1780 CLINICAL AND SYSTEMATIC REVIEWS

CME

Isolated anti-HBc: The Relevance of Hepatitis B Core

REVIEW

Antibody—A Review of New Issues

Tiffany Wu, MD1, Ryan M. Kwok, MD2 and Tram T. Tran, MD3

Hepatitis B core antibody (anti-HBc) is considered the most sensitive serological marker for history of hepatitis B virus
(HBV) infection. In a subset of anti-HBc carriers, anti-HBc is present in the absence of hepatitis B surface antigen
and hepatitis B surface antibody—a serological pattern known as “isolated anti-HBc” (IAHBc). IAHBc has been of
clinical interest over the past several years, with growing data to suggest its role as a serological marker for occult HBV
infection (OBI). This article reviews the clinical significance and association of IAHBc with hepatitis C virus (HCV)
co-infection, risk of HBV reactivation during direct-acting antiviral therapy for HCV as well as immune suppression,
and development of hepatocellular carcinoma (HCC). Hepatitis B core-related antigen is also highlighted as an
emerging laboratory assay that may identify OBI and predict HCC development in non-cirrhotic patients receiving
nucleoside/nucleotide analog therapy.
Am J Gastroenterol 2017; 112:1780–1788; doi:10.1038/ajg.2017.397; published online 31 October 2017

INTRODUCTION Occult HBV infection

Hepatitis B core antibody (anti-HBc) is recognized as an
important serological marker in identifying patients infected
or exposed to hepatitis B virus (HBV). Increasing interest has
focused on patients positive for anti-HBc and negative for both
hepatitis B surface antigen (HBsAg) and antibody (anti-HBs)—
a serological pattern called “isolated anti-HBc” (IAHBc) (1).
Traditionally, this pattern is considered to be evidence of prior
infection; however, recent findings suggest a greater clinical sig-
nificance. Herein, we elaborate on several clinical implications of
potential future tests and strategies for management of patients
with IAHBc.
The persistence and detection of serum or liver HBV DNA in
the absence of serum HBsAg is defined as occult HBV infec-
tion (OBI) (2). Most studies identifying OBI among cohorts of
chronically infected HBV patients have been positive for anti-
HBc with or without concomitant anti-HBs positivity. Status
of occult infection has primarily been associated with the sup-
pression of viral replication and gene expression; however, it
has also been seen in patients with mutant forms of HBV with
undetectable HBsAg. OBI is recognized among patients with
prior HBV exposure and is significant in various clinical con-
texts including viral transmission, reactivation, and progression
of liver disease (3).

DEFINITIONS/TERMS
Isolated anti-HBc
The presence of anti-HBc in the absence of HBsAg and anti-HBs
is known as IAHBc, also defined in some studies as “anti-HBc
alone.” Current literature has used the “isolated anti-HBc” nomen-
clature to refer specifically to HBsAg-negative, anti-HBc-positive
patients, often stratifying this population into anti-HBs-positive
and -negative subgroups. In this review, we report only findings
relevant to the IAHBc serological profile as defined by absence of
both HBsAg and anti-HBs.
HEPATITIS B CORE ANTIGEN AND ANTIBODY:
CLINICAL IMPLICATIONS
Hepatitis B core antigen (HBcAg), a viral nucleocapsid protein, is
the most immunogenic component of HBV. Typically contained
within the viral envelope, HBcAg in liver tissue is poorly acces-
sible to host B cells until infected hepatocytes are damaged and
lyse, stimulating B-cell antibody production (4). High T-cell
immunogenicity of HBcAg also enhances humoral response
(1). During acute infection, IgM class antibodies to HBcAg pre-

1
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA; 2Division of Gastroenterology and Hepatology, Walter Reed National Military
Medical Center, Bethesda, Maryland, USA; 3Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA. Correspondence:
Tram T. Tran, MD, Cedars-Sinai Medical Center, 8900 Beverly Boulevard, Los Angeles, California 90048, USA. E-mail: Tram.Tran@cshs.org
Received 25 May 2017; accepted 19 September 2017

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 The Relevance of Hepatitis B Core Antibody 1781

dominate. Over time, IgM levels decline although total IgG levels of normal, factors other than anti-HBV T-cell response may
persist with slowly decreasing titers for 10–20 years or more (4). contribute to elevations in ALT (4).
If reactivated, IgM re-emerges confirming a chronic hepatitis B

(CHB) exacerbation (5). Antibody to HBcAg is only produced in
the presence of viral infection and is not a serological response to
HBV vaccination. As such, anti-HBc is considered the most sensi-
tive marker for a history of HBV infection, given its persistence
even after viral clearance (4). Assays for serum levels of HBcAg
are not currently available in the United States and circulating
HBcAg is not routinely detected in any phase of HBV infection.
In contrast, anti-HBc is readily obtainable and may be quanti-
fied through various types of immunoassays. Currently available
assays use human or mouse-monoclonal core antibodies, detec-
tion systems involving enzymes, fluorescence, or chemilumines-
cence, as well as variable reaction kinetics differing in incubation
steps, temperature, and time (1).
Hepatitis B envelope antigen (HBeAg) and hepatitis B envelope
antibody, HBV DNA, and serum alanine aminotransferase (ALT)
help to classify patients into phases correlating with the natural
history of CHB and associated changes on liver histology (5,6).
Previous studies have quantified the values of anti-HBc among
the four phases of CHB infection. Anti-HBc levels are highest in
the immune active and immune reactivation phases and lowest
in immune tolerant and inactive phases. Elevation of anti-HBc
during immune active and reactive phases suggests a role for this
antibody in the immune response to chronic HBV infection (5).
In addition, anti-HBc levels correlate with serum ALT levels and
individuals with higher ALT tend to have higher anti-HBc levels.
However, this correlation only applies to values of ALT less than
five times the upper limit of normal. In ALT >5 times upper limit
REVIEW
ISOLATED ANTI-HBC
IAHBc may represent several clinical entities including a false
positive test result, the window phase of acute HBV when anti-
HBs is not yet detected, the late stage of prior infection after anti-
HBs has fallen to undetectable levels, or OBI (1,2).
See Figure 1 for a proposed algorithm to evaluate a patient with
IAHBc.
Depending on the type of assay used as well as the prevalence
of infection, false positives may occur in patients with a finding
of IAHBc. Although modifications have been made to improve
test specificity, confirming anti-HBc status may be appropriate in
certain clinical scenarios (1). Alternatively, it is important to con-
sider the window phase of acute infection as anti-HBs and hepa-
titis B envelope antibody immune complexes and their antigen
counterparts may not be detectable by conventional assays. Repeat
anti-HBc testing several months later may be indicated wherein
HBsAg, anti-HBs, HBeAg, and hepatitis B envelope antibody
would be detectable. Patients who have undergone viral clearance
may also lose the ability to produce anti-HBs after long periods
of time. Reasons for this chronic decline are unclear, although it
has been previously hypothesized to result from a waning T-cell
response (1).
If IAHBc is confirmed, consideration of subsequent testing
should be pursued to evaluate for OBI. Kang et al, described rates
of occult infection ranging from 0% to 22.5% though source of
HBV DNA sampling may contribute to differences among studies

Isolated anti-HBc

Repeat with different immunoassay

for confirmatory testing

Negative

Positive

Likely false
positive result

Check anti-HBs in 1–3 months

Anti-HBs positive Anti-HBs negative

Likely window phase of Evaluate for occult HBV

acute HBV infection infection with assay for
HBV DNA PCR

Figure 1. Methodology to evaluate a patient initially found with isolated hepatitis B core antibody (anti-HBc). Adapted from “The underlying mechanisms
for the ‘anti-HBc alone’ serological profile,” by RA Ponde, DD Cardoso, and MO Ferro, 2010, Archives of Virology, 155, p. 154.

© 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

1782 Wu et al.

(2). Table 1 provides an updated range of 1.7% to 41%, report- phase and 11 patients were found to be false positive. Of the 351
ing on subjects who are HBsAg negative, anti-HBc positive, and IAHBc patients, 10 were positive for HBV DNA, whereas the other
HBV DNA positive among a sample of studies from 2001 to 2015. 341 did not have detectable HBV DNA in serum. Of these 10 HBV
REVIEW

Methods of HBV DNA quantification may vary given differences
in measurement of DNA in serum vs. liver tissue. Variation may
also result from differences in sample size or virological features of
studied patient populations including co-morbidities, prevalence
or endemicity of populations, and assay sensitivity (7).
A study by Launay et al. (8) retrospectively categorized 362
patients with IAHBc sera into the clinical entities described in the
algorithm. Only one patient was found to be within the window
DNA-positive subjects, 6 had high levels of viremia. This particular
study cited a prevalence of 2.8% of occult HBV among patients
with IAHBc. The authors hypothesized this may have been an
underestimate since only one data point was gathered, potentially
excluding patients with intermittent viremia. In addition, screen-
ing assays may not have been sensitive enough to detect very
low levels of viremia. Notably, HBsAg was detected in two of
these patients when retested using a different, multivalent assay.

Table 1. Summary of studies of IAHBc (HBsAg negative and anti-HBc positive) HBV DNA-positive patients (2,47–61)

Study (year of publication) HBV DNA positive (%) HBV DNA detection ALT, if available High-risk Clinically relevant
(serum or liver) limit (copies per ml) comorbidities outcomes

Jilg et al. (47) Germany 5/65 (7.7) Serum 100 to 10,000 Nested Not reported Yes (HCV)
PCR
Kleinman et al. (48) USA 4/107 (3.7) Serum 10–100 Enzymatic Not reported NA
detection of amplified
DNA
Alhababi et al. (49) UK 6/151 (4) Serum 100–400 Nested PCR Not reported No HBV DNA+ pts were not
identified among co-infected
HIV+ or HCV+ patients within
the study population
García-Montalvo et al. (50) 13/158 (8.2) Serum 30–300 Nested PCR Not reported NA
Mexico
Knoll et al. (51) Germany 16/39 (41) Liver 50–100 Quantitative Normal to 2× ULN Yes (HCV) HBV DNA+ less often
PCR by Taqman detected in IAHBc patients
with cirrhosis or HCC
Banerjee et al. (52) India 39/171 (22.8) Serum 100–1000 Quantitative Not reported NA
PCR by Taqman
El-Zaatari et al. (53) Lebanon 11/203 (5.4) Serum <400 Nested PCR Not reported No
Vitale et al. (54) Italy 5/119 (4.2) Serum 100 Nested PCR Not reported No
Gibney et al. (55) Australia 1/35 (3) Serum 100 Nested PCR Not reported No Lower rate than expected of
HBV DNA positivity among a
highly endemic population
Kang et al. (2) Korea 4/230 (1.7) Serum <60 to 110 Quantitative 18–33 No
PCR by Taqman
Ramezani et al. (7,56) Iran 12/40 (30) Serum Not reported Not reported Yes (HD, HIV+) HBV DNA+ more prevalent in
high-risk patients (HIV+ and
hemodialysis)
Tramuto et al. (57) Italy 3/58 (5.2) Serum Not reported 22 Yes (HIV) HIV+identified as a risk factor
for HBV DNA+
Rios-Ocampo et al. (58) 6/302 (1.9) Serum 18–224 IU ml−1 Nested Not reported No
Columbia PCR
Jutavijittum et al. (59) Laos 12/75 (16) Serum 1110 Quantitative PCR Not reported No
by Taqman
Antar, et al. (60) Egypt 5/80 (6.2) Serum 3–11481 IU ml−1 Not reported No
Enzymatic detection of
amplified DNA
Kishk et al. (61) Egypt 5/27 (18.5) Serum <2.0–4.5 log Enzymatic 9–22 No
detection of amplified
DNA
ALT, alanine aminotransferase; Anti-HBc, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepato-
cellular carcinoma; HIV, human immunodeficiency virus; IAHBc, isolated hepatitis B core antibody; NA, not available; ULN, upper limit of normal.

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This suggests a mutant form of HBsAg initially undetected on
conventional screening. This may represent “false occult HBV,” for
which IAHBc may be a significant risk factor (8).
ISOLATED CORE ANTIBODY-POSITIVE HEPATITIS B
AND HEPATITIS C CO-INFECTION
Patients with IAHBc are more frequently co-infected with hepa-
titis C virus (HCV) when compared with patients with positive
anti-HBs (9). Moreover, anti-HBc positive patients have been
associated with more active hepatitis C. A study by Wedemeyer
et al. (10) found that IAHBc occurred more frequently when com-
paring HCV RNA-positive and negative patients (22% vs. 13%,
P<0.0001). The authors suggested mechanisms of increased HCV
replication in patients with IAHBc, including the cross-reactivity
of immune response. For instance, the presence of anti-HBs and
partial resolution of HBV may have implied a stronger immune
response to both viruses, allowing for HCV suppression. Subse-
quent loss of anti-HBs may then allow for increased viremia and
activity of HCV.
An alternative explanation for HCV co-infection and IAHBc
suggests that chronic HCV dominates immune response over
HBV. HCV core protein may directly suppress transcription of
HBV RNA (11). HCV proteins may also limit HBsAg expres-
sion, resulting in lower level of viremia, as well as enhance clear-
ance of HBsAg (12). Sheen et al. (13) observed a rate of HBsAg
clearance 2.5 times faster in co-infected patients vs. patients with
HBV mono-infection. Thus, the serological pattern of IAHBc may
actually result from increased HCV viremia.
IAHBc may represent potential for OBI among patients
with chronic HCV, who are already at high-risk for related liver
injury (2). In one cohort study, up to 22.5% of IAHBc patients with
Table 2. Summary of HBV reactivation risk in IAHBc (HBsAg negative and anti-HBc positive) individuals receiving therapies specific to
gastrointestinal and hepatic diseases
Therapy GI/liver indication
DAA therapy HCV treatment
Traditional immunosuppressive agents (azathioprine, Inflammatory bowel disease
6-mercaptopurine, methotrexate)
TNF-α inhibitors (etanercept, adalimumab, infliximab) Inflammatory bowel disease
Anthracycline derivatives (doxorubicin) Hepatocellular carcinoma
B-cell-depleting agents (rituximab) Extrahepatic manifestations of Hepatitis C
virus infection
Autoimmune hepatitis
Anti-HBc, hepatitis B core antibody; DAA, direct-acting antiviral; GI, gastrointestinal; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus;
IAHBc, isolated hepatitis B core antibody; TNF-α , tumor necrosis factor-α .
a
Tang et al. (19).
b
Loggi et al. (20).
c
Yeh et al. (21).
d
Reddy et al. (22).
e
Prophylaxis to continue at least 6 months after discontinuation of therapy. Patients may reasonably opt out of prophylaxis if they value avoiding long-term antiviral use
and cost over the risk of reactivation.
f
Prophylaxis to continue at least 12 months after discontinuation of therapy.
© 2017 by the American College of Gastroenterology
The Relevance of Hepatitis B Core Antibody 1783
chronic HCV had detectable HBV DNA in serum (14). It is pro-
posed that simultaneous HCV infection downregulates synthesis
of HBsAg and induces mutations, making it undetectable by con-
REVIEW
ventional assay (2,15). If this mechanism holds true, then total
anti-HBc level may be used as a surrogate biomarker for occult
HBV or liver damage in HCV co-infection.
REACTIVATION RISK OF HEPATITIS B WITH ISOLATED
CORE ANTIBODY
Although HBV reactivation has been studied extensively, charac-
teristics of reactivation among IAHBc patients is less well defined.
Table 2 provides a summary of reactivation risk in IAHBc patients
receiving therapies specific to gastrointestinal and hepatic diseases.
Further research needs to be done to define risk among IAHBc
patients in other medical and surgical interventions such as loco-
regional therapies and hepatectomy for hepatocellular carcinoma.
HCV direct-acting antiviral therapy
HCV treatment and the alteration of immune synergy in co-infec-
tion must take into consideration the risk of HBV reactivation. In
October of 2016, the US Food and Drug Administration issued
a drug safety Boxed Warning after identifying 29 cases of HBV
reactivation in hepatitis B and C co-infected patients undergoing
treatment with HCV direct-acting antiviral (DAA) therapies. Of
the 29 cases, two patients died and one required liver transplanta-
tion. Notably, HBV co-infected individuals were excluded from
clinical trials evaluating the safety of DAA medications. There-
fore, HBV reactivation had not been reported as an adverse drug
event (16).
Joint American Association for the Study of Liver Diseases and
Infectious Diseases Society of America guidelines recommend all
Reactivation risk Prophylaxis
a,b,c
Low Monitor for reactivation and treat
if clinically evident
Lowd Monitor for reactivation and treat
if clinically evident
Moderate (1–10%)d Recommendedd,e
Moderate (1–10%)d Recommendedd,e
d
High (>10%) Recommendedd,f
The American Journal of GASTROENTEROLOGY
1784 Wu et al.
patients undergoing HCV DAA therapy be evaluated for HBV
coinfection by measuring HBsAg, anti-HBs, and anti-HBc levels
(17). For patients with positive HBsAg, HBV DNA level should
REVIEW
be measured prior to starting DAA therapy. For patients meeting
treatment criteria for HBV treatment, therapy should be given
before or at the same time as treatment for HCV. Among patients
with IAHBc serology, there is currently insufficient data to pro-
vide clear recommendations for monitoring during or after DAA
therapy (17).
Since the release of recommendations by US Food and Drug
Administration and American Association for the Study of Liver
Diseases, several independent investigators have sought to identify
the overall risk of HBV reactivation in the setting of DAA therapy.
Belperio et al. (18) performed a retrospective evaluation of over
62,000 HCV-infected patients. Data were considerably limited
by availability of testing results, with HBV DNA values provided
for 0.9% of patients with ALT elevation. The study identified nine
unique patients who demonstrated HBV reactivation during DAA
treatment, most of whom had normal or less than 2 times the
upper limit of normal ALT with rare occurrence of severe hepa-
titis. Only one of the nine cases was known to have IAHBc (18).
Several retrospective studies have reported no HBV reactiva-
tion events among IAHBc patients during DAA treatment. Tang
et al. (19) found no reactivations among 68 patients from the
Baltimore Veterans Affairs Medical Center database, who had
IAHBc and chronic HCV for which DAA treatment was initiated
between December 2014 and August 2016. Two patients demon-
strated a rise in ALT above the upper limit of normal, however both
normalized without intervention (19). Loggi et al. (20) similarly
reported no reactivation events in a study of 42 IAHBc patients
undergoing DAA treatment between January 2015 and January
2016. Yeh et al. (21) also found no episodes of HBV reactivation
among 57 IAHBc patients on DAA treatment between December
2013 and August 2016.
Although these studies reveal minimal to no risk of reactivation
among IAHBc patients undergoing DAA therapy, identifying such
patients through evaluation of HBV DNA level, prior to initiation
remains essential. Providers should recognize the potential risk
and monitor for signs of HBV reactivation as currently suggested
in guidelines and initiate treatment as appropriate (17).
Immune suppressive therapy
HBV reactivation is a key consideration when initiating immuno-
suppressive medications. The 2015 American Gastroenterological
Association guidelines summarized the prevention and treatment
of HBV reactivation during immunosuppressive therapy. When
considering IAHBc patients, the use of antiviral prophylaxis is
categorized by level of risk of reactivation, with types of immu-
nosuppression categorized into low-, moderate-, and high-risk
groups depending on perceived intensity of therapy and associ-
ated risk. Low reactivation risk is defined as <1% and includes
traditional immunosuppressive agents such as azathioprine,
6-mercaptopurine, and methotrexate, as well as use of corticos-
teroids for up to one week. Moderate reactivation risk is higher
at 1–10% and includes anthracycline derivatives, tumor necrosis
The American Journal of GASTROENTEROLOGY
factor (TNF)-α inhibitors, other cytokine and integrin inhibi-
tors, tyrosine kinase inhibitors, and use of corticosteroids for
more than 4 weeks. High reactivation risk is defined as ≥10% and
includes B-cell-depleting agents (22).
Two notable classes of immune suppression agents that have
been associated with HBV reactivation in the setting of IAHBc
patients include: rituximab and anti-tumor necrosis factor inhibi-
tors.
Rituximab, the monoclonal antibody against CD20 antigen of B
cells, has well-known complications of use including HBV reacti-
vation (23). Retrospective studies describe reactivation rates rang-
ing from 8.9 to 23.8% among IAHBc patients, with reactivation
occurring up to one year after completion of therapy (24,25). How-
ever, one prospective study among patients undergoing rituximab-
containing chemotherapy for lymphoma reported up to 41.5%
cumulative 2-year reactivation rate (26). More recently, rituximab
has been used in the setting of desensitization for transplantation
and immune suppression in this context has also been associated
with HBV reactivation with a median time to reactivation at 11
months. Cases have included severe hepatitis and death due to
hepatic failure (27). Other reports of reactivation have similarly
carried poor prognoses during rituximab use (28). Ofatumumab,
another B-cell-depleting agent similar to rituximab, has limited
data on HBV reactivation; however, it is also deemed high risk
given the analogous mechanism of action (23).
Tumor necrosis factor -α inhibitors (anti-tumor necrosis fac-
tor), such as etanercept, infliximab, and adalimumab, have also
been associated with HBV reactivation. Rates of reactivation have
been much lower than that in rituximab, with retrospective stud-
ies citing as low as 1.7% in IAHBc patients (29). A recent multi-
center, observational study of patients with spondyloarthritis and
previously resolved HBV infection showed no reactivation among
IAHBc patients. After 75 months of follow-up, HBV DNA was
undetectable and HBsAg remained negative (30).
Separate from immunosuppressive drugs, hematopoietic stem
cell transplant has also been linked to HBV reactivation among
IAHBc patients. Retrospective studies describe a range of reacti-
vation rates from 6.5 to 19.7% (31–33). Yet, a prospective study
showed a much higher upper limit at 40.8% cumulative 2-year
reactivation rate, with two important determinants of reactivation
being chronic graft-vs.-host disease and age >50 years old (34).
Regarding screening before initiation of therapy, both the
American Gastroenterological Association and American Asso-
ciation for the Study of Liver Diseases agree on recommendations
to screen for HBV, specifically in patients at moderate or high risk,
before immunosuppressive therapy (35). Screening with HBsAg
and anti-HBc, however, is not recommended among patients at
low risk (22).
HCC RISK WITH ISOLATED CORE ANTIBODY
CHB is associated with a significant increased risk for develop-
ment of HCC. HBV accounts for up to 60% of total HCC
cases in developing countries and 23% of cases in developed
countries (36). Various mechanisms are described in HBV-related
VOLUME 112 | DECEMBER 2017 www.nature.com/ajg

carcinogenesis including integration of HBV DNA into host
genome, viral protein expression, chronic inflammation, and
cytokine induction of fibrosis and liver cell proliferation (36).
In addition, patients with CHB may have additional risk factors
associated with HCC development including sex, age, tobacco
and alcohol use, chemical carcinogens, hormonal factors, and
genetic susceptibility (37).
Previous studies have shown that anti-HBc is more common
than HBeAg or HBV DNA in patients with HCC (38). As previ-
ously mentioned, anti-HBc has been examined as a surrogate for
OBI. In this setting, investigators sought to identify an association
between OBI and HCC. In a prospective study of IAHBc patients
with non-HBV, non-HCV cirrhosis, carcinogenesis rates in patients
with positive HBV DNA and negative HBV DNA were 27% and
11.8%, respectively, at 5-year follow-up, and 100% and 17.6%,
respectively, at 10-year follow-up (P=0.0078, log-rank test). HBV
DNA positivity increased rate of carcinogenesis by a hazard ratio
of 8.25 (95% confidence interval 2.01–33.93, P=0.003). During the
observational period, the median time from diagnosis of cirrhosis
to HCC was 5.6 years. Despite being a single cohort study, these
findings suggested OBI to be an independent risk factor for hepa-
tocarcinogenesis (39).
Another study examined patients with non-HBV, non-HCV
HCC, in an area endemic to HBV. Over 40% of the cohort popu-
lation were IAHBc, further suggesting OBI as a potential link to
HCC development (40). These findings may suggest a benefit to
HCC screening among IAHBc patients, although further studies
are required to make this recommendation.
Anti-HBc has also been shown to be prognostically significant in
HCC recurrence after curative resection. In a study of HBV-related
HCC cases by Li et al. (36), anti-HBc positivity was found to be an
independent prognostic factor for recurrence free survival. Among
patients positive for anti-HBc, recurrence free survival rates were
lower than those without anti-HBc at 1-,3-, and 5-years (77.9%,
58.6%, and 46.9%, vs. 92.5%, 72.1%, and 65.9%, respectively,
P<0.001). However, overall survival was not significantly different
between anti-HBc-positive and -negative patients. Anti-HBc
positivity was also associated with early intrahepatic recurrence,
possibly indicating a more invasive phenotype of HCC. Neverthe-
less, among HBsAg-negative patients, anti-HBc positivity had no
prognostic significance (36). This suggests that IAHBc may not be
as telling as the role of anti-HBc in the presence of HBsAg.
HEPATITIS B CORE-RELATED ANTIGEN
Hepatitis B core-related antigen (HBcrAg) is emerging as a poten-
tially clinically useful serological marker of HBV infection. This
assay detects an amino acid sequence shared collectively by the
HBcAg, HBeAg, and a 22 kDa precore protein. As described pre-
viously, HBcAg is a structural unit of viral capsids and is trans-
lated from viral pregenomic RNA. HBeAg is a non-structural
immunomodulating secretory protein and is translated from
HBV precore mRNA. The 22 kDA precore protein, also desig-
nated as p22cr, is similarly translated from precore mRNA. The
three components share a 149-amino acid sequence, which is not
© 2017 by the American College of Gastroenterology
The Relevance of Hepatitis B Core Antibody 1785
dependent on HBV DNA formation, and is detected altogether by
antibodies to HBcrAg in the assay (41,42).
HBcrAg has been found to correlate significantly with HBV
REVIEW
covalently closed circular DNA (cccDNA), the template for
HBV RNA transcription within hepatocyte nuclei. Direct meas-
urement of cccDNA requires liver biopsy and is therefore not a
practical marker for infection. Similar correlation has been iden-
tified between HBcrAg-cccDNA and HBV DNA-cccDNA. How-
ever, HBV DNA is not a useful surrogate for cccDNA, as it often
becomes undetectable with nucleos (t)ide analog treatment (41).
Currently, assays for HBcrAg are available in Asia and Europe but
not yet commercially available in the United States or Canada.
HBcrAg has been studied for distribution patterns across the
phases of HBV infection. High levels of HBcrAg have correlated
with HBeAg-positive phases of infection, which is expected given
the shared components of the amino acid sequence. HBcrAg levels
correlate strongly with serum HBV DNA during immune clear-
ance and HBeAg-negative reactivation, suggesting its role in sign-
aling viral replication (43).
HBcrAg thereby can assist in differentiating between HBeAg-
negative active and quiescent disease. Studies have reported
patients initially classified as quiescent infection by HBV DNA,
ALT, or liver biopsy, who also expressed higher levels of HBcrAg
and demonstrated an increased chance for HBV reactivation
(43). As such, HBcrAg may serve a role as a surrogate marker for
immune activation.
HBcrAg has also been detected in up to 40% of CHB patients
who have achieved HBsAg seroclearance, or who are designated
as occult carriers of HBV (42). When identified as a potential
marker for occult HBV, various investigators have sought to assess
HBcrAg as a surrogate of disease activity as well as HCC. In a study
by Tada et al. (37) elevated levels of HBcrAg were independently
associated with HCC incidence (hazard ratio 5.05; 95% confidence
interval 2.40–10.63, P<0.001). HBcrAg was also found to be supe-
rior to other continuous HBV serological markers for predicting
HCC development among patients not receiving NA therapy (37).
In a study of HBV reactivation in IAHBc patients by Seto et al.
(44), HBcrAg-positivity was shown to be a significant risk factor for
reactivation events in patients undergoing high-risk immunosup-
pression of rituximab therapy (hazard ratio 2.94, 95% confidence
interval 1.43–6.07, P=0.004). Of note, a separate cohort of patients
in the same study, undergoing hematopoietic stem cell transplant,
did not show a significant correlation between HBcrAg-positivity
and HBV reactivation. However, in the rituximab cohort, patients
positive for HBcrAg had a significantly higher 2-year cumulative
reactivation rate than HBcrAg negative patients (71.8% vs. 31%,
P=0.002) (44). Given its clinical significance as a risk factor for
reactivation, the use of HBcrAg may be a valuable supplemental
test. Positive HBcrAg implies persistence of HBV infection, despite
loss of HBsAg. As such, HBcrAg may be used as a marker to screen
for patients with IAHBc, who are at-risk for reactivation and would
benefit from prophylaxis.
Among patients treated with nucleos (t)ide analog therapy,
Honda et al. (45) reported that HBcrAg positivity was also inde-
pendently associated with HCC development. Presence of HBcrAg
The American Journal of GASTROENTEROLOGY
1786 Wu et al.

Table 3. Statistical analysis of HBcrAg related to markers and outcomes of chronic hepatitis B infection

Marker Phase of infection Correlation coefficient (r) P-value

REVIEW

a
cccDNA Not reported 0.70 <0.0001
Serum HBV DNA levelb Overall 0.87 <0.0001
IT 0.45 0.0130
IC 0.66 <0.0001
ENH 0.74 <0.0001
ENQ 0.18 0.054
HBsAg levelb Overall 0.78 <0.0001
IT 0.47 0.0095
IC 0.53 <0.0001
ENH 0.40 0.0045
ENQ 0.47 <0.0001
Outcome Hazard ratio 95% CI P-value
HBV reactivation risk in setting of rituximab therapyc 2.94 1.43–6.07 0.004
d
HCC development 5.05 2.40–10.63 <0.001
HCC development in setting of nucleoside analog therapye 3.53 1.52–9.63 0.0025
cccDNA, covalently closed circular DNA; CI, confidence interval; ENH, HBeAg-negative hepatitis; ENQ, HBeAg-negative quiescent phase; HBcrAg, hepatitis B core-
related antigen; HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; IC, immune clearance; IT, immune tolerance.
a
Wong et al. (41).
b
Maasoumy et al. (43).
c
Seto et al. (44).
d
Tada et al. (37).
e
Honda et al. (45).

was indicative of cccDNA activation, HBV replication in the liver,
and was found to be predictive of HCC (45). In a separate study,
higher levels of HBcrAg, both pre- and post-nucleos (t)ide analog
treatment, were associated with risk of HCC development. These
patients had otherwise undetectable HBV DNA. When stratified
by cirrhosis status, cirrhotic patients had no significant difference
in HBcrAg levels among those with and without HCC. However,
for non-cirrhotic patients, median HBcrAg level was signifi-
cantly higher in patients with HCC compared with those without
(P=0.030) (46). This finding may suggest the utility of HBcrAg in
predicting HCC development in non-cirrhotic patients.
Table 3 summarizes the association between HBcrAg and vari-
ous markers and outcomes of CHB.
In clinical practice, HBcrAg has many potential roles as a rel-
evant marker for disease activity. Given its correlation to active
viral replication, high levels of HBcrAg may be used to identify
occult infection when screening patients at risk of reactivation
before immunosuppressive therapy. This serological marker may
also help to predict HCC development in the setting of nucleos (t)
ide analog therapy, especially among non-cirrhotic patients.
SUMMARY
Anti-HBc is currently considered the most sensitive serological
marker for a patient’s history of HBV infection given its long-term
persistence in the bloodstream. The serological pattern of IAHBc
has been of clinical interest over the past several years, with grow-
ing data suggesting a role as a marker for OBI. IAHBc has impor-
tant clinical implications in the setting of co-infection with HCV,
HBV reactivation risk with HCV DAA therapy and immuno-
suppression, as well as the progression of liver disease and HCC
development. HBcrAg is emerging as an important laboratory
assay that may serve as a surrogate marker for infection, identify-
ing occult cases of HBV through additional serological studies,
and, more importantly, as a potential marker for HBV clearance
for future therapies.
CONFLICT OF INTEREST
Guarantor of the article: Tiffany Wu, MD.
Specific author contributions: T. Wu conducted literature review.
T. Wu, R. Kwok, and T. Tran wrote and developed the manuscript.
Financial support: None.
Potential competing interests: None.
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