Journal of The Association of Physicians of India Vol.

63 November 2015

43

Review Article

Management of Chronic Hepatitis B Infection in

India
Deepak N Amarapurkar1, Kaushal Madan2, Dharmesh Kapoor3
Abstract
Chronic hepatitis B (CHB) infection is a substantial global health problem
with highest prevalence observed in the sub-Saharan Africa and East
Asia. India lies in the intermediate endemicity zone with prevalence
ranging from 0.1% to 11.7%. The predominant route of transmission is
horizontal and the most commonly occurring genotypes are A and D. The
high mortality and morbidity associated with CHB constitutes significant
health and economic burden in developing countries like India. Antiviral
agents decrease HBV DNA load and prevent disease progression. Several
regional and country expert associations have developed treatment
guidelines for appropriate management of CHB; however, various
factors like prevalence, disease awareness, immunization status, cost
implications, availability of resources, type of transmission and emerging
significance of HBV genotypes have influenced the management of
CHB in a country. This article focuses on experts recommendations on
CHB management including initiation, monitoring and termination of
treatment with emphasis on borderline cases. The article also throws
light on the challenges to optimum management and provides preferred
therapeutic approaches in Indian perspective.

Overview of Chronic
Hepatitis B Infection

hronic hepatitis B (CHB)

infection is a significant health
problem world wide with India
categorized into intermediate
zone of prevalence. 1 Considering
an average carrier rate of 5% the
total number of HBV carriers in the
country was estimated to be about
50 million. Unlike in other parts of
Asia, horizontal transmission, via
intra-familial transmission is the
main route of HBV transmission
in India. 2
Genotypes A and D are prevalent
in the Indian subcontinent but a
changing trend is being witnessed
with emergence of genotypes B, E,
F and G, which could be attributed
to immigration, trafficking and use

of banned drugs. 2,3 Accumulating

evidence clearly indicates
significant influence of HBV
genotypes on disease prognosis;
genotype B is associated with less
p r o g r e s s i ve l i ve r d i s e a s e t h a n
genotype C while genotype D
has a less favourable prognosis
than genotype A. 4 Association of
genotype A and D with disease
severity and poor response was
also observed in Indian patients. 5-8
The natural course of the disease
may be broadly divided into three
phases as presented in Figure 1.
The duration of these phases differ

based on geographical locations,

type of transmission and genotypes.
The sustained clinical remission
(inactive phase) and longer inactive
state with low HBV DNA (<2000
units/mL) is found to be associated
with favourable long term clinical
outcomes. 9 A sero-reversion to
HBeAg positive status may occur
in upto 4-20% cases. Among those
who remain HBeAg-negative,
0-30% experience hepatitis flares
or reactivation of the disease which
is recognised as a variant form of
immune clearance phase. 10 The
phenomenon of HBeAg-negative
chronic hepatitis is on the rise
worldwide; a retrospective analysis
of CHB infection in India revealed
a h i g h p e r c e n t a g e p r e va l e n c e
(61%) of HBeAg-negative chronic
hepatitis patients. 11 The HBsAg
seroconversion is considered as a
state closest to cure and usually
confers the best surrogate marker
of improved survival. However
HCC may still occur, if cirrhosis
h a d a l r e a d y d e ve l o p e d b e f o r e
HBsAg seroclearance. 4
Treatment strategies have
evolved rapidly with the
i n t r o d u c t i o n o f n e we r a g e n t s
including parentral antivirals
[interferon-alpha (IFN-), peginterferon-alpha 2a (Peg-IFN-2a)]
and oral nucleoside/nucleotide
analogues (NUC) [lamivudine
(LAM), adefovir (ADV), entecavir
(ETV), telbivudine (LdT), and

Consulting Gastroenterologist and Hepatologist, Department of Gastroenterology and Hepatology, Bombay

Hospital and Medical Research Centre, Mumbai, Maharashtra; 2Senior Consultant, Gastroenterologist and
Hepatologist, Department of Gastroenterology, Medanta Medicity, Gurgaon, Haryana; 3Senior Consultant,
Hepatology, Department of Gastroenterology, Global Hospital, Hyderabad, Telangana
Received: 22.01.2015; Accepted: 07.04.2015
1

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Journal of The Association of Physicians of India Vol. 63 November 2015

Vertical
Transmission

Horizontal
Transmission

Immune Tolerant
Phase
HBeAg +ve,  HBV DNA
normal ALT &
absent to mild liver
inflammation

Immune Clearance
Phase
HBeAg +ve,  HBV DNA
ALT & moderate to
severe liver
inflammation

Inactive Phase
Anti-HBe +ve,
undetectable
HBV DNA, normal ALT
& near-normal histology
Sero-conversion
Anti-HBs +ve
undetectable HBV DNA
& normal ALT
*

Reactivation to
HBeAg -ve CHB
Anti HBe +ve, fluctuating
HBV DNA, fluctuating ALT
&  liver inflammation
Sero-reversion
HBeAg +ve,  HBV DNA
&  ALT

Immune tolerant phase is very short in case of horizontal transmission

Fig. 1: Transmission and natural history

tenofovir (TDF)]. Definitions

of some common terminologies
and diagnostic criteria have been
elaborated in Table 1.

Recommendations for
Management in India
Several professional societies
like the American Association
for the Study of Liver Diseases
(AASLD), the European Association
for the Study of the Liver (EASL)
and Asian Pacific Association for
the Study of the Liver (APASL)
have developed guidelines to assist
physicians in the management of
CHB patients. These guidelines are
flexible and the recommendations
put forth by them may be applied
by the physicians in view of its
applicability in a given situation.
Practicing most of these
recommendations may be
challenging in resource-limited
settings like India. Bristol-Myers
Squibb (BMS) has deliberated
an educational initiative, PATH
(Professionals Acting Together
on Hepatitis) to help physicians

address the challenges faced in

the diagnosis and management of
CHB patients. An India specific
consensus statement was developed
based on the feedback given by
experts in the field of hepatology
to questionnaire on evaluation and
management of CHB including
special categories as well as
borderline cases. An educational
module developed based on all the
guidelines and expert consensus
was also presented in a continuing
medical education forum.
This article reviews
recommendations of the three
professional society guidelines
(AASLD, EASL and APASL and
provides recommendations of
Indian experts.
A. Management of CHB
Counseling and Prevention of
Transmission
Educating patients and
spreading awareness about HBV
infection is crucial for successful
antiviral therapy and can curb the
spread of this infection. Published
guidelines recommend proper

counseling of patients on prevention

of transmission of HBV, advice on
lifestyle (activity, diet, alcohol use,
etc.) and other predisposing factors
as well as vaccination of high risk
patients (sexual and household
members in close contact with
patients/ carriers, HBsAg positive
mothers, healthcare workers,
dialysis patients, incarcerated
patients, etc.). Additionally, use
of hepatitis B immune globulin
(HBIG) is advocated for infants
born to infected mothers along
with hepatitis B vaccine (at delivery
followed by complete vaccination
series).4,12,13 Experts in India suggest
at least two sessions of counseling,
one at initial visit and the other
after investigations with focus on
alleviating undue anxiety of the
patient. The main discussion points
include stage of the disease and its
prognosis, prevention of disease
transmission, available treatment
options, their side effects and
the importance of compliance to
therapy.
Initial Evaluation of Newly
Diagnosed Patients
Initial evaluation, advised by all
guidelines, allows staging of the
disease and further assesses the
need for treatment and surveillance.
It should include medical history,
physical examination, laboratory
investigations [liver profile, liver
imaging and viral markers (HBeAg,
HBeAb, IgM anti-HBc, HBV DNA
load)] to assess liver disease and
HBV replication status. In addition
to this, Indian experts also suggest
obtaining information on family
history of HCC/cirrhosis which is
a risk factor for advanced disease.
Decision to Treat
Serum HBV DNA, serum ALT
levels and liver disease stage (based
on liver biopsy and/r non-invasive
markers of fibrosis and/or imaging)
are the criteria for treatment
initiation, however, the cut-off
values and the need for liver biopsy
prior to treatment initiation differs
among the guidelines (Table 2). In
line with the global guidelines,

Journal of The Association of Physicians of India Vol. 63 November 2015

Table 1: Definitions and Diagnostic Criteria

Definitions
Biochemical response

Biochemical response is defined as normalization of ALT

levels
Serological response for HBeAg Serological response for HBeAg applies only to patients with
HBeAg-positive CHB and is defined as HBeAg loss with
seroconversion to anti-HBe.
Serological response for HBsAg Serological response for HBsAg applies to all CHB patients
and is defined as HBsAg loss with development of anti-HBs
Histological response

Complete response
Virological response
Primary non-response

Virologic relapse

Virologic breakthrough
Viral rebound

HBeAg reversion
Biochemical breakthrough
Genotypic resistance

Phenotypic resistance

Hepatic decompensation

Hepatitis flare

Histological response is defined as decrease in

necroinflammatory activity without worsening in fibrosis
compared to pre-treatment histological findings.
Complete response is defined as sustained off-treatment
virological response together with loss of HBsAg
Virological response is defined as undetectable levels of HBV
DNA and loss of HBeAg in patients initially HBeAg positive
Primary non-response is defined as decrease in serum HBV
DNA by < 2 log10 IU/mL after at least 24 weeks of therapy in
complaint patient
Virologic relapse is defined as increase in serum HBV DNA
of 1 log10 IU/mL after discontinuation of treatment in at least
2 determinations more than 4 weeks apart
Increase in HBV DNA by >1 log10 above nadir after
achieving virologic response, during continued treatment
Increase in serum HBV DNA to > 20,000 IU/mL or above
pre-treatment level after achieving virologic response, during
continued treatment
Reappearance of HBeAg in a person who was previously
HBeAg-negative, anti-HBe-positive.
Increase in ALT above upper limit of normal after achieving
normalization, during continued treatment
Detection of mutations that have been shown in in
vitro studies to confer resistance to the NA that is being
administered
In vitro confirmation that the mutation detected decreases
susceptibility (as demonstrated by increase in inhibitory
concentrations) to the NA administered.
Significant liver function abnormality as indicated by
raised serum bilirubin and prolonged prothrombin time or
occurrence of complications such as ascites.
Abrupt increase of serum ALT

Undetectable serum HBV DNA Serum HBV DNA below detection limit of a PCR-based assay
Diagnostic criteria
Chronic hepatitis B
1. HBsAg+ve for > 6 months
2. Serum HBV DNA:

HBeAg+ve: >20,000 IU/mL

HBeAg-ve: 2,000-20,000 IU/mL

3. Persistent or intermittent elevation in ALT levels

Inactive carrier state

4. Liver biopsy: Mild/Moderate/severe necroinflammation

1. HBsAg+ve for >6 months
2. HBeAg-ve and anti-HBe +ve
3. Serum HBV DNA <2,000 IU/mL
4. Persistently normal ALT levels

Resolved hepatitis B

5. Liver biopsy: Absence of significant inflammation

1. Previous known history of acute or chronic Hep B or the
presence of anti-HBc anti-HBs
2. HBsAg-ve
3. Undetectable serum HBV DNA

Marginal ALT elevation

4. Normal ALT levels (40 IU/ml for Indians)

ALT between 1-1.5 ULN

45

physicians in the subcontinent

also suggest initiating treatment
immediately in all patients
having evidence of active CHB
with decompensated cirrhosis,
a c u t e o n c h r o n i c l i ve r f a i l u r e ,
patients with high risk for disease
progression and development of
HCC as well as patients undergoing
immunosuppressive therapy.
On the other hand, treatment is
not recommended in patients
who have low HBV DNA (<2000
IU/ml), persistently normal
alanine transaminase (ALT), and
histological evidence of mild liver
d i s e a s e a s we l l a s c h i l d r e n i n
immune-tolerant phase.
The upper limit of normal (ULN)
of ALT has shown variability due
to heterogeneity within target
populations and differences
in the commercial assays. The
appropriate normal cut-off to
determine the risk of disease
progression in Indian patients has
been set to 40 IU/ml. In HBeAgnegative patients a stringent HBV
DNA criterion of >2000 IU/ml is
considered for starting therapy.
Guidelines slightly differ in the
recommendations of liver biopsy
in patients above 40 years of age
and borderline ALT with AASLD
and APASL advocating biopsy if
HBV DNA level is >20,000 IU/ml. 4,12
EASL recommends cut-off of HBV
DNA >2000 IU/ml in patients over
30 years of age and/or with a family
history of HCC or cirrhosis. 13
Horizontal transmission being
prevalent in the country, advanced
disease sets in around the age of 40
years with higher chances of HBeAgnegative disease. Therefore, experts
advocate liver biopsy whenever
there is uncertainty about initiating
a treatment based on laboratory
investigations especially in patients
above 40 years.
Monitoring and Decision to Stop
Treatment
All patients on CHB therapy
should be closely monitored
for response, tolerability and
adherence to treatment. Experts

46

Journal of The Association of Physicians of India Vol. 63 November 2015

Table 2: Recommendations for Treatment Initiation

Parameters
HBeAg
HBV DNA ALT
(IU/ml)

Positive

> 2000

< ULN

Recommendations of Guidelines
APASL (2012)4
AASLD (2009)12
EASL (2012)13
[UL: DNA= 2000 IU/ml; [UL: DNA= 20,000 IU/ml; [UL: DNA= 20,000 IU/ml;
ALT= 40 IU/ml]
ALT= 40 IU/ml]
ALT= 30 (men) and
19 (women) IU/ml]
Monitor 3-6 months.
Monitor (3-6months)
Monitor 3-6months;
Liver biopsy and
frequent monitoring if ALT
therapy if age > 30 years
become elevated
or family h/o HCC.
Liver biopsy if age >40
Treat if moderate or
years, ALT persistently high
greater inflamation
normal or family history of
HCC and then decide

Positive

> 2000

> ULN

Monitor 3-6 months.

Liver biopsy
recommended.
Treat if moderate or
greater inflamation

Liver biopsy if age >40

years.
Treat if moderate or
greater inflamation

Indian experts
[UL: DNA= 2000 IU/ml;
ALT= 40 IU/ml]
Monitor 3 monthly ALT
for at least one year;
treat if ALT level rises. If
uncertainty exists (because
of fluctuating ALT or
DNA, family history of
HCC, etc) biopsy can be
advised.

Liver biopsy if age >40

years; treat if moderate or
greater inflamation
If HBV DNA >20000, ALT
Monitor 3 monthly ALT
1-2 X ULN and age >40 yrs. for at least one year;
then consider liver biopsy to treat if ALT level rises. If
decide treatment
uncertainty exists (because
of fluctuating ALT or
DNA, family history of
HCC, etc) biopsy can be
advised

Liver biopsy if age >40

years; treat if moderate or
greater inflamation
Positive
> 20,000
> 2 X ULN Start treatment without Treat if persistent ALT
Observe for 3-6 months
If decompensation is
biopsy
(3-6months)/ concern for and treat if no spontaneous imminent start treatment
decompensation.
HBeAg loss
immediately, else 2 x ULN
If DNA <2,00,000 observe Consider liver biopsy prior (persistent) is acceptable
3-6months for HBeAg
to treatment if compensated level for treatment
seroconversion if no
Immediate treatment
decompensation
if icteric or clinical
decompensation
No treatment.
Negative < 2000
< ULN
No treatment.
No treatment.
Monitor ALT every 3
Monitor
Monitor 6-12 monthly
months for 1st year and then Monitor
6-12 months
Negative 2000-20,000 < ULN
No treatment.
No treatment.
Not Applicable
No treatment.
Monitor ALT every 3
Monitor 3 monthly. Liver
Monitor 3 monthly.
months and HBV DNA biopsy if pt 40 yrs.
Decide treatment on
every 6-12 months for Decide treatment on
biopsy
3 years
biopsy
Fibroscan might be
useful
Monitor ALT, HBV DNA 3 No treatment.
Negative 2000-20,000 1-2 X ULN Not applicable
No treatment.
months. Consider biopsy if Monitor 3 monthly.
Monitor 1-3 monthly.
Liver biopsy if pt 40 yrs. persistent
Decide treatment on
biopsy
Decide treatment on
biopsy
Treat
Negative 2000-20,000 > 2 X ULN Not applicable
Treat if ALT persists
Treatment may be
or concern for
considered particularly if
decompensation
they are older patients or
those with cirrhosis
Negative > 20,000
> 2 X ULN Start treatment without Treat
Treat if persistent
Treat
biopsy
ALT: Alanine transaminase; HBV DNA: Hepatitis B virus deoxyribonucleic acid; UL: Upper limit; ULN: Upper limit of normal

world over consider normalization

of serum ALT levels, decrease in
serum HBV DNA level, loss of
HBeAg, HBeAg seroconversion
and HBsAg loss to be important
response indicators. For patients
on IFN therapy, HBV DNA levels
should be monitored every 3 to

6 months; in HBeAg-positive
patients, the HBeAg /anti-HBeAg
status is to be monitored every 6
months as per the American and
European guidelines 12,13 while the
APASL advocates a more frequent
3 monthly monitoring. 4 If treated
with a NUC, liver panel should be

performed every 3 months whereas

HBV DNA levels and HBeAg/antiHBeAg status need monitoring
every 3 to 6 months.
For their known side effects,
patients on IFN therapy require
frequent monitoring of blood

Journal of The Association of Physicians of India Vol. 63 November 2015

47

Table 3: Recommendations for Termination of Treatment

Guideline

Non-cirrhotic patients
HBeAg positive

AASLD (2009)12 HBeAg seroconversion and

undetectable serum HBV
DNA and completed at
least 6 months additional
treatment after appearance
of anti-HBe
HBsAg clearance
EASL (2012)13
OR
HBeAg seroconversion
with HBV DNA <2000 IU/
ml and normal ALT and
completed 12 months
additional treatment after
appearance of anti-HBe
APASL (2012)4 HBeAg seroconversion
with undetectable HBV
DNA maintained for at
least 12 months

Compensated cirrhosis

Decompensated
cirrhosis

HBeAg negative

HBeAg-positive

HBeAg-negative

HBsAg clearance

HBeAg seroconversion and

completed at least 6 months
of consolidation therapy

HBsAg clearance
Life-long
and completed at
treatment
least 6 months of
consolidation therapy

HBsAg clearance
OR
Undetectable HBV DNA
and normal ALT after long
term treatment

HBsAg loss and anti-HBs

seroconversion

HBsAg loss
Life-long
and anti-HBs
treatment
seroconversion
and completed at
least 12 months of
consolidation therapy

OR
Confirmed anti-HBe
seroconversion and
completed at least 12 months
of consolidation therapy

HBsAg clearance
Not applicable
OR
Undetectable HBV DNA
documented on three
separate occasions 6
months apart after at least
2 years treatment

Not applicable

Not applicable

Indian Experts
Seroconversion HBeAg loss with persistent Undetectable HBV DNA
Life-long treatment
Life-long treatment
Life-long
treatment
below 40 years undetectable serum HBV documented on three
DNA and Completed 12
separate occasions 6
months apart after at least
month of consolidatum
therapy
2 years treatment
Seroconversion HBsAg clearance
HBsAg clearance
above 40 years
ALT: Alanine transaminase; HBV DNA: Hepatitis B deoxyribonucleic acid; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen

counts and liver panel; AASLD

and EASL guidelines recommend
m o n t h l y m o n i t o r i n g 12,13 w h i l e
APASL recommends monitoring
every 3 months. 4 Also, the thyroid
stimulating hormone should be
monitored every quarter. Those on
TDF/ADV therapy need monitoring
of renal function as it causes
nephrotoxicity, proximal tubular
damage, Fanconi syndrome,
osteomalacia while muscle
we a k n e s s a n d c r e a t i n e k i n a s e
should be monitored for patients on
LdT and lactic acidosis in patients
on ETV. 4,12,13
Te r m i n a t i o n o f t r e a t m e n t
depends on HBeAg status,
HBV DNA levels, age and/
or disease progression and the
recommendations are tabulated
in Table 3. Experts in India have
given importance to patients age
at seroconversion while deciding
treatment goal; patients achieving
seroconversion after 40 years of age
have additional criteria of HBsAg
clearance. A life-long treatment

is advocated in patients with

compensated or decompensated
cirrhosis.
Hepatocellular Carcinoma
Surveillance
The AASLD guidelines
recommend screening for HCC in
HBV carriers, who are at high risk
of HCC, every 6-12 months 12 while
European group recommends
HCC surveillance in CHB patients
in whom cirrhosis has developed
b e f o r e H B s A g l o s s . 13 T h e r i s k
factors for HCC in Indian patients
are gender, age, family history
of HCC, heavy use of alcohol,
history of sero-reversion, cirrhosis,
HBV genotype C, core promoter
mutation and co-infection with
H C V. S c r e e n i n g t o o l s i n c l u d e
alpha-fetoprotein (AFP) and
ultrasound (US); the sensitivity,
specificity and diagnostic accuracy
of US is higher and hence is the
preferred tool. Almost a third of
patients with HCC in India have
normal values of AFP. 14 Indian
experts believe a well-organized

HCC surveillance can be effective at

reducing disease-specific mortality
with acceptable cost-effectiveness
among selected patient groups. 15
HCC screening is advocated in
cirrhotic patients and high-risk
non-cirrhotic patients including
inactive carriers >50 years. Experts
prefer US however do not deny AFP
as a survelliance tool.
Pa r t i a l R e s p o n s e / N o n Response / Breakthrough
Frequently viruses undergo
mutations which can decrease
the response to NUCs. Noncompliance to these agents is
the main reason for mutations
which may further result in partial
response, no response or viral
breakthrough. Physicians suggest
assessing compliance of patients
with primary non-response to any
NUC. Genotyping of HBV strains in
compliant patients with a primary
non-response or viral breakthrough
may help in formulating a
rescue strategy. In patients with
primary non-response to ADV,

48

Journal of The Association of Physicians of India Vol. 63 November 2015

a rapid switch to TDF or ETV is

recommended. Patients with partial
response to LAM/LdT (at week
24)/ADV (at week 48) or with viral
breakthrough may be switched to
ETV/TDF. It is advisable to get 3
monthly DNA for the first year
as it is the indicator of response
as well as compliance. Treatment
with same antiviral agents may
be continued in patients with
declining HBV DNA levels if there
is an increase in viral response and
a low risk of resistance with long
term therapy (drugs with higher
genetic barrier to resistance, such
as entecavir or tenofovir will have
lower risk of resistance with long
term therapy).
B. Management of Special
Population
Pediatric Population
HBV infection in children is
mostly asymptomatic and therefore
the disease burden is likely to be
underappreciated; there is limited
information on CHB in Indian
children. According to a clinic
study conducted in 460 children
of different age groups in north
India, 4.35% tested HBsAg-positive
with highest (6.09%) prevalence
in 1-4 years of age and the least
in 10-14 years age group. 16 Few
other studies, assessing HBsAg
positivity, revealed that prevalence
varies in different regions in India
and the overall positivity ranges
from 1.3-12.7%. 17 Most children
with HBV infection are considered
to be in the immunotolerant phase
when treatment is not indicated.
All guidelines view children with
overt hepatic decompensation as
candidates for treatment. Children
with elevated ALT levels should be
observed for spontaneous HBeAg
seroconversion before initiating
treatment with IFN and LAM. In
general a conservative approach is
warranted in children because of
apparent lack of long term benefits
and the risk associated with drug
therapy.
Pregnancy
HBV infection can affect the

outcome of pregnancy leading to

spontaneous abortion, stillbirth or
prematurity in addition to risk of
vertical transmission. Studies from
different parts of the country have
revealed a prevalence of 0.9 to 9%
of HBsAg positivity in pregnant
women. 18,19 IFN-based therapy may
be preferred for women who wish
to conceive in future and wish to try
a finite duration therapy in order
to become HBV negative before
becoming pregnant, although the
chances of achieving this result are
very low. Pregnant women with a
low HBV viral load do not require
i m m e d i a t e t r e a t m e n t ; p a s s i ve
immunizat ion and act ive HBV
vaccination of the newborn reduces
chance of acquiring infection in
such cases. Antiviral therapy in
pregnancy could be limited to
patients with high HBV viral
load; therapy is advised during
third trimester of pregnancy and
should be continued for atleast
12 weeks after delivery in order
to reduce the risk of mother
to child t ransmission. 20 IF N is
contraindicated during pregnancy
and Category B drugs such as LdT
or TDF are recommended. Women
who have significant liver disease
may continue anti-viral treatment
throughout their pregnancy and for
long duration even after delivery
(such patients themselves have an
indication for anti-viral therapy.
However, safety of these drugs has
not been established in breast-fed
infants.
Hepatic Decompensation
All guidelines advocate
prompt initiation of treatment
using NUCs in patients with liver
decompensation regardless of HBV
DNA levels; this will lead to clinical
stabilization and will minimize
the need of transplant. IFN is
contraindicated in this setting
because of the risk of serious
bacterial infection and possible
e x a c e r b a t i o n o f l i ve r d i s e a s e .
Potent NUCs with good resistance
profile such as ETV or TDF are
preferred. EASL recommends dose
adjustment of all NUCs in patients

with low creatinine clearance (<50

ml/min). 4,12,13
Co-infection with HCV, HDV
or HIV
Hepatitis B virus, hepatitis
C virus (HCV), hepatitis delta
virus (HDV) and human
immunodeficiency virus (HIV)
share similar transmission routes.
Concurrent infection with these
viruses in general complicates the
natural course of CHB resulting in
more severe and progressive liver
disease. 4 Indian epidemiological
studies on co-infections have been
performed only in HIV positive
patients with reported prevalence
of 5.3% to 9%. 21-23 Insufficient data
exists to reach firm conclusions on
the management of patients coinfected with HCV and/or HDV.
However, it is generally agreed
that the dominant virus should
be identified before deciding
therapeutic strategy. If HCV is
dominant, finite Peg-IFN therapy
in combination with ribavirin can
achieve a sustained virological
response. However, since there
exists a potential risk of HBV
reactivation during treatment or
after clearance of HCV, HBV DNA
monitoring is recommended and
HCV therapy may be followed
by NUCs for HBV. In patients coinfected with HDV, high doses of
IFN/peg-IFN have demonstrated
long term beneficial effects. For HIV
co-infected patients it is globally
recommended that peg-IFN or
ADV should be initiated in patients
who do not require highly active
antiretroviral therapy whereas
patients requiring treatment
against both HBV and HIV should
receive therapies effective against
both viruses e.g. LAM+TDF or
emtricitabine +TDF.4,12 Patients with
HIV/HBV co-infection generally
have lower ALT levels, hence a
liver biopsy is considered to stage
the disease. Treatment experiences
in patients co-infected with HIV
in Indian settings remains poorly
documented. However, one study
in a cohort of HIV/HBV co-infected
patients demonstrated positive

Journal of The Association of Physicians of India Vol. 63 November 2015

treatment outcomes with TDF/

LAM. 24
Immunosuppression
Chemotherapy

Reactivation of HBV with

increase in serum HBV DNA and
ALT level has been reported in
20-50% of HBV carriers receiving
i m m u n o s u p p r e s s i ve o r c a n c e r
chemotherapy. 12 Screening and
vaccination of HBV seronegative
patients is highly recommended.
Pre-emptive oral antiviral therapy
is advocated for HBsAg-positive
patients and HBsAg-negative
patients with detectable HBV
DNA levels; treatment should be
continued for at least 12 months after
cessation of immunosuppressive
treatment. HBsAg-negative patients
with antibodies against HBV core
protein (anti-HBc) but undetectable
serum HBV DNA should be
followed carefully by means of ALT
and HBV DNA testing regardless
of anti-HBs status and should be
treated with NUC therapy upon
HBV reactivation even before ALT
elevation is evident. Treatment
guidelines recommend protection
of at-risk patients with NUC of high
antiviral potency and low risk of
resistance.
Co-morbidities
Nucleotide/nucleoside
analogues are cleared by the kidneys
with nucleotide analogues having
more nephrotoxic potential. Serum
creatinine levels and estimated
creatinine clearance should be
determined before starting NUC
in all patients. High renal risks
include decompensated cirrhosis,
creatinine clearance <60 ml/min,
poorly controlled hypertension,
proteinuria, uncontrolled diabetes,
active glomerulonephritis,
concomitant nephrotoxic drugs,
solid organ transplantation.
Therefore elderly patients or
patients with one or more of the
above conditions must be closely
monitored for renal parameters
and dose adjustments may be
considered. Indian physicians also
recommend close monitoring of

patients receiving NUCs and advice

monitoring of creatinine clearance
rather than only creatinine value.
C. Management of Borderline
Cases
The natural course of disease
may present a dilemma while
managing certain sub-groups of
immune-tolerant patients and
inactive carriers. Guidelines do not
recommend therapy in immunetolerant patients; however the
importance of age, duration of
infection, ALT levels, family history
of cirrhosis/HCC, the severity of
histology and other comorbidities
cannot be neglected. A similar
challenge is to monitor relapse in
inactive carriers and distinguish
between inactive carriers and
HBeAg-negative chronic hepatitis.
A definite indication for the
treatment in patients with HBV
DNA within defined threshold is
the ALT level of >2 times ULN.
Studies have however shown that
a substantial proportion of CHB
patients with marginally elevated
or persistently normal ALT who
remain ineligible for therapy have
significant histological damage. 25
Management of such patients
should be individualized based on
liver histological status. Treatment
can be deferred in patients who
show minimal necroinflammation
and mild (stage 1) fibrosis. Liver
biopsy provides more sensitive
and specific information on liver
disease progression. However,
liver biopsy is invasive and carries
a risk of complication, albeit low.
The limitations of liver biopsy can
be overcome by use of a rapid, noninvasive transient elastography
(Fibroscan); a study by Goyal et
al, revealed that fibroscan could
avoid liver biopsy in 70% patients
with an accuracy>90% in CHB
p a t i e n t s . 2 6 H o we ve r , o w i n g t o
resource constraints, facilities
of biopsy or fibroscan may be
unavailable and in such situations
a risk impact assessment score
along with the HBV DNA level
may be useful to guide treatment
decisions. A similar risk impact

49

score is deduced based on age,

gender, ALT levels, BCP mutations,
HCC in first-degree relatives and
those with low albumin/platelet
values for cirrhosis. In this system,
a numerical score has been assigned
for each risk factor and if the score is
3 and the HBV DNA is > 2,000 IU/
mL, treatment is advised. 27 Experts
have recommended AST/ALT ratio
reversal (even if ALT is marginally
raised), low albumin, low platelet
count and mild splenomegaly on
USG as useful indicators of fibrosis
in India; presence of such indicators
should reduce the threshold for
doing a liver biopsy.
Patients with marginally
elevated or persistently normal
ALT may be categorized based on
the HBeAg status and HBV DNA
levels to strategize management
(Figure 2).
HBeAg Positive Patients
Those with marginally elevated
ALT and/or HBV DNA <20,000
IU/mL require biopsy if HBV
DNA increases or remains stable
over 6 months. Treatment can be
delayed, if the HBV DNA levels
decrease as patients may undergo
spontaneous seroconversion except
in pregnant females and healthcare
professional where treatment
initiation is advocated. Patients
with PNALT, persistently high
HBV DNA levels and prolongation
of HBeAg positive status are at
increased risk of HCC and disease
progression. Biopsy is suggested
in patients between 30 to 40 years
of age. Treatment is advocated in
patients >40 years of age. However,
age of treatment initiation should
be reduced in those with positive
family history for HCC. 28
HBeAg Negative Patients
Those with marginally elevated
ALT and/or HBV DNA between
2,000 and 20,000 IU/mL need
c l o s e m o n i t o r i n g w i t h a l i ve r
biopsy before initiating therapy.
Patients with PNALT and/or HBV
DNA >2000 IU/mL need frequent
monitoring of ALT. 28

50

Journal of The Association of Physicians of India Vol. 63 November 2015

HBeAg

Positive

HBV
DNA

ALT
Levels

Recommendations

Negative

< 20,000

NA

Marginally
Elevated

Persistently
Normal

Marginally
Elevated

Treat patients
>40 years of
age
Treat <30
years with
positive family
history of HCC
Biopsy for
patients
between 30 to
40 years

Monitor ALT
every month
and HBV DNA
every 3-6
months
Biopsy
recommended
if age >40 yrs/
family h/o HCC
and before
initiating
therapy

Follow-up 6-12
months
Biopsy mandatory
for increasing/stable
HBVDNA over
6months or age
>40 yrs or family h/o
hepatocellular
carcinoma
Treatment may help
if ALT levels
between 1 & 2 ULN

2000- 20,000

> 2000

Persistently
Normal

Biopsy mandatory
Do not treat if
minimal necroinflammation with
HBV DNA > 20,000
IU/ml
Monitor ALT 3-4
times/ year & HBV
DNA once/year

Fig. 2: Recommendations for borderline cases

Barriers to Effective
Management in India
Important factors that need to be
taken into account for optimization
of anti-viral therapy include the
severity of liver disease, duration
of recommended therapy, rapidity
of action and the adverse effect
profile of the drugs. Emergence
of drug resistance with oral
antiviral agents is also a major
challenge confronting clinicians.
Thus, prevention of antiviral
drug resistance and appropriate
management of viral breakthrough
is an added treatment goal.
Guidelines recommend selection
of drugs with high potency and
low risk of resistance; therefore
most guidelines advocate initial
treatment with ETV, TDF or pegIFN. 4,12,13
There is insufficient safety and
efficacy data on antiviral agents
i n I n d i a . 2 9 - 3 1 F e w s t u d i e s h a ve
reported positive outcomes with
antivirals. ETV has been associated
with significantly higher rates of
serological, viral and biochemical
improvement with no resistance

observed upto 40 weeks of

treatment. 32,33 ADV was found to be
less potent though the frequency of
resistance mutations was low.31 TDF
and LdT were reported to reverse
d e c o m p e n s a t i o n a n d i m p r o ve
hepatic functional status with
significant reduction in HBV DNA
levels. 34-36 LAM-resistant mutations
observed in 27% patients, were
strongly associated with longer
treatment duration. 37
Though all approved agents are
available in India, treatment with
guideline recommended first-line
agents is a challenge, the major
hurdle being unaffordability due
to high cost of therapy. The cost
of oral anti-viral therapy ranging
from 76 to 1707 US$ for CHB/
compensated cirrhosis, to 15,000
US$ for HCC patients and may be as
high as 20,000 US$ in patients with
decompensated cirrhosis. 38 Due to
cost constraints, patients either
discontinue therapy or skip/split
the dose, delay refills, avoid new
prescriptions or use generics. This
results in inadequate management
and increases the risk of resistance/
virologic breakthrough. 39,40 Thus,
in countries like India with low

per capita income, patients

preference also becomes an
important factor in deciding drug
therapy. The advocated first line
agents may therefore have to be
substituted with cost-effective
older agents or combinations
thereof. 29-31 Jayakumar, et al in
their study have demonstrated
comparable efficacy of LAM/
ADV combination with ETV and
TDF as monotherapy. 41 Therefore
for patients with compensated
cirrhsois, ETV, LdT, TDF or their
combinations, whereas for others
a LAM/ADV combination can be a
good alternative to more expensive
first line treatments. Similarly in
chronic hepatitis with or without
grade II fibrosis-monotherapy
with either TDF or ETV or LdT
or IFN can be recommended in
patients who can afford wheras
monotherapy with LAM may
be advised in others with close
monitoring of viral breakthrough
or non-response.
In India, ETV, LdT and TDF
can be recommended in compliant
patients who can afford good
treatment while LAM/ADV
combination may be advised for
non-affording patients with well
compensated cirrhosis while LAM
alone may be advised in those
with grade II fibrosis. De-novo
combination is advised in fibrotic
patients with high viral load (Table
4).
The cost constraint, together
with lack of awareness of disease,
lack of screening programs, social
stigma, limited resource allocation
(laboratories / staff and HCPs),
and sub-optimal management and
limited reimbursement of drugs/
tests are other obstacles to effective
management of CHB in India.

Conclusions
This article serves as guidance
to clinicians while formulating
strategies for management of CHB
patients in India. Experts have
adapted recommendations of the
three international guidelines.

Journal of The Association of Physicians of India Vol. 63 November 2015

Table 4: Recommendations of Treatment for Indians

Liver status

HBeAg
status

Compensated
liver disease
Compensated
liver disease

Positive

HBV DNA Therapy

levels
Affordable and/or
(copies /ml) compliant
>5 logs
ETV/LdT/IFN

Negative >3 logs

Monotherapy:

ETV/LdT
Combination therapy 6 monthly for HBV DNA
LdT + TDF OR

Compensated
cirrhosis
Fibrosis
(grade II)

ETV + TDF
Positive/ >3 log and < LAM + ADV/TDF OR Negative 9 logs
LdT + ADV/TDF
Positive/ >9 logs
LdT / ETV / TDF
Negative
Positive <9 logs
LdT/ETV/IFN/TDF
3 monthly for HBV DNA

Liaw YF, Brunetto MR, Hadziyannis S. The

natural history of chronic HBV infection and
geographical differences. Antiviral Therapy
2010; 15:25-33.

10. Kim BK, Revill A, Ahn SH. HBV genotypes:

relevance to natural history, pathogenesis
and treatment of chronic hepatitis B.
Antiviral Therapy 2011; 16:1169-1186.
11. Amarapurkar DN, Baijal R, Kulshrestha
PP, Agal S, Chakraborty MR, Pramanik SS.
Profile of Hepatitis B e antigen-negative
chronic hepatitis B [abstract]. Indian J
Gastroenterol 2002; 21:99-101.

ETV/IFN/TDF

12. Lok ASF, McMahon BJ. AASLD Practice

Guideline Chronic Hepatitis B: Update
2009. Hepatology 2009; 50:661-97.

ETV/LdT/TDF

If PCR positive in 6 months,

start combination therapy
3 monthly for resistance
If resistance, add second drug
3 monthly for HBV DNA

13. EASL Clinical Prac tice Guidelines:

Management of chronic hepatitis B virus
infection. European Association for the
Study of the Liver. Journal of Hepatology
2012; 57:167-185.

Negative >9 logs

Acute failure

Positive

Acute failure

Negative Positive

LdT/ETV/TDF

Acute failure
Notes:

Negative Negative

If resistance, add second drug

If transplant candidate, start antiviral

HBeAg positive:- Low viral load for LAM is <6 log and for Others is <7 log
HBeAg negative:- Low viral load for LAM: <5 log and for Others is Others: <6 log
For fibrotic patients with high viral load, consider de-novo combination
Use IFN with caution
ADV: Adefovir; ETV: Entecavir; HBV DNA: Hepatitis B deoxyribonucleic acid; IFN: ;
LAM: Lamivudine; LdT: Telbivudine; PCR: Polymerase chain reaction; TDF: Tenofovir

H o we ve r , c o m m e n d a t i o n s l i k e
substituting biopsy with cirrhosis
score and potent expensive drugs
with cost effective combination
therapy will be appropriate in
management of CHB in resource
limited Indian setting.

the hepatitis B virus genotype distribution

in the last decade among the HBV carriers
from eastern India: Possible effects on the
disease status and HBV epidemiology. J
Med Virol 2013; 85:1340-1347.
4.

Acknowledgements

Professional medical writing

support and editorial assistance
was provided by DiagnoSearch
Life Sciences (P) Ltd., funded by
Bristol-Myers Squibb.

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