Compact genomic structure of HBV. This structure, with overlapping genes, permits HBV to code for multiple proteins. The S gene codes for the "major" envelope protein, HBsAg. Pre-S1 and pre-S2, upstream of S, combine with S to code for two larger proteins, "middle" protein, the product of pre-S2 + S, and "large" protein, the product of pre-S1 + pre-S2 + S. The largest gene, P, codes for DNA polymerase. The C gene codes for two nucleocapsid proteins, HBeAg, a soluble, secreted protein (initiation from the pre-C region of the gene) and HBcAg, the intracellular core protein (initiation after pre-C). The X gene codes for HBxAg, which can transactivate the transcription of cellular and viral genes; its clinical relevance is not known, but it may contribute to carcinogenesis by binding to p53.
A minimum follow-up of 1 year with alanineaminotransferase (ALT) levels at least every 3–4 months and serum HBV DNA levels is required before classifying a patient as inactive HBV carrier.ALT levels should remain persistently within the normal range according to traditional cut-off values(approximately 40 IU/ml)  and HBV DNA should be below 2000 IU/ml.
Family history of hcc , persistent elevations of alt in 1-2 >normal range.
If NA therapy is given only for the prevention of perinatal transmission, it may be discontinued within the first 3 months after delivery.The safety of NA therapy during lactation is uncertain. HBsAg can be detected in breast milk, but breast feeding may not be considered a contraindication in HBsAg-positive mothers. Tenofovir concentrations in breast milk have been reported, but its oral bioavailability is limited and thus infants are exposed toonly small concentrations.
Some persons may test positive for anti-HBc but not HBsAg or anti-HBs. The finding of isolated anti-HBc can occur for a variety of reasons. (1) Anti-HBc may be an indicator of chronic HBV infection; in these persons, HBsAg had decreased to undetectable levels but HBVDNA often remains detectable, more so in the liver than in serum. This situation is not uncommon among persons from areas with high prevalence of HBV infection and in those with human immunodeficiency virus (HIV) or hepatitisC virus (HCV) infection.27 (2) Anti-HBc may be a marker of immunity after recovery from a prior infection. In these persons, anti-HBs had decreased to undetectable levels but anamnestic response can be observed after one dose of HBV vaccine.28 (3) Anti-HBc may be a false positive test result particularly in persons from low prevalence areas with no risk factors for HBV infection. These individuals respond to hepatitis B vaccination similar to persons without any HBV seromarkers.10,28,29 (4) Anti-HBc may be the only marker of HBV infection during thewindow phase of acute hepatitis B; these persons should test positive for anti-HBcIgM.
Chronic HEP B
CHRONIC HEPATITIS B
PG IN GENERAL MEDICINE
Introduction and epidemiology
Natural History, Clinical features
Liver Biopsy and Noninvasive Assessment
Introduction & Epidemiology
Definition - Chronic necroinflammatory disease of the liver
caused by persistent infection with hepatitis B virus.
Approximately one third of the world’s population has
serological evidence of past or present infection with HBV
and 350–400 million people are chronic HBV surface
antigen (HBsAg) carriers.
Up to 2 million die each year from HBV infection, making it
the 9th leading cause of death worldwide.
Worldwide Prevalence of
Chronic Hepatitis B
World Health Organization
Centers for Disease Control and Prevention.
Hepatitis B is classified into 8 genotypes(A-H)
Genotype A & D are predominant in USA &
Genotype B & C are predominant in Asia.
Hepatitis B belongs to family Hepadnaviridae.
It contains circular partially single stranded &
partially double stranded DNA of 3.2 kb.
HBV has compact genomic structure
HBV infected cells produce 3 particulate forms
1.42nm, double shelled spherical particle(intact
2.27nm particle (nucleocapsid core).
3.22nm (spherical and filamentous
form),represent excess viral envelope protein.
Concentration of HBsAg & virus particles in
blood may reach 500 µg/ml & 10 trillion
Pre -core mutant ,it occurs due to single base
substitution from G to A in the second last codon of
pre C gene at nucleotide 1896. This mutation
prevents translation of HBeAg.
2. Mutation in core promoter region prevents
transcription of the coding region of HBeAg &
results in HBeAg negative phenotype.
3. Escape mutants, it occurs due to single amino acid
substitution at position 145 of immunodominant a
determinant common to all subtypes of HBsAg. It
results in loss of neutralizing activity by anti HBs.
HBV virions bind to surface receptors and are
Viral core particles migrate to the hepatocyte
nucleus, where their genomes are repaired to form a
covalently closed circular DNA (cccDNA) that is the
template for viral messenger RNA (mRNA)
The viral mRNA that results is translated in the
cytoplasm to produce the viral
surface, core, polymerase, and X proteins.
There, progeny viral capsids assemble, incorporating
genomic viral RNA (RNA packaging).
This RNA is reverse-transcribed into viral DNA. The
resulting cores can either bud into the endoplasmic
reticulum to be enveloped and exported from the cell
or recycle their genomes into the nucleus for
conversion to cccDNA.
They vary from asymtomatic infection to end
stage fatal hepatic failure.
Fatigue is most common symptom.
Persistent or intermitent jaundice is a feature of
Acute exacerbations when superimposed on
cirrhosis leads to decompensation.
Extra hepatic manifestations include
arthritis, arthralgias,iummune complex
GN, generalized vasculitis (PAN).
Aminotransferase elevations tend to be modest for
chronic hepatitis B but may fluctuate in the range of
Alanine aminotransferase (ALT) tends to be more
elevated than aspartate aminotransferase (AST);
however, once cirrhosis is established, AST tends to
Alkaline phosphatase activity tend to be normal or
only marginally elevated.
In severe cases, moderate elevations in serum
bilirubin (3–10 mg/dL)] occur.
Hyperglobulinemia and detectable circulating
autoantibodies are distinctly absent in chronic
hepatitis B (in contrast to autoimmune hepatitis).
Histologic features in chronic hepatitis are increase in
size of hepatocytes and ground glass appearance.
Abundant ground glass appearance indicates active viral
Immunofluorescence and electron microscopy shows
HBcAg inside hepaocyte nuclei of affected cell.
Serological assays for various Hepatitis B
antigens & antibodies.
2. HBV DNA by Southern hybridization, in-situ
hybridization, or PCR.
3. Detection of HBsAg or hepatitis B core antigen
(HBcAg) in liver tissues by
Liver biopsy and non invasive
monitoring of hepatic fibrosis
There are three primary reasons for performing a liver biopsy:
1) it provides helpful information on the current status of the
2)it identifies features useful in the decision to embark on
3) it may reveal advanced fibrosis or cirrhosis that
The biopsy is assessed for grade and stage of the liver
injury, but also provides information on other histological
features that might have a bearing on liver disease
The grade defines the extent of necroinflammatory
activity, while the stage establishes the extent of fibrosis or
the presence of cirrhosis
Non invasive monitoring of
aspartate aminotransferase:platelet ratio index (APRI)
commercially available assays of : α2macroglobulin,α2-globulin, γ-globulin, apolipoprotein
A-I, γ-glutamyltransferase, total bilirubin, and
the assays are typically much better at detecting
advanced fibrosis and cirrhosis than mild-to-moderate
Combining assays(e.g., APRI and FibroSURE or
HepaScore) appears to increase the diagnostic
accuracy and may eliminate the need for liver biopsy
in more than half of patients.
Goals and End Points of Hepatitis
Prevention of long-term negative clinical outcomes
(eg, cirrhosis, liver transplantation, HCC, death) by
durable suppression of HBV DNA.
Ideal end point is induceing HBsAg loss or seroconversion.
Sustained decrease in serum HBV DNA level to
Decrease or normalize serum ALT
Improve liver histology
Induce HBeAg loss or seroconversion in HBeAg-positive
DEFINITION OF ANTIVIRAL
Responses can be divided into
biochemical, serological, virological and
Biochemical response is defined as normalisation
of ALT levels.
Serological response for HBeAg applies only to
patients with HBeAg-positive CHB and is defined
as HBeAg loss and seroconversion to anti-HBe.
Serological response for HBsAg applies to all
CHB patients and is defined as HBsAg loss and
development of anti-HBs.
Virological responses on IFN/PEGIFN therapy:
Primary non-response has not been well established.
Virological response is defined as an HBV DNA
concentration of less than 2000 IU/ml. It is usually
evaluated at 6 months and at the end of therapy as
well as at 6 and12 months after the end of therapy.
Sustained off-treatment virological response is defined
as HBV DNA levels below 2000 IU/ml for at least 12
months after the end of therapy
Virological responses on NA therapy:
Primary non-response is defined as less than 1
log10 IU/ml decrease in HBV DNA level from
baseline at 3 months of therapy.
Virological response is defined as undetectable HBV
DNA by a sensitive PCR assay. It is usually
evaluated every 3– 6 months during therapy
depending on the severity of liver disease and the
type of NA.
Partial virological response is defined as a decrease
in HBV DNA of more than 1 log10 IU/ml but
detectable HBV DNA after at least 6 months of
therapy in compliant patients.
Virological breakthrough is defined as a confirmed
increase in HBV DNA level of more than 1 log10
IU/ml compared to the nadir (lowest value) HBV
Histological response is defined as decrease in
necroinflammatory activity (by ≥2 points in HAI or
Ishak’s system) without worsening in fibrosis
compared to pre-treatment histological findings.
Complete response is defined as sustained offtreatment virological response together with loss
Indications for treatment
Serum HBV DNA levels.
Serum ALT levels.
Severity of liver disease.
May also take into account are age,health
status,family history of HCC, cirrhosis & extra
What Is an Elevated ALT Level?
Reference ranges for ALT laboratories
Men: 4-60 IU/L; women: 6-40 IU/L
Both AASLD and US treatment algorithms recommend
lower ULN levels for ALT when making treatment-initiation
30 IU/L for men
19 IU/L for women
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.
Prati D, et al. Ann Intern Med. 2002;137:1-10. Lok AS, et al. Hepatology. 2009;50:661-662.
Asian-Pacific consensus statement
on the management of chronic
hepatitis B: a 2012 update
Recommendations for First-line
• Peginterferon alfa-2a
– Exceptions: pregnancy, chemotherapy
prophylaxis, decompensated cirrhosis, acute infection
EASL. J Hepatol. 2009;50:227-242. Liaw YF, et al. Hepatol Int. 2008;2:263-283.
Lok AS, et al. Hepatology. 2009;50:661-662.
IFN- α was the first approved therapy for chronic hepatitis
It is no longer used to treat hepatitis B.
For immunocompetent adults with HBeAg-reactive
chronic hepatitis B, a 16-week course of IFN given
subcutaneously at a daily dose of 5 million units, or three
times a week at a dose of 10 million units is used.
In HBeAg-negative chronic hepatitis B, more protracted
courses, lasting up to 11/2 years, have been reported to
result in sustained remissions documented to last for
Complications of IFN therapy include systemic "flu-like"
symptoms; marrow suppression; emotional lability
, autoimmune reactions (especially autoimmune
thyroiditis); alopecia, rashes, diarrhea, and numbness and
tingling of the extremities. With the possible exception of
autoimmune thyroiditis, all these side effects are
When to Consider PegIFN
• Favorable predictors of
In HBeAg+ve CHB
– Low HBV DNA
– High ALT
– Genotype A or B > C or
– Not advanced disease.
– Generally young people
– Young women
wanting pregnancy in
– Absence of
Concomitant HCV infection
1. Lok AS, et al. Hepatology. 2009;50:661-662. 2. Lok AS. Hepatology. 2010;52:743-747. 3. Janssen HL,
et al, Lancet. 2005;365;123-129. 4. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. 5. Flink HJ, et al.
Am J Gastroenterol. 2006;101:297-303.
Potential Barriers to HBV
Patient resistance or cultural beliefs about treatment
Potential adverse effects (particularly interferon)
Challenges with long-term therapy
Understanding endpoints and monitoring strategies
Lack of symptoms
Lack of ability to cure disease with current regimens in
For IFN/PEG-IFN based
In HBeAg-positive CHB, predictors of anti-HBe
seroconversion are low viral load (HBVDNAbelow
2000 IU/ml), high serum ALT levels (above 2–5
times ULN), HBV genotype and high activity
scores on liver biopsy (at least A2). HBV
genotypes A and B have been shown to be
associated with higher rates of anti-HBe
seroconversion and HBsAg loss than genotypes
D and C, respectively, after treatment with PEGIFN.
For NAs treatment
In HBeAg-positive CHB, factors predictive of anti-
HBe seroconversion are low viral load (HBV DNA
below 2 IU/ml), high serum ALT levels, high
activity scores on liver biopsy . HBVgenotype
does not influence the virological response to any
TREATMENT IN HIV CO-INFECTED
HIV-positive patients with CHB were at increased risk
of cirrhosis and HCC .
The indications for therapy are the same as in HIV-
negative patients, based on HBV DNA levels, serum
ALT levels and histological lesions.
In agreement with recent HIV guidelines, it is
recommended that most co-infected patients should be
simultaneously treated for both HIV and HBV de novo
Tenofovir combined with emtricitabine or lamivudine
plus a third agent active against HIV are indicated.
In a small number of patients with CD4 count
>500/ml, HBV can be treated before the
institution of anti-HIV therapy; PEGIFN, adefovir
and telbivudine, which are not proven to be active
against HIV, should be preferred.
However, if any of these two NAs with a low
barrier to resistance does not reach the goal of
undetectable HBV DNA after 12 months of
therapy, treatment of HIV infection should be
TREATMENT IN HDV COINFECTED Pt’S
Chronic infection after acute HBV-HDV hepatitis is
less common, while chronic delta hepatitis develops
in 70–90% of patients with HDV superinfection.
Active co-infection with HDV is confirmed by
detectable HDV RNA, immuno-histochemical staining
for HDV antigen, or IgM anti-HDV.
(PEG-)IFN is the only drug effective against HDV.
The efficacy of (PEG-)IFN therapy can be assessed
during treatment (after 3–6 months) by measuring
HDV RNA levels.
More than 1 year of therapy may be necessary, as
there may be some benefit from treatment
TREATMENT IN HCV COINFECTED Pt’S
In HBV-infected patients, HCV co-infection
accelerates liver disease progression and
increases the risk of HCC.
HBV and HCV replicate in the same hepatocyte
However, HBV DNA level is often low or
undetectable and HCV is responsible for the
activity of chronic hepatitis in most patients.
Thus, patients should usually receive treatment
Pre-emptive therapy before immunosuppressive
therapy or chemotherapy
HBsAg-positive candidates for chemotherapy and
immunosuppressive therapy should be tested for HBV
DNA levels and should receive pre-emptive NA
administration during therapy (regardless of HBV DNA
levels) and for 12 months after cessation of therapy.
When HBV DNA levels are<2000IU/ml & finite and
short duration of immunosuppression is
scheduled,Lamivudine is used.otherwise Entecavir or
Tenofovir are used.
HBsAg-negative, anti-HBc positive patients with
detectable serum HBV DNA should be treate similarly
to HBsAg positive patients.
HBsAg-negative, anti-HBc positive patients with
undetectable serum HBV DNA and regardless of antiHBs status who receive chemotherapy and/or
immunosuppression should be followed carefully by
means of ALT and HBV DNA testing and treated with
NA therapy upon confirmation of HBV reactivation
before ALT elevation.
Unresolved issues and unmet needs
(1) Improve knowledge and prognosis of the natural history
and indications for treatment, particularly in HBeAgpositive immunotolerant patients and HBeAg-negative
patients with serum HBV DNA levels below 20,000 IU/ml.
(2) Assess the role of non-invasive markers (serum and
biophysical) for the evaluation of the severity of liver
disease and for the follow-up of treated and untreated
(3) Further clarify the role of serum HBsAg levels in the
evaluation of the natural history, prediction of therapeutic
responses and treatment individualisation.
(4) Assess host genetic and viral markers to determine
prognosis and optimise patients’ management.
(5) Assess the impact of early diagnosis and early treatment
(7) Identify markers that predict successful NA
(8) Assess the safety and efficacy of the combination of
with a potent NA (entecavir or tenofovir) to increase
anti-HBe and anti-HBs seroconversion rates.
(9) Develop and assess new drugs and therapeutic
particularly immunomodulatory therapies, to enhance
of HBeAg and HBsAg and subsequent seroconversion.
(10) Assess long-term impact of therapy on the
cirrhosis and its complications and HCC.
(12) Develop effective and optimum treatment for
POST EXPOSURE PROPHYLAXIS OF HB IF
SOURCE IS HBSAG +
HBIG *1 dose(.06ml/kg)&initiate HBV
Known non responder
HBIG *1 dose(.06ml/kg)&initiate HBV
vaccine or HBIG *2 doses,
Antibody response not known
Test for antibodies if adequate no
treatment; if inadequate HBIG *1
dose(.06ml/kg)& HBV VACCINE
HEPATITIS B PROPHYLAXIS OF NEW BORN TO
HBSAG + MOTHER
AGE OF INFANT
WITH IN 12 HOURS
Asian-Pacific consensus statement on the
management of chronic hepatitis B: a 2012
EASL Clinical Practice Guidelines: Management
of chronic hepatitis B virus infection(2012).
HARRISONS INTERNAL MEDICINE
Some persons may test positive for anti-HBc but notHBsAg or
anti-HBs. The finding of isolated anti-HBc canoccur for a variety
of reasons. (1) Anti-HBc may be anindicator of chronic HBV
infection; in these persons,HBsAg had decreased to
undetectable levels but HBVDNA often remains detectable, more
so in the liver thanin serum. This situation is not uncommon
among personsfrom areas with high prevalence of HBV infection
and inthose with human immunodeficiency virus (HIV) or
hepatitisC virus (HCV) infection.27 (2) Anti-HBc may be amarker
of immunity after recovery from a prior infection.In these
persons, anti-HBs had decreased to undetectablelevels but
anamnestic response can be observed after onedose of HBV
vaccine.28 (3) Anti-HBc may be a false positivetest result
particularly in persons from low prevalenceareas with no risk
factors for HBV infection. These individualsrespond to hepatitis B
vaccination similar to personswithout any HBV
seromarkers.10,28,29 (4) Anti-HBcmay be the only marker of
HBV infection during thewindow phase of acute hepatitis B;
these persons shouldtest positive for anti-HBc IgM.