Pegylated Interferon For Treatment of Chronic Hepatitis B Virus Infection

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Pegylated interferon for treatment of chronic hepatitis

B virus infection
AUTHOR: Anna SF Lok, MD
SECTION EDITOR: Rafael Esteban, MD
DEPUTY EDITOR: Jennifer Mitty, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2024.

This topic last updated: Aug 01, 2023.
INTRODUCTION
Chronic hepatitis B virus (HBV) infection is a serious liver disorder that can result in cirrhosis,
liver failure, and hepatocellular carcinoma. It remains a major global health problem
affecting an estimated 316 million persons of whom roughly 550,000 die annually from HBV-
related liver disease [1].
Interferons (IFN) have antiviral, antiproliferative, and immunomodulatory effects. Although

standard IFN was initially used, it has been replaced by pegylated interferon (PegIFN).
This topic will review the use of IFN-alfa for the treatment of adults with chronic HBV. Topic
reviews that provide a more general overview of the treatment of HBV in adults and children
are found elsewhere. (See "Hepatitis B virus: Overview of management" and "Management
of hepatitis B virus infection in children and adolescents".)
MECHANISM OF ACTION
Although interferon (IFN) has been used as treatment for chronic hepatitis B virus (HBV)
infection for 40 years, its exact mechanisms of action are still unclear. IFN is thought to
induce specific genes that interfere with several steps in the HBV lifecycle, including: virus
entry; uncoating of the virion; transcription of viral DNA into RNA; translation of viral RNA
into proteins; and assembly of nucleocapsids [2]. It may also augment cell-mediated
immunity, thereby promoting clearance of HBV-infected hepatocytes. Increasing data
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suggest that NK cells may play an important role in IFN-mediated immune clearance of HBV
[3-6]. (See "Characteristics of the hepatitis B virus and pathogenesis of infection", section on
'Replication cycle' and "Characteristics of the hepatitis B virus and pathogenesis of infection",
section on 'Pathogenesis of infection'.)
IFN's effect on HBV transcription appears to be partly mediated by epigenetic modifications

of the HBV covalently closed circular DNA (cccDNA) minichromosome [7,8]. In addition, IFN
can induce degradation of cccDNA by induction of APOBEC3s (DNA editing enzymes) that can
degrade foreign, but not host, DNAs and accelerate decay of HBV nucleocapsids [9,10]. These
findings may explain why IFN treatment results in a higher rate of hepatitis B e antigen and
hepatitis B surface antigen loss, and a more durable response compared with nucleos(t)ide
analogue treatment. (See 'Virologic response' below and 'Studies of interferon therapy'
below.)
GOALS OF THERAPY
Virologic response — A positive response to interferon (IFN) is characterized by suppression

of hepatitis B virus (HBV) DNA and loss of hepatitis B e antigen (HBeAg) (in patients who were
initially HBeAg-positive). This is followed by loss of hepatitis B surface antigen (HBsAg) in
some patients during the course of follow-up [11-16]. Assessment of off-treatment response
is important with IFN treatment, since loss of HBeAg and HBsAg, and seroconversion to
hepatitis B e antibody and hepatitis B surface antibody may be delayed. (See 'Monitoring'
below.)
Most responders are able to maintain their virologic response after cessation of treatment
during follow-up of 5 to 10 years, unless they become immunocompromised [11,17-19]. As
examples:
● One of the largest reports with long-term follow-up focused on 165 patients with
HBeAg-positive chronic HBV who were treated with IFN between 1978 and 2002 [20].
Response to treatment was defined as HBeAg loss within 12 months after the end of
therapy. Patients were followed for a median of 8.8 years. Fifty-four patients (33
percent) responded. Relapse occurred in only seven of the responders (13 percent).
Loss of HBsAg during long-term follow-up was observed in 52 percent of responders,
compared with only 9 percent of nonresponders.
● Another report focused on 266 patients treated with PegIFN with or without
lamivudine, of whom 37 percent lost HBeAg during treatment [14]. Of 172 patients with
follow-up data, 81 percent of those who lost HBeAg within 24 weeks of completing a 48-
week course of treatment continued to be HBeAg-negative up to three years after
cessation of treatment. Loss of HBsAg was achieved in 30 percent of patients who lost
HBeAg (58 percent of those with genotype A and only 6 percent with non-A genotypes).
● A third study included a total of 315 patients with HBeAg-negative HBV who were
followed for three years after treatment with PegIFN (with or without lamivudine) or
with lamivudine alone for 48 weeks [16]. Three years after treatment, the proportion of
patients with normal serum alanine aminotransferase (ALT) levels was significantly
higher in patients treated with PegIFN (31 versus 18 percent). Similarly, more patients
treated with PegIFN achieved HBV DNA levels of ≤10,000 copies/mL (approximately
2000 international units/mL) (28 versus 15 percent) and HBsAg loss (9 versus 0 percent).
This study found that approximately 25 percent of HBeAg-negative patients treated
with PegIFN for 48 weeks had a durable response when virologic response was defined
as HBV DNA ≤10,000 copies/mL (approximately 2000 international units/mL) and
approximately 14 percent had a durable response when virologic response was defined
as HBV DNA ≤400 copies/mL (approximately 80 international units/mL).
● In a study that examined long-term durability of IFN-induced HBsAg loss in 238 patients
followed for a median of 160 weeks after treatment cessation, cumulative relapse
(reappearance of HBsAg and/or HBV DNA on at least two occasions four to eight weeks
apart), ranged from 0.84 percent at 26 weeks to 9.66 percent 597 weeks after treatment
cessation [21].
Disappearance of HBV DNA in serum, as determined by polymerase chain reaction (PCR)

assay, occurs in 50 to 100 percent of patients who clear both HBeAg and HBsAg. This usually
occurs at the time the patient becomes HBsAg-negative; disappearance of HBV DNA is
seldom achieved in patients who clear HBeAg but remain HBsAg-positive [11]. Although IFN
is associated with a higher rate of HBsAg loss compared with nucleos(t)ide analogues, loss of
HBsAg occurs in only 5 to 10 percent of patients who receive PegIFN when assessed 24
weeks after completing a one-year course [2]. In addition, it is rarely observed in Asian
patients and those infected with non-A genotypes [19,22].
Patients treated with combination therapy of PegIFN and lamivudine are significantly more
likely to achieve a virologic response (eg, HBV DNA suppression, HBeAg seroconversion, and
HBsAg loss) compared with those treated with lamivudine monotherapy, but responses are
similar to those treated with PegIFN monotherapy [23-25]. More detailed descriptions of the
trials evaluating the efficacy of IFN are found below. (See 'Pegylated interferon with or
without lamivudine' below.)
Clinical response — A sustained viral response, particularly in those who clear both HBeAg
and HBsAg, is almost invariably accompanied by normalization of ALT, a decrease in
necroinflammatory activity, and overtime a decrease in fibrosis as well [26]. However,
residual damage, as manifested by portal inflammation and fibrosis, may still be present
[20,27].
Available data from long-term follow-up studies suggest there is a decreased incidence of
HCC, and improved overall survival and survival free of hepatic decompensation among
patients who received IFN [12,15,28-30]. However, data are scant, since in most studies the
duration of follow-up was short. In addition, these benefits were mainly observed in patients
who achieved a sustained response [12,15,17,20,28,31,32].
The benefits of IFN on HCC have also been demonstrated by several meta-analyses [33-36].
In one analysis, the relative risk of HCC among those treated with interferon compared with
those who were untreated was 0.59 (95% CI 0.43-0.81) [34]. Meta-analysis of studies
including IFN-containing regimens found a 30 to40 percent reduction in HCC risk compared
to untreated patients [33,34].
WHOM TO TREAT
The decision to initiate antiviral therapy for the treatment of chronic hepatitis B virus
infection (HBV) is primarily based upon the presence or absence of cirrhosis, the alanine
aminotransferase (ALT) level, and the HBV DNA level ( table 1). A detailed discussion of the
indications for antiviral therapy is found elsewhere.
Selection of patients — For individuals who require treatment of chronic HBV infection,
PegIFN should be considered as an option for treatment-naïve, immunocompetent patients.
Contraindications to IFN are discussed below. (See 'Contraindications' below.)
PegIFN may be most suitable for patients who desire a finite duration of treatment (eg,
young adults and women planning to conceive in the future), particularly if they are HBeAg-
positive and are infected with HBV genotype A, and if a week 12 stop rule will be applied.
However, interferon has been associated with more side effects compared with nucleos(t)ide
analogues. Thus, the decision to use PegIFN or a nucleos(t)ide analogue as primary therapy
should be made after careful discussion with the patient. (See 'Predictors of response' below
and 'Response to treatment' below and 'Adverse reactions' below and "Hepatitis B virus:
Overview of management", section on 'Choice of initial agent'.)
Predictors of response — In general, antiviral therapy for HBV is most likely to benefit
patients with active liver disease (elevated serum ALT concentration or chronic hepatitis on
liver biopsy) and HBV DNA levels >20,000 international units/mL for hepatitis B e antigen
(HBeAg)-positive patients and >2000 international units/mL for HBeAg-negative patients
( table 1). (See "Hepatitis B virus: Overview of management".)
In addition, a number of other factors have been found to predict response with PegIFN
[23,37-47]. For patients who are HBeAg positive, predictive factors include:
● Genotype A; this genotype is associated with a higher rate of HBeAg seroconversion

and HBsAg clearance than genotypes B, C, or D
● Viral load <2 x 108 international units/mL
● Pretreatment serum ALT level >2 times the upper limit of normal
● Rapid decline in HBsAg level during the first 12 to 24 weeks of treatment
An illustrative study of the predictive value of pretreatment factors included a total

of 721 patients who received PegIFN in two previous trials [23,38,41]. The likelihood
of sustained HBeAg loss (defined as undetectable HBeAg and HBV DNA levels <2000
international units/mL six months after stopping treatment) could be predicted by
pretreatment levels of HBV DNA and ALT and the HBV genotype [41]. The likelihood
of response varied across these predictors, ranging from as high as 54 percent in
patients with genotype A, an ALT ≥2 times the upper limit of normal, and an HBV
DNA <9 log copies/mL (<2 x 108 international units/mL), to as low as 7 percent in
patients with HBV genotype D, an ALT level ≤2 times the upper limit of normal, and
an HBV DNA of ≥9 log copies/mL. The predictive accuracy of these observations
requires additional validation.
One study reported long-term follow-up of 267 HBeAg-positive patients treated with
standard or PegIFN followed for a median of 11.5 years [48]. The 5- and 10-year cumulative
incidence of HBsAg loss were 14 and 32 percent, respectively. Baseline factors associated
with a higher rate of HBsAg loss were male sex, White race, genotype A, age ≥40 years, and
cirrhosis. Both HBeAg loss and HBsAg loss were associated with improvement in clinical
outcomes. Data in similar untreated patients are not available for comparison.
Predictors of response to PegIFN in HBeAg-negative patients have been described but have
not been confirmed:
● One study found that a marked elevation in serum ALT (>10 times the upper limit of
normal or more than 300 U/L) levels during therapy was predictive of a normal ALT and
histologic improvement six months after stopping PegIFN therapy [24].
● Polymorphisms of IL28B have been shown to be strong predictors of response to

PegIFN in patients with chronic hepatitis C. The favorable variant rs12979860 (C versus
T) in the IL28B region was shown to be associated with a higher rate of sustained
response to PegIFN in a study of HBeAg-negative chronic HBV [49], but the predictive
value of IL28B in hepatitis B studies is inconsistent.
In contrast, studies suggest that IFN is not effective for the following groups:
● HBeAg+, HBV DNA+, with normal serum ALT – IFN treatment is not warranted in these
patients since the response rate is less than 10 percent [50-53]. This profile is frequently
seen in Asian patients, particularly in children who were infected perinatally.
Although an initial study suggested that Asian patients who were HBeAg+ and HBV
DNA+ responded poorly to IFN treatment [51], a subsequent trial found that Chinese
adults with elevated serum ALT levels responded to IFN at a similar rate as White
patients (39 percent) [52].
● HBeAg-, HBV DNA undetectable or low (<2000 international units/mL), with normal ALT
levels – These inactive carriers do not require treatment unless there is evidence of
cirrhosis since virus replication is low and liver inflammation is inactive. These patients
should be monitored to make sure they are in the inactive state as patients with HBeAg-
negative chronic hepatitis may also have intermittently undetectable HBV DNA and
normal ALT.
Contraindications — IFN should not be used in patients with the following comorbid
conditions given the potential for adverse reactions (see 'Adverse reactions' below):
● Decompensated cirrhosis because there is a high risk of serious infections and hepatic
failure [54,55]. IFN treatment appears to be safe and effective for patients who have
cirrhosis but no clinical or biochemical evidence of decompensation or signs of portal
hypertension. However, caution must still be exercised, as decompensation can occur in
patients who develop ALT flares during treatment.
● A history of suicidal tendency or active psychiatric illness.
● Autoimmune illness.
● Severe leukopenia or thrombocytopenia.
● Concurrent severe systemic (eg, cardiopulmonary) disorders.
In addition, IFN should not be used in women who are pregnant given concerns for
pregnancy loss [56]. Thus, women of childbearing potential should have pregnancy tests
throughout the course of treatment ( table 2). (See "Hepatitis B and pregnancy", section on
'Safety of antiviral agents in pregnancy'.)
TREATMENT REGIMEN
PegIFN-alfa 2a should be given at a dose of 180 mcg once weekly for 48 weeks. The
approach to treatment is described in the figure ( algorithm 1). PegIFN has replaced
standard IFN. The attachment of polyethylene glycol to standard IFN (pegylation) reduces its
rate of absorption following subcutaneous injection as well as its renal and cellular clearance
and immunogenicity. These effects enhance the half-life of PegIFN, allowing it to be dosed
once a week.
Alternative regimens to enhance the efficacy of PegIFN are being evaluated. These include
combining PegIFN with nucleos(t)ide analogues [57-61], extending the duration of treatment
in hepatitis B e antigen (HBeAg)-negative patients [38], and adding PegIFN or switching to
PegIFN after hepatitis B virus (HBV) DNA has been suppressed with nucleos(t)ide analogues.
Although studies suggest some benefit, there is insufficient evidence to incorporate these
approaches into routine care. More detailed descriptions of these studies are found below.
(See 'Pegylated interferon with or without lamivudine' below and 'Combination with other
nucleos(t)ide analogues' below.)
MONITORING
Patients receiving interferon (IFN) therapy should be assessed for evidence of toxicity, as well
as for virologic, serologic, and biochemical response both during treatment and after
therapy has been completed [62]. We monitor patients at weeks 4, 12, 24, 36, and 48 during
treatment, and weeks 12, 24, and 48 post treatment ( table 2).
Response to treatment — Several endpoints are used to assess the efficacy of hepatitis B
treatment ( table 3).
● Hepatic panel – A hepatic panel should be obtained at baseline and all assessment
visits ( table 2). Because alanine aminotransferase (ALT) flares are common during
IFN treatment, the biochemical response to treatment is generally assessed using data
obtained 6 and 12 months after completion of IFN treatment.
● HBV DNA – We check the hepatitis B virus (HBV) DNA at baseline, at week 12, and then
at all other assessment visits.
● HBeAg and anti-HBe – For hepatitis B e antigen (HBeAg)-positive patients, we check

HBeAg and hepatitis B e antibody (anti-HBe) at baseline, week 24 and 48 on treatment,
and then every 12 to 24 weeks until 48 weeks post treatment.
● HBsAg – Hepatitis B surface antigen (HBsAg) should be measured in patients who were
HBsAg-positive, and have undergone HBeAg seroconversion, and in HBeAg-negative
patients with an undetectable HBV DNA. For such patients we monitor the HBsAg at
baseline, at week 48, and then again at weeks 24 and 48 weeks post treatment.
If quantitative HBsAg testing is available, this should be measured at 12 weeks, since

on-treatment declines in the HBsAg level at 12 weeks are associated with a favorable
response. Studies have found that a lack of, or an insufficient decline in, HBsAg level
after 12 weeks of PegIFN is associated with a high negative predictive value (>95
percent) of off-treatment response [39,63-72]. This has prompted suggestions to use a
week 12 HBsAg response as a stop rule to avoid futile treatment and to minimize cost
and adverse events [73].
However, there is no unified stop rule that can be applied to all HBV genotypes, and the
proposed stop rules have not been validated in prospective studies.
Adverse reactions — Adverse events associated with IFN therapy can be severe and may
require dose reduction or discontinuation of treatment. The major side effects of IFN include
an initial flu-like syndrome, which occurs in approximately 90 percent of patients [2]. Other
side effects include fatigue, anorexia and nausea, diarrhea, weight loss, hair loss, emotional
lability and depression, bone marrow suppression, and induction of autoantibodies, which
can result in thyroid abnormalities in up to 30 percent of patients, or enhancement of
autoimmune diseases [74,75].
In addition to clinical assessment, we obtain the following laboratory tests to assess adverse
events:
● Complete blood count with differential at all assessment visits ( table 2).
● Thyroid stimulating hormone at baseline, weeks 12, 24, and 48 on treatment, and week
12 post treatment.
Hepatitis flares — IFN therapy is associated with flares (at least twofold increase over
baseline) in serum ALT concentrations in 30 to 50 percent of patients [76]. This response is
thought to reflect immune-mediated lysis of infected hepatocytes and may be considered an
indicator of a favorable response. (See "Characteristics of the hepatitis B virus and
pathogenesis of infection".)
To monitor for flares, we obtain a hepatic panel at baseline and all assessment visits
( table 2). In general, IFN should be continued in patients with hepatitis flares. However,
treatment may need to be discontinued or IFN dose reduced if the flare is severe and
accompanied by symptoms or an increase in the serum bilirubin concentration, addition of
nucleos(t)ide analogues may ameliorate these severe flares though supporting evidence is
lacking.
In one study, the pattern of HBV DNA surrounding the flare was highly predictive of the
likelihood of achieving loss of HBeAg. In this trial that compared PegIFN alfa-2b with or
without lamivudine in HBeAg-positive patients, 67 patients (25 percent) experienced a total
of 75 hepatitis flares with approximately similar rates in the combination and monotherapy
groups [77]. There was no significant difference in the rates of HBeAg loss among those with
and without a flare. However, flares that occurred after an increase in HBV DNA levels
(referred to as "virus-induced" flares because they probably reflect increased expression of
viral antigens) were not associated with HBeAg loss. In contrast, flares that were followed by
a decrease in HBV DNA titers (referred to as "host-induced" flares because they likely reflect
immune mediated lysis of infected hepatocytes) were significantly associated with HBeAg
loss (58 percent compared with 20 percent for virus-induced flares). Loss of HBsAg was
observed only in patients with a host-induced flare.
TREATMENT OF NONRESPONDERS
The optimal treatment of patients who do not respond to a course of interferon include
observation or treatment with a nucleos(t)ide analogue. A second course of interferon (IFN)
is generally not recommended. For those who are treated with a nucleos(t)ide analogue,
entecavir and tenofovir are preferred. Existing studies indicate that these patients respond
just as well as those who are IFN-naïve. (See "Hepatitis B virus: Overview of management".)
STUDIES OF INTERFERON THERAPY
Multiple studies have evaluated the efficacy of interferon (IFN) therapy for treatment of
chronic HBV. The initial studies used standard interferon-alfa; however, this agent is no
longer available for clinical use.
Standard interferon — The use of standard interferon-alfa is effective in improving virologic

outcomes in patients with chronic hepatitis B virus infection (HBV). However, for those who
are hepatitis B e antigen (HBeAg) negative, relapse is common after cessation of treatment.
Several studies in IFN-naïve or IFN-experienced patients have compared the combination of
standard IFN and lamivudine with IFN or lamivudine monotherapy.
● HBeAg-positive – Multiple studies have evaluated the efficacy of standard IFN in

HBeAg-positive chronic HBV [78]. The following benefits were found in a meta-analysis
of studies comparing treatment with standard IFN for three to six months with placebo
(with all estimates reported after 6 to 12 months of post-treatment follow-up) [78].
Although standard IFN is no longer used, data from these early studies provide
evidence of a beneficial effect of IFN compared with no treatment.
• More frequent loss of viral replication markers (HBeAg) – 33 versus 12 percent with
placebo
• More frequent loss of HBV DNA (by hybridization assay) – 37 versus 17 percent
• More frequent loss of hepatitis B surface antigen (HBsAg) – 7.8 versus 1.8 percent
• The treated patients were also much more likely to seroconvert to hepatitis B e
antibody and to show normalization in alanine aminotransferase (ALT) levels.
● HBeAg-negative – Treatment with standard IFN in patients who are HBeAg-, HBV
DNA+, with elevated serum ALT (many of whom are infected with a precore variant) has
been associated with a decrease in serum HBV DNA and ALT levels, but relapse is
common after cessation of treatment [79,80]. A longer course of therapy (24 months)
appeared to be more effective in inducing a sustained response [31,81]. (See
'Treatment regimen' above.)
Pegylated interferon with or without lamivudine — Pegylated interferon (PegIFN) has

replaced standard interferon because it is associated with higher rates of response and
requires less frequent dosing [47,82]. (See 'Treatment regimen' above.)
Approval of PegIFN alfa-2a was based upon two studies in patients with HBeAg-positive and
HBeAg-negative chronic HBV where PegIFN was compared with lamivudine or combination
therapy with PegIFN plus lamivudine [23,24]. In the trials described in this section, PegIFN
and lamivudine were started simultaneously in the combination therapy group. Overall,
these studies did not show a benefit of combination therapy compared with PegIFN
monotherapy in inducing off-treatment virologic response or loss of HBeAg and HBsAg.
However, combination therapy did decrease the emergence of lamivudine-resistant HBV
compared with lamivudine monotherapy. Similar findings were found in trials evaluating
PegIFN-alfa-2b.
● HBeAg-positive
• In the licensing trial for PegIFN alfa-2a, 814 patients with HBV DNA >500,000
copies/mL (approximately 100,000 international units/mL) and ALT 1 to 10 times the
upper limit of normal were randomly assigned to PegIFN alfa-2a (180 mcg once
weekly) alone, or in combination with lamivudine (100 mg daily), or to lamivudine
monotherapy [23]. Patients were treated for 48 weeks and assessed after 24 weeks
of follow-up.
At week 72, all endpoints were significantly more likely to be reached in the two
groups receiving PegIFN alfa-2a compared with the group that received lamivudine
monotherapy. Endpoints for the PegIFN groups (monotherapy and combination
therapy) compared with the group that received lamivudine monotherapy were as
follows: HBeAg seroconversion in 32 and 27 versus 19 percent; HBV DNA <100,000
copies/mL (approximately 20,000 international units/mL) in 32 and 34 versus 22
percent; HBeAg loss in 34 and 28 versus 21 percent; and ALT normalization in 41 and
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39 versus 28 percent. Eight patients in each of the two groups who received PegIFN,
but none in the lamivudine monotherapy group, lost HBsAg.
Serious adverse events occurred in 4 percent, 6 percent, and 2 percent of patients

and in the groups that received PegIFN monotherapy, combination therapy, and
lamivudine monotherapy, respectively. Among those who received lamivudine
monotherapy, two patients developed liver failure after cessation of treatment, and
at week 48, lamivudine-resistant mutations were detected in 27 percent (compared
with 4 percent in the combination therapy group).
• The dose and duration of PegIFN alfa-2a were supported in a trial that compared 90
versus 180 mcg weekly doses of PegIFN alfa-2a given for 24 or 48 weeks [63]. The
study included 544 patients (mostly Asians with genotypes B or C) randomly
assigned to one of four treatment arms. HBeAg seroconversion rate was highest in
the 48-week 180 mcg group (36 percent) compared with 26 percent for the 48-week
90 mcg group, 23 percent in the 24-week 180 mcg group, and 14 percent in the 24-
week 90 mcg group. The 24-week duration of treatment was significantly inferior to
the 48-week duration, and the 90 mcg dose was significantly inferior to the 180 mcg
dose. It is unclear if these results apply to patients with adult-acquired infection or
genotype A infection.
• The use of PegIFN alfa-2b was evaluated in a trial that included 266 patients who
were randomly assigned to receive PegIFN alfa-2b with lamivudine (100 mg daily) or
placebo for 52 weeks [38]. The PegIFN dose was 100 mcg weekly for the first 32
weeks and 50 mcg weekly from week 32 to 52. At week 78, the proportion of
patients achieving HBeAg loss was similar in the monotherapy and combination
therapy groups (36 versus 35 percent). The response rates were also similar with
regards to suppression of HBV DNA and changes in serum aminotransferase levels.
However, HBeAg loss occurred more commonly in patients infected with HBV
genotype A (47 percent) or B (44 percent) than those infected with genotype C (28
percent) or D (25 percent), and in those with host-induced hepatitis flares during
treatment.
Long-term follow-up of 172 (65 percent) patients at a mean of 3.0±0.8 years after
completion of the initial trial found that 37 percent had lost HBeAg and 11 percent
had lost HBsAg [14]. Among the initial responders, 81 percent had sustained HBeAg
loss and 30 percent had HBsAg loss.
• In another trial, 100 Chinese patients were randomly assigned to either PegIFN-alfa-
2b (1.5 mcg/kg per week, maximum 100 mcg) for 32 weeks plus lamivudine (100 mg
daily) for 52 weeks or lamivudine monotherapy for 52 weeks [25]. The rate of
sustained response (defined as HBeAg seroconversion and HBV DNA level <500,000
copies/mL [approximately 100,000 international units/mL] at least 24 weeks after

the end of treatment) was significantly higher in the combination therapy group (36
versus 14 percent). There were no significant differences in the proportion of
patients with normalization of serum ALT or histologic improvement. Lamivudine-
resistant mutations were detected more often in the monotherapy group compared
with the combination therapy group (40 versus 21 percent). A follow-up report found
that the overall rate of HBeAg seroconversion increased to 60 percent by year 5 post
treatment, and two patients had lost HBsAg [19].
● HBeAg-negative
• The licensing trial for HBeAg-negative patients included a total of 537 patients who
were randomly assigned to receive PegIFN alfa-2a (180 mcg weekly) plus placebo or
lamivudine (100 mg daily), or lamivudine monotherapy for 48 weeks [80].
Approximately two-thirds of patients were Asian, and 22 to 31 percent had bridging
fibrosis or cirrhosis. After 24 weeks of follow-up, the percentage of patients with
normalization of serum ALT levels or HBV DNA levels below 20,000 copies/mL
(approximately 4000 international units/mL) was significantly higher in those who
received PegIFN monotherapy or combination therapy compared with lamivudine
monotherapy. Rates of sustained suppression of HBV DNA to below 400 copies/mL
(approximately 80 int. units/mL) were also significantly higher in the PegIFN
monotherapy or combination therapy groups compared with lamivudine
monotherapy (19 and 20 versus 7 percent, respectively). Loss of HBsAg occurred in
seven patients in the PegIFN monotherapy group and five in the combination
therapy group compared with none in the lamivudine group.
A subsequent report described outcomes of patients with follow-up for up to three

years post-treatment [25]. The proportion of patients with a normal ALT was
significantly higher with PegIFN monotherapy or combination therapy with
lamivudine compared with lamivudine alone (31 and 31 versus 18 percent,
respectively). HBV DNA levels ≤10,000 copies/mL (approximately 2000 international
units/mL) were also more likely in those who received PegIFN monotherapy or
combination therapy compared with lamivudine monotherapy (28 and 25 versus 15
percent, respectively). HBsAg loss occurred in 8 percent in each of the two groups
that received PegIFN but none in the lamivudine monotherapy group.
These data indicate that 25 to 30 percent of patients with HBeAg-negative chronic

HBV had sustained biochemical/clinical remission after a one-year course of PegIFN.
However, only 59 percent of patients entered the long-term follow-up study.
Intention to treat analysis, including all patients in the original trial, showed that ALT
normalization was observed in only 20 percent of patients who received PegIFN
monotherapy, 20 percent of those who received combination therapy, and with 8

percent of those who received lamivudine. Similarly, HBV DNA levels ≤10,000
copies/mL (approximately 2000 international units/mL) were observed in 18 and 16
versus 7 percent of these groups, respectively.
• A second trial explored the benefits of extending the duration of PegIFN to 96 weeks
[38]. In this trial, 128 patients with HBeAg-negative chronic HBV genotype D were
randomly assigned to one of three treatment arms: PegIFN alfa-2a (180 mcg weekly)
for 48 weeks, PegIFN alfa-2a (180 mcg weekly) for 48 weeks followed by 135 mcg
weekly for an additional 48 weeks, or combination of PegIFN alfa-2a (180 mcg
weekly) and lamivudine (100 mg/day) for 48 weeks followed by PegIFN alfa-2a (135
mg weekly) for 48 weeks. At 48-week post-treatment follow-up, a higher proportion
of patients who received PegIFN monotherapy for 96 weeks achieved a virological
response (HBV DNA <2000 international units/mL: 29 versus 12 percent) compared
with those who received PegIFN for only for 48 weeks. Combination treatment was
not associated with a higher virological response as compared with PegIFN alfa-2a
alone, but only 13 patients in the combination treatment group completed follow-
up. There were no significant differences in adverse events or discontinuation rates
in the two groups that received PegIFN monotherapy. Nevertheless, given the
higher costs, the clinical benefits of extended therapy with PegIFN alfa-2a need to
be validated in larger studies.
● The efficacy of PegIFN in patients with lamivudine-resistant M204V/I mutations has not
been well studied. In one study of 16 patients who received PegIFN, only two patients
underwent HBeAg seroconversion and achieved sustained virologic suppression and
ALT normalization [83]. However, in a randomized study, where HBeAg-positive patients
with lamivudine resistance received lamivudine for 12 weeks in conjunction with either
PegIFN for 48 weeks (n = 155) or adefovir for 72 weeks (n = 80), significantly more
patients treated with PegIFN achieved HBeAg seroconversion six months after
treatment (15 versus 4 percent) [84]
Combination with other nucleos(t)ide analogues — Different strategies of combining

PegIFN and nucleos(t)ide analogues have been proposed. Most studies have adopted an
approach that involves the simultaneous start of both PegIFN and nucleos(t)ide analogues to
simplify the study design. However, others have adopted an add-on or sequential approach,
where patients start a nucleos(t)ide analogue first and PegIFN is then added or nucleos(t)ide
analogues are initiated and the patient is then switched to PegIFN; these approaches are
based on the rationale that IFN may be more effective in patients with lower levels of
viremia.
A meta-analysis of these different strategies included 33 studies of de novo combination

therapy, 15 studies of add-on therapy, and 12 studies of switch therapy [85]. Compared with
nucleos(t)ide analogue monotherapy, de novo combination therapy improved the probability
of HBeAg loss (relative risk [RR]1.62, 95% CI 1.33-1.97) and HBsAg loss (RR 15.59, 95% CI 3.22-
75.49), but rates of HBeAg loss and HBsAg loss were similar to that of IFN monotherapy.
When IFN was added on to nucleos(t)ide analogue therapy or nucleos(t)ide analogue therapy
was switched to IFN, there was also improved HBsAg loss compared with nucleos(t)ide
analogue monotherapy (RR 4.52 [95% CI 1.95-10.47] and RR 12.15 [95% CI 3.99-37.01],
respectively). By contrast, when IFN was switched to a nucleos(t)ide analogue, there was no
improvement in HBsAg loss compared with nucleos(t)ide analogue monotherapy, although
the rates of achieving undetectable HBV DNA and HBeAg loss were higher.
● PegIFN and entecavir
• In a randomized, open-label study, 218 treatment-naïve Chinese HBeAg-positive

patients were randomized to receive 48 weeks of PegIFN alfa2a (180 mcg weekly)
alone, or with 24 weeks of entecavir (0.5 mg daily) added prior to or after initiation
of PegIFN [57]. HBeAg seroconversion assessed 24 weeks post-treatment was 31
percent in PegIFN monotherapy group, 25 percent in entecavir add-on group, and
26 percent in the entecavir pre-treatment group indicating a short course of
entecavir administered in the manner designed in this study did not offer any
additional benefit.
• In another randomized, open-label study, 175 HBeAg-positive patients receiving

entecavir monotherapy (0.5 mg daily) were randomized to receive add-on PegIFN
alfa2a (180 mcg weekly) from week 24 to 48 or to continue entecavir monotherapy
[58]. Responders (those with HBeAg loss and serum HBV DNA <200 international
units/mL at week 48) discontinued entecavir at week 72 and all patients were
followed to week 96. Although response was more common in the PegIFN add-on
group compared with those who received entecavir monotherapy, the differences
were not significant at week 48 (19 versus 10 percent) or at week 96 (31 versus 20
percent).
• In a third study, 200 patients who were HBeAg-positive and had received entecavir
(0.5 mg daily) for 9 to 36 months, with HBeAg <100 PEIU/mL and HBV DNA <1000
copies/mL (approximately 200 international units/mL), were randomized to continue
entecavir monotherapy or to switch to PegIFN alfa 2a (180 mcg weekly) for 48
weeks, after an eight-week overlap with entecavir [59]. At 48 weeks, patients
switched to PegIFN had significantly higher rates of HBeAg seroconversion
compared with those who continued entecavir monotherapy (14.9 versus 6.1
percent). In addition, eight patients switched to PegIFN, but none who continued
entecavir monotherapy cleared HBsAg. Although the results of this study appear
encouraging, the patients included were highly selected since all had low HBeAg
titers and roughly 50 percent in each group had already lost HBeAg at the time of
randomization.
62 patients who completed 48 weeks of PegIFN alfa-2a therapy were followed up for
48 weeks off treatment [60]. At one year post treatment, the HBeAg seroconversion
rate increased from 18 percent post-treatment to 39 percent. In addition, sustained
HBsAg loss was documented in six of seven patients, and sustained HBV DNA
suppression was achieved in 27 of 45 (60 percent) with an end-of-treatment
response. While these results were impressive, follow-up data of patients who
continued entecavir were not provided; thus, it is not possible to conclude if
switching to PegIFN offered any advantage.
• In a fourth study, 77 HBeAg-positive patients with compensated liver disease who

were treated with entecavir or tenofovir disoproxil fumarate (TDF) for >12 months
and had a serum HBV DNA <2000 international units/mL were randomized to
continue monotherapy with entecavir or TDF, or to receive add-on therapy with
PegIFN for 48 weeks [86]. At 96 weeks, those receiving add-on therapy achieved
HBeAg seroconversion and HBV DNA suppression to <200 international units/mL
more frequently (18 versus 8 percent), although this difference was not statistically
significant.
● PegIFN and tenofovir – In a randomized trial of 751 patients (58 percent HBeAg-
positive), individuals received one of four regimens: (A) tenofovir (300 mg daily) plus
PegIFN alfa2a (180 mcg weekly) for 48 weeks, (B) tenofovir plus PegIFN for 16 weeks
followed by tenofovir alone for 32 weeks, (C) tenofovir monotherapy for 120 weeks, and
(D) PegIFN monotherapy for 48 weeks [61]. A significantly greater proportion of
patients receiving combination therapy for 48 weeks had HBsAg loss at 72 weeks
compared with those receiving monotherapy with tenofovir or PegIFN (HBsAg loss was
achieved in 9.1, 2.8, 0, and 2.8 percent patients in groups A to D, respectively). HBsAg
loss occurred more commonly in HBeAg-positive patients and in those with genotype A
infection. These data suggest the combination of PegIFN and tenofovir may enhance
rate of HBsAg loss, but the benefit is mainly observed in patients infected with HBV
genotype A. In a follow-up study, there was little to no further increase in HBsAg loss at
120 weeks, with rates of HBsAg loss in groups A to D being 10, 3.5, 0, and 3.5 percent,
respectively [87].
● PegIFN and adefovir – One trial evaluated 24 patients (HBeAg-positive or HBeAg-

negative) treated with 48 weeks PegIFN plus adefovir followed by 96 weeks of adefovir
monotherapy [88,89]. At week 144, 12 of 15 patients who were HBeAg-positive had lost
HBeAg while ALT levels normalized in 23 patients, and histologic improvement was
observed in 11 of 16 patients who had follow-up liver biopsies. Two patients developed
adefovir resistance. Although the results appeared promising, very few patients were
studied and adefovir has weak antiviral activity; thus, this combination is not
recommended.
● PegIFN and telbivudine – This combination should not be used. A randomized trial
designed to enroll 300 HBeAg-positive patients who would receive telbivudine alone or
with PegIFN alfa-2a, and PegIFN alfa-2a alone was terminated early because of serious
adverse events with peripheral neuropathy occurring in 1/54, 7/50, and 0/54 patients,
respectively [90]. Although myopathy, peripheral neuropathy, and increased creatine
kinase levels had been observed in patients receiving telbivudine monotherapy, the
addition of PegIFN appeared to increase the risk of peripheral neuropathy.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Management of
hepatitis B".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Hepatitis B (The Basics)")
● Beyond the Basics topic (see "Patient education: Hepatitis B (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS

● Chronic hepatitis B virus (HBV) infection is a serious liver disorder that can result in
cirrhosis, liver failure, and hepatocellular carcinoma. It remains a major global health
problem affecting an estimated 316 million persons of whom roughly 550,000 die
annually from HBV-related liver disease. (See 'Introduction' above.)
● Interferon (IFN)-alfa is thought to induce specific IFN-stimulated genes that inhibit HBV
transcription. IFN's effect on HBV transcription appears to be partly mediated by
epigenetic modifications of the HBV covalently closed circular DNA minichromosome.
(See 'Mechanism of action' above.)
● A positive response to IFN is usually defined as the loss of serum HBV DNA, and
hepatitis B e antigen (HBeAg) (in patients who were HBeAg-positive), followed by loss of
hepatitis B surface antigen (HBsAg) in some patients. Assessment of off-treatment
response is important with IFN treatment, since loss of HBeAg and HBsAg may be
delayed. A successful virologic response is usually associated with decreased
necroinflammatory activity, reduced liver damage, and decreased incidence of
hepatocellular carcinoma. (See 'Goals of therapy' above.)
● Pegylated IFN (PegIFN) should be considered as a treatment option for adult patients
with chronic HBV infection. IFN may be most suitable for patients who desire a finite
duration of treatment, such as young adults, and women who are planning to conceive
in the future, since IFN has been associated with more side effects compared with
nucleos(t)ide analogues. (See 'Selection of patients' above.)
● IFN is most likely to benefit patients with replicative infection (HBV DNA levels >20,000
international units/mL for HBeAg-positive patients and >2000 international units/mL for
HBeAg-negative patients) and active liver disease (serum alanine aminotransferase >2
times the upper limit of normal or chronic hepatitis on liver biopsy). Among such
patients who are HBeAg-positive, those who are genotype A and have an HBV DNA <2 x
108 international units/mL are more likely to have a favorable response. (See 'Predictors
of response' above.)
● IFN is contraindicated in patients with decompensated cirrhosis, a history of suicidal

tendency or active psychiatric illness, autoimmune illness, severe leukopenia or
thrombocytopenia, and concurrent severe systemic disorders. In addition, IFN should
not be used in women who are pregnant given concerns for pregnancy loss. (See
'Contraindications' above.)
● PegIFN-alfa 2a should be administered subcutaneously at a dose of 180 mcg once

weekly for 48 weeks. The approach to treatment is described in the figure
( algorithm 1). (See 'Treatment regimen' above.)
● Patients receiving IFN therapy should be assessed for evidence of toxicity, as well as for
virologic, serologic, and biochemical response both during treatment and after therapy
has been completed. We monitor patients at weeks 4, 12, 24, 36, and 48 during
treatment, and weeks 12, 24, and 48 post treatment ( table 2). (See 'Monitoring'
above.)
● Patients who do not respond to IFN can be treated with nucleos(t)ide analogues.
Entecavir and tenofovir are preferred. Existing studies indicate that these patients
respond just as well as those who are IFN-naïve. (See 'Treatment of nonresponders'
above.)
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REFERENCES
1. Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of

hepatitis B virus infection in 2016: a modelling study. Lancet Gastroenterol Hepatol
2018; 3:383.
2. Konerman MA, Lok AS. Interferon Treatment for Hepatitis B. Clin Liver Dis 2016; 20:645.
3. Gill US, Peppa D, Micco L, et al. Interferon Alpha Induces Sustained Changes in NK Cell
Responsiveness to Hepatitis B Viral Load Suppression In Vivo. PLoS Pathog 2016;
12:e1005788.
4. Micco L, Peppa D, Loggi E, et al. Differential boosting of innate and adaptive antiviral
responses during pegylated-interferon-alpha therapy of chronic hepatitis B. J Hepatol
2013; 58:225.
5. Stelma F, de Niet A, Tempelmans Plat-Sinnige MJ, et al. Natural Killer Cell Characteristics
in Patients With Chronic Hepatitis B Virus (HBV) Infection Are Associated With HBV
Surface Antigen Clearance After Combination Treatment With Pegylated Interferon Alfa-
2a and Adefovir. J Infect Dis 2015; 212:1042.
6. GBD 2019 Hepatitis B Collaborators. Global, regional, and national burden of hepatitis B,
1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet
Gastroenterol Hepatol 2022; 7:796.
7. Belloni L, Allweiss L, Guerrieri F, et al. IFN-α inhibits HBV transcription and replication in
cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear
cccDNA minichromosome. J Clin Invest 2012; 122:529.
8. Dandri M, Petersen J. Mechanism of Hepatitis B Virus Persistence in Hepatocytes and Its

Carcinogenic Potential. Clin Infect Dis 2016; 62 Suppl 4:S281.
9. Lucifora J, Xia Y, Reisinger F, et al. Specific and nonhepatotoxic degradation of nuclear
hepatitis B virus cccDNA. Science 2014; 343:1221.

10. Xu C, Guo H, Pan XB, et al. Interferons accelerate decay of replication-competent
nucleocapsids of hepatitis B virus. J Virol 2010; 84:9332.
11. Korenman J, Baker B, Waggoner J, et al. Long-term remission of chronic hepatitis B after
alpha-interferon therapy. Ann Intern Med 1991; 114:629.
12. Niederau C, Heintges T, Lange S, et al. Long-term follow-up of HBeAg-positive patients

treated with interferon alfa for chronic hepatitis B. N Engl J Med 1996; 334:1422.
13. Moucari R, Korevaar A, Lada O, et al. High rates of HBsAg seroconversion in HBeAg-
positive chronic hepatitis B patients responding to interferon: a long-term follow-up
study. J Hepatol 2009; 50:1084.
14. Buster EH, Flink HJ, Cakaloglu Y, et al. Sustained HBeAg and HBsAg loss after long-term
follow-up of HBeAg-positive patients treated with peginterferon alpha-2b.
Gastroenterology 2008; 135:459.
15. Papatheodoridis GV, Manesis E, Hadziyannis SJ. The long-term outcome of interferon-
alpha treated and untreated patients with HBeAg-negative chronic hepatitis B. J Hepatol
2001; 34:306.
16. Marcellin P, Bonino F, Lau GK, et al. Sustained response of hepatitis B e antigen-negative
patients 3 years after treatment with peginterferon alpha-2a. Gastroenterology 2009;
136:2169.
17. Lau DT, Everhart J, Kleiner DE, et al. Long-term follow-up of patients with chronic
hepatitis B treated with interferon alfa. Gastroenterology 1997; 113:1660.
18. Yuen MF, Hui CK, Cheng CC, et al. Long-term follow-up of interferon alfa treatment in
Chinese patients with chronic hepatitis B infection: The effect on hepatitis B e antigen
seroconversion and the development of cirrhosis-related complications. Hepatology
2001; 34:139.
19. Wong VW, Wong GL, Yan KK, et al. Durability of peginterferon alfa-2b treatment at 5
years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology
2010; 51:1945.
20. van Zonneveld M, Honkoop P, Hansen BE, et al. Long-term follow-up of alpha-interferon
treatment of patients with chronic hepatitis B. Hepatology 2004; 39:804.
21. Wu Y, Liu Y, Lu J, et al. Durability of Interferon-induced Hepatitis B Surface Antigen
Seroclearance. Clin Gastroenterol Hepatol 2020; 18:514.
22. Lok AS, Chung HT, Liu VW, Ma OC. Long-term follow-up of chronic hepatitis B patients
treated with interferon alfa. Gastroenterology 1993; 105:1833.
23. Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa-2a, lamivudine, and the
combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005; 352:2682.
24. Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and
the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J
Med 2004; 351:1206.
25. Chan HL, Leung NW, Hui AY, et al. A randomized, controlled trial of combination therapy
for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with
lamivudine alone. Ann Intern Med 2005; 142:240.
26. Papatheodoridis GV, Petraki K, Cholongitas E, et al. Impact of interferon-alpha therapy
on liver fibrosis progression in patients with HBeAg-negative chronic hepatitis B. J Viral
Hepat 2005; 12:199.
27. Fong TL, Di Bisceglie AM, Gerber MA, et al. Persistence of hepatitis B virus DNA in the
liver after loss of HBsAg in chronic hepatitis B. Hepatology 1993; 18:1313.
28. Fattovich G, Giustina G, Realdi G, et al. Long-term outcome of hepatitis B e antigen-
positive patients with compensated cirrhosis treated with interferon alfa. European
Concerted Action on Viral Hepatitis (EUROHEP). Hepatology 1997; 26:1338.
29. Lin SM, Sheen IS, Chien RN, et al. Long-term beneficial effect of interferon therapy in
patients with chronic hepatitis B virus infection. Hepatology 1999; 29:971.
30. Janssen HL, Gerken G, Carreño V, et al. Interferon alfa for chronic hepatitis B infection:
increased efficacy of prolonged treatment. The European Concerted Action on Viral
Hepatitis (EUROHEP). Hepatology 1999; 30:238.
31. Lampertico P, Del Ninno E, Viganò M, et al. Long-term suppression of hepatitis B e
antigen-negative chronic hepatitis B by 24-month interferon therapy. Hepatology 2003;
37:756.
32. Lin SM, Yu ML, Lee CM, et al. Interferon therapy in HBeAg positive chronic hepatitis
reduces progression to cirrhosis and hepatocellular carcinoma. J Hepatol 2007; 46:45.
33. Sung JJ, Tsoi KK, Wong VW, et al. Meta-analysis: Treatment of hepatitis B infection
reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther 2008; 28:1067.
34. Yang YF, Zhao W, Zhong YD, et al. Interferon therapy in chronic hepatitis B reduces
progression to cirrhosis and hepatocellular carcinoma: a meta-analysis. J Viral Hepat
2009; 16:265.
35. Lok AS, McMahon BJ, Brown RS Jr, et al. Antiviral therapy for chronic hepatitis B viral
infection in adults: A systematic review and meta-analysis. Hepatology 2016; 63:284.
36. Ikeda K, Saitoh S, Suzuki Y, et al. Interferon decreases hepatocellular carcinogenesis in
patients with cirrhosis caused by the hepatitis B virus: a pilot study. Cancer 1998; 82:827.
37. Marcellin P, Xie Q, Woon Paik S, et al. Final analysis of the international observational S-
Collate study of peginterferon alfa-2a in patients with chronic hepatitis B. PLoS One
2020; 15:e0230893.
38. Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in
combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.
Lancet 2005; 365:123.
39. Sonneveld MJ, Rijckborst V, Boucher CA, et al. Prediction of sustained response to
peginterferon alfa-2b for hepatitis B e antigen-positive chronic hepatitis B using on-
treatment hepatitis B surface antigen decline. Hepatology 2010; 52:1251.
40. Flink HJ, van Zonneveld M, Hansen BE, et al. Treatment with Peg-interferon alpha-2b for
HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype. Am J
Gastroenterol 2006; 101:297.
41. Buster EH, Hansen BE, Lau GK, et al. Factors that predict response of patients with
hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa. Gastroenterology
2009; 137:2002.
42. Lampertico P, Liaw YF. New perspectives in the therapy of chronic hepatitis B. Gut 2012;
61 Suppl 1:i18.
43. Sonneveld MJ, Wong VW, Woltman AM, et al. Polymorphisms near IL28B and serologic
response to peginterferon in HBeAg-positive patients with chronic hepatitis B.
44. Tseng TC, Yu ML, Liu CJ, et al. Effect of host and viral factors on hepatitis B e antigen-
positive chronic hepatitis B patients receiving pegylated interferon-α-2a therapy. Antivir
Ther 2011; 16:629.
45. Wu X, Xin Z, Zhu X, et al. Evaluation of susceptibility locus for response to interferon-α
based therapy in chronic hepatitis B patients in Chinese. Antiviral Res 2012; 93:297.
46. Boglione L, Cariti G, Di Perri G, D'Avolio A. Sequential therapy with entecavir and
pegylated interferon in a cohort of young patients affected by chronic hepatitis B. J Med
Virol 2016; 88:1953.
47. He Y, Yin J, Xu H. Efficacy and Safety of Pegylated Interferon for the Treatment of Chronic
Hepatitis B in Children and Adolescents: A Systematic Review and Meta-analysis. Pediatr
Infect Dis J 2020; 39:1121.
48. Choi HSJ, van Campenhout MJH, van Vuuren AJ, et al. Ultra-Long-term Follow-up of
Interferon Alfa Treatment for HBeAg-Positive Chronic Hepatitis B Virus Infection. Clin
Gastroenterol Hepatol 2021; 19:1933.
49. Lampertico P, Viganò M, Cheroni C, et al. IL28B polymorphisms predict interferon-

related hepatitis B surface antigen seroclearance in genotype D hepatitis B e antigen-
negative patients with chronic hepatitis B. Hepatology 2013; 57:890.
50. Lok AS. Antiviral therapy of the Asian patient with chronic hepatitis B. Semin Liver Dis
1993; 13:360.
51. Lok AS, Lai CL, Wu PC, Leung EK. Long-term follow-up in a randomised controlled trial of
recombinant alpha 2-interferon in Chinese patients with chronic hepatitis B infection.
Lancet 1988; 2:298.
52. Lok AS, Wu PC, Lai CL, et al. A controlled trial of interferon with or without prednisone
priming for chronic hepatitis B. Gastroenterology 1992; 102:2091.
53. Lai CL, Lok AS, Lin HJ, et al. Placebo-controlled trial of recombinant alpha 2-interferon in
Chinese HBsAg-carrier children. Lancet 1987; 2:877.
54. Hoofnagle JH, Di Bisceglie AM, Waggoner JG, Park Y. Interferon alfa for patients with
clinically apparent cirrhosis due to chronic hepatitis B. Gastroenterology 1993; 104:1116.
55. Perrillo R, Tamburro C, Regenstein F, et al. Low-dose, titratable interferon alfa in
decompensated liver disease caused by chronic infection with hepatitis B virus.
56. Trotter JF, Zygmunt AJ. Conception and pregnancy during interferon-alpha therapy for
chronic hepatitis C. J Clin Gastroenterol 2001; 32:76.
57. Xie Q, Zhou H, Bai X, et al. A randomized, open-label clinical study of combined
pegylated interferon Alfa-2a (40KD) and entecavir treatment for hepatitis B "e" antigen-
positive chronic hepatitis B. Clin Infect Dis 2014; 59:1714.
58. Brouwer WP, Xie Q, Sonneveld MJ, et al. Adding pegylated interferon to entecavir for
hepatitis B e antigen-positive chronic hepatitis B: A multicenter randomized trial (ARES
study). Hepatology 2015; 61:1512.
59. Ning Q, Han M, Sun Y, et al. Switching from entecavir to PegIFN alfa-2a in patients with
HBeAg-positive chronic hepatitis B: a randomised open-label trial (OSST trial). J Hepatol
2014; 61:777.
60. Han M, Jiang J, Hou J, et al. Sustained immune control in HBeAg-positive patients who
switched from entecavir therapy to pegylated interferon-α2a: 1 year follow-up of the
OSST study. Antivir Ther 2016; 21:337.
61. Marcellin P, Ahn SH, Ma X, et al. Combination of Tenofovir Disoproxil Fumarate and
Peginterferon α-2a Increases Loss of Hepatitis B Surface Antigen in Patients With
Chronic Hepatitis B. Gastroenterology 2016; 150:134.
62. Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000--summary of a
workshop. Gastroenterology 2001; 120:1828.
63. Liaw YF, Jia JD, Chan HL, et al. Shorter durations and lower doses of peginterferon alfa-2a
are associated with inferior hepatitis B e antigen seroconversion rates in hepatitis B
virus genotypes B or C. Hepatology 2011; 54:1591.
64. Moucari R, Mackiewicz V, Lada O, et al. Early serum HBsAg drop: a strong predictor of
sustained virological response to pegylated interferon alfa-2a in HBeAg-negative
patients. Hepatology 2009; 49:1151.
65. Piratvisuth T, Marcellin P. Further analysis is required to identify an early stopping rule
for peginterferon therapy that is valid for all hepatitis B e antigen-positive patients.
Hepatology 2011; 53:1054.
66. Piratvisuth T, Marcellin P, Popescu M, et al. Hepatitis B surface antigen: association with
sustained response to peginterferon alfa-2a in hepatitis B e antigen-positive patients.
Hepatol Int 2013; 7:429.
67. Sonneveld MJ, Hansen BE, Piratvisuth T, et al. Response-guided peginterferon therapy in
hepatitis B e antigen-positive chronic hepatitis B using serum hepatitis B surface
antigen levels. Hepatology 2013; 58:872.
68. Marcellin P, Bonino F, Yurdaydin C, et al. Hepatitis B surface antigen levels: association
with 5-year response to peginterferon alfa-2a in hepatitis B e-antigen-negative patients.
Hepatol Int 2013; 7:88.
69. Rijckborst V, Hansen BE, Ferenci P, et al. Validation of a stopping rule at week 12 using
HBsAg and HBV DNA for HBeAg-negative patients treated with peginterferon alfa-2a. J
Hepatol 2012; 56:1006.
70. Peng CY, Lai HC, Li YF, et al. Early serum HBsAg level as a strong predictor of sustained
response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Aliment
Pharmacol Ther 2012; 35:458.
71. Brunetto MR, Moriconi F, Bonino F, et al. Hepatitis B virus surface antigen levels: a guide
to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B.
72. Rijckborst V, Hansen BE, Cakaloglu Y, et al. Early on-treatment prediction of response to
peginterferon alfa-2a for HBeAg-negative chronic hepatitis B using HBsAg and HBV DNA
levels. Hepatology 2010; 52:454.
73. Fried MW, Piratvisuth T, Lau GK, et al. HBeAg and hepatitis B virus DNA as outcome
predictors during therapy with peginterferon alfa-2a for HBeAg-positive chronic
hepatitis B. Hepatology 2008; 47:428.
74. Fattovich G, Giustina G, Favarato S, Ruol A. A survey of adverse events in 11,241 patients
with chronic viral hepatitis treated with alfa interferon. J Hepatol 1996; 24:38.
75. Marcellin P, Lau GK, Zeuzem S, et al. Comparing the safety, tolerability and quality of life
in patients with chronic hepatitis B vs chronic hepatitis C treated with peginterferon
alpha-2a. Liver Int 2008; 28:477.
76. Nair S, Perrillo RP. Serum alanine aminotransferase flares during interferon treatment of
chronic hepatitis B: is sustained clearance of HBV DNA dependent on levels of
pretreatment viremia? Hepatology 2001; 34:1021.
77. Flink HJ, Sprengers D, Hansen BE, et al. Flares in chronic hepatitis B patients induced by
the host or the virus? Relation to treatment response during Peg-interferon {alpha}-2b
therapy. Gut 2005; 54:1604.
78. Wong DK, Cheung AM, O'Rourke K, et al. Effect of alpha-interferon treatment in patients
with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann Intern Med
1993; 119:312.
79. Fattovich G, Farci P, Rugge M, et al. A randomized controlled trial of lymphoblastoid
interferon-alpha in patients with chronic hepatitis B lacking HBeAg. Hepatology 1992;
15:584.
80. Brunetto MR, Giarin M, Saracco G, et al. Hepatitis B virus unable to secrete e antigen and
response to interferon in chronic hepatitis B. Gastroenterology 1993; 105:845.
81. Lampertico P, Del Ninno E, Manzin A, et al. A randomized, controlled trial of a 24-month
course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus
DNA without hepatitis B e antigen in serum. Hepatology 1997; 26:1621.
82. Cooksley WG, Piratvisuth T, Lee SD, et al. Peginterferon alpha-2a (40 kDa): an advance in
the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat 2003;
10:298.
83. Leemans WF, Flink HJ, Janssen HL, et al. The effect of pegylated interferon-alpha on the
treatment of lamivudine resistant chronic HBeAg positive hepatitis B virus infection. J
Hepatol 2006; 44:507.
84. Sun J, Hou JL, Xie Q, et al. Randomised clinical trial: efficacy of peginterferon alfa-2a in
HBeAg positive chronic hepatitis B patients with lamivudine resistance. Aliment
Pharmacol Ther 2011; 34:424.
85. Liu J, Wang T, Zhang W, et al. Effect of combination treatment based on interferon and
nucleos(t)ide analogues on functional cure of chronic hepatitis B: a systematic review
and meta-analysis. Hepatol Int 2020; 14:958.
86. Chi H, Hansen BE, Guo S, et al. Pegylated Interferon Alfa-2b Add-on Treatment in
Hepatitis B Virus Envelope Antigen-Positive Chronic Hepatitis B Patients Treated with
Nucleos(t)ide Analogue: A Randomized, Controlled Trial (PEGON). J Infect Dis 2017;
215:1085.
87. Ahn SH, Marcellin P, Ma X, et al. Hepatitis B Surface Antigen Loss with Tenofovir
Disoproxil Fumarate Plus Peginterferon Alfa-2a: Week 120 Analysis. Dig Dis Sci 2018;
63:3487.
88. Wursthorn K, Lutgehetmann M, Dandri M, et al. Peginterferon alpha-2b plus adefovir
induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B.
89. Lutgehetmann M, Volzt T, Quaas A, et al. Sequential combination therapy leads to

biochemical and histological improvement despite low ongoing intrahepatic hepatitis B
virus replication. Antivir Ther 2008; 13:57.
90. Marcellin P, Wursthorn K, Wedemeyer H, et al. Telbivudine plus pegylated interferon
alfa-2a in a randomized study in chronic hepatitis B is associated with an unexpected
high rate of peripheral neuropathy. J Hepatol 2015; 62:41.
Topic 3661 Version 29.0
GRAPHICS
Recommendations for initial treatment of chronic hepatitis B in nonpregnan

adults
HBV DNA
HBeAg ALT Treatment strategy
(PCR)
Patients without cirrhosis*
+ >20,000 ≤2 x ULN ¶ Treatment is not recommended, because current

international treatment has low efficacy in inducing HBeAg
units/mL seroconversion. Treatment may be considered in
older patients (>40 years) and in those with family
history of HCC.
Patients should be monitored Δ and treatment

considered if ALT becomes elevated >2 x ULN, liver
biopsy shows moderate/severe inflammation or
fibrosis ◊ (eg, METAVIR score ≥F2), and/or
noninvasive testing suggests moderate/severe
fibrosis.
+ >20,000 >2 x ULN ¶ Observe for 3 to 6 months if compensated and treat

international if no spontaneous HBeAg loss.
units/mL
Immediate treatment if severe hepatitis flare (eg,
icteric or clinical decompensation).
ETV, TAF, TDF, or PegIFN alfa are preferred for initial

therapy. § ¥
End-point of treatment – Seroconversion from

HBeAg to anti-HBe. ‡
Duration of therapy:
PegIFN alfa: 48 weeks.
ETV, TAF, or TDF: Continue for at least 12

months after HBeAg seroconversion.
– >2000 >2 x ULN ¶ ETV, TAF, TDF, or PegIFN alfa are preferred for initial
international therapy. § ¥
OR
units/mL
1 to 2 x ULN ¶ if
liver biopsy shows End-point of treatment – HBsAg loss.
moderate/severe
necroinflammation
Duration of therapy:
or significant
fibrosis ◊ (eg,
METAVIR score PegIFN alfa: One year.
≥F2) or non-
invasive testing ETV, TAF, or TDF: Several years or indefinite. †

shows significant
fibrosis
– ≤2000 ≤ULN ¶ Monitor and treat if HBV DNA and ALT increase as
international described above.
units/mL
Patients with cirrhosis*
+/– Detectable Any ALT Compensated:
HBV DNA >2000 international units/mL – Treat

with ETV, TAF, or TDF. § ¥ Treatment should be
continued indefinitely.**
HBV DNA <2000 international units/mL –

Consider treatment particularly if ALT elevated
close monitoring if treatment is not initiated.
Decompensated:
Treat immediately, regardless of ALT or HBV

DNA levels. ETV preferred. § ¥ TDF may be used
with close monitoring of renal function. Refer
for liver transplant.
+/– Undetectable Any ALT Compensated: Observe, recheck HBV DNA during
follow-up, evaluate for other causes of cirrhosis if
HBV DNA remains undetectable.
Decompensated: Refer for liver transplant, recheck

HBV DNA during follow-up, evaluate for other causes
of cirrhosis.
ALT: alanine aminotransferase; anti-HBe: antibody to hepatitis B e antigen; ETV: entecavir; HBeAg:
Hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCC: hepatocellular
carcinoma; PegIFN alfa: pegylated interferon alfa; TAF: tenofovir alafenamide; TDF: tenofovir
disoproxil fumarate; ULN: upper limit of normal.
* Based upon findings on noninvasive testing or liver biopsy performed during the initial evaluation.
Patients with advanced fibrosis determined by noninvasive methods should be evaluated using a
second method, and if results are concordant, consider managing the same way as patients with
cirrhosis.
¶ The American Association for the Study of Liver Diseases (AASLD) recommends using an ALT >35 U/L
for men and >25 U/L for women as the upper limit of normal (ULN) rather than local laboratory
values.
Δ Refer to UpToDate topic on "Hepatitis B virus: Overview of management" for a discussion of

monitoring.
◊ Refer to UpToDate topic on "Hepatitis B virus: Overview of management" for a discussion of

indications for biopsy.
§ Adefovir, lamivudine, and telbivudine are not recommended due to a high rate of resistance after
the first year and/or weak antiviral activity.
¥ Refer to UpToDate topic on "Hepatitis B virus: Overview of management" for a discussion of which
agent to use.
‡ Up to 50% of patients who achieve HBeAg seroconversion can experience a virologic relapse after
discontinuing treatment with oral agents. Thus, some providers prefer to treat until HBsAg-loss.
† For most patients, antiviral therapy should be continued indefinitely. However, treatment
discontinuation may be considered in persons without cirrhosis who have demonstrated loss of
HBsAg and in selected patients who have had undetectable serum HBV DNA for >3 years and agree to
close monitoring after stopping treatment. Persons who stop antiviral therapy should be monitored
every month for the first six months. Refer to the UpToDate topic on management of hepatitis B virus
infection for a detailed discussion of the risks and benefits of stopping antiviral therapy in this setting.
** This includes HBeAg-positive adults with cirrhosis who seroconvert to anti-HBe on therapy.
References:
1. Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD
2018 hepatitis B guidance. Hepatology 2018; 67:1560.
Graphic 58520 Version 22.0
Monitoring of patients receiving interferon therapy for the treatment of HBV
Assessment point Laboratory tests
Baseline CBC with differential

Hepatic panel*
HBV DNA
HBeAg and anti-HBe ¶
HBsAg
Quantitative HBsAg Δ
INR
TSH
Creatinine
Triglycerides
Glucose
Pregnancy test ◊
Week 4 CBC with differential

Hepatic panel*

Hepatic panel*
HBV DNA
Quantitative HBsAg Δ
TSH
Pregnancy test ◊

Hepatic panel*
HBV DNA
TSH
Pregnancy test ◊

Hepatic panel*
HBV DNA
HBsAg §
TSH
Pregnancy test ◊
Week 12 post- CBC with differential

treatment Hepatic panel*
HBV DNA
TSH

HBV DNA
HBsAg §

HBV DNA
HBsAg §

HBV DNA
HBsAg §
ALT: alanine aminotransferase; AST: aspartate aminotransferase; anti-HBe: hepatitis B e antibody;

CBC: complete blood count; HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBV:
hepatitis B virus; INR: international normalized ratio; TSH: thyroid stimulating hormone.
* Hepatic panel includes: ALT, AST, albumin, bilirubin, and alkaline phosphatase.
¶ Only for patients who are HBeAg-positive at baseline.
Δ If available to assess utility of continued therapy.
◊ Only for women of childbearing age.
§ Only for HBeAg-negative patients if HBV DNA is undetectable and for HBeAg-positive patients who
have undergone HBeAg seroconversion.
Adapted from: Konerman MA, Lok AS. Interferon treatment for hepatitis B. Clin Liver Dis 2016 (in press).
Strategy for the treatment of HBeAg positive chronic HBV infection with
interferon
* FDA approved dose and duration, a shorter duration of treatment may be sufficient.
Endpoints for assessing efficacy of IFNa in chronic HBV infection
Suppression of HBV replication
Clearance of HBV DNA from serum
Clearance of HBeAg with or without the development anti-HBe antibodies
Improvement in liver disease

Normalization in ALT level
Decrease in necroinflammatory activity on liver biopsies
Eradication of HBV (which is seldom achieved)
Clearance of HBsAg with or without the development of anti-HBs antibodies
Clearance of HBV DNA from serum (by PCR); rare in patients who remain HBsAg positive
Disappearance of HBV DNA from liver
Prevention of cirrhosis and hepatocellular carcinoma and improvement in survival

Scanty data

Pegylated Interferon For Treatment of Chronic Hepatitis B Virus Infection

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21/2/24, 20:00 Pegylated interferon for treatment of chronic hepatitis B virus infection - UpToDate

Official reprint from UpToDate®

Pegylated interferon for treatment of chronic hepatitis

Literature review current through: Jan 2024.

Interferons (IFN) have antiviral, antiproliferative, and immunomodulatory effects. Although

IFN's effect on HBV transcription appears to be partly mediated by epigenetic modifications

Virologic response — A positive response to interferon (IFN) is characterized by suppression

Disappearance of HBV DNA in serum, as determined by polymerase chain reaction (PCR)

● Genotype A; this genotype is associated with a higher rate of HBeAg seroconversion

● Viral load <2 x 108 international units/mL

● Rapid decline in HBsAg level during the first 12 to 24 weeks of treatment

An illustrative study of the predictive value of pretreatment factors included a total

● Polymorphisms of IL28B have been shown to be strong predictors of response to

● A history of suicidal tendency or active psychiatric illness.

● Severe leukopenia or thrombocytopenia.

● Concurrent severe systemic (eg, cardiopulmonary) disorders.

● HBeAg and anti-HBe – For hepatitis B e antigen (HBeAg)-positive patients, we check

If quantitative HBsAg testing is available, this should be measured at 12 weeks, since

STUDIES OF INTERFERON THERAPY

Standard interferon — The use of standard interferon-alfa is effective in improving virologic

● HBeAg-positive – Multiple studies have evaluated the efficacy of standard IFN in

Pegylated interferon with or without lamivudine — Pegylated interferon (PegIFN) has

Serious adverse events occurred in 4 percent, 6 percent, and 2 percent of patients

copies/mL [approximately 100,000 international units/mL] at least 24 weeks after

A subsequent report described outcomes of patients with follow-up for up to three

These data indicate that 25 to 30 percent of patients with HBeAg-negative chronic

monotherapy, 20 percent of those who received combination therapy, and with 8

Combination with other nucleos(t)ide analogues — Different strategies of combining

A meta-analysis of these different strategies included 33 studies of de novo combination

● PegIFN and entecavir

• In a randomized, open-label study, 218 treatment-naïve Chinese HBeAg-positive

• In another randomized, open-label study, 175 HBeAg-positive patients receiving

• In a fourth study, 77 HBeAg-positive patients with compensated liver disease who

● PegIFN and adefovir – One trial evaluated 24 patients (HBeAg-positive or HBeAg-

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Basics topic (see "Patient education: Hepatitis B (The Basics)")

SUMMARY AND RECOMMENDATIONS

● IFN is contraindicated in patients with decompensated cirrhosis, a history of suicidal

● PegIFN-alfa 2a should be administered subcutaneously at a dose of 180 mcg once

Use of UpToDate is subject to the Terms of Use.

1. Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of

8. Dandri M, Petersen J. Mechanism of Hepatitis B Virus Persistence in Hepatocytes and Its

hepatitis B virus cccDNA. Science 2014; 343:1221.

12. Niederau C, Heintges T, Lange S, et al. Long-term follow-up of HBeAg-positive patients

49. Lampertico P, Viganò M, Cheroni C, et al. IL28B polymorphisms predict interferon-

patients. Hepatology 2009; 49:1151.

89. Lutgehetmann M, Volzt T, Quaas A, et al. Sequential combination therapy leads to

Recommendations for initial treatment of chronic hepatitis B in nonpregnan

Patients without cirrhosis*

+ >20,000 ≤2 x ULN ¶ Treatment is not recommended, because current

Patients should be monitored Δ and treatment

+ >20,000 >2 x ULN ¶ Observe for 3 to 6 months if compensated and treat

ETV, TAF, TDF, or PegIFN alfa are preferred for initial

End-point of treatment – Seroconversion from

PegIFN alfa: 48 weeks.

ETV, TAF, or TDF: Continue for at least 12

invasive testing ETV, TAF, or TDF: Several years or indefinite. †

Patients with cirrhosis*

+/– Detectable Any ALT Compensated:

HBV DNA >2000 international units/mL – Treat

HBV DNA <2000 international units/mL –

Treat immediately, regardless of ALT or HBV