistance to adefovir were randomized to tenofovir also effective against telbivudine and entecavir resistance.Hepatol Int (2016) 10:1–98 43 year. the presence of lamivudine and/or adefovir In treatment-naı¨ve patients who had an adequate primary resistance-associated mutations at baseline had no impact virological response.6 % of HBeAg-negative No tenofovir resistance was observed in either treatment patients. treatment options (Fig. Unfortunately. Prior exposure or documented resistance to ente- bivudine resistance are the rtM204I and rtM204V muta. Factors that contribute to primary nonresponse below LOQ at the end of 168 weeks. with HBV DNA levels were suppressed reduced antiviral potency compared to other NAs. and it plateaus around 60 % after 5 years. 5).g. strategy is associated with increased cost and non- Tenofovir Acyclic nucleoside phosphonate: 1000-fold adherence.6 % of combination group and 89 % of the monotherapy group. This patients receive and fail sequential monotherapy. and sequential monotherapy). barriers to resistance from different classes may help delay These include rtT184G ± rtS202I ± rtM250V. lamivudine resistance is assumed to 22 %. Adefovir: acyclic nucleoside phosphonate The first In a second Phase IIb study. no tenofovir resistance has been observed in pression are all factors associated with increase rate of patients with prior lamivudine resistance in studies of resistance. As enced (refractory) patients. drug resistant HBV variants are becoming more prevalent. line therapies because of cost and access barriers. such a be used to treat adefovir resistance. around 10 %/year in HBeAg-positive and 5 %/ addition of emtricitabine did not improve efficacy—HBV year in HBeAg-negative patients.

if HBV DNA is still detectable (so-called 3:8:8 For patients who develop drug resistance ‘‘Roadmap Approach’’)—invalid. preferred because of their potency and minimal risk of cavir and tenofovir) (A1). 24 weeks. and (2) that the treat- 3:8:7 For patients who develop drug resistance while ment be modified (switch or add a second agent) after on ETV. ADV) A181T/V R S S R I Double (ADV. logical monitoring should be performed to detect viral breakthrough and genotypic resistance. Early detection and modification of antiviral therapy should optimize long-term 3. switching to TDF is indicated (B1).9 Treatment of patients with chronic HBV outcomes (Table 9). combination telbivudine and adefovir monotherapy. and those on immunosuppression).44 Hepatol Int (2016) 10:1–98 Table 8 Cross-resistance profiles amongst the five NAs [332] Pathway HBV variants LAM LdT ETV ADV TDF Wild-type S S S S S L-Nucleoside (LAM/LdT) M204 l/V R R I S S Acyclic phosphonate (ADV) N236T S S S R I Shared (LAM. Close monitoring of HBV DNA levels every 123 . used for the treatment of well-compensated cirrhosis [258]. exposure. antiviral potency (achieves complete viral suppression 3:8:5 For patients who develop drug resistance while within the first 6 months). Switch to Peg-IFN 3:8:4 For patients who develop drug resistance while on LAM or LdT. resistance. switching to TDF have already failed one class. appropriate viro- ETV plus TDF is indicated (C2). switching to either ETV or TDF The availability of tenofovir and entecavir as first line monotherapy is indicated (A1). those with highest viral load monotherapy is indicated (B1). LdT. without prior lamivudine ing is also important to prevent treatment interruption. telbivudine and adefovir) (A1). appro- ADV resistance (previous LAM/LdT) Switch to TDF priate testing to confirm genotypic drug resis- Switch to LAM/TDF tance should be performed with a validated ETV resistance (no previous LAM/LdT) Switch to TDF test. TDF) A181T/V ? N236T R R S R R D-Cyclopentane (ETV) L181M ? M204V/I ± I169 ± T184 ± S202 ± M250 R R R S S Multi-drug resistance A181T ? N236T ? M204V R R R R R Table 9 Strategies to manage treatment failure—first and second line 3:8:2 Regular monitoring for viral breakthrough should be performed in patients receiving an LAM/LdT resistance Switch to TDF agent with low barrier to resistance (lamivu- Add ADV dine.9. Patient education and monitor- on ADV therapy. Rescue therapy should be instituted as Add ADV early as possible in case of drug resistance Multidrug resistance Switch to ETV/TDF (A1). In the compliant patient.1 Treatment of patients with compensated cirrhosis its management in chronic HBV infection 3:8:1 The best strategy for drug resistance is Peg-IFN in regimens similar to those used in CHB can be prevention through patient education on com. monotherapies with tenofovir or entecavir are potency and high barrier to resistance (ente. LAM then ETV resistance Switch to TDF 3:8:3 Patients with viral breakthrough evident by Add ADV more than 1 log IU/ml increase of HBV DNA ADV resistance (no previous LAM) Switch to ETV from the nadir should be counseled about Switch to TDF compliance. infection with severe liver disease 3:8 Recommendations: treatment failure to therapy and 3. drugs has made the two previous APASL recommenda- 3:8:6 For patients who develop drug resistance while tions—(1) that combination of NAs without cross-resis- on ADV rescue therapy for prior lamivudine/ tance should be used in highest risk patients (those who telbivudine resistance. switching to TDF is indicated (A1). (A181T ? N236T ? M204V). associated with multidrug resistant mutations In patients receiving long-term therapy with lamivudine. pliance and selection of an agent with high Among NAs.

and these patients may be candidates for 3:9:2:6 NA therapy should usually be continued for liver transplantation. hepatitis B after liver transplantation’’ section). beyond the point of no return. Some patients with advanced hepatic disease with a been reported in patients with prolonged suppression of high Child–Pugh or MELD score may have progressed viral replication [295].Hepatol Int (2016) 10:1–98 45 3 months during the first year of therapy and until HBV closely monitored in this setting. apy is complex.12 Prevention and treatment of recurrent rhotic patients. 297]. monotherapies with tenofovir or entecavir are preferred (A1). of chronic HBV infection including those developing Recent studies have shown that both drugs are not only acute on chronic liver failure effective. Thus. 298]. Entecavir or virological remission under NA(s) (A1). However. requiring liver transplantation. as exacerbations of to be adjusted in patients with low creatinine clearance hepatitis B may occur in patients with cirrhosis requiring (0 ml/min). The dose of all NAs needs DNA undetectability is important. 3:9:2:5 The dose of all NAs needs to be adjusted in Patients with decompensated cirrhosis should be treated in patients with low creatinine clearance specialized liver units. therapy is complex. clinical and laboratory parameters should be response do not clear the virus. The licensed entecavir dose for patients with decompensated cirrhosis is 1 mg (instead of 0. spective of HBV DNA level. 3:9:2:3 Peg-IFN is contraindicated in decompen- 3:9:1:4 Monitoring for HCC is mandatory despite sated cirrhosis (A1). as the application of antiviral extra caution and monitoring is recom. Indi- advance decompensated cirrhosis (MELD score [20). 3:9:1 Recommendations: treatment of patients with com. tenofovir should be used. long-term monitoring for HCC is manda. plantation will decrease the risk of HBV recurrence in the NA therapy should usually be continued for life in cir. patients with cirrhosis require Patients with decompensated cirrhosis may show slow long-term therapy. monotherapies with tenofovir HBsAg positive cirrhotic patients with or entecavir are preferred (A1). is high in these patients even under effective NA therapy. virological remission under NA(s) (A1). irrespective of 3:9:1:3 NA therapy should usually be continued for HBV DNA levels (A1). urgent management. since there with NA(s) inducing HBV DNA undetectability at trans- is still a risk of developing HCC [296. but are generally safe in these patients [164. liver units. In that situation. NA(s) and then transplantation may be avoided. and may not benefit. and therefore long-term HCC surveillance is mandatory Regression of fibrosis and even reversal of cirrhosis have [299]. viduals who do not mount a broad and vigorous immune Therefore. and these patients may mended to prevent and diagnose hepatic be candidates for liver transplantation (A1). in order to prevent reactiva- 3:9:2:7 Monitoring for HCC is mandatory. 3:9:2:4 Among NAs. graft (see ‘‘3.5 mg for patients with compensated liver disease) once 3. individuals with a vigorous and Lactic acidosis has been reported to develop with some broad immune response to the virus develop an acute self- NAs.9. vent the progression to decompensated liver disease [86]. as the application of antiviral ther- (0 ml/min) (A1). hepatic decompensation. treatment tory despite virological remission under NA(s). The HCC risk suppression of HBV DNA can stabilize patients and pre. 3:9:2 Recommendations (treatment of patients with pensated cirrhosis decompensated cirrhosis) 3:9:1:1 Peg-IFN in regimens similar to those used 3:9:2:1 Patients with decompensated cirrhosis in CHB can be used for the treatment of should preferably be treated in specialized well-compensated cirrhosis (A1). The antivi- ral treatment should not be delayed while 3. 3:9:2:2 Antiviral treatment is indicated in all 3:9:1:2 Among NAs. thus Nonetheless. despite tion. in treated patients with limited infection that may result in acute hepatitis. with careful monitoring for resistance clinical improvement over a period of 3–6 months under and flares. life in cirrhotic patients (B1). but develop persistent 123 . particularly entecavir.2 Treatment of patients with decompensated cirrhosis waiting for the HBVDNA results. Peg-IFN is contraindicated in this setting. In such Clinical studies indicate that prolonged and adequate cases. decompensation (A1). Upon exposure to HBV. life-long treatment is recommended.10 Treatment of patients with reactivation daily. Antiviral treatment is indicated irre- life in decompensated cirrhotic patients (B1).

46 Hepatol Int (2016) 10:1–98

infection and become chronically infected with HBV. HBV Spontaneous reactivation hepatitis B
persists in the body even after serological recovery from
acute hepatitis B; so individuals who have been exposed to Spontaneous reactivation of hepatitis B can occur in both
HBV are at risk for reactivation of hepatitis B replication HBeAg-positive and -negative patients [302, 303]. Spon-
when the immune imbalance occurs, which can lead to taneous reactivation of chronic HBV infection can occur in
flare or exacerbation of hepatitis [300]. The severity of the the immune clearance phase affecting 40–50 % of HBeAg-
flare depends on the state of underlying liver disease and positive patients, and can be prolonged when there is
may range from mild flare of hepatitis to acute on chronic repeated unsuccessful clearance of HBeAg [304]. Reacti-
liver failure. As patients suffering from severe acute vation of chronic HBV infection at the HBeAg-negative
exacerbation of CHB may not have underlying liver cir- phase is seen in 15–30 % of HBeAg-negative patients, and
rhosis, they may recover to a relatively normal liver is occasionally associated with HBeAg seroreversion
function, in contrast to those suffering from end-stage liver [301].
cirrhosis. It is therefore important to recognize this In Far Eastern regions, 23–38 % of patients have been
important clinical presentation of CHB. reported to develop jaundice and hepatic decompensation
Reactivation of chronic HBV infection has two com- (acute on chronic liver failure) during biochemical exac-
ponents, i.e., reactivation of HBV replication and flare (or erbation of CHB [305, 306]. These exacerbations may be
exacerbation) of hepatitis. Reactivation of HBV replication associated with significant mortality.
should be defined as a marked increase in HBV replication
(C2 log increase from baseline levels or a new appearance Pathogenesis of spontaneous reactivation of hepatitis B
of HBV DNA to a level of C100 IU/ml) in a person with virus infection
previously stable or undetectable levels or detection of
HBV DNA with levelss C20,000 IU/ml in a person with no Acute hepatitis flare is precipitated by the reactivation of
baseline HBV DNA [22, 300]. The types of reactivation HBV infection. The reasons for reactivated infection are
should be described as follows: exacerbation of CHB or unknown, but are likely explained by changes in the
reactivation of past hepatitis B. The latter can be further immunological control of viral replication.
defined as reverse HBsAg seroconversion (reappearance of Influence of HBV genotypes on reactivation has also
HBsAg), or appearance of HBV DNA in serum in the been assessed. There is a possibility that the immuno-
absence of HBsAg. genicity of the different genotypes is different. Genotype B
This reactivation of HBV replication may lead to flare HBV may associate with more vigorous immune response
(or exacerbation) of hepatitis, which is characterized by an that leads to a higher chance of successful immune clear-
abrupt elevation of the serum ALT level, although there is ance, but also a higher risk of hepatic decompensation
no consensus definition or diagnostic criterion. It usually during the hepatitis flare. On the contrary, genotype C
refers to an abrupt increase in serum ALT to [5 times the HBV is associated with less vigorous and prolonged,
upper limit of normal and more than twice the baseline abortive immune clearance, which is more likely to cause
value [23, 301]. Severe hepatitis flare means reactivation progressive liver damage, and eventually, liver cirrhosis
with the presence of coagulopathy with prolonged pro- and HCC [307].
thrombin time (prolonged by more than 3 s) or INR Several HBV mutant strains, including mutations in
increased to[1.5. Severe hepatitis flare may lead to ACLF. precore, core promoter, and deletion mutation in pre-S/S
Flare (or exacerbation) of hepatitis in CHB infected genes, have been reported. Viral populations in the immune
patients is common and may be caused by a number of tolerance phase mostly consist of exclusively wild-type
factors (Table 10). virus or HBeAg-positive strains with little or no

Table 10 Causes of acute hepatitis flares of hepatitis in chronic hepatitis B virus infected patients
Spontaneous reactivation of hepatitis B virus replication
Due to immunosuppressive medications: cancer chemotherapy, antirejection drugs, corticosteroids
Cessation of anti-viral agents
Emergence of drug resistance
Due to antiviral therapy: interferon, corticosteroid withdrawal
Due to superimposed infections with other hepatotropic viruses: hepatitis A/E virus, hepatitis C virus, hepatitis delta virus
Caused by interaction with HIV infection: reactivated hepatitis, effect of immune reconstitution therapy
Other hepatotropic insults: drugs, alcohol


Hepatol Int (2016) 10:1–98 47

precore/core promoter mutants or HBeAg-negative strains endemicity, the possibility of reactivation of chronic HBV
[308]. Spontaneous reactivation of CHB may also occur in infection is high, which may be the first presentation of
response to HBV genotypic variation. Chronic infection CHB or compensated cirrhosis, which was asymptomatic
with precore mutant is often associated with multiple flares before exacerbation. Hence, a possibility exists that a
interspersed with periods of asymptomatic infection [309]. proportion of patients with suspected acute hepatitis B
It is possible that the absence of HBeAg in patients har- might actually be suffering from CHB and manifesting
boring precore mutant HBV may permit a more vigorous clinically for the first time during a period of severe reac-
immunological response to core peptides expressed on the tivation [23]. In areas of intermediate to high HBV
surface of hepatocytes. Episodic flares have been attributed endemicity, endemic for chronic HBV infection, reactiva-
to increases in the concentration of precore mutants and tion (flare or exacerbation) accounts for 27–70 % of pre-
changes in the proportion of precore to wild-type HBV sumed acute hepatitis [23, 317, 318].
[310]. It has been suggested that disease exacerbations are The symptoms and biochemical parameters of severe
uncommon during the earliest phase of chronic HBV at a acute reactivationof CHB can be very similar to those of
time when wild-type HBV predominates, and that flares acute hepatitis B [23]. Hence, severe acute reactivation of
become common with the gradual emergence of the pre- CHB might be misdiagnosed as acute hepatitis B in some
core variant [310]. These flares have been thought to sub- cases. Patients with severe spontaneous acute reactivation
side with time as the genetic heterogeneity disappears and of CHB can have positive IgM anti-HBc, which may again
patients become exclusively infected with precore HBV be confused with the diagnosis of acute hepatitis B. Levels
[311]. Multiple exacerbations of hepatitis due to reacti- [600 Paul–Ehrlich units/ml or IgM anti-HBc ([1:1000)
vated HBV infection have been described in patients with suggest an acute HBV infection with high inflammatory
BCP mutation, either alone, or in association with precore activity. In all other situations, concentrations are lower or
mutation [312, 313]. undetectable [23, 319]. One study suggests that a low titer
Reactivation seems to occur more commonly in male of IgM anti-HBc (:1000) and high HBV DNA level
homosexuals, patients who are infected with human ([0.5 pg/ml, which equals *141,500 copies/ml) are useful
immunodeficiency virus (HIV), concurrent with bacterial to identify severe acute reactivation (flare or exacerbation)
infections or surgery, and when there is emotional or of CHB from acute hepatitis B [23]. However, HBV DNA
physical stress [314]. Pregnancy and postpartum may also may sometimes become undetectable at the peak of the
be a risk factor [315]. Liver injury during these sponta- biochemical exacerbation due to vigorous immune clear-
neous flares appears to be mediated by expanded numbers ance. The presence of BCP mutation and precore stop
of T cells that are reactive to HBeAg and HBcAg which codon mutations have been suggested to differentiate sev-
are cross-reactive at the T cell level. Measurement of ere acute exacerbation of CHB from acute hepatitis B in
lymphocyte proliferation in response to these viral anti- Japanese series, but its use in clinical practice needs further
gens has shown that increased T-cell responses occur in validation [319].
the early phase of acute flares and subside after recovery A previous history of CHB or a positive family history
from acute exacerbation and HBeAg seroconversion of CHB may suggest reactivation (flare or exacerbation);
[316]. whereas recent history of at-risk blood, percutaneous or
Once acute on chronic liver failure (ACLF) develops, sexual exposure may suggest acute hepatitis B.
the immunological changes seen in the inflammatory pro- Liver biopsy showing evidence of chronicity may sug-
cess are very similar to those of severe sepsis [317]. As the gest chronic infection.
ACLF progresses, the resulting inflammatory responses in In uncertain cases of acute hepatitis B versus severe
the liver and its associated cellular immune dysfunction reactivation of CHB, one can manage these patients as
can result in multi-organ failure. severe reactivation cases and repeat hepatitis B surface
antigen testing (HBsAg) 6 months later. In over 95 % of
Diagnosis acute hepatitis B acquired in adulthood, HBsAg will be
cleared on the follow-up testing; however, a small per-
The typical presentation of severe spontaneous reactivation centage of patients with acute reactivation of chronic HVB
in a patient with CHB is a short onset of jaundice and very infection may also clear HBsAg.
high ALT level, sometimes preceded by prodromal con- As CHB infected patients still can acquire another viral
stitutional symptoms. If signs of chronic liver disease are infection that causes acute hepatitis, other viral hepatitis
present, the diagnosis could be easy, however, some (A, C, D and E) must be excluded by serological assays. If
patients presenting with severe acute reactivation of CHB suspected, other etiologies (Table 1) should also be
may not have had an earlier diagnosis of chronic HBV excluded before a diagnosis of spontaneous reactivation of
infection. In countries with intermediate and high CHB is made.


48 Hepatol Int (2016) 10:1–98

Outcome been described. One regression model, using the presence
of hepatorenal syndrome, liver cirrhosis, positive HBeAg,
The clinical presentation of acute spontaneous reactivation low albumin and prolonged PT, was found to be superior to
of CHB infection depends on the underlying severity of the MELD score in predicting 3-month mortality [329].
liver disease and other factors. Another model based on the presence of hepatic
In a Chinese study on evaluation of prognostic factors in encephalopathy, hepatorenal syndrome, positive HBeAg,
severe reactivation (flare or exacerbation) of chronic HBV liver cirrhosis and prolonged PT was also found to be
infection, at admission the following parameters were superior to both the MELD and Child–Pugh score [325]. In
independently associated with adverse outcome: pre-ex- a recent study from China compared a logistic regression
isting cirrhosis, high Child–Pugh score, low albumin level, based model (based on presence of hepatic encepahalopa-
high bilirubin level, prolonged PT and low platelet count. thy, hepatorenal syndrome, cirrhosis, HBeAg status,
For the subsequent stay in the hospital, these factors were Prothrombin time and age) with Child–Turcotte–Pugh
as follows: high peak bilirubin level, long peak PT, long (CTP) classification, King’s College Hospital (KCH) cri-
duration to reach the peak PT, development of teria, model for end-stage liver disease (MELD), MELD
encephalopathy, and presence of ascites. There was also a combined with serum sodium (Na) concentration
trend for a longer time to reach peak bilirubin level to be an (MELDNa), and integrated MELD (iMELD) for predicting
independent factor associated with adverse outcome [320]. short-term prognosis of patients with HBV-related acute-
In one study from Taiwan on HBeAg-positive noncir- on-chronic liver failure (ACLF). It was found that the
rhotic patients with acute exacerbation, 5.1 % of the regression model, MELD, MELDNa and iMELD had
exacerbation episodes resulted in hepatic decompensation, similar accuracy in predicting the short-term prognosis in
and serum HBV DNA level was the only significant risk patients with liver cirrhosis, while regression model was
factor (p = 0.003). A serum HBV DNA cutoff value of superior to MELD, MELDNa and iMELD in predicting the
1.55 9 109 copies/ml predicted decompensation with a short-term prognosis of HBV-ACLF patients without liver
sensitivity of 85.7 %, a specificity of 85.5 %, a negative cirrhosis. CPT score and KCH criteria fared poorly [330].
prediction value of 99.1 %, and a positive prediction value Further studies to externally validate these models would
of 24.0 % [321]. be needed.
Owing to their limited hepatic reserve, cirrhotic patients Acute Physiology and Chronic Health Evaluation
are expected to recover more slowly from the hepatic insult (APACHE) II and III, Simplified Acute Physiology Score
and are more prone to complications including sepsis, (SAPS) II, and Mortality Prediction Model II, SOFA and
gastrointestinal bleeding and acute renal failure. Many its modifications have been used to prognosticate critically
studies have found that patients with pre-existing liver ill patients with liver failure [331, 332].
cirrhosis and more serious hepatic dysfunction (prolonged
prothrombin time, elevated serum bilirubin and high Treatment
Child–Pugh score) have a higher risk of mortality [322,
323]. Patients need intensive supportive care, including close
Once the disease reaches the stage of acute on chronic monitoring and treatment of complications.
liver failure (ACLF), the prognosis is extremely poor, with In severe spontaneous reactivation of CHB when
3-month mortality rates without liver transplantation immune activity is already excessive, interferon-based
reported to be around 50–55 % [324]. Different predictive treatment may aggravate the hepatic decompensation, and
models have been used in prognosticating acute-on-chronic is thus contraindicated. Oral nucleos(t)ide analogs are the
liver failure due to reactivation of CHB. MELD is the most treatment of choice.
commonly used prediction model. MELD score has been In initial case series or cohort studies of Lamivudine in
found in many studies to be more objective when compared patients with severe acute exacerbation, some showed
to Child–Pugh score in predicting survival in chronic HBV dramatic effects [333], whereas others could not demon-
infection patients with ACLF [325, 326]. It has been found strate any survival benefit of lamivudine treatment [323,
that a MELD score of[30 is associated with high mortality 334, 335], possibly related to the delayed commencement
([90 % despite using antivirals), a MELD 0–23 is of lamivudine. A study from Taiwan suggests that the
associated with low mortality with use of antivirals beneficial effect of antiviral therapy on short-term survival
(16–17 %) and MELD in between these ranges is associ- depends on the timing of treatment. Among consecutive
ated with intermediate mortality (44–51 %) with antiviral CHB patients with severe acute exacerbation treated with
treatment [327, 328]. lamivudine, all 25 patients who had baseline bilirubin
A number of logistic regression models based on both below 20 mg/dl survived. Among patients with low
laboratory parameters and organ dysfunction have also (0 mg/dl) baseline serum bilirubin level, lamivudine


p = 0.54. On the other hand. 67 %) was [347]. Corticos- [341]. 40. together with continuous lamivu- short-term survival as compared to lamivudine [346].68. In a DDLT setting. dexamethasone meta analysis found that there was no significant difference treatment was an independent factor influencing survival. 95 % CI (0. 0. toric controls who did not receive lamivudine (5/20 1.29. and survival has been shown to pression of HBV replication. 11 patients died at placebo). RR 0.77. decline in viral load were predictors of good outcome In one study.003].26. One dine. Patients with ACLF receiving tenofovir plus reactivation of HBV infection that included 11 randomized telbivudine against tenofovir alone had significant controlled trials (including 654 patients. patients received tenofovir and 12 received tenofovir plus analysis of antiviral therapy in ACLF due to spontaneous telbivudine). RR deceased and living donor transplants are viable and very 0. spontaneous reactivation of HBV infection concluded that The definitive treatment for severe reactivation (flare or antiviral treatment with nucleos(t)ide analogues signifi. 95 % CI (0.4 vs. vation of hepatitis B were randomized to receive either Once ACLF develops. One randomized placebo-controlled trial found that the ment [341]. p \ 0. There was reactivation have shown successful 5-year survival above no significant difference in the prognosis of patients treated 90 % [350. 343. predictor of mortality in univariate analysis in ACLF-B at p = 0.45. the end of the 3-month follow-up period. 69 patients of severe spontaneous reacti- [337]. Use of bioartificial HBV DNA higher than 105 copies/ml) compared with liver support systems is controversial and the results of a lamivudine [342].Hepatol Int (2016) 10:1–98 49 treatment has definite survival benefit as compared to his. similar to that of the untreated historical controls (9/11. Recently. no waiting list constraints. a lot research has been conducted in an pared to patients receiving no treatment [340].5 %. however.35] [339].32).01] compared to those who did not.15.7 %.03. This finding needs further confirmation. there are Several studies have found that despite a faster sup.10. have other studies have found comparable efficacy of entecavir been used in chronic HBVinfection with ACLF. 20 %. the prognosis of spontaneous tenofovir monotherapy or dual therapy of tenofovir plus reactivation of HBV infection is poorer as compared to telbivudine. One RCT from India found improved 3-month survival 82 %) [336].005] and 12-month survival [OR 4.013). a major concern. 40. exacerbation) with ACLF is liver transplantation.80 vs. the have similar survival benefit as compared to telbivudine. A those treated with lamivudine still had a 3-month mortality more than 2-log reduction in HBV DNA levels at 2 weeks of 50.89).43).5 %. plantation results from the East in patients with HBV 0. However. or better long-term (52 weeks) survival but not 10 mg daily for 5 days. 351]. 1.32). entecavir treatment was either be comparable to DDLT.96. the availability of the organ becomes 95 % CI (0.0005] [338]. it was found that nucleoside analogues signifi. 95 % CI (1. Among ten deaths cantly improved 1-month [OR 2. In a recent and lamivudine in the short term [329. p \ 0. or had attempt to improve the dreadful outcome in HBV ACLF.65). telbivudine.4 %. lamivudine [36.84).02). mortality rate of the patients who received lamivudine although telbivudine had a better renoprotective effect when bilirubin was above 20 mg/dl (23/35. p = 0. eight had received tenofovir alone (p = 0. not associated with improved short-term survival as com. When compared with controls. based on their anti-inflammatory activity. 95 % CI 24–36 weeks of follow-up was presence of septic shock. RR 0. fovir disoproxil fumarate. and long study. 3.01] as well as incidence useful options with very good results [350]. with entecavir or lamivudine [36.35] [339].62. 344]. 95 % CI (0. (1. 18.11. 95 % CI (1. Of all patients. Both cantly lowered 3-month mortality [44. p = 0.41). teroids. 25 patients had ACLF (13 patients who don’t develop features of ACLF.3 %. higher overall mortality as compared to lamivudine treat. A p = 0. 73. A more recent study found a survival benefit with tenofovir (57 %) in comparison to placebo (15 %) in lamivudine-treated patients when compared to controls among patients with acute exacerbation of chronic HBV in patients with a MELD score of 30 or less. or teno. In living donor transplant cases. A low pre-treatment HBV DNA and a rapid was found to be an independent predictor of survival [348].45. and 314 treated with NAs or Of the 69 patients enrolled into study. Liver trans- of reactivation [1. RR 0. Lactic acidosis has been hypothesized as randomized controlled multicenter study in ACLF patients a possible cause of increased mortality with entecavir failed to identify any survival benefit [353]. 3. p = 0. In one meta. e antibody positivity and high five studies on nucleos(t)ide analogues in ACLF due to baseline MELD score [349]. One study has found entecavir to patients died. Another meta-analysis of tenofovir monotherapy.77. in ACLF. 56 patients received intravenous dexamethasone term [345]. infection presenting as acute-on-chronic liver failure. in the prognosis of patients treated with entecavir or with a rapid decline in serum bilirubin in the first 5 days 123 . 340 treated with improvement in MELD score at week 4 and week 12 and NAs such as lamivudine entecavir. 10.4 vs. 3-month [OR 2.8 vs. improvement in acute kidney injury compared to baseline. or higher mortality when treatment was started administration of granulocyte-colony stimulating factor early but with high DNA levels (bilirubin 5 mg/dl and improved survival after 2 months [352].

However. As a matter of course.1 among patients with severe liver failure vs. All patients with HBV-related cirrhosis should be 3:10:4 The severity of such reactivation depends screened for HCC. HCC. The anticipated survival benefit from early (e. two detection of HBV DNA. the prognosis is patients. if there is a log chronic HBV-infected subjects without cirrhosis is some- reduction. of those in HBV-endemic regions are attributable to chronic HBV infection [357]. drugs. Obviously.5 %/year or greater in patients with cirrhosis [5 times the upper limit of normal and [359.000/year of life gained are considered cost-effective [359]. without cirrhosis.11 HCC screening in chronic HBV infection economic situation. 6.. seems to be absent or minimal in Child–Pugh class C and once ACLF develops. interven- [355].50 Hepatol Int (2016) 10:1–98 being predictive of survival [354]. In many Western countries. surveillance with USG and AFP more than thrice the baseline value (B1). should be excluded (Table 10) (A1). level at week 2 after nucleos(t)ide analogs Defining the population who should be screened among should be done. such as 0. immediately without delay or waiting for although cancer stage and treatment distribution were the HBV DNA results (A1). surveillance corticosteroid treatment in combination with nucleotide for HCC has been widely applied in patients with chronic analogue has sufficient virological effect against severe HBV infection. As mentioned above. this 3:10 Recommendations: treatment of patients with reac- threshold cost is not applicable in most Asian countries. there was no difference in overall survival (7. and a rapid An important issue related to the surveillance program is decline of HBV DNA is conspicuous in survived patients cost-effectiveness. the threshold recommendations on HCC [356]. better in those under a surveillance program than those 3:10:6 Liver transplantation should be considered without it. the efficacy 3:10:1 Reactivation of HBV replication should be of surveillance unambiguously depends on the incidence of defined as a marked increase in HBV HCC in the target population. detection of HCC was offset by a high incidence of liver- 3:10:7 Assessment of reduction of HBV DNA failure-related mortality. and the degree of benefit from a treatment in terms of line HBV DNA (B1). Trevisani et al. tions that can be achieved at a cost of\$50. However. including those and should be determined depending on the economic sit- developing acute on chronic liver failure uation of each country. However. surveillance becomes cost-effective when the risk refers to an abrupt increase in serum ALT to of HCC is 1. replication (C2 log increase from baseline levels or a new appearance of HBV DNA Who should be screened? to a level of C100 IU/ml) in a person with previously stable or undetectable levels or In determining the target population for surveillance. In a more recent study. According to several cost-effectiveness 3:10:2 Flare (or exacerbation) of hepatitis usually models. each Asian country differs greatly in the 3. surveillance the patient should be considered for liver becomes cost-effective in chronic HBV-infected subjects transplantation (B1).0 months). with levels points should be taken into consideration: the incidence of C20. However. if the cutoff cost-benefit is $50. the benefit of surveillance on the severity of underlying liver disease.2 %/ year.000 IU/ml in a person with no base. Since the cost-effectiveness infection have been covered in detail in APASL consensus greatly depends on the incidence of HCC. program could prolong the patient’s survival in Child–Pugh 3:10:5 Nucleos(t)ide analogs should be started class B patients.2 %/year in hepatitis B infected subjects without cir- superimposed hepatotropic viruses. in Child–Pugh class C patients. incidence of HCC for surveillance should be determined More than 50 % of HCC cases worldwide and 70–80 % individually in each country. tivation of chronic HBV infection. The relative risk of HCC in Outcome calculators for predicting HCC Until now. toxins or rhosis [361]. 360]. acute exacerbation of chronic HBVinfection. [362] reported that a surveillance very poor (A1).000/year of life gained and the incidence of HCC exceeds 0. that of normal population [358]. and therefore the result of cost-effec- tiveness analysis performed in a specific country is not HCC screening and surveillance in patients with HBV applicable to other countries.g. it suggests poor prognosis and what complicated. MELD [30) (B1). As a result. patient’s survival. chronic HBV-infected subjects was about 100–223 times several prediction scores have been developed and 123 . becomes cost-effective once the incidence of HCC exceeds 3:10:3 Other causes of hepatitis flares.

patients. or their combi- Diagnosis. lower resistance rates such as entecavir or tenofovir could 0. Recently. the score suppress HBV replication. [363] reported that 3:11:4 Surveillance for HCC should be performed the incidence rates of HCC are significantly associated with by USG and AFP (B2).Hepatol Int (2016) 10:1–98 51 validated to calculate the risk of HCC in patients with patients with chronic HBV infection and chronic HBV infection in the community and clinic be used to determine the target population settings. After LT. and the incidence of preferably every 3 months in cirrhotics HCC was higher in patients without clinical cirrhosis who and those at high risk of HCC (C2). immediate reinfection of the graft by circulating HBV 3:11 Recommendations: HCC screening in chronic HBV particles. showed LSM [13 kPa than in those with clinical cirrhosis 3:11:6 Contrast enhanced CT and MRI should be who showed LSM B13 kPa. These results strongly sug. antivirals should be used before 3:11:2 Current HCC risk prediction scores can transplantation to achieve undetectable HBV DNA levels accurately stratify the risk of HCC in 123 . recurrence [366]. HBV reinfection is the consequence of an tests for HCC [356]. induced by vitamin K absence-II).89 vs. the primary goal of antiviral therapy is to prevent HBV recurrence and to USG. 3:11:3 The threshold incidence of HCC for Liver stiffness as predictor of HCC development Liver surveillance should be determined individ- stiffness. only patients who develop persistently detectable HBV The APASL consensus recommendations on HCC rec- DNA are shown to be at risk for clinical disease and graft ommended USG and AFP every 6 months as surveillance loss [365]. However. which is much higher than the threshold incidence (0. has been ually based on the economic situation of used to assess the degree of liver fibrosis and it correlates each country (B1). B after liver transplantation [364] modified their CU–HCC score with LSM (LSM– HCC score).. and clinical criteria and LSM was 13.81). Jung et al.4 %. Their use is clinical diagnosis of cirrhosis in developing models for the also recommended in the screening of prediction of HCC. value ( kPa).2 %/year) for surveillance in noncirrhotic 3. Detailed review on the diagnostic per- formance of each test as a surveillance test is beyond the Recurrence of HBV infection after LT is defined as the scope of this guideline for the management of CHB.4–100 %) at 5 years. and excluded future HCC with high negative predictive value delay or obviate the need for liver transplantation in some (99.54 %/person-year even in patients with the lowest LSM obtained in all cirrhotics at presentation (B1). Antiviral therapy before LT may prevent HBV recurrence after LT by reducing the level of viremia to Modalities and frequency for screening extremely low levels. 3:11:1 Surveillance for HCC is recommended in There is a direct relationship between HBV viral load at high-risk populations with chronic HBV transplantation (i. mechanisms. dations on HCC [356]. or both. The observed incidence of HCC was 3:11:7 A baseline CECT or CEMRI should be 0.12 Prevention and treatment of recurrent hepatitis chronic HBV-infected subjects. They reappearance of circulating hepatitis B surface antigen were well summarized in APASL consensus recommen- (HBsAg) with or without detectable HBV DNA. well with liver fibrosis stage. [105 copies/ml) and the rate of HBV infection (B2).83–0. Lens culinaris agglu- tinin-reactive fraction of AFP (AFP-L3). measured by transient elastography. used regularly for confirmation of suspicious gested that LSM can be a complement or alternative to the lesions on US screening (A1). this study population. By applying the cutoff value of 11.e. and risk factors for HBV nations have long been used as surveillance tests for HCC recurrence after LT- in Asian countries. LSM per se was not useful in patients with advanced cirrhosis with high determining the subgroup of patients for surveillance in suspicion of development of HCC (C2). Wong et al. prothrombin prevent graft loss. However. AFP. Thus. 3:11:5 Surveillance by USG and AFP should be The discordance rate in the diagnosis of cirrhosis between performed every 6 months (B2).75–0. for surveillance (B1). des-c-carboxyprothrombin (DCP. the degree of elevated liver stiffness measurement (LSM). or a later reinfection from HBV particles coming infection from extrahepatic sites such as peripheral blood mononu- clear cells. improve liver function. and the AUROCs of LSM–HCC score were Antiviral therapy using newer nucleos(t)ide analogues with higher than those of CU–HCC score (0.

prophylaxis regimen is necessary for those patients with a ciated with low rates of recurrence include surrogate high risk of HBV recurrence: high pretransplant HBV markers for low levels of viral replication (including DNA levels. escape mutants. In one study on 183 patients receiving com- first major milestone in the prevention of post-transplant bination prophylaxis with antiviral therapy (mostly LAM HBV recurrence. (0. or on a fixed schedule. the high after 5 years of follow-up.000 IU/day) was associated with a lower frequency Indefinite combination therapy with HBIG plus a of HBV recurrence [368]. In addition. lower after HBIG withdrawal to a combination of LAM/ADV effectiveness in patients with high levels of HBV replica. Strategy of HBIG withdrawal after a ways: at a frequency dictated by the maintenance of defined period of combination prophylaxis has been stud- specific anti-HBs levels. An alternative approach is to switch frequent clinic visits and laboratory monitoring. anti-HBs levels are plus IMHBIG at 2000 IU monthly [377]. antiviral therapy [373]. and HDV coin. However. HCC at LT. 7. recurrence occurs (i. Combination prophylaxis with low-dose IM HBIG Prevention of HBV recurrence after LT. High of HBIG administered 6 months after LT have also been rates of graft reinfection leading to severe flares and loss of shown to be effectivel. or isting antiviral drug resistance). In medium-term and long-term nucleos(t)ide analogue may not be required in all liver follow-up. None of the maintained at [500 IU/l during 1–3 months. after which the patients were more expensive [372]. IM low-dose (1000–1500 IU every 1–2 months). 18 months. IV low-dose (3000–6000 IU advent of antiviral therapy further changed the landscape of monthly). but is were used in the first month. limited supply. but 22–41 % at 3 years majority of patients using potent antivirals allows the use after LT. 3. Recurrence of HBIG. and 9 %. Several meta-analyses have shown or for a finite duration (median duration 12 months). namely. LT for CHB was a relative contraindication. that combination prophylaxis was significantly superior to Cumulative rates of HBV recurrence at 1. withdrawal of HBIG after a prophylactic monotherapy (started before transplantation finite period or prophylaxis regimens without HBIG. HBIG monotherapy reduced HBV monotherapy) plus HBIG given either IV high-dose recurrence by a rate of approximately 70 % [368]. fulminant HBV. preex- fection). with a recurrence Prior to the availability of effective HBV prophylaxis in the rate as low as 4 % at 4 years [374].0004) [371]. generally 10. IV HBIG has been administered in two different transplant recipients. need for compliance [378]. 6. The (10. some studies reported that high IV HBIG dosage HBV recurrence in one systematic review (1 vs. showed that positivity for HBeAg and high viral load at transplant. HIV or HDV coinfection. showed ability to achieve undetectable HBV DNA before LT in the a 10 % recurrence rate at 1 year.e. were HBIG containing prophylaxis regimens In conventional associated with HBV recurrence [376]. and at [100 IU/l thereafter. those with limited antiviral options if HBV HBeAg-negative status. Subcutaneous regimens 1980s. parenteral administration. those with a high risk of chemotherapy used for HCC are independently associated HCC recurrence. Alternative approaches have been studied. HCC recurrence.000 IU/day) . Multivariate analysis [369–371]. which was related to poor LAM cost. The and continued after transplantation without HBIG).52 Hepatol Int (2016) 10:1–98 to reduce the risk of HBV recurrence.e. Also. high-dose HBIG and LAM approach is simpler and requires less monitoring. the combi- protocols. [379] or a combination of emtricitabine/TDV [380] or tion before LT. but later recurrences developed in four patients The use of IV HBIG has limitations.000 IU/day) versus low HBIG dosage p = 0. The latter ied. The target levels for anti-HBs titers randomized to receive either LAM monotherapy or LAM vary with time after LT: generally. and the potential selection of HBsAg entecavir [381]. HBIG is used at high dose to neutralize HBsAg nation of HBIG and a newer nucleos(t)ide analogue during the anhepatic phase and the first postoperative week (tenofovir or entecavir) was shown to be superior to the (i. with some advantage in tolerability graft occurred in the absence of antiviral therapy. respectively.1 %.. post-LT prophylaxis.000 IU monthly). and 5 years antivirals or HBIG alone in preventing HBV recurrence were 3. which include the use of low-dose intramuscular (IM) HBIG-free prophylactic regimens LAM. Other factors asso. a more cautious approach to a was observed mainly in patients with a high level of HBV 123 .. [250 IU/l patients developed HBV recurrence during the first until 6–12 months. due to the emergence of escape mutations in the of prophylaxis regimens that minimize the dose or duration YMDD motif of the polymerase gene [382]. (400–800 IU IM) plus lamivudine decreases costs by more than 90 % compared to an IV regimen. but not the post transplant HBIG regimen. and those with a risk of noncompliance to with an increased risk of HBV recurrence [367]. In the early post transplant combination of HBIG and LAM in reducing the risk of period. subcutaneous HBIG. when used as a HBIG. (C10. In a study of 29 patients. The use and the possibility of self-administration by patients at of hepatitis B immune globulin (HBIG) after LT was the home [375].

entecavir and tenofovir (n = 30. patients received entecavir (n = 126. or peripheral blood mononuclear cells even 10 years after LT in a proportion of HBV Assess risk status transplanted patients who are HBsAg-negative.Hepatol Int (2016) 10:1–98 53 replication prior to drug exposure [382]. HBsAg positivity after transplant without seroclearance 71.HCC at LT . to keep an-HBs levels >100 mIU/mL for 1 year Patients with undetectable HBV DNA levels at the time of • High potency NAs [Tenofovir or transplant can be considered for HBIG free regimens by Entecavir] using high potency NAs [tenofovir or entecavir]. (A1). there were no episodes of monthly. have also demonstrated the efficacy of this therapeutic 3:12:2 A lifelong prophylactic therapy is needed approach [386.Presence of drug-resistant HBV apy in most patients [388. The pre-LT HBsAg level was significantly (12–117) months. weekly for 3 weeks. High potency NAs[ Tenofovir or Entecavir] intramuscularly/ IV daily for 7 days.000 IU intravenous tion and decrease the risk of recurrent disease after trans. All patients received 10. tenofovir (n = 20. -Undetectable HBV DNA levels at LT . to keep antiHBs levels [100 mIU/ml for 1 year.5 %). However. and those with a plus/minus LAM prophylaxis without HBIG). two patients (including one with non- higher in those who had HBV recurrence/persistence compliance) had HBV recurrence [391]. fol- ance (n = 10). donor LT. the 3:12:1 Antivirals (tenofovir or entecavir) should survival was excellent at 83 % at 8 years. HBIg free regimens can be used. no patient risk of noncompliance to antiviral therapy [373]. NAs are used. 17 % for 3 months. 387]. with no mortality be used before transplantation to achieve related to HBV recurrence [385].8 %) had HBV DNA [2000 IU/ml infection.000 IU/day) No HBIg • 10.. During follow-up of 43 DNA level. HBIG in anhepatic phase followed by 600–1000 IU intra- plantation.5 %) had persistent before LT. 6). HBV flares or graft loss secondary to recurrent HBV Thirty-five patients (19. HBV DNA persists in serum. 1-year post-transplantation seems 10 IU/ml before LT. however. when compared with HBIG-free protocols. The use of HBIG is likely tectable HBV DNA levels at the time of to result in a higher rate of HBsAg negativity due to the transplant). In a study investigating the efficacy of ETV as muscularly daily for 7 days. Therefore. who underwent LT (40 % of these patients received ADV or intolerance). 389]. 390]. 3:12:3 Among low risk patients (i. Among had recurrent HBV infection [383].. some studies reported that a high IV HBIG dosage (C10. with unde- laxis in many transplant centers. no cases of HBV recurrence were to be safe and feasible [379. India included 176 patients (at least [12 months follow- The availability of more potent antivirals with a higher up) with HBV cirrhosis/HCC who received secondary barrier to resistance could increase the proportion of prophylaxis with indefinite entecavir/tenofovir after living- patients with undetectable HBV DNA before transplanta. HBIG remains part of the antiviral prophy.HIV /HDV coinfecon antiviral therapy is currently the standard of care after LT . In the early post transplant period. or a combination of (n = 8) or reappearance of HBsAg after initial seroclear. 98 % had undetectable HBV DNA. and then monthly.Poor compliance to anviral therapy for CHB. In another study on use them.Detectable HBV DNA levels at LT .3 %). ated with a lower frequency of HBV recurrence [369]. In a study on 61 with limited antiviral options if HBV recurrence occurs LAM-resistant patients treated with ADV on the wait-list (i. compared with those who did not [223]. fact that the passive anti-HBs antibodies will bind with High potency NAs (entecavir or tenofovir) HBsAg. those LT 123 .e. HBIG free prophylaxis should not be used for those Fig. and then monoprophylaxis in 80 patients. weekly for 3 weeks. One of these patients had a very low HBV lowed by entecavir alone). After LT. HBIG withdrawal may be considered if high potency of a combination prophylaxis using LAM and ADV with. pre-existing drug resistance. 6 Prophylaxis for prevention of HBV graft recurrence following patients with high pretransplant HBV DNA levels. A recent large 3:12 Recommendations: prevention and treatment of long-term cohort study of 362 CHB post-LT patients recurrent hepatitis B after liver transplantation receiving only NAs without HBIG showed that at year 8 after LT. Moreover. those with a HCC at LT. supporting the use of long-term prophylactic ther. life-long . However. These reservoirs may serve as a source of HBV reinfection in the Low-risk paents High-risk paents future. This clearly shows that undetectable HBV DNA levels to reduce HBIG-free regimen is safe and effective. HIV or HDV coinfection. The timing of HBIG withdrawal is still out BIG in 18 patients who had HBV DNA below 3 log controversial. and many studies the risk of HBV recurrence (A1). leading to a further reduction in detection rate should be used for life (B1) (Fig. A recent study from observed after a median follow-up of 22 months [384]. 11.000 IU IV HBIG in an-hepac phase followed by 600-1000 IU versus a low HBIG dosage (0.000 IU/day) was associ. liver.e. A total of 18 patients (22.

95 % CI 1. treated for both HIV and HBV de novo [409]. those with HIV/HBV coinfection. HBV can be treated before the 123 . do not fit in the HIV setting due to the lack cohort of adult patients with primary HIV infection (sero- of or residual activity of these molecules against HIV and conversion window B6 months) has shown that HBV their relatively weak activity against HBV. 95 % CI entecavir (ETV) may be needed in case TDF cannot be 1. In the Swiss HIV Cohort Among patients with CD4 count [500/ml who are Study.13 Treatment of chronic HBV infection in special lated mortality [405]. 449 therapy) 10. Thus. emtricitabine (FTC) and and tenofovir (TDF) have chronic HBV infection could upregulate HIV replication. patients revealed a 3. such as adefovir (ADV) or telbivudine duration of HIV infection. then weekly for 3 weeks. To minimize the influence of Other NAs. there is a strong rationale for areas where HBV is less endemic (North America. 3 years of HAART. long-term tenofovir combined with emtricitabine or lami- with coinfection more common in areas of high prevalence vudine therapy [407]. Europe. HBIg may be faster progression of hepatic fibrosis and a higher risk of discontinued. Similarly. phase should be given. Tenofovir combined with emtricitabine or [397. despite similar virological effective- resistant HBV. and liver-re- 3. entecavir and tenofovir have activity composite endpoint of AIDS defining illnesses and death against both HIV and HBV. hepatic decompensation. Lamivudine A persistent state of immune activation in patients with (LAM).46. the overall prevalence of chronic HBV immunological. and then HBV infection [403]. it should be administered only in the context of diagnosis of primary HIV infection [400].6-fold–6. with HBV coinfection [401].8-fold relative risk of pro- including two reverse transcriptase inhibitors with anti- gression to AIDS compared to those without coinfection HBV activity.20–2. mostly due to kidney toxicity. but the risk of developing cir- Approximately 15–25 % of the HIV infected population in rhosis is negligible in HBV/HIV coinfected patients on Asia and Africa has concurrent chronic HBV infection. Superinfection or coinfection with patient groups hepatitis D virus may further exacerbate the complications in patients with HIV/HBV coinfection [406]. In HBV coinfected patients. 398]. and HCC than HBV- or tenofovir) should be continued monoinfected patients [395.1 Coinfection with HBV and HIV Treatment of HIV may lead to flares of hepatitis B due to immune reconstitution. duration of HIV infection. Clinical observational studies have monthly. presence of drug. patients who tested positive for HBsAg had unwilling to start HAART. both anti-HBV and anti-HIV activities. irrespective of and Australia). HIV or HDV coinfection. virological or histological considerations infection among HIV-infected persons is estimated to be [408]. 7). ness of antiretroviral therapy compared to patients without HCC at LT or poor compliance to antiviral HBV infection [504 cells/ll (95 % CI 496–511) vs. to keep antiHBs levels[100 mIU/ demonstrated that HIV/HBV-coinfected patients may have ml for 1 year. all HBsAg-positive hazards ratio for an AIDS or death event was almost double patients should be screened for HIV before these drugs are (adjusted hazards ratio 1. patients with 600–1000 IU intramuscularly/IV daily for HIV infection have a higher risk of chronicity after acute 7 days. Most coinfected patients should be simultaneously 6–14 % [394–396].16–10. a prospective observational (LdT) therapy. other reports failed to confirm these lamivudine plus a third agent active against HIV are indi- results [399]. Early prospective cohort studies of HIV/HBV-coinfected the best option is triple combination of antiretrovirals. with HIV-monoinfected patients. For most patients. early dual anti-HIV and anti-HBV therapy. In another study a fully suppressive HIV treatment [411].13. However. examining the interactions of HBV and HIV using the Lamivudine. it was found that the of the risk of HIV resistance. After 1 year. This discrepancy was likely related to the cated [409. 3.000 IU IV HBIG in anhepatic cells/ll (95 % CI 428–469)] [402]. 404]. 410] (Fig. High potency NAs (entecavir cirrhosis.54 Hepatol Int (2016) 10:1–98 3:12:4 Among high-risk patients (detectable HBV significantly impaired CD4 recovery during the first DNA levels at LT.80.69) for those used in the treatment of HBV infection. end-stage liver disease. Treatment with coinfection (adjusted hazards ratio 3. followed by Compared to HIV-uninfected subjects. Because ETV displays ical progression that was defined as the occurrence of a weak activity against HIV and may select for resistance CD4 cell count 50 cells/ll 3 months or more after mutations.32) was an independent predictor of immunolog- used. had a higher risk of acute hepatitis. for both viruses [392] and rates approaching 25 % in Given the faster progression of liver disease in HIV– countries where the viruses are highly endemic [393]. compared simultaneously. and are contraindicated as among HIV-infected individuals who had a seroconversion single agents for hepatitis B in coinfected patients because window of B3 years in a large cohort. especially HBV genotype B.

7 Treatment of CHB infection in HIV infected HIV/HBV Co-infecon individuals Consider early dual an-HIV and an-HBV Among paents with CD4 count therapy. conventional HBV vaccination schedule should be used. while HIV infection increases 123 . Peginterferon (Peg-IFN) alpha envelope genes in the HBV genome. HBV develops more quickly in HIV-HBV coinfected patients coinfection accelerates immunological [413]. 1. polymerase. FTC. PEGIFN. treatment of HIV infection the vaccine are poorer in HIV infected persons compared should be envisaged. An initial resistance. LdT. In these individ- FTC. vaccine escape. bivudine. Accordingly. when combination antiretroviral therapy ing. Transmission of drug-resistant HBV strains lack of decompensated cirrhosis. in patients with low CD4 counts sponding drug and cross-resistance to other antivirals. 6. However. Accordingly. and to a lesser extent. The response rate and durability of after 12 months of therapy. should be experienced used. if Adefovir or Telbivudine use does not lead to the goal of undetectable HBV DNA aer 12 months of therapy. No mutations have been uniformly associ. and preclude the success of rescue antiviral is initiated. low HBV-DNA. mended [418]. the Changes in M204 I or V are usually responsible for LAM. adefovir and tel. or [500. This may unwilling to start HAART who have normal CD4 counts translate into failure in diagnostic tests. Some protection from HBV vaccine may ated with significant loss of susceptibility to TDF in vivo. HAART including Tenofovir plus Add or Substute Lamivudine or one NRTI with Tenofovir Emtricitabine as part of HAART * Peg-IFN may be used if genotype A. two NAs (adefovir and telbivudine) with a low barrier to HIV-infected adults without protective HBsAb titers resistance do not reach the goal of undetectable HBV DNA should be vaccinated. >500/ml unwilling to start HAART. causing patients in very specific situations. elevated ALT. in the case of lack of achievement of protective anti-HBs There is some cross-resistance to ADV in the presence of titers ([10 mIU/ml) revaccination using double-dose and/ A181S plus M204 I mutations in patients who have failed or 3–4 injections (months 0. and 12) is recom- LAM therapy. if any of these has also been reported [415]. HBeAg(?). cross-resistance is almost univer. whereas more changes (L180M uals.* Adefovir# and Telbivudine#. (00 cells/ml) and uncontrolled HIV replication. including the occurrence of liver and increases the risk of hepatotoxicity enzyme flares. which are not proven to be Lamivudine naive Lamivudine acve against HIV. LAM resistance could be considered as therapy for CHB in coinfected mutations may result in changes in the HBsAg. HBV can be treated virological or histological consideraons before the instuon of an- HIV therapy. because of overlapping polymerase and should be preferred [409]. interventions due to cross-resistance with other antivirals. Additionally. with ETV. leading to loss of susceptibility to the corre. and they are influenced by Oral anti-HBV drugs may select changes at the HBV both CD4 counts and plasma HIV-RNA levels [416. institution of anti-HIV therapy. success of HBV immunization is low. which are not proven to be active against HIV. PegIFN. and LdT resistance. be expected even in the case of anti-HBs titers dropping although anecdotal reports have pointed out that A194T in to 0 mIU/ml. Selection of LAM resistance in CHB is associated and clinical progression of HIV infection with poor outcomes. sal with LAM. previous antiretroviral therapy for at least 6 months plus M204V plus T250) are usually needed for ETV may increase HBV vaccine response rates. with HIV-negative persons. which occasionally may be life-threaten. the context of LAM resistance mutations might account for 3:13:1 Recommendations: coinfection with HBV and HIV TDF resistance in HBV [412]. and both [414]. low HBV-DNA and high ALT # However. treatment of HIV infecon should be considered. irrespecve of immunological. such as in patients diminished HBs antigen–antibody binding. 417].Hepatol Int (2016) 10:1–98 55 Fig. Resistance to LAM in HBV is more common and 3:13:1:1 In HIV/HBV-coinfected patients.

permanently suppress both viruses [419]. and ultimately prolong the survival lack of achievement of protective anti. Therefore. Simultaneously. Thus. of patients. virological or histologi. including the development of liver cir- HBV and are contraindicated as single rhosis (LC) and HCC. and 12) is infected patients. HBs titers ([10 mIU/ml). with HCV/HBV coinfection among the 320 million chronic 3:13:1:3 Tenofovir combined with emtricitabine HBV positive subjects would be approximately 3. 6. patients with thalassemia. HBV is endemic.13. in the case of development of HCC. 8 Treatment of HBV– HCV coinfected patients HBsAg-posive & An-HCV-posive Acve HCV / Acve HCV / Acve HBV / Inacve HCV / Inacve HBV Acve HBV Inacve HCV Inacve HBV • Treat HCV: P+R • Treat HCV: P+R • Observe HBV Observe HBV Treat HBV: P or NUC Observaon reacvaon response & reacvaon Or • Treat HCV & HBV: P+R+NUC P: Peg-IFN α R: ribavirin NUC: nucleos(t)ide analogue the risk of hepatitis events. 5). Moreover. patients because of the risk of HIV In addition to cross-sectional data.56 Hepatol Int (2016) 10:1–98 Fig. cirrhosis. all HBsAg-posi.8 or lamivudine plus a third agent active million. irrespective of lence of anti-HCV positivity worldwide is approximately immunological. revaccination These goals can be achieved by eradicating both viruses using double-dose and/or three to four after providing an effective antiviral therapy for dually injections (months 0. Accumulating data exist to reach firm recommended (B1). an the long-term goal is to reduce or terminate hepatic initial conventional HBV vaccination necroinflammation.2 Coinfection with HBV and HCV end-stage liver disease related to chronic HBV infection (A1). group of coinfected patients (B1) (Fig. 3:13:1:8 In HBV-HIV coinfected patients. need attention and require effective antiviral treatments. the number of individuals cal considerations (B1). before these drugs are used in the treat. 1. a substantial proportion of the patients early dual anti-HIV and anti-HBV ther. in areas where the disease in HIV-HBV coinfected patients. prevent progression to cirrhosis and the schedule should be used. based study finding supported the effect of HCV/HBV tive patients should be screened for HIV coinfection on the cumulative incidences of HCC [422]. Most patients with chronic hepatitis C have a hepatitis C 3:13:1:2 Given the faster progression of liver virus (HCV) monoinfection. However. entecavir and tenofovir In patients with dual chronic hepatitis B and C. and 3.2–12. 3:13:1:5 Lamivudine. and patients with hemophilia. are coinfected with hepatitis C and B [419]. patients dually infected with hepatitis C and B ment of HBV infection (A1). HCV/HBV coinfections can also be against HIV should be used (A1). such as people who use intravenous drugs. conclusions on the management of patients with HCV 123 . a long-term community- resistance (A1). Treatment goals and strategies The primary goal of the 3:13:1:7 HIV-infected adults without protective treatment of HCV and HBV coinfection is to eliminate or HBsAb titers should be vaccinated (A1). If the preva- apy should be considered. found in people at risk of parenteral hepatotropic viral 3:13:1:4 Peg-IFN can be used in a highly selected transmissions. are generally more severe than those agents for hepatitis B in coinfected in patients with either hepatitis B or hepatitis C [420. 3:13:1:6 Adefovir and telbivudine should not be used in coinfected patients (A1). the have activity against both HIV and disease outcomes. 1–4 % in the general population. 421].

0 %. therapy is not well defined [432]. 6). in order United States. decreased by 35. follow-up. and 59 %. In long-term follow-up of patients for which virus is dominant before designing approximately 4 years. and then to treat were tested HDV RNA positive at least once during further the patients accordingly (B1) (Fig. those patients with HCV mono-infection When standard interferon was used at nine million units (A1). The benefit of anti-HCV therapy in dually infected undetected. while chronic delta hep- an open-label. compared to no treatment or low dose at three million units given three times a week for 48 weeks. 77. approximately 30 % of dually infected patients lost surface antigen stays positive. Active coinfection with HDV is confirmed which patients with HCV genotype 1 infection received by detectable HDV RNA. and it was also concluded by the investigators to 3:13:2:2 In HBV–HCV coinfected patients who closely monitor patients post-Peg interferon therapy. HBV DNA levels are often low or undetectable and In the coinfected host. levels. in patients Although late relapses have been documented. treatment cation. or IgM anti-HDV [432]. 50 % of the high- 123 . a significant number of patients the treatment strategy. the sus. Patients with diagnosis of active HDV infection may be difficult. A proportion of coin. in fection [430]. If HBV is dominant. performed by Hedrich and colleagues in patients who were HDV RNA negative 6 months after pegylated interferon 3:13:2 Recommendations: coinfection with HBV and treatment. it is generally HDV which is the HCV is usually responsible for the activity of chronic dominant virus because it suppresses HBV through repli- hepatitis in most patients. sustained virological response in HCV genotype 1-infected Peg-IFN is effective against HDV. If HCV is dominant. antiviral treatment may those who are HDV RNA negative 6 months after therapy be selected using the same criteria as for with interferon alfa 2a therapy. Weekly For patients with HCV genotype 2/3 infections.3 %). Although HDV can only infect HBsAg positive patients atocyte without interference [424]. while oping HCC. Chronic infection after acute HBV- mono-infection [425–428]. the risk of devel. the fected patients may have fluctuating serum HBV DNA prevalence of HDV has not shown a significant decline. This has been demonstrated in HDV hepatitis is less common. pegylated interferon alfa 2a treatment was given HCV for 48 weeks with or without adefovir and resulted in 28 % 3:13:2:1 It is important to determine the viral of the patients having undetectable HDV RNA 6 months loads of individual viral infections and post-treatment [435]. the to clarify the respective pathogenic role of each virus prevalence of HDV is showing an increasing trend [430]. 62. However. as well as an increased risk of a sustained HCV clearance rate comparable to that in HCV liver cancer [431]. all-cause mortality. patients was further confirmed in another large population. Compared with the patients off-treatment virological response with undetectable HDV in an untreated dually infected cohort. It is generally agreed that the dominant virus 3. 12–18 months [433]. as there may be some benefit from treatment (SVR) was durable in approximately 97 % of the patients prolongation [434]. the optimal duration of during a 5-year post-treatment follow-up [427]. 8) [423]. The HCV sustained virological response necessary. even are HCV viremic.2 vs.Hepatol Int (2016) 10:1–98 57 coinfection. and liver-related mortality some also lose HBsAg [430. More than 1 year of therapy may be respectively. multicenter study involving atitis develops in 70–90 % of patients with HDV superin- 321 Taiwanese patients with active HCV infection. RNA and accompanying improvement in histology. HDV patients remain HBsAg within 5 years after the start of Peg-IFN-based infective even if the HBV or HDV viral titers are low or therapy. comparative. Australia and some European countries. immuno-histochemical staining Peg-IFN alfa 2a 180 lg weekly and ribavirin for HDV antigen. in a study who received active anti-HCV therapy. HBV and HCV replicate in the same hep. as HCV genotypes 2 or 3 received Peg-IFN alfa 2a 180 lg HDV RNA assays are not standardized and HDV antigen weekly and ribavirin 800 mg daily for 24 weeks. 3–6 months) by measuring HDV RNA levels.3 Coinfection with HBV and HDV should be identified before designing a therapeutic strategy (Fig. thus indicating the need for longitudinal evaluation Recent studies also confirm that even in countries like of viral loads before starting any antiviral therapy.8 and 84. The efficacy of Peg- patients was comparable between 161 HBV/HCV patients IFN therapy can be assessed during treatment (after and 160 HCV mono-infection patients (72. 432]. However. [423]. but can cause severe liver injury that may result in should be aimed toward this virus. Further. fulminant hepatic failure and rapid progression to cirrhosis Peg-IFN therapy in combination with ribavirin can achieve and hepatic decompensation. So long as the hepatitis B more. (1000–1200 mg) daily for 48 weeks [426]. The and IgM anti-HDV assays are not widely available. injection of pegylated interferon is currently used for tained virological response values were 82. and HBV vaccine has been available for a long time.13. respectively. Around 25–40 % of treated patients have a sustained based survey in Taiwan [429].

and is significantly more infectious than either It was also concluded from the study that any beneficial hepatitis C or HIV. trials with large sample sizes and less risk of bias were obstetrical. The con- from Pakistan. and dental procedures. treatment of HBeAg-positive CHB [280]. Case reports compared to no complete responses in any of those in the have appeared in which successful treatment of HBV and low-dose or no treatment group. it is important to determine which tectable HDV RNA and normalization of ALT at the end of virus is dominant and the patient should be treatment when compared with pegylated interferon alfa 2a treated accordingly with pegylated inter- monotherapy. The real role of its allied health fields should be screened for HBV infection. However levels of HDV RNA suppression feron alfa for 12–18 months. dentistry.4 Health care workers of patients. in his assessment of hepatitis B surface antibody to determine study using pegylated interferon and adefovir. Thus. NAs treatment might be con- although most of them relapsed after clearance of HDV sidered in some patients who have active HBV replication RNA [436]. be ineffective in the management of Hepatitis D alone or in Vaccination (three-dose series) should be followed by combination with interferon. semen. cyclosporine A. In a recent study from Germany by Nikongolo [442]. showed 123 . treatment and beyond (A1). respectively [438]. a to rigorously in all health-care settings for the protection of myristoylated a preS/2–48my2 peptide.5 % as a combined response concentrations. it is important to prevent it was suggested that HBV and HDV entry via sodium operator injuries and blood exposures during exposure- taurocholate co transporting polypeptide is inhibited by prone surgical.13. which translates into does not seem to cure Hepatitis D in most patients. entecavir [445] and pegylated interferon and tenofovir and vival and liver histology for the high dose treatment group. adefovir and entecavir have been found to viders and students should receive hepatitis B vaccine.58 Hepatol Int (2016) 10:1–98 dose group had a complete biochemical response defined significant decline in HBsAg titers using adefovir [444]. feces. it was found to be ineffective in CHD. Myrcludex-B. with blood. HDV. A Cochrane review concluded that interferon alfa containing the lowest concentrations. Patients 24 weeks after the end of therapy were not significantly should be monitored for 6 months post- different [437]. The long term follow-up HDV have been reported using pegylated interferon and up to 12 years demonstrated significantly improved sur. This rate seems to cor- necessitate prolonged treatment [439]. this drug may help reduce the Chronic HBV infection in itself should not preclude the incidence of HBV and HDV after more studies demonstrate practice or study of medicine. and dental procedures provide a potential route needed before interferon can be recommended or refuted of HBV transmission to patients as well as to heath care [441]. two major reviews have not been able to def- 3:13:3 Recommendations: coinfection with HBV and initely show that either type of interferon therapy is supe- HDV rior to the other. in addition to virological which could be significant as a predictor for successful response negative HDV RNA at the end of the treatment. use is yet to be determined in HBV-HDV management Testing should include a serological assay for HBsAg. limit the establishment of HDV infection in vivo and HCWs and students of surgery. by normalization of ALT. It was the lowest risk of HBV transmission. after 1 year of HBV can survive in dried blood outside the body for up to entecavir treatment. dentistry. sustained virological response. HBs and Total anti-HBc. A systematic review by Alavian and col. Wedemeyer. carried out. Standard precautions should be adhered agement of HBV and HDV coinfection. However. one recent systematic review of randomized trials found that 1 year of high dose interferon 3:13:3:1 In patients with coinfection of HBV and alfa monotherapy achieved higher levels of unde. serum and wound exudates carrying the highest concen- was seen in 23. All noninfected health-care pro- Lamivudine. sweat and breast milk [440]. emtricitabine [446]. In a recent study relate with serum HBV DNA concentrations. workers (HCWs). which was centration of HBV varies across body fluids. Percutaneous injuries also concluded from this review that more randomized sustained by health-care workers during certain surgical. vaginal fluid and saliva carrying moderate responses and in only 12.1 % for virological and biochemical trations. with a reported transmission rate of up effect of nucleoside–nucleotide analogue treatment may to 30 % from needlestick injuries. or delayed the increase in HBV viremia. In the future. In a study from Turkey using entecavir for chronic hepatitis D. ant- [443]. defined as negative HDVRNA at 24 weeks post-treatment. medicine. however. Therefore. and urine. with persistent or fluctuating serum HBV DNA levels Although no head-to-head comparison trials have been above 2000 IU/ml [447]. 7 days. leagues comparing standard and pegylated interferon alfa found sustained virological response rates in 19 and 29 % 3. obstetrical. surgery. has been shown to both patient and provider [448]. or allied its usefulness and where it would actually fit in the man- health professions.

and provider’s hands are outside a body cavity (e. needle tips or sharp tissues (spicules of bone HBsAg-positive. patient blood exposure. Retrospective studies have evaluated the rate of HBV sure of a patient to the blood of an HBV-infected health. cardiothoracic. hepatitis e-antigen negativity. nasogastric. it usually happens via provider-to- major oral or maxillofacial surgery (e. Establishing defined as procedures in which there is a risk that injury to a threshold for the limitation of EPPs would have to the physician may result in the exposure of the patient’s account for a 3 log10 safety margin to account for assay open tissues to the blood of the physician. or lumbar puncture) or highly confined anatomic site Category I procedures. or have review and Table 11 Classification of patient care procedures Procedures known or likely to pose an increased risk of percutaneous Category II—all other invasive and noninvasive procedures injury to a HCW that have resulted in provider-to-patient transmission of hepatitis B virus (HBV) These procedures are limited to major abdominal. where the procedures (Category II. revaccination [448]. endotracheal. These include surgical and obstetrical/ Techniques that have been demonstrated to increase the risk for gynecological procedures that do not involve the techniques listed for health-care provider percutaneous injury and provider digital Category I. and medical and dental students who are instruments. administering medication by injection. wherein the affected be tested for HBeAg and anti-HBe and for HBV viremia. and in the patient in a manner similar to the reverse situation (i. general physical or eye examinations or blood pressure checks) Internal examination with a gloved hand that does not involve the use of sharp devices (e. procedures are another route of HBV transmission. EPPs are ml. and outside the patient’s body throughout. 32 % of these instances. if a percutaneous injury occurs. and procedures that involve external physical touch Endoscopic or bronchoscopic procedures (e.. A DNA.g.g. rectal. up to Transmission of HBV by HCWs to patients In the health 9 % in gynecological surgery [455. and 2 % in care setting.9 9 105 IU/ml (106 copies/ procedure (EPP) that is mainly of concern. vaginal deliveries. with conversion factor of 5. CDC has classified patient care procedures into two surgeons represent the largest group of HCWs involved in categories (Table 11). 454].9 % of operations. especially those that have been implicated in Dental procedures other than major oral or maxillofacial surgery HBV transmission. oral) 123 . handled with standard post-exposure prophylaxis.. who do not perform exposure-prone or teeth) inside a patient’s open body cavity. placing and maintaining peripheral and central presence of a health care provider’s fingers and a needle or other intravascular lines. HCWs who are HBsAg positive should invasive surgery is. Percutaneous injuries be handled with post-exposure prophylaxis and testing of have been reported to occur in 6.Hepatol Int (2016) 10:1–98 59 vaccination immunogenicity. HBV transmission is not negligible.e. sharp instrument or object (e. 456].g. The risk of infected patient) [449]. given the achieve low or undetectable levels of circulating HBV paucity of surgical precision and control in this context..g. the instigating sharp instrument prophylaxis for providers exposed to the blood of an HBV. are not ordinarily performed by students fulfilling Insertion of tubes (e. an EPP. in fact. abdominal and pose low or no risk for percutaneous injury to a health-care provider. Expo.1 % [459]. fracture reductions). restrictions of their activities or study.g. The proportion of patients the most frequent route leading to establishment of HBV infected with HBV secondary to transmission from an infection is through needlestick injury. caesarean section. Surgery procedures but who practice non. transmission may occur via several routes. 458]. in the performance of any procedure. the rate in cardiotho- racic surgery is reported to be 6–13 % [453. and or. repair of major traumatic injuries. even when there Exposure of a HCW to the blood of an HBV-infected is handling of sharp instruments.or minimally invasive performed within a confined anatomical space. and providers who do not procedure is considered to be non-exposure-prone (NEPP) have protective concentration of anti-HBs ([10 mIU/ml) when the hands and fingertips of the physician are visible should undergo.g..5 and 13. should tact during specific types of EPPs.26 copies/IU). Most effective transmissions have occurred when the It is the regular performance of an exposure-prone HCW carried HBV DNA [1. table) should not be subject to any hands or fingertips may not always be completely visible. transmission from affected physicians through blood con- care provider. and These and similar procedures are not included in Category I as they orthopedic surgery.. They do not need to also carries an elevated risk of transmission.. A NEPP can become an patient in the performance of any procedure. provider-to-patient HBV transmission [450]. Any type of variability [452]. vaginal hysterectomy. touches the patient wound once again [452]. bone spicule) in a poorly visualized performing needle biopsies. palpation of a needle tip in a body cavity and/or the simultaneous phlebotomy. or urinary the essential functions of a medical or dental school education rectal catheters) examination. vaginal. thus. but general surgery [457. physician’s gloved hand is in constant contact with sharp HCWs. Invasive surgical infected HCW is between 0. should be EPP if a patient is uncooperative [451]..

not preclude anyone from the practice or testing is repeated to determine if elevations above a study of medicine. and school applicants.e. The status of the copies/ml in 18 HCPs with either interferon-a or various individual could vary depending on the NAs [462].0 or -4. response to therapy. but should be encouraged to be and treatment failures might both present as higher-than. as they may require antiviral therapy 3:13:4:5 HCWs who perform exposure-prone pro- even if they do not fulfill the typical indications for treat. as drug therapy is added or modified. The mean reduction of 3.13. and other insti. 3:13:4:3 All non-infected health-care providers Hospitals.60 Hepatol Int (2016) 10:1–98 oversight by an expert review panel. viremia can be suppressed to accept- be guided by an institutional expert review panel regarding able levels in the majority HCWs by 3 months of entecavir the procedures that they can perform and prospective or tenofovir therapy. DNA levels 000 IU/ml are reached more often and 3:13:4:6 HBV-infected HCWs can conduct expo- much faster in HBeAg-negative chronic HBV-infected sure-prone procedures if a low subjects. for the protection of the patient and the care workers also need special attention regarding starting provider (A1). An HBV DNA level of allied health professions (A1). because they have lower baseline levels of vir. or threshold are transient [460]. anti-HBs and total anti-HBc (A1). 3:13:4:1 Chronic HBV infection in itself should ing. immunotolerant HBeAg-positive subjects typically have baseline viremia levels [108 IU/ml. i. Thus. (000 IU/ml) or undetectable HBV emia and possibly a higher turnover of HBV-containing viral load is documented by regular hepatocytes. HBV-infected HCWs can conduct 1 year [465].0 log10 baseline level they should receive medical care for their condition by needed roughly 52 weeks [196]. those listed under Category ment. screened for HBV infection. care providers. respectively. and if nee. Testing ded. students. HCWs with very high viremia oversight of their practice [461].. regarding the procedures that they can apy on the transmission rate to patients is limited. 3:13:4:4 Standard precautions should be adhered to rigorously in all health-care settings Treatment of HCWs for reduction of Infectivity Health. investigated and treated (A1). threshold (1000 IU/ml) values. as compared to HBeAg-positive subjects. to reduce direct transmission during exposure-prone I activities (Table 11). Confidentiality of the [108 IU/ml may need longer therapy. while subsequent retesting occurs. should therapy [464].9 log10 copies/ml When females in the childbearing age require antiviral [463]. antiviral therapy. surgery. One study on tenofovir therapy showed that the therapy. for example. exposure-prone procedures if a low or undetectable HBV 3:13:4 Recommendations (health care workers) viral load is documented by regular testing at least every 6 months unless higher levels require more frequent test. were found after 3 months of those listed under Category I activities (Table 11). dentistry.e. dentistry. i. 3:13:4:2 HCWs and students of surgery. Such 1000 IU/ml or its equivalent is an appropriate threshold to HCWs should not be isolated or discrim- adopt [460].7 log10 copies/ml within approximately those performing exposure-prone procedures. [460]. cedures. by an institutional expert review panel Published evidence for the efficacy of antiviral ther. The testing at least every 6 months (B1).5 Chronic HBV infection and pregnant females viremia obtained in HBeAg-positive patients with ente- cavir within 1 year was reported to be 6. tenofovir and entecavir. while patients with [9. decreases of -4. or allied health fields should be procedures. medical and dental schools. However.5 HCWs who perform exposure-prone procedures. log10 units/ml. This will require the HBV. but most of them health-care provider’s or student’s HBV serological status will reach acceptable or even undetectable levels within should be maintained. In a direct comparison of appropriate clinicians [460]. modifications or additions to the health-care provi. should be guided procedures to patients. infected HCW to abstain from performing exposure-prone medicine.. Spontaneous fluctuations of HBV DNA levels inated. confirmed (A1). should include a serological assay for der’s drug therapy and other reasonable steps are taken HBsAg. as recommended for from 7. 12 weeks. and students should receive hepatitis B tutions should have written policies and procedures for the vaccine and their immunization status be identification and management of HBV-infected health. One perform and prospective oversight of Dutch study reported reduction of viremia to 000 their practice (B1). the issue of pregnancy must be discussed before mean value in patients with moderately high viremia fell 123 .3 to 3.

sion with the patient. Among the currently available NAs. Several issues are suggested during IFN treatment. but unknown in humans) by the US plan should be fully discussed with the FDA. 3:13:5:2 In pregnant females with chronic HBV nization of the newborns. ral treatment is considered. optimal females who have unexpected pregnancy during antiviral large-scale screening methods. The recommended using either tenofovir or starting point of maternal treatment in most studies is telbuvidine for those mothers with HBV 28–32 weeks of gestation. It is a pregnancy category B stable liver disease. especially when antivi- ADV. especially regarding for mothers indicated for antiviral treatment during the first the risks of maternal liver disease status. major risk factors are maternal HBeAg tenofovir is the drug of choice for and high viral load [469. pregnant female maternal ALT flares. whereas LAM. postnatal immunoprophylaxis. be stopped at birth and when breastfeed- Breastfeeding is not discouraged in mothers with chronic ing starts. The treatment atogenic in animals. and the least chance of viral of HBV. results are based on non-randomized. Despite postnatal active/passive immu. Maternal HBeAg. 481]. the treatment plan should be fully discussed. The transmission that occurs during perinatal target population for short-term NAs treatment for preg. especially after cessation of NAs 123 . and cost-effectiveness of treatment. LdT or TDF [471–478]. or in the mothers and child beyond 1 year post delivery. vertical trans- mission of HBV. open label clinical 3:13:5:3 For reduction of risk of mother-to-infant studies using either LAM. drug with adequate safety data in HIV- mester. period. mother-to-infant transmission of infection who need antiviral therapy. and ALT level should be checked defects (2. For prevention of mother. Category B NAs (LdT and TDF) may be considered patient and relatives. delivery) is recommended in females without ALT flares NAs could be administered after discus- and without pre-existing advanced liver fibrosis/cirrhosis. and other of treatment. The resistance (B1).Hepatol Int (2016) 10:1–98 61 starting treatment. short-term maternal NAs starting nant females to reduce maternal HBV transmission is from 28 to 32 weeks of gestation is maternal HBV viral load above 6–7 log10 IU/ml [469]. even in patients Continuation of NAs treatment after delivery may be with lower DNA levels. There has ALT flares detected during the treatment been insufficient data regarding maternal ALT flare rates period. The NAs could necessary according to maternal liver disease status. IFN-based therapy is preferable for its finite duration flares in the LdT or LAM treated group [476]. Safety data from the Antiretroviral Pregnancy pregnancy. such prevention strategy for the population. HBV DNA Registry has demonstrated no increased rates of birth status. vertical transmission data in HIV-positive females. long-term plan for treatment and resistance. mothers indicated for antiviral treatment to-infant transmission that occurrs during theperinatal during the first through third trimester of period. trimester [468]. Since. and ETV are classified as category C drugs (ter. long-term plan for treatment and next 3:13:5:1 The issue of pregnancy and maternal– pregnancy [466.8 % 46/1982) with TDF exposure during the first during pregnancy (A1). considering risks and benefits for the mother and fetus on 3:13:5 Recommendations: chronic HBV infection and issues regarding risks of maternal disease progression. 470]. Some studies reported increased rates of ALT years. starting from the second or third tri. In pregnant females with still not well understood. breastfeeding is 3:13:5:4 Breast-feeding is discouraged during not generally encouraged during NAs therapy because of maternal NAs treatment. fetal development. if there is no contraindication HBV infection if newborns have received appropriate to stopping NAs (B2). For those with uncertainty of safety to newborns [479. Pregnancy is discouraged during IFN therapy studies using TDF reported comparable or possibly bene- because of IFN’s anti-proliferative effect. through third trimester of pregnancy. continuation of antiviral before and after delivery. short-term maternal NAs used in mothers of pregnancy. but unknown in humans). such as the long-term safety of chronic HBV infection who need antiviral therapy. However. 467]. the HBV transmission could occur even Cessation of NAs therapy (at delivery or 4–12 weeks after with lower maternal HBV DNA levels. childbearing age. after careful examination to DNA above 6–7 log10 IU/ml (B2). HBV still occurs. Contraception is ficial effects for the mothers [472. If pregnancy is planned in approaching postpartum. has been documented to reduce maternal viral load positive females and least chance of viral and decrease perinatal mother-to-infant transmission. TDF has more safety fetal development. exclude maternal systemic disorder and fetal anomalies. fetal–child health should be notified in LdT and TDF are classified as category B drugs (no risk in chronically HBV-infected female in the animal studies. 480].

13. mediated by HBAg-HBAb immune complexes in the former and by HBV originating 3:13:6 Recommendations: chronic HBV infection in from renal cells in the latter. Viral antigen- Chronic HBV infection has a pivotal influence on induced induction and deposition of immune complexes. liferative.7 Extrahepatic manifestations of chronic hepatitis B disease status may be indicated (B2). and cellular immune injury.. Peg. Membranous glomeru- IFN or NAs can be used for chronic HBV infection lonephritis (MGN) is the most common type. and telbivudine. NAs represent areas endemic for HBV infection. However. tenofovir remains the agent of choice related IgA nephropathy is a less severe form of renal disease for patients with renal dysfunction and prior resistance to and usually evolves with an indolent course. Tubulo-reticular inclusions in the endoplas- tation and receive immunosuppressive agents should mic reticulum of endothelial cells of the glomerular and receive anti-HBV prophylaxis with NAs.e. an agent with promising 484]. Patients with renal bodies. seem is characterized by deposition of HBsAg in both the to be the preferred options for NA-naive patients with mesangial and capillary walls. aggressive course with progression to acute renal failure has HBsAg positive patients who undergo renal transplan. with proteinuria. and usually presents as the first-line treatment option for chronic HBV-infected nephrotic syndrome. In children. Although. it is largely attributed to an immune- mediated injury of organs other than the liver. of 348 patients with PAN revealed that patients with HBV- 123 . may be iden- necessary drug dose adjustments according to creatinine tifiable in the glomerular capillary wall. may be involved in the patho- patients with CKD. Immune complexes are deposited only in the basement replacement therapy. in adults it can In general. peritubular capillaries have been identified on electron IFN should be avoided in renal transplant patients because microscopy [486]. ciated with HBeAg seroconversion. on dialysis and renal trans- genesis of IgA nephropathy [487]. nephrotoxicity. most clinicians are antigens. heart and nervous system. HBsAg. However. although an other NAs. depending on the HBV viremia been identified in the glomeruli. HBeAg and HBcAg have also any renal dysfunction. the first-line treatment options for chronic HBV-infected patients with any level of Polyarteritis nodosa Polyarteritis nodosa (PAN) is a gen- renal dysfunction and renal replacement eralized necrotizing vasculitis. glomerulonephritis is from 0. i. Glomerulonephritis The incidence of HBV-related renal patients under anti-HBV therapy should be fol. concerned and therefore avoid using this agent in this which are deposited in sites outside the liver [485]. kidneys. the heightened immune response results in increased there are no definite conclusions about the risk of amounts of circulating immune complexes containing HBV tenofovir-associated nephrotoxicity. or a direct viral reaction may occur in extrahepatic disease should be screened for HBV infection and tissues such as the skin. but also the clinically in three forms. Membranoproliferative glomerulonephritis (MPGN) data for even improvement in creatinine clearance. acute and chronic HBV infection. and HBV-associated PAN therapy. It has been suggested that both humoral of the risk of rejection. While the pathogenesis on dialysis and in renal transplant patients remains controversial. complement components. membranopro- stage of liver disease and the renal disease status. an agent without signs of lead to chronic renal failure in up to 30–50 % of cases [483. In chronic HBV infection. i. In particular. Several extrahepatic conditions have been described during 3. edema and hyperten- patients with any level of renal dysfunction and renal sion. pathogenesis HBV-PAN is largely attributed to immune- 3:13:6:2 Peg-IFN should be avoided in renal complex deposition (with antigen excess) in the vessel walls transplant patients because of the risk of of the skin. up to clearance as well as the potential nephrotoxicity and 60 % may experience spontaneous remission. HBV- setting. Remission of clinical and plant patients laboratory manifestations of nephropathy with successful 3:13:6:1 NAs (entecavir or telbivudine) represent antiviral treatment have been demonstrated [488–491]. Physicians should be aware of the membrane where HBV antigens. been reported.13. However. usually asso- long-term drug efficacy.. However. HBV seronegative patients should be vaccinated.6 Chronic HBV infection in patients with CKD. Peg. muscles. immunoglobulins. especially in patients with renal dysfunction. joints and kidneys. though vaccine responsiveness is impaired. membranous. A recent study rejection (A1). levels and the severity of renal dysfunction. patients with CKD undergoing haemodialysis and renal reaction with tissue antigens by HBV-induced auto anti- transplant with complex issues [482]. etc.e.1 to 25 % and may present lowed not only for the treatment efficacy. NAs should be dose adjusted (HBV-PAN) represents a typical form of classic PAN.62 Hepatol Int (2016) 10:1–98 treatment according to maternal liver 3. The based on creatinine clearance rates (A1).. and IgA nephropathy. entecavir.

joints of the knees. flat-topped. ifestations) and acute HBV infection high concentrations of HBsAg have been detected in the (Guillain–Barre´ syndrome and. Lichen planus. and does not recur [501]. and skin man- circulating immune complexes. While the association of this syndrome with HBV infection was reported as early as Cryoglobulinemia Patients with chronic HBV infection 1976. anorexia. and unclear whether the virus itself or an immune-mediated weakness. orchitis. of small. both acute and chronic HBV infection. it can be mistaken for acute can be useful in addition to NA therapy in rheumatoid arthritis. 499]. the Epstein–Barr virus. the [504]. however. are not uncommon. as well as renal and neu. abdominal immune complex deposition. patients with chronic HBV infection are usually related to 123 . Raynaud phenomenon. Effective treatment of associated with acute hepatitis B responding to nucleoside the underlying chronic HBV infection with currently analogue and intravenous immunoglobulin treatment [505]. it may present with protracted purpura. This serum sickness-like regional therapy of HCC syndrome ends abruptly with the onset of clinical hepatitis with few significant sequelae. arthralgia. or papular acrodermatitis of dence of HBV infection in PAN patients to be between 30 childhood. The prevalence of HBV. is characterized by small.. When nephritis is present. The resolution of arthritic lesions paral- 3. myalgia. levels. Guillain–Barre´ syndrome Guillain–Barre´ syndrome clonal IgM and monoclonal IgG). in the West. The pathogenesis is related also to mixed cryoglobulinemia. and hypertension compared small vessel necrosis. thus. Other than Antiviral therapy.e. as well as large may respond to antiviral therapy (B1). scaly plaques on the skin and mucous include malaise. has been found to be highly prevalent in Erythematous skin lesions and palpable purpura and nodules Turkish patients who are seropositive with HBsAg [502]. responsible for these symptoms of the central nervous system rological complications. a chronic recurrent rash composed more frequently in European and North American patients. hepatitis A virus. CHB Serum sickness-like syndrome A transient serum sick. distal extremities of infants and young children. has demonstrated good efficacy in the manage. 3:13:7:2 HBsAg positive patients with extra-hepatic polyarthralgia or overt arthritis with joint swelling and manifestations and active HBV replication edema of small joints of the hands and feet. weakness. Morning stiffness and a ‘‘gel’’ 3:13:7:4 Plasmapheresis. combined with corticosteroids and plasma HBV. fever. type II (monoclonal IgM and polyclonal IgG) and type III (poly. jaundice sets in and leaves no demonstrable permanent joint destruction. The polyarthritis is 3:13:7:3 Peg-IFN may worsen some immune medi- characteristically asymmetrical and is often associated with ated extra-hepatic manifestations (B1). available nucleos(t)ide analogues generally leads to clinical 3:13:7 Recommendations: extrahepatic manifestations of and serological resolution of cryoglobulinemia [498. (GBS) is a rare extrahepatic involvement associated with associated cryoglobulinemia ranges from 0 to 15 % [496. A recent case report described a patient with GBS clinical course can rapidly be fatal. Mostly patients will be on antiviral ther- Dermatological manifestations The skin rashes in apy. polyarteritis nodosa.13. flat. cardiomyopathy. polygonal bumps that may coalesce but rarely in Asian patients [492]. 495]. erythematous. Prior reports have estimated the inci. neutrophilic infiltration and pain. PAN is observed purpura. Constitutional symptoms together into rough. erythematous skin lesions. enterovirus. 3:13:7:1 Extrahepatic manifestations may be asso- ness-like ‘‘arthritis–dermatitis’’ syndrome occurs in ciated with both CHB infection approximately 10–20 % of patients during the prodrome of (glomerulonephritis. They present typically as palpable to patients with non-HBV-related PAN. cytome- exchanges. corticosteroids or IVIG phenomenon are present. The manifestations can range from fever. It may be associated also with the sicca syn. coxsackie. HIV are also ment of HBV-PAN [494. may present with mixed cryoglobulinemia. While both HBsAg 497]. these figures have declined papular or papulovesicular rash that occurs in the face and remarkably in parallel with those of HBV infection [493]. and weight loss. galovirus. assault or a vasculitis-related injury to the myelin sheath is drome. The Gianotti-Crosti syndrome. acute hepatitis B [500]. a serum synovial fluid with associated reduction in complement sickness-like syndrome) (B1). this association remains controversial [503]. and 70 %. i.8 Patients before and/or after curative or local– lels those of HBsAg clearance. and HBV DNA have been detected in cerebrospinal fluid. Once HCC develops. implicated as etiological agents. Clinically. as the majority will have underlying cirrhosis. it is with or without ulcerative skin lesions. ankles and wrists. treatment for HBV will depend on the stage of disease. it typically disappears when severe immune-mediated cases (C2). and during the acute phase.Hepatol Int (2016) 10:1–98 63 PAN had more frequent peripheral neuropathy. adenovirus. membranes. However.

the NA group (1468 be limited and compromised in the post-operative period.001) [521]. and 62. cohort study from Taiwan of 4051 untreated versus 518 HBV recurrence after liver transplantation has always NA-treated CHB patients with resected HCC.3.6 % respectively.0 % (range 0–70. patients) showed a median recurrence-free survival of Therefore. There is also the potential 0–47.0–100.0 % (range 0–56. HCC recurrence occurs in up to 41–50 % presence of high viral load significantly increased overall of patients within 2 years after resection (early recurrence) HCC recurrence risk after curative therapy. p = 0. post-hepatectomy recurrence and survival in patients with 95 % CI 3. Pre-trans- there was a higher rate of cirrhosis in the latter (38. (OR 0.7 vs. Antiviral therapy is important for undergoing resection for HBV-related HCC. A meta-analysis also demonstrated the beneficial effects of Longer survival has been shown in patients receiving antiviral therapy with regards to HCC recurrence (OR 0.97. p \ 0. a potent.3–150.55–0. the overall necrosis and regeneration of remaining hepatocytes.6 %) at 1 year. Upregulation 94. flares of hepatitis may lead to decompensation 85.59. and which can severely lated HCC recurrence remains controversial [523–525].67. as these patients are more vul- treatment should be pursued as long-term therapy may help nerable to the development of hepatic decompensation with prevent hepatitis flare-ups and inhibit hepatocarcinogenesis life-threatening complications such as hepatic to the greatest extent [516]. 520]. and 47. p \ 0.0 % (range for untreated patients [509]. which median survival in the NA group (1468 patients) was may induce DNA mutations and instability. p \ 0.3 %) also impart a state of immunosuppression in the early post.0 %) at showed that the absence of antiviral treatment was a risk in 5 years (all p \ 0. These median survival rates were significantly operative period. For all recipients with high load of 20.64 Hepatol Int (2016) 10:1–98 For non-surgical patients. p = 0. tumor recurrence [514]. and 54.4–90.0 %) at 1 year. With a better liver function reserve at Routine prophylactic NA therapy for HCC patients with the time of recurrence. In a recent patients undergoing resection.0 %) at 1 year.0–89. In a nationwide interferon. a high viral load prior to independently associated with a significantly lower HCC chemotherapy or locoregional therapy results in higher recurrence risk (HR 0.0 % (range 19.6 vs.0 % (range 24. which occurs in as many as 19 % of Interferon treatment as tertiary prevention of HBV-re- patients within the first 1 year.0 % (range 0–100.7 %) increase the risk of distant metastasis [512]. and 73. 95 % CI 0. diffusion of primary tumors.6–81.0 %) at 1 year.0 %) at 3 years. a greater proportion of patients in HBV-DNA levels 000 IU/ml before liver resection may the antiviral group could receive curative treatment for also be considered. after liver resection. In contrast.5–86.5.5 % respectively.35–0. thereby increasing the risk of HBV higher than the corresponding values in the non-NA group reactivation [510]. In the same increased risk of recurrent HCC due to the process of review on 15 studies reporting overall survival. while most late recurrence There is also improvement in recurrence-free survival stems from de novo tumors spontaneously arising in the and overall survival with NAs treatment among patients remnant diseased liver. Surgery and anesthesia may 11. NA use was HBV DNA. even though been a major problem for HBV-related HCC. Use of interferon treatment in HCC patients may be com- Since NAs cannot completely eradicate HBV.0 %) at 5 years (all p \ 0.81. 95 % CI 0. high resistance NAs should be given 123 . as the hepatic reserves will systematic review of 19 studies. The aim is to prevent HBV reactivation recurrence [522].04). lifelong plicated and even risky. 81. plant HBV DNA level and antiviral treatment was a major 48. p = 0. encephalopathy and ascites.0 %) at 3 years. the risk of HCC recur. A high pre-operative viral load has been (5541 patients): 78. transplantation [526]. An HBV DNA of [2000 IU/ml at Thus. reduce liver function and survival [515].0 % (range A cohort of 72 resected patients with HBV-relatedHCC 0–85.13. use of antiviral therapy improves the long-term the time of resection was a significant risk factor (RR 22.02–0.001) [521].0 % (range after curative resection [511]. safer and better tolerated than decreases HCC recurrence after resection.0 % (range 4.69.001). Two recent surgical removal of the tumor by resection or LT is the only meta-analyses including 20 studies demonstrated that the curative option.0 % (range 59. 91. in general. at 5 years. risk factor associated with HBV recurrence after liver rence was lower in the NA-treated patients (43. rates of severe hepatitis during chemotherapy [506].0 %) at 3 years. 95 % CI 0.0–100. at 5 years. whereas and in up to 20 % of patients more than 2 years later (late antiviral therapy had potential beneficial effects in pre- recurrence) [508].02) [518]. 74. HBV-related HCC. and liver-related mortality For the overwhelming majority of patients with HCC. nucleos(t)ide Various studies have found that antiviral therapy analogues are.001). TACE with the additional of antiviral therapy [507].001).0 % (range of adhesion molecules on cells lining sinusoids may 60. These values were significantly higher than the Viral load and hepatic inflammatory activity have been corresponding ones for the non-NA group (5200 patients): associated with late recurrences after HCC resection [513].0 % (range 42. associated with worse overall and recurrence free survivals 56. 57.0 %) at 3 years.7–90. Most early recurrence appears to reflect venting recurrence [519.001) [517].

These rates are much lower than those (14–16 %/ The Oxford dictionary states that ‘A young human being year) observed in children infected horizontally after the below the age of puberty or below the legal age of majority perinatal period [534. NAs in combination with improved blood screening [531]. Although in children and In highly endemic areas. This spontaneous vent is rarely observed in HBV infection vary between different regions of the world. but aminotransferase levels return to the age of 18 years’ [529]. most infections are transmitted adolescents.9 Chronic HBV infection in children than 3 years and in 4–5 % of children older than 3 years [533]. ferent countries may have different age settings for chil- liver disease progresses very slowly. drug use). despite the high- 1–2 weeks before. The UN convention has been normal and HBV DNA becomes very low or undetectable.. In countries of intermediate endemicity. as the pathogenesis 30 years [536. and infected hepatocytes are therefore not resection or LT). neous seroconversion rates (loss of HBeAg and develop- ment of anti-HBe) in these perinatally infected children are low. The affected children are usually 3:13:8:3 HBIG should be given to recipients with asymptomatic and have normal growth. The complete resolution of HBV of HBV takes critical clinical turns in ‘child’. to HBeAg [309]. typically into late childhood patients with HBV-related HCC (at least or adolescence. In these to have undergone early seroconversion (suggesting that countries. the host T-cell response is sup- chemotherapy. in this phase. as rence after transplantation [527]. 537]. tattooing. section).01 and 0.6–1 %/year) [538]. pressed. occurring in fewer than 2 %/year of children younger 3. surgery. whereas in areas of low person-year) [538. Generally. ranging from 18 to 20 years. Sponta- after LT to prevent HBV recurrence (B1). However. locoregional therapies. In 123 . if they have attacked. and in this phase. Natural history of chronic HBV infection in children The 3:13:8 Recommendations: patients before and/or after vast majority of children infected at birth are immune- curative or local–regional therapy of HCC tolerant with high HBV DNA levels in serum and the 3:13:8:1 NAs treatment should be given to presence of HBeAg for years.Hepatol Int (2016) 10:1–98 65 as early as possible before transplantation. 535]. especially infection is characterized by loss of HBsAg and appearance around 16–18 years of age. Alanine aminotransferase (ALT) levels are fre- detectable serum HBV-DNA (B1). with cirrhosis (80 %). 1–5 % of HBeAg-positive countries) or through horizontal transmission from child to children develop cirrhosis [536. during and after level HBV replication. The most recent data about 90 % of newborns who acquire HBVperinatally showed entecavir or tenofovir were more effective NAs develop chronic HBV infection In contrast. HBIG should be related infections have become very rare because of given during the anhepatic phase. the age of voting rights differ long-term follow-up of children in low replicative phase in different countries. children (0. chronic HBV infection is generally a mild from mother to child vertically/perinatally (mainly in Asian disease with a benign course. should be regarded as ‘child’. and histological 3:13:8:2 Because NA therapy cannot completely changes are minimal. and sexual or parenteral transmission (e. On the other hand. of children who acquire the virus in the first 6 years of life ment of recurrent hepatitis B after liver transplantation’’ and 5 % of adults become chronically infected [532]. The After achievement of anti-HBe seroconversion. high viral loads in anhepatic phase. while transfusion- be severe enough to lead to cirrhosis and HCC) [538]. and body piercing necroinflammation during seroconversion to anti-HBe may may be relevant sources of infection. The age at the time of low dose HBIG have been proved to reduce HBV recur. The immune-active phase is characterized by elevation followed by combination therapeutic of aminotransferase and fluctuating serum HBV-DNA modalities with NAs and low-dose HBIG levels. lifelong treatment is HBeAg can induce tolerance of helper T cells of newborns needed (B2). child during early childhood (mainly in African countries) Between 0.000 infection occurs in all age groups.13. dental care. HBV acquisition is the major determinant of chronicity. 539]. The without signs of cirrhosis at the time of seroconversion definition of ‘child’ is of utmost importance for the treat- have demonstrated no progression to cirrhosis over about ment of chronic HBV-infected patients. quently normal or slightly increased. Also. ratified by 192 of 194 member countries. Children developing HCC are endemicity. 537].12 Prevention and treat. Transplacental transfer of maternal eradicate HBV.g. This phase may lead to seroconversion. Transmission modalities for of anti-HBs. dif- This state is the low replicative phase. Available data on dren in medical set-up. infection occurs primarily in adult life through more likely to be males (70 %).03 % of children with chronic HBV [530]. serum Nations Convention defines child as ‘a human being below HBsAg persists. only 25–50 % using this strategy [528] (see ‘‘3. HBV infection develop HCC during childhood (32 per 100.

and the Treatment options for children with chronic HBV infec- limited number of drugs labelled for use in this age group tion The US Food and Drug Administration (FDA) [540]. could prove HBeAg seroconversion occurs earlier in IFN-a-treated useful to avoid liver biopsy. low-serum HBV-DNA disease. controlled trial of IFN-a in children with HBV infection As the upper limit of normal (ULN) for ALT levels in showed a virological response (defined as negativeHBeAg pediatric age has not yet been established. lamivudine.66 Hepatol Int (2016) 10:1–98 adult patients. Various studies have shown that factors warrant antiviral treatment. As response to currently available antivirals in children However. entecavir. After confir- mation of the low replicative phase (normal ALT and HBV Indications of treatment in children with chronic HBV DNA 000 IU/ml). DNA levels. although the of fibrosis is recommended before considering treatment in seroconversion may lag by 1–3 years [545. their side effects. controls (p = 0. decision to start 12 months of age.2 % HBV DNA levels is important. levels. It is not yet approved for use in at increased risk of developing HCC [71]. approved five medications for treatment of children with The need for treatment should be evaluated at each CHB: IFN-a. The risk of HCC is higher in individuals with a levels should be measured every 3 months within the first family history of HCC [71]. Loss of In the presence of high ALT levels. frequent histology [541. histological untreated children may have similar rates of HBeAg assessment of the degree of inflammation and of the stage seroconversion as IFN-a-treated children. and co-existing liver diseases (Table 12). adefovir. as they are its prolonged half-life. not yet well-identified children. year to rule out HBeAg-negative hepatitis. female gender. IFN-a has the advantages of (IFN)-a and NA is more likely when at least moderate a long-lasting response and no risk of mutants induction. noninvasive methods to assess the shown a higher efficacy with respect o IFN-a. with CHB. HBeAg positivity. it is advised that and HBV-DNA) in 26 % of treated patients versus 11 % of the normal limit should be as per the local laboratory ULN. 542]. It remains to be estab- present. major disadvantages are the high-cost. family history of IFN-a Results of a large. long-term follow-up studies suggest that is partial and limited to specific subgroups. mild evolution of the disease during childhood. treatment is based on ALT levels. as raised ALT levels and pediatric studies because of the rarity of HCC during variable levels of HBV-DNA may indicate imminent childhood. The not been established for children with mild inflammation or latter could be reduced by the use of pegylated IFN-a. a family history of HCC may warrant treatment which requires a single weekly administration because of even in children with mild histological changes. especially during follow-up. 544]. but no conclusion can be drawn from 12 months is recommended. degree of hepatic fibrosis. In summary. With certain groups (Table 12). the development of severe be done every 6 months. developing HCC is still to be clarified in the pediatric In HBeAg-negative children. necroinflammation or moderate fibrosis is found at liver however. patients should be monitored with infection Decision to treat must take into account the ALT every 3 months and HBV DNA every 6–12 months. and at therapy compared with controls. HCC. The role of viral genotype in the risk of seroconversion that would not require treatment. complications in few. fibrosis. Response to both interferon respect to nucleoside analogs. assessment of serum HBsAg occurred in 10 % of treated patients versus 1. as these methods evaluate more fibrosis than Lamivudine A large multicenter trial of LAM in children necroinflammatory activity. and age years [543. these noninvasive methods cannot substitute for lished whether shifting the time to seroconversion by liver biopsy in the decision to treat a child or an adolescent 12–36 months reduces long-term damage to the liver [531]. an observation period of HBeAg positivity. Currently. multinational. follow-up visit. the efficacy of current antivirals. in order to initiate antiviral drugs at the tenofovir. IFN-a can be used in children older than earliest signs of liver damage. the risk of HCC surveillance with liver ultrasound and AFP should disease progression later in life. sufficient data is lacking in children. as high HBV DNA values of controls [542]. children with elevated ALT levels at the time of starting However. although studies in adults HBV patients have not fully validated. and the need for thrice-weekly injections. ALT and HBV DNA population. Although still children.03) after 24 weeks of therapy. the long-term risk of both HCC and cirrhosis In HBeAg-positive children with elevated serum ALT is directly correlated to serum HBV DNA levels and levels ([19 upper normal limit). HBV adefovir and tenofovir in children aged 12 years and older. Although the benefit of treatment has side-effects. assessment of liver disease severity (either and entecavir starting from 16 years of age. and recently. 546]. as in adults. [547] showed that 23 % of the children in the treatment 123 . such as FibroScan. whereas low levels should associated with response to treatment are elevated ALT instigate investigations to exclude other causes of liver levels ([29 upper normal limit). lamivudine starting at 3 years of age. histology and/or noninvasive methods). randomized.

If no seroconversion. randomized trial normal. Treat if moderate to severe inflammation or significant fibrosisa 000 \ULN Monitor every 3 months. Monitor every 3 months. Histology not needed HBeAg-negative CHB 1–29 ULN Rule out other causes of elevated ALT. or with family h/o HCC or cirrhosis. 549]. Histology not t needed CHB 1–29 ULN Follow-up for 1 year to see for spontaneous seroconversion. Treat if no HBeAg-positive seroconversion. Treat if moderate to severe inflammation or significant fibrosisa a A family history of HCC may warrant treatment even in children with mild histological changes. However. ADV is safe and treatment in children have confirmed both the efficacy in well tolerated in children. or with family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosisa Persistently normal Monitor every 3 months. Biopsy if ALT persistently elevated. Treat if moderate to severe inflammation or significant phase) fibrosisa 2000–20. Monitor every 3 months. and no important resistance- reducing serum HBV DNA and the high mutation rate associated mutations have been observed in the pediatric [548. Biopsy if ALT persistently elevated. Biopsy if ALT persistently elevated. but not in The response to treatment was especially in children younger children after beneficial virological effects were with higher ALT values and histological activity (among not observed in children between 2 and 12 years of age children with ALT greater than five times the upper limit of in the primary efficacy. Biopsy if ALT persistently elevated. Treat if moderate to severe inflammation or significant fibrosisa Persistently normal Monitor ALT every 3 months and DNA 6–12 monthly. Biopsy if ALT persistently elevated or family h/o (immune tolerant HCC or cirrhosis. 123 . or with family h/o HCC or cirrhosis.000 [29 ULN Follow-up for 1 year to see for spontaneous seroconversion.000 Any ALT Rule out other causes of elevated ALT if normal ALT. 19 % of children developed response after 12 months of ADV treatment compared LAM resistant mutants. Biopsy if ALT persistently elevated. setting [551]. of adolescents ([12 years) with CHB. multicenter. Biopsy if ALT persistently elevated or with family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosisa Persistently normal Monitor every 3 months. Treat if moderate to severe inflammation or significant fibrosis Noncirrhotic [2000 [29 ULN Treat. compared to 13 % Adefovir ADV dipivoxil is approved for the treatment in the placebo group. or with family h/o HCC or cirrhosis. Other smaller studies of LAM with 0 % in the placebo group [550]. Histology not needed. or with family h/o HCC or cirrhosis. 24 % in the where 23 % of adolescents reached a virological placebo group). assess severity of liver disease by biopsy. Treat if moderate to severe inflammation or significant fibrosisa [ULN Rule out other causes of elevated ALT. or with family h/o HCC or cirrhosis. Monitor every 3 months. Biopsy if ALT persistently elevated. Monitor every 3 months.Hepatol Int (2016) 10:1–98 67 Table 12 Indications of treatment in children with chronic HBV infection HBV DNA ALT Treatment (IU/ml) Decompensated Detectable Any Treat. Consider LT of no stabilization cirrhosis Compensated Detectable Any Treat cirrhosis Severe reactivation Detectable Elevated Treat immediately of chronic HBV Noncirrhotic [20. Treat if moderate to severe inflammation or significant fibrosisa 000 [ULN Rule out other causes of elevated ALT. HBeAg loss occurred in 50 % vs. as they are at increased risk of developing HCC group cleared HBV-DNA and HBeAg.

hepatitis and cirrhotic patients need long-term treatment conversion and the impact on the development of HCC. week 72. resistance entecavir for ([16 years age) may be preferred in such patients with high viremia 123 . but the recommendations should be as for the Normalization of ALT levels occurred in 74 % of treated adults. in order to them the first-line NA treatments for adolescents. adefoviris is no longer recommended because of the Tenofovir In a recent double-blind. cents. placebo) in CHB adolescents 12 to8 years possible if seroconversion to anti-HBe is achieved on of age. Lamivudine is the only NA currently approved for younger children. (Table 13). the rare children with HBeAg-negative chronic long-term studies are needed to evaluate the rate of sero. Because weekly for 6 months. It is likely that. as it is already widely used (and been approved by the FDA for treatment of adolescents FDA licensed) for patients older than 2 years of age with over the age of 16. as seroconversion to anti-HBe contraindications to IFN. a virological response in 89 % of treated patients treatment. off-treatment response.68 Hepatol Int (2016) 10:1–98 Entecavir ETV is more effective than LAM and ADV in Although not yet approved for the treatment of CHB the treatment of CHB in adults. On the basis of these inpatients 2 years of age. three times The basic principles remain the same as for adults.5 mg once daily (for nucleoside-naı¨ve patients). the use of tenofovir might be encouraging results and a good safety profile. if allowed by the age. Duration of treatments with NA has not been was seen regardless of previous HBV therapies [552]. The recommended regi- men is 5–10 million units per square meter. ETV has safe in younger children. transplantation should be considered if Table 13 Management of antiviral resistance in children with chronic HBV infection Lamivudine Switch to tenofovir (for [12 years old) resistance Switch to IFN (2 years of age) Adefovir If the patient was NA-naive before adefovir. trial on the use of tenofovir (300 mg once daily for A finite-duration treatment with tenofovir or entecavir is 72 weeks vs. Since the approval of tenofovir for adoles- 16 years are ongoing. Its use should be limited to the rare Currently. Patients should be monitored after discontinuation patients. In initiate antiviral drugs at the earliest patients older than 12 years of age. Tenofovir therefore appears to be a promising Patients who do not undergo HBeAg seroconversion on agent for the treatment of CHB in adolescents. Tenofovir or entecavir. In case of non-response 3:13:9 Recommendations: chronic HBV infection in at the end of IFN treatment. IFN-a is the only treatment licensed of therapy adjustment is based on the patient’s age for treating children younger than 3 years of age. studies in adults show of the low number of effective drugs that are approved. has made uated at each follow-up visit. who. and to special populations with with elevated ALT levels. The recommended treatment dose is the main aim in this patient population. IFN-a is the for lamivudine is 3 mg/kg/day (maximum 100 mg/day). For Peg-IFN. only available treatment offering a chance of sustained administered orally once daily. No resistance to tenofovir developed through because of the possibility of post-treatment flares. The recommended and detectable HBV DNA require urgent dose for tenofovir is 300 mg once daily. as soon as results of trials using Peg-IFN in children are available. with NA. switch to entecavir (for [16 years age) or tenofovir (for [12 years age). wait for at least 12 months children before considering other therapies. as response 3:13:9:3 Children with decompensated cirrhosis rate is high and resistance is less likely. a finite-duration IFN-a therapy remains the young children unresponsive to IFN-a and requiring treatment strategy of choice for HBeAg-positive children immediate treatment. established. placebo-controlled higher risk of resistance and the lower response rate. and for entecavir antiviral treatment with NA(s). for patients [16 years old) is the best choice. Clinical trials in children younger than HIV infection. the highest HBeAg seroconversion rate with 48-week when resistance to an NA develops in children. although treatment. Liver is 0. The recent FDA approval of tenofovir and entecavir. the decision treatment schedules. tenofovir (or entecavir signs of liver damage (C2). 3:13:9:2 The need for treatment should be eval- which have high genotypic barriers to resistance. however. as response may be achieved during the 6 months following the end of IFN-a 3:13:9:1 Any person up to the age of 18 years treatment. it will Treatment failure and antiviral resistance become the recommended drug. will be considered as a child (A1). are the Treatment strategy for chronic HBV infection in children first choice. rarely require therapy.

age. 3:13:9:4 Patients with moderate to severe activity 3:13:9:13 No sufficient data are available for use or significant fibrosis with any ALT of noninvasive markers in children and. as these methods evaluate without delay and irrespective of HBV more fibrosis than necroinflammatory DNA levels (A1). of age. hepatitis and cirrhotic patients need rhotic chronic HBV-infected patients if long-term treatment with NA (B1). level should be considered for treatment at present. these noninvasive methods (A1). tenofovir. and entecavir 12 months is recommended. the rare HBV DNA every 6–12 months (B1). developing HCC (B2).000 IU/ml genotypic barriers to resistance. normal limit should be as per the local and recently. a family The natural course of HBV infection is determined by the history of HCC may warrant treatment interplay between virus replication and the host’s immune even in children with mild histological 123 . [16 year of age). ALT and 3:13:9:16 In case of no response at the end of IFN HBV DNA levels should be measured treatment. HIV infection (B1). ALT levels and variable levels of HBV. at least 12 months should every 3-months within the first year to elapse before considering other thera- rule out HBeAg-negative hepatitis. widely used (and FDA-licensed) for 3:13:9:11 Patients who are not considered for patients older than 2 years of age with treatment should be followed up regu. an observation period of aged 12 years and older. it is advised that the IFN-a. they have persistently elevated ALT 3:13:9:18 The recent FDA approval of tenofovir levels [2 times upper limit of normal ([12 years of age) and entecavir (for (ULN) (at least 1 month between obser. children with HBeAg-negative chronic 3:13:9:9 Treatment may be started in pre-cir. 3:13:9:15 Currently.Hepatol Int (2016) 10:1–98 69 patients do not stabilize with medical changes. larly (Table 13) (B1). 3:13:9:19 Although not yet approved for the 3:13:9:10 Patients with compensated cirrhosis and treatment of CHB in patients 2 years detectable HBV DNA should be con. the use of tenofovir might be sidered for treatment even if ALT levels safe in younger children. a finite-duration IFN-a ther- DNA may indicate imminent serocon. 000 IU/ml). 3:13:9:12 Although the benefit of treatment has 3.14 Treatment of acute HBV infection not been established for children with mild inflammation or fibrosis. has if they are HBeAg-positive and made them the first-line NA treatments [2000 IU/ml if HBeAg-negative. used in children older than 12 months of 3:13:9:7 In HBeAg-positive children with ele. as they are at increased risk of management (A1). IFN-a can be laboratory ULN (C2). lamivudine. 3:13:9:8 In HBeAg-negative children. 3:13:9:17 Patients who do not undergo HBeAg itored with ALT every 3 months and seroconversion on treatment. cannot substitute for liver biopsy in the 3:13:9:5 Children with severe reactivation of decision to treat a child or an adolescent chronic HBV infection should be treated with CHB. as response may be achieved After confirmation of the low replicative during the 6 months following the end phase (normal ALT and HBV DNA of IFN-a treatment (B1). 3:13:9:6 As the upper limit of normal (ULN) for 3:13:9:14 The US FDA approved five medications ALT levels in pediatric age has not yet for treatment of children with CHB: been established. as it is already are normal (B1). with elevated ALT levels (A1). adefovir and tenofovir in children normal limit). without a liver biopsy (B1). entecavir. lamivudine starting at 3 years of vated serum ALT levels ([19 upper age. adefovir. pies. apy remains the treatment strategy of version that would not require treatment choice for HBeAg-positive children (C1). as raised starting from 16 years of age (A1). which have high vations) and HBV DNA [20. activity (C2). patients should be mon. even for adolescents (A1).

HBeAg to anti-HBe serological resolution. Mild enlargement acute phase. and finally. and subsequently HBsAg to anti-HBs 123 . icteric and con. The serum of the spleen or lymph nodes occur uncommonly. as severity of injury. months into convalescence. anti-HBe. of serum aminotransferases usually occurs within tem. anti-HBc induction is partially T tations range from subclinical or anicteric hepatitis to cell independent. development of clinically significant acute and chronic nausea and pain in the right upper quadrant. with ALT being higher than AST. there valescence phases. Anti-HBc appears with the Individuals who do not mount a broad and vigorous onset of the disease as the first anti-HBV antibody. T cell immunity acute self-limited infection that may result in acute hep. increase and rapid clearance of virus. an aberrant response can lead to fulminant hepatitis. and preicteric. The course of acute hepatitis B is divided onset. detection of HBsAg and IgM anti-HBc. in both direct and indirect fractions.70 Hepatol Int (2016) 10:1–98 response. The serum bilirubin concentration may be normal in It is clear that replication and persistence of HBV is not patients with anicteric hepatitis. of the icteric phase. markers of HBV replication. Persistent elevation of serum ALT for more patterns. followed by HBV antibod. In subjects who have been previously vaccinated. The convalescent phase of hepatitis The differential diagnosis of HBsAg-positive acute hep- B begins with the resolution of jaundice. leading to blunted viral load 40–140 days). anti-pre-S. except with protracted severe disease. fulminant hepatitis. later in the infection period. atitis includes reactivation (flare or exacerbation) of hep- erally the last symptom to abate and may persist for many atitis in chronic HBV-infected patients. most typically to smooth muscle. but develop per. from the liver nor to the pathogenesis of hepatitis. From the incubation period to the onset is earlier engagement of innate and adaptive immunity at of symptoms or jaundice. symptoms of fatigue and anorexia typically worsen. Variable degrees of jaundice are present. copies to very low levels [554]. Studies in acutely HBV-infected chim. suppresses viral replication originating from these cccDNA atitis. HBeAg generate the symptoms of acute hepatitis [553]. most of than 6 months may indicate progression to chronic hep- the effector molecules associated with the adaptive cellular atitis. into the incubation period. The onset of hepatitis B is typically insidi. In patients who recover. normalization HBV infection does not stimulate the innate immune sys. the average being 2–3 weeks. and HBV DNA. Jaundice can last from a few days to Diagnosis several months. only other common physical finding in acute hepatitis B is values up to 1000–2000 IU/l are typically seen during the a mild and slightly tender hepatomegaly. Upon exposure to HBV. while 30 % develop disappearance of HBsAg. the other HBV antibodies. Laboratory testing during the acute phase of acute The physical signs of typical acute hepatitis B are not hepatitis B reveals elevations in the concentration of ala- prominent. In contrast to During the acute phase of hepatitis B (AVH-B). However. individuals with a vig. decades and possibly for life. Various auto-antibodies can appear during the course immune response are induced. The bilirubin is Pathogenesis variably increased. ies. it averages 75 days (range much lower viral loads. anti-HBs formed during convalescence and later may Clinical manifestations enhance opsonization of HBsAg and block de novo infection of hepatocytes by released HBV. Fatigue is gen. resolution. How- ever. Serum albumin rarely falls cytopathic per se. and in some cases. This explains the presence of anti-HBc icteric hepatitis. Itching and pale stools may occur. manifes. In contrast. which may take months after icteric hepatitis. are also present. The nine and aspartate aminotransferase levels (ALT and AST). alkaline phosphatase and lactic dehydrogenase are usually only mildly elevated (less than threefold). which recognizes pathogen-associated molecular 1–4 months. of acute hepatitis B. poor appetite. even after serological seroconversion. Recovery is accompanied High disease activity usually leads to clinical and by the disappearance of HBV DNA. even in those patients who do not build up an efficient Approximately 70 % of patients with acute hepatitis B immune response. small amounts of cccDNA persist in the liver orous and broad immune response to the virus develop an for years. but later cytolytic immune responses follow and phase of infection. HBV elimination starts several weeks before onset of The diagnosis of acute hepatitis B is based upon the the disease with T-cell-dependent noncytolytic mecha. These anti- sistent infection and become chronically infected with bodies probably contribute neither to virus elimination HBV. then immune response do not clear the virus. The prothrombin panzees and woodchucks showed that no host response to time can increase and is the most reliable marker of viral replication occurred during the incubation phase. During the initial nisms. With the onset HBV infection [555]. with nonspecific symptoms of malaise. thus preventing ous. anti-SHBs. Serological resolution is defined by the have subclinical or anicteric hepatitis.

quantitative analysis of highly con. In all other situations. patients present during the window period when The meaning of the term anti-HBs is somewhat HBsAg has become negative but anti-HBs is not yet pos. A decrease in is determined primarily by the age at infection. and (2) to identify 12 months from the onset may develop chronic infection an acute hepatitis in some hepatitis B patients. low viral antigen Patients who have a coagulopathy. 97 % in predictive power for differentiating patients with CHB with the groups that received lamivudine and placebo. HBV DNA and HBeAg hepatitis B cases. achieving a ([1:1000) suggest an acute HBV infection with high response rate of 86 % [564]. and they often In acute infections. acute flare from acute hepatitis B. with the consequence that samples taken in the late The rate of progression from acute to chronic hepatitis B acute phase may be HBsAg negative [557]. Hence. occurring in % of icteric cases. It usually platelet count (BAP) score was calculated. others the entire with fulminant hepatitis B in whom virus clearance tends to antibody spectrum against all three surface proteins be more rapid. serum bilirubin levels [10 mg/dl or hepatic cence. where HBsAg may have been eliminated very rapidly. The rate is HBsAg concentration by more than 50 % within the first approximately 90 % for a perinatally acquired infection. but before anti-HBs. Levels[600 Paul–Ehrlich units/ml or IgM anti-HBc encephalopathy) with 100 mg of lamivudine. high levels of HBsAg at 12 weeks and HBV DNA Anti-HBc immunoglobulin (Ig)M (anti-HBc IgM) may at 8 weeks were useful for discriminating between the be useful in two situations: (1) to distinguish an acute patients who lost HBsAg within 12 months and those who hepatitis caused by HBV from a hepatitis of different eti.6. 319]. 123 . HBV antigens elicit immune-mediated liver injury in exposed contacts. HBsAg decreases with an initial half-life Fulminant hepatitis B is an atypical course for acute hep- of 8 days until it has been completely removed from serum atitis B infection. Treatment Predominant TH1 immune response in AVH-B favors cell- mediating viral clearance.Hepatol Int (2016) 10:1–98 71 seroconversion. A was an independent risk factor for progression to chronic cating progression to chronicity if the values remain infection following AVH-B in Japan [562]. the lack of response to therapy was also observed in found that peak bilirubin level. During acute infection. are deeply jaundiced. IgM anti-HBc is the sole marker of acute including pre-S1 and pre-S2. and % for an adult-acquired infection [561]. it was dine. 4 weeks indicates resolving acute infection in [95 % of 20–50 % for infections between the age of 1 and 5 years cases [558]. rithmically for weeks–months from undetectable to typical final concentrations of 10. During resolving acute hepatitis B. indi. Genotype centrated HBsAg is an excellent prognostic marker. HBsAg concentrations rise loga. therefore. after weeks–months. In addition. did not. The first randomized clinical inflammatory activity. Rarely. ambiguous. In Japanese stable or increase. faster. There was also no platelet count within the first 8 weeks had the highest difference in HBsAg loss after 12 months (94 vs. patients. particularly [563]. infection leads to significantly increased production of Whether patients should be treated with nucleos(t)ide HBV specific antibodies (mainly Anti HBe/Anti HBc) in therapy is unsettled since few studies have addressed the chronic HBV infection or its exacerbation in comparison to benefits of antiviral therapy during acute infection. anti. In a study on domized to lamivudine for 3 months and 40 to placebo) patients with a protracted clinical course of [2 months and showed no biochemical or clinical benefit to lamivu- with elevated liver enzymes and positive HBV DNA. Tests should be quantitative because anti. response in chronic HBV infection favors antibody pro. If the acute HBV infec- tion is resolved. AST and HBe appears after anti-HBc. anti- HBV infection. coexist with HBsAg. [2 strongly suggested an acute flare of CHB [560]. while TH2-mediated immune Treatment for acute HBV is mainly supportive. concentra. which is more common in patients against the small HBsAg protein (SHBs). and a score of disappears earlier than anti-HBs. in fulminant disease.000 ng/ml with Outcome of acute hepatitis B 2–4 days of doubling time [556]. In this setting. peak AST levels and least the subset of patients with severe AHB. pre-S antibodies appear before anti-SHBs.000–100. Bilirubin. Only those who fail to clear HBV within ology in a chronic HBV-infected patient. prospective case series treated 15 patients with severe AHB HBc IgM is also positive in CHB and during convales. In about 25 % of acute resolving Typically. those with fulminant hepatitis B or HDV coinfection. appropriate measures should be taken to prevent infection duction. trial included a total of 71 patients with AHB (31 ran- tions are lower or undetectable [23. in a dose-dependent manner. the elimination of HBsAg proceeds much become undetectable as hepatic failure supervenes. load and subsequent resolution of infection in AVH-B as are encephalopathic or cannot tolerate oral intake should compared to persistent viral antigenemia in chronic HBV generally be hospitalized. One AVH-B [559]. Some understand it to mean antibodies only itive. (INR [1.

30. indicated in certain subgroups of patients as follows: 3:14:7 Interferon is contraindicated (A1). Antivirals other than lamivudine have when given as monotherapy. (b) severe 3:14:8 When the distinction between true severe AVH-B: individuals who fulfill any two of the following acute hepatitis B and spontaneous reactiva- criteria: (1) hepatic encephalopathy.5 %). 3:14:5 Tenofovir. The optimal duration of lamivudine prophylaxis was not 123 . HCC). or chemotherapy These indications outline the limitations in differentiat- ing AVH-B from reactivation of chronic HBV infection.6. with some promising preliminary 3:14:6 The duration of treatment is not estab- results with the use of entecavir [570. anthracyclines). 25 % placebo) and seroconvert to anti-HBs without antivi- and incidence of acute liver failure (20 vs. lamivu- with a capacity for improving the prognosis of these dine or adefovir are acceptable options patients [567–569]. viral factors (high baseline HBV Interferon should be avoided because of the increased DNA. antiviral therapy is not indicated in the vast or indefinitely in those who undergo liver majority of patients with acute hepatitis B. in small case reports or series of of treatment should be short (C2). and (3) international normalized ratio NA treatment should be administered (A1).72 Hepatol Int (2016) 10:1–98 respectively) [565]. but may be transplantation (C2). breast cancer. Telbivudine. 3:14:3 Patients with fulminant hepatitis B must be the better the results obtained.63) [579]. adefovir. should be short. as the duration of treatment HBsAg and anti-HBc prior to initiation of treatment. 571]. [10. another RCT that included 3:14:2 More than 95–99 % of adults with acute 80 AVH-B patients showed statistically significant differ. DNA load was a good predictor for the treatment outcome 3:14:4 Treatment is only indicated for patients [566]. (2) serum bilirubin tion of chronic HBV infection is difficult. demonstrating the safety and efficacy of this antiviral drug. tinued until HBsAg clearance is confirmed. 42.13. 95 % CI liver biopsy in doubtful cases can help to 0. (a) patients with fulminant acute hepatitis B. Thus. All candidates for chemotherapy dine. treatment should be con- 573]. lamivu- (steroid. and to reduce the delay/premature termina- infection and exclude the diagnosis of tion of chemotherapy (RR 0. as the duration been investigated so far. The efficacy of prophylactic anti-viral therapy in pre- 3:14:1 Establishing a diagnosis of acute HBV is venting HBV reactivation in HBsAg(?) patients was firmly important. telbivudine. entecavir or tenofovir are acceptable options and immunosuppressive therapy should be screened for- when given as monotherapy. HBeAg positivity). and (c) a pro- tracted course [such as persistent symptoms or marked 3. However. especially if it is increasing. tenofovir [572. The ral therapy (A1). Lamivudine was exposure.15 Antiviral prophylaxis jaundice (bilirubin [10 mg/dl) for more than 4 weeks after before immunosuppressive therapy presentation]. However.24]. severe or protracted acute hepatitis B (C2). Higher vaccine doses may be required to achieve 3:14 Recommendations (acute viral hepatitis B) anti-HBs response in immunocompromised patients. reactivation-related mortality (RR 0. Increased incidence of HBV reac- transplantation and reduction of HBV DNA levels would tivation was associated with cancer types (lymphoma. acute severe hepatitis B. Chemotherapy-induced HBV reactivation and hepatitis An argument can be made for treating all of the above flare is a common complication in HBsAg(?) cancer groups of patients using an NA. and types of anti-cancer therapy risk of hepatic necro-inflammation. patients with severe acute or with fulminant hepatitis B or for those with fulminant hepatitis B were treated with lamivudine. study also showed that the sooner the treatment is initiated. In a few other studies. sidered.94). as majority of adult patients established by two randomized trials in lymphoma patients presenting as acute hepatitis B have reac- and meta-analysis involving clinical trials and cohort tivation of CHB. reduce the risk of recurrent hepatitis B after transplant. entecavir. positive HBeAg and IgM used in all of these studies and was shown to reduce the antiHBc with low HBV DNA levels and risk of HBV reactivation [risk ratio (RR) 0. Treatment can be stopped after confir- Vaccination of HBV seronegative patients should be con- mation that the patient has cleared HBsAg.27–0. 95 % establish the diagnosis of acute HBV CI 0. and telbivudine [574]. HBV reactivation (B1). A definite history of studies of various cancer types [576–578].41. HBV infection will recover spontaneously ences in mortality (7. (INR) [1. 95 % CI 0.0 mg/dl. given its safety and the fact patients.5 % lamivudine vs. with the incidence ranging from 20 to 70 % in that many of these patients may ultimately need liver previous reports [575].07–0.1–0. and a rapid decline of HBV evaluated for liver transplantation (A1). lished.

patients who are neg. 600]. despite the firmation of HBV reactivation before ALT elevation [25]. HBsAg-negative patients with positive anti-HBc antibodies plant recipients [583]. The cumulative risk of hepatitis-re. anti-HBc positive patients who receive term. and biological agents (e. tion. resistance. Hsu et al.g. and current recommendation for HBV DNA reactivation was confirmed) entecavir treatment the duration of anti-viral prophylaxis is 6–12 months after in lymphoma patients who received rituximab-CHOP completion of chemotherapy [25. prophylactic anti-viral The frequency of monitoring can range from 1 to 3 months. though baseline anti-HBs titer was proposed. It is not known chemotherapy. and be treated with NA therapy upon con- vation has been reported [584–586]. death was noted. The optimal duration of pro- regimens [587–592]. reported prospective 3:15:1 All candidates for chemotherapy and follow-up of HBV DNA and entecavir therapy upon HBV immunosuppressive therapy should be DNA reactivation in lymphoma patients who received screened for HBsAg and anti-HBc prior to rituximab-based chemotherapy [593. Therefore. 581]. HBc positive patients with detectable serum HBV DNA tumor necrosis factor-a-blocking agents). depending on the 3:15:2 Prophylactic anti-viral therapy should be sensitivity of the HBV DNA test and the diagnostic criteria given to HBsAg(?) cancer patients who for HBV reactivation.. should be treated similarly to HBsAg positive patients. 594]. lated mortality in these early. the incidence and and/or immunosuppression regardless of anti-HBs status. cytotoxics. and confirmed that prophylactic entecavir whether more potent anti-viral agents. No risk factors for HBV reactivation were because of their lower rate of treatment-induced HBV identified. [595] compared pro. should be tested for HBV DNA. both during therapy (regardless of 123 . immune suppression or on HBV synthesis [582]. everolimus is approved for the treatment of prophylactic anti-HBV in high-risk lymphoma patients of neuroendocrine tumor and renal cell carcinoma (as with resolved HBV infections. anti- including steroid. DNA testing. lack of randomized clinical trials. This may be due to the effectiveness of different preventive strategies are clearly effects of everolimus (and other mTOR inhibitors) on needed. RCT has clearly demonstrated the efficacy mycin) inhibitor. if they are anti-HBs negative and/or if close with ‘resolved’ HBV infection (i. can further improve the prophylactic effi. atitis flare in patients with HBV DNA reactivation was vation-related mortality. and its cost-effectiveness is not yet established. monitoring of HBV DNA is not guaranteed [597–599]. and no HBV-related liver decompensation or considered if prolonged anti-viral therapy is indicated. and long-term anti. ative for HBsAg but positive for anti-surface (anti-HBs) or NA prophylaxis is also recommended for anti-HBc anti-core (anti-HBc) antibodies) is also mostly reported in positive patients receiving bone marrow or stem cell lymphoma patients who received rituximab-containing transplantation [599. and who receive chemotherapy these patient populations are lacking. these agents should be 0 %. the incidence of HBV-related hep- cacy in reducing the risk of HBV reactivation or reacti. However. Huang et al. immunosuppressive agents are not well defined [596]. therapy is recommended for HBsAg(?) patients who depending on the type of immunosuppressive therapy and received immunosuppressive agents for auto-immune and comorbidities. receive cytotoxic or immunosuppressive phylactic entecavir treatment and therapeutic (started when therapy. in which 3:15 Recommendations: antiviral prophylaxis before no preventive strategies were adopted. retrospective series. such as entecavir treatment significantly reduced the risk of HBV reactiva- and tenofovir. undetermined. Further studies to identify single-agent). is also com. was about 1 %. Two immunosuppressive therapy or chemotherapy prospective studies exploring different preventive strate- gies were recently reported. phylaxis for these indications is not known.. Although prospective studies in tectable serum HBV DNA. However. tion. anti-HBc positive patients with unde- and rheumatic diseases. of HBV DNA reactivation was 10–40 %. viral therapy is recommended for HBsAg(?) organ trans. Incidence and severity of HBV reactivation in patients Immunosuppressive therapy is required for patients who with resolved HBV infection who received other undergo solid organ transplantation. and fatal HBV reacti. severity of HBV reactivation has generally correlated with should be followed carefully by means of ALT and HBV the extent of immune suppression. In these studies.e.Hepatol Int (2016) 10:1–98 73 explored in these studies. The incidence initiation of treatment (A1). HBsAg-negative. 105]. Some experts recommend prophylaxis in all rheumatic diseases. However. and breast cancer (in combination with host and viral risk factors for HBV reactivation and cost- hormonal therapy) [580. the duration may be long. the optimal preventive strategy remains apies. Immunosuppressive therapy. In the case of mTOR (mammalian target of rapa. rituximab and/or combined regimens for hematological Chemotherapy-induced HBV reactivation in patients malignancies. Physicians should be aware of the potential life-threatening HBV reactivation has also been reported in HBsAg(?) consequence of HBV reactivation in this patient popula- cancer patients who received other molecular target ther. monly used in patients with inflammatory bowel disease HBsAg-negative. HBsAg-negative.

mostly from studies from Taiwan. With the and management availability of both hepatitis B immune globulin (HBIG) and hepatitis B vaccine (at first plasma-derived. anti-HBc positive patients of life. the banning of recapping showed that maternal HBV DNA levels and needles. However. Multivariate analysis concerning the disposal of sharps. Six percent of fathers and 67 % of siblings were with undetectable serum HBV DNA and also HBsAg-positive. including intravenous drug use. 6. HBV DNA of [8 log10 copies/ml) for HBsAg (and anti-HCV as well as anti-HIV) in the is associated with failure of prophylaxis [126.8 % in the group receiving vaccine in hospital situation. All failures occurred in infants born of HBeAg-positive mothers with Transfusion services pre-delivery HBV DNA C6 log10 copies/ml. tattoos. but NAT has become mandatory in are needed to compare the efficacy and more developed countries. there was marked reduction in the infant infection rate [125]. ear piercing and needle prick injuries vaccine alone group. Since it transfusion services in most countries in Asia. DNA [601].16 Public health issues for HBV: prevention HBsAg-positive fathers and even aunts [603]. Further studies potential limitation. In one of the most carefully planned It has been well established that HBV can be spread by studies. mothers became HBsAg-positive during the first 6 months 3:15:5 HBsAg-negative. the transfer of blood from syringes into containers. However.1 %) were HBsAg- needles and sharps boxes.74 Hepatol Int (2016) 10:1–98 HBV DNA levels) and for 12 months after with the use of potent immunosuppressors. The great expense for such testing is a containing chemotherapy]. This would require the use of a with resolved HBV infection [HBsAg(-) nucleic acid test (NAT) to quantify small amount of HBV and anti-HBc(?) who receive rituximab. is possible that mothers with HBV DNA levels between 6 123 . of the hepatitis B virus: vaccination and antiviral treatment 3:15:4 HBsAg-negative patients with positive anti- HBc antibodies should be tested for HBV The risk of maternal to child transmission of HBV had DNA. education and surveillance positive at age 7–12 months [605].2 % in the control group to 21. later Needles and other sharp instruments recombinant). The use of disposable needles/instruments is assays for. since such recipients may develop sev- HBV reactivation in lymphoma patients ere/fulminant hepatitis B. mothers have a higher chronic HBV positivity rate com- suppression regardless of anti-HBs status pared to those born of HBeAg-negative mothers. and be treated to 25–30 % of infants born of HBeAg-negative mothers with NA therapy upon confirmation of HBV also become chronic HBsAg positive. Up to 63 % of infants born of HBsAg-positive positive patients (C1).0 % in the accupuncture.0001 for all countries. The importance of imple- retrospective study of 869 HBsAg-positive mothers and menting safe sharps practices in the hospital setting cannot their infants who had received HBIG with three does of be over emphasized.9 % in the group receiving awareness and by public education. especially anti- cessation of therapy to reduce the incidence CD20s such as rituximab and ofatumumab. and better ear piercing. anti-HBc positive been well documented. In more developed vaccine plus multiple doses of HBIG (p B 0. [602]. patients with detectable serum HBV DNA prior to the development of the hepatitis B vaccine in 1981 should be treated similarly to HBsAg. 606]. it has recently been shown in a more difficult to implement. showing that reactivation before ALT elevation (C1). that 27 infants (3. reduced from 73. up ALT and HBV DNA testing. HBV DNA. It has subsequently also been shown by sequence analysis of HBV mutations that post-natal transmission can occur from 3. proving should be followed carefully by means of that transmission is related to high viral load. Other smaller studies also confirm that high maternal viral load (in the There has been widespread implementation of screening study of Wiseman et al. Infants born of HBeAg-positive who receive chemotherapy and/or immuno. With increased knowledge of. cost-effectiveness of different preventive strategies (prophylactic antiviral therapy vs. HBeAg-negative mothers can also have high viral load. disposable needles are used for accupuncture and groups) [604]. Prevention of maternal to child transmission regular HBV DNA monitoring) (B1). the infant chronic HBV positivity state was contaminated needles. increasingly important for transfusion services to screen for 3:15:3 Physicians should be aware of the risk of occult hepatitis B. risk factors for immunoprophylaxis failure. Other than the use of disposable hepatitis B vaccine. This can be prevented by raising plus one dose of HBIG and 2. HBsAg-negative. detectable HBV DNA in the cord blood were independent and needle disassembly should be enforced. it becomes and severity of HBV reactivation (A1).

17 Occult HBV infection Education of public and health care professionals will help in identification of persons at risk for viral hepatitis. Booster doses are probably medical personnel should be a priority (A1). patients are considered as having their practice. Around 50–60 % of these patients are positive for anti-HBs [612]. one of which follow the vaccine 3:16:5 Increasing the awareness of the public and recipients for 22 years [606]. They are doctors. A 6-year study to delineate the outcome of acute HBV infection in this from China reported that the training of general practi- regard. (both anti-HBs and anti-HBc negative). The management of CHB requires a shift in focus from For the first group. HBsAg seroclearance. maternal treatment can significantly reduce the also be having OBI. 123 . antiviral therapy when their HBV DNA levels are C6 log10 3:16:4 Universal hepatitis B vaccination of new- copies/ml. not necessary for immune competent subjects. These patients have been identified only by syringes and transfusion sets. tioners (GPs) of village clinics in Hebei province improved For the second group. Appropriate training for Occult hepatitis B (OBI) infection is defined by medical personnel is important. More longitudinal studies are required risk of transmission of HBV to the baby.e. medical man- agement. which indicates that the For the third group. personnel 3. primary OBI. This HBV infection.Hepatol Int (2016) 10:1–98 75 and 8 log10 copies/ml can still induce immuonprophylaxis 3:16:3 Transfusion services should be encouraged failure in their infants. for at least 6 months and are undergoing subsequent 3:16 Recommendations: public health issues for HBV. have fallen to very low levels (0 mIU/ml). 3:16:7 A shift in focus from tertiary care to community and primary care settings is Increasing the awareness of the public and medical needed (A1). the subjects ments for care. entering into the last phase of prevention and management chronic HBV infection. Better understanding of sequent follow-ups. including possible roles for nurse practi- may have acute hepatitis B with resolution of the disease or tioners or hepatitis coordinators besides primary care become chronically infected with hepatitis B. There have been long-term follow-up studies of borns should be enforced (A1). respectively. In the former group.1 %. subjects would need to play an increasingly important role in hepatitis B have positive or negative anti-HBs and anti-HBc in sub- screening. particularly those working therefore regarded as subjects with past infection and in high prevalence areas. There are three groups of sub- care settings jects in whom HBV DNA is detectable with concomitant undetectable serum HBsAg. however. exposed recently. vaccinated infants. where in called acute HBV infection [610. Depending on the could also include an exploration of alternative arrange- immune status at the time of contacting HBV. It is estimated that 3:16:2 Hospitals should strongly enforce the imple- upto a total of 20 % of OBI patients are negative for all mentation of safe sharps practices (A1). i.. it is advisable to treat mothers with to use NAT as screening tests (B1). Primary care services. and Definition and patient category ensure appropriate counseling. detectable HBV DNA in serum and/or liver in patients who are tested negative for serum HBsAg by the most sensitive Shift in focus from tertiary care to community and primary commercial assays [609]. diagnosis. The chronic HBV positivity persistently detectable HBV DNA without prior docu- rate of 2-year-old children (mothers are HBsAg negative) mentation of HBsAg positivity before the presentation. dropped from 11. the sterilization of needles. testing and monitoring. 3:16:1 The general public should be educated OBI can also be serologically classified into sero-posi- concerning care in using needles and other tive (anti-HBs and/or anti-HBc positive) or sero-negative sharp instruments (A1). in providing support and advice to priority populations will subsequent follow-ups. because of 3:16:6 Appropriate training for medical personnel good anamnestic responses even after the anti-HBs titers at various levels is important (A1). and community organizations subjects with chronic HBV infection. and treatment [607]. 611]. subjects are in the window phase of tertiary care to community and primary care settings. It is. important to note that hepatitis B and C and its management is also required for studies have shown that HBV DNA may still be some primary care practitioners and non-hepatology spe- detectable in some of these subjects even after years of so- cialists such as those involved in antenatal care. patients have known chronic HBV training of GPs decreases the transinfection rate of HBV infection with previous documentation of HBsAg positivity [608]. These subjects may some cases. for instance.6 to 2.

These data are grossly underestimated. OBI may still be associated rate [622]. minute amounts of HBV which are insufficient to mount intense and specific immune responses.9 from five prospective studies of HBV from OBI during and after immunosuppressive [634]. pre-S2. espe. and S genes and their regu. and (3) low 123 . escape detection by commercial HBsAg assays [619]. at least more than 90 % of OBI subjects. in particular. HBV disease activity [628] and also the chance of loss of logically negative OBI patients may likely be infected with HBsAg seroclearance [629].9 [640]. it has been shown that OBI leading to these complications include (1) persistent human genomic constitutions. This was confirmed by another meta-analysis that therapy (including anti-CD20) indirectly suggests that the included 14 studies showing increased risk of HCC in OBI OBI state is kept by immune-mediated suppression of subjects with an OR of 8. Although There are several studies addressing the issue of trans- the viremia level (HBV DNA) is generally quoted as lower missibility of HBV through the blood products from OBI than 200 IU/ml [613]. with an script and HBsAg [625]. 638]. Proposed recipients who received bone marrow/organs from donors mechanisms include mutations of viral genomes. e. G145R). status of the recipients [631]. There is a wide range of estimation of the prevalence of Second. 621]. the blood/ ficult even when using existing standardized and sensitive product volume received by the recipients.. Several reported in the setting of coinfection with chronic hepatitis studies have found that there are significantly more C infection [634]. the risk is relatively low (1–3 %) [630].g. sug- those of overt chronic HBV infection [621. latory regions [623. Another better accepted postulation is that in minimal or no necroinflammation and fibrosis in liver OBI patients. According to several studies. Clinical scenarios of OBI Prevalence of OBI OBI is of particularly interest in three main clinical areas. 636]. whether HBV is transmissible from OBI patients. OBI reported in different countries. histological features. anti-HBs status in the donors and the recipients. 40 % [635. A longitudinal follow-up study conducted in replication capacity. 624].76 Hepatol Int (2016) 10:1–98 serological markers of HBV infection [613]. recent meta-analysis recruiting 16 studies revealed that posed to explain the marked decrease in pre-S2/S tran. 633]. These sero. It has been shown that while HBV transmission is patients will have HBV DNA levels of 0 IU/ml in the possible. namely. studies have shown that there is an absence of genic role of OBI. an the etiology for development of cirrhosis and HCC is well immense immune suppressive effect on the HBV. term complications. There has been a practice of anti-viral prophylaxis being given to recipients receiving Pathogenesis of OBI bone marrow or solid organ donations from OBI subjects. 623]. what are the clinical manifestations of OBI. This can either be due to intrinsically low viral with the development of liver cirrhosis and HCC. genome as well as with its free episome [642]. However. nearly all relevant mutations in the genomic HBsAg coding region OBI patients will have normal liver biochemistry and [620.8 to sites of the pre-S1. and long- 18 % [614–618]. such that they DNA. reactivation adjusted odds ratio of 2. It ranges from to including liver function. who are anti-HBc positive with or without detectable HBV cially over the surface gene (e. Additive gesting that OBI is associated with increased risk of HCC effects from these mutations may restrain the virus [637. First.. These low levels of HBV DNA as well as affecting the chance of infection of recipients include the their fluctuations make the detection of this condition dif. Possible mechanisms for virus replication [626]. (2) persistent oncogenic role of the polymorphisms (SNP) affecting the immune responses. OBI increased the risk of development of HCC. the HBV is replicating at an extremely low histology [632. The estimated frequency of OBI in genomic mutations and rearrangement in splice donor patients with cryptogenic liver cirrhosis ranges from 4. In fact. On the other hand. the HLA DP low-grade inflammation leading to or continuing with region as illustrated by studies using single nucleotide existing cirrhosis [641]. A involving the Pre-S2/S RNA splicing has also been pro.g. Other studies reported greater 45–80 % of patients with apparently unidentifiable nucleoside and amino acid diversities in OBI compared to cause of HCC have had HBV detected in the liver. and the immune HBV DNA assays. Post-transcriptional mechanism Japan confirmed OBI increased the risk of HCC [639]. Many centers advocate the use of nucleos(t)ide analogs for Mechanisms leading to OBI remain obscure. liver cirrhosis and HCC? Finally. OBI as replicative activities or extrinsic factors. There are many studies examining the possible patho- However. HBV genome with its possible integration into the human are associated with the chance of HBV chronicity [627]. and this is related to the fact that most of the OBI patients what is the risk of reactivation of HBV from OBI patients have extremely low HBV DNA levels in the serum (and who have undergone immunosuppressive therapy? liver tissues are generally not easily assessible). Factors serum [616].

should be performed in patients with HBV reactivation in OBI subjects undergoing cirrhosis and/or HCC in which no causes immunosuppressive therapy has recently gained increasing are identifiable (B1).15 seroclearance still require continuous fol- Antiviral prophylaxis before immunosuppressive therapy low-up for the development of cirrhosis- or chemotherapy’’ section). Monitoring should be more frequent for HBV DNA at baseline should have HBV DNA and in patients receiving potent B cell depletion liver function checked at regular intervals of 1–3 months agents. there is no good data on the fre- immunotherapeutic approaches designed to either boost the quency of monitoring of HBV DNA and HBsAg during HBV-specific T cell component of the immune response or and after immunosuppressive therapy. anti-HBc positive subjects that whenever HBV DNA is detectable in the serum of with or without positive anti-HBs should be HBsAg-negative and anti-HBc/anti-HBs-positive patients closely monitored by HBV DNA during and at baseline. related complications and HCC (A1). recent study adopting 4 weekly HBV DNA monitoring in The efficacy and feasibility of these approaches will. all of the patients achieved excellent Antiviral therapies targeting hepatitis B virus-infected control [594]. need to be carefully evaluated in humans. attention because of the potential fatal hepatic decompen. In addition.Hepatol Int (2016) 10:1–98 77 levels of HBV transcriptional activities with viral protein 3:17:3 HBV DNA measurement in serum and liver synthesis (e. Suspicion should to be a bile salt transporter known as sodium taurocholate be raised in all HBsAg-negative subjects co-transporting polypeptide (NTCP) [645]. 3:17:4 Chronic hepatitis B patients with HBsAg sation if the condition is not treated promptly (see ‘‘3. there are insufficient data to recommend whe- recently been developed that directly target HBV-infected ther routine antiviral prophylaxis right at the initiation of hepatocytes by inducing cccDNA degradation or by immunosuppressive therapy or postponement of antiviral inhibiting HBV entry or the expression of viral proteins. on which agents are being used (for example patients on rituximab should be checked more frequently). X protein and truncated preS–S protein) (if available) by highly sensitive assays with transforming properties [643].1 Newer therapies and immunomodulatory baseline. Concerning the antiviral treatment. rituximab and prompt entecavir treatment once the HBV DNA is detectable.g. therapies patients should be treated with nucleos(t)ide analogues. e. The region with or without positive anti-HBs or anti- between amino acids 21–47 of the Pre-S1 present in L- HBc (C1).. ligand derived from the pre-S1 domain of L-HBsAg blocks 123 . anti-CD20. anti-HBc positive patients receiving however. Antiviral treatment unil at least 12 months after the last cycle of immuno. HBsAg-negative. 3:17:2 Sensitive nucleic acid tests should be used Cyclosporine (known to inhibit NTCP) analogues without to screen all blood donations from HBsAg- its immunosuppressive properties and oxysterols [646] may negative subjects. tools for the treatment of CHB. Promising therapies have To date. For those with undetectable HBV DNA at 4. According to a to directly stimulate the intrahepatic innate response [644]. 598]. HBsAg in virus binds to the hepatocyte membrane. The frequency of monitoring depends detectable (B1).g. HBV DNA levels are more sensitive indices of reactivation than liver 4 Newer therapies and future perspectives function since they become detectable before ALT levels start to increase. a synthetic lipopeptide detectable in these products (A1). It has also been suggested that patients should be treat pre- The limited efficacy of the currently available antiviral emptively if they are anti-HBs negative or if close follow- treatments requires the development of new therapeutic up cannot be assured [597. Myrcludex-B. hepatocytes 3:17 Recommendations: occult HBV infection The life cycle of the virus begins with its attachment to the 3:17:1 Occult hepatitis B infection is not an appropriate hepatocyte receptor. which is now recognized uncommon disease entity. Patients who are negative therapy. agents until HBV DNA becomes undetectable is more HBV-infected hepatocytes may also be targeted by appropriate.. antiviral treatment should be given as in the at least 12 months after immunosuppressive case of HBsAg-positive patients. once HBV DNA is detectable on follow-up. should be started once the HBV DNA is suppressive therapy. it is recommended 3:17:5 HBsAg negative. Transfusion products thus constitute possible drugs for development against should be discarded if HBV DNA is HBV for the future.

future regimens may include such 10. Six weeks of Myrcludex administration. These findings indicate that the drug acts at early nucleocapsid interaction and glucosidase inhibitors pre- stages in the life cycle of the virus by modulating hepatic venting glycosylation of HBsAg are potential drugs at this cholesterol uptake and interfering with lipid transport. as life cycle of the virus are Bay 41-4109 [653]. terized. It also blocked replication effective unless there is an obvious effect on already of HBV genotypes A and D in culture by inhibiting RNase infected hepatocytes harboring transcriptionally active H activity with an estimated EC50 of 5 lM and a CC50 of cccDNA. such compounds could be used in future uncoating and delivery of the resulting naked nucleocap. Thus. SCID mice [647]. most likely due to the repeated involves a number of stages. and TIM-3 (T-cell immunoglobulin domain which are recycled to the nucleus from the cytoplasm. CTLA-4 (cytotoxic T-lymphocyte-associated unable to prevent the replenishment of the cccDNA pool protein 4). the polymerase engineering HBV-specific T cells through the transfer of engages. 661]. SLAM (signalling lymphocyte activation from maturing HBV-DNA containing nucleocapsids.1 ± 1. stage of the viral life cycle [657]. the processes of endocytosis. which are believed to therapeutic vaccines targeting different HBV proteins play a role in induction of T cell exhaustion. if chemical derivatives of b-thu- drugs only in combination with others. molecule). 123 . vaccine based on immunogenic complexes potentially be achieved by using RNA interference-based composed of HBsAg and antihuman HBsAg antibodies therapeutics that target expression of specific viral RNAs [662]. In this form. being the tem. their and H in biochemical assays with IC50 values of 5. In the last few years.7 use as monotherapy regimens is unlikely to prove very and 2. such as HBsAg and HBeAg. and cccDNA-specific transcrip. Improving HBV-specific T cell immunity by yield viral proteins. Viral messenger RNAs are translated in the cytoplasm to 664]. cccDNA is quite exposure of these cells to large quantities of HBsAg and stable and behaves as a minichromosome. step-wise loss of their effector functions [658]. pathways that may represent new targets for antiviral therapy in the case of HBV infection [649]. HBeAg. Potential approaches include HBV proteins. Therefore. new strategies aimed at inhibitory receptors has been shown to partially recover improving cccDNA clearance have been developed. 666]. Exhausted virus specific T cells express inhibi- plate for viral transcript synthesis by host RNA polymerase tory molecules. such as PD-1 (programmed cell death II. be identified. regimens of combined therapy with nucleos(t)ide ana- sids to the nuclear pores are initiated. Blocking cytes. viral replication markers when the cells were infected with Peptidomimetic compounds that would prevent HBsAg- HBV.78 Hepatol Int (2016) 10:1–98 de novo HBV infection both in vitro and in vivo. Therapeutic vaccination aimed at eliciting the tion activator-like effector nucleases (TALENs) [651].9 ± 0.3 ± 1. This or functionally exhausted. efficiently blocked cell-to-cell virus spread cation take place within the nucleocapsid and involve and cccDNA amplification [648]. Although the above RNAse H.7 lM.7 lM. Ezetimibe was tested logues [656]. This could [660. immunity followed by translocation to the nucleoplasm of the released HBV-DNA. an event that leads to recruitment of core protein HBV-specific T cell receptors (TCR) or HBV-specific dimers triggering encapsidation of the complex into the chimeric antigen receptors (CARs) represents another nucleocapsid. the subsequent steps in virus nucleic acid repli- animal model. but include lymphotoxin-b receptor (LT-b R) activation of the in vivo efficacy of this approach is still uncharac- HBV-infected cells [650]. or TLR-mediated or anti CD40-mediated stimu- [652]. lation of intrahepatic monocytes or dendritic cells [663. Most HBV-specific antiviral agents have thus far been protein 1). and acquire a progressive and effect efficient clearance of cccDNA-containing hepato. HBV-specific T cells are deleted converted into a double-stranded cccDNA molecule. Once synthesized. A potential drug targeting RNase H is b-thu- drugs appear to block HBV at the point of entry and japlicinol. These the exhausted T cells of CHB patients in vitro [659]. Immunotherapeutic approaches: restoration of adaptive Nucleocapsid disassembly occurs at the nuclear pore. using the HepaRG cell model and was shown to inhibit the Maturing nucleocapsids in the final stages of morpho- establishment of intrahepatic cccDNA and expression of genesis bud through the endoplasmic reticulum membrane. Three inhibitors that act at this stage in the novel approach [665. Within the nucleus. respectively. Following encapsidation of the polymerase and pgRNA initiated either 3 days or 3 weeks post infection in the same complex. which inhibited the enzyme from genotypes D therefore prevent the infection of new hepatocytes. An patient’s immune system represents another attractive alternative approach is to modulate the expression of viral therapy for HBV. GLS4 [654] demonstrated after pretreatment of human chimeric uPA/ and NVR-1221 [655]. the rcDNA is During CHB infection. or to and mucin domain 3). japlicinol with improved efficacy and reduced toxicity can Following attachment.

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S.2 Unresolved issues and unmet needs Open Access This article is distributed under the terms of the Creative Commons Attribution 4. formation or destroying infected hepatocytes. L. R. H. Falck-Ytter Y. Z. K.org/licenses/by/4. on pharmacogenetics and predicted responses.51:403–410 Peg-IFN with a potent NA (entecavir or tenofovir) to 5. et al. F.0 International License (http://crea The challenges in the management of hepatitis B are still tivecommons. Lee. mimic remains one of the main obstacles to complete eradication the activation of innate immunity during the early phase of of the virus during chronic infection. IFN-a. C. Ott JJ. 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