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Author proofs done*****

REVIEW ARTICLE

FLARES ON AND OFF THERAPY DURING

CHRONIC HBV INFECTION: PATHOGENESIS,
SIGNIFICANCE AND MANAGEMENT

Deepak N. Amarapurkar
Department of Gastroenterology, Bombay Hospital and Medical
Research Centre, Mumbai, India

Correspondence: Dr. Deepak Amarapurkar, Ameya Society, New Prabhadevi

Road, Prabhadevi, Mumbai 400 025, India. E-mail: amarapurkar@gmail.com
DOI: 10.4103/0972-9747.58803

ABSTRACT
Approximately 400 million people worldwide are chronically
infected with the hepatitis B virus (HBV). Chronic infection with
HBV can lead to progressive liver diseases including cirrhosis, liver
failure, and hepatocellular carcinoma. During treatment of chronic
hepatitis B (CHB) patients, flares of inflammatory activity are a
well known phenomenon. Flares can be life threatening but have
also been associated with virological response. While, interferon
induced flares have been attributed to the stimulatory effect of
IFN, and may precede HBeAg seroconversion, Lamivudine related
flares are seen during treatment and after withdrawal of lamivudine,
which are probably caused by reoccurrence of HBV replication,
and have been associated with decompensation of liver disease.
These flares play an important role in the treatment with Peg-IFN
α-2b alone or in combination with lamivudine, and patients with
pre-existing cirrhosis are at greater risk for experiencing a flare.
Furthermore, host induced flares but not virus induced flares
may herald a response to therapy. For optimisation of treatment,
it is necessary to understand the virological and immunological
mechanisms which induce the specific flare patterns. This article
reviews the pathogenesis, significance and management of flares

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encountered during and after cessation of treatment of patients

with chronic HBV infection.
Key words: Acute exacerbation, ALT, chronic hepatitis B,
flare-up, hepatitis B virus, HBV reactivation, hepatitis e antigen,
interferon, seroconversion.

Hepatitis B virus (HBV) is a hepadna virus with a 3,200 base

pair genome which is partially double stranded DNA. The HBV
genome has four overlapping open reading frames with four major
genes designated pre-S/S, C, P and X. Four major serotypes and
seven genotypes of hepatitis B have been identified.1,2 HBV is not
directly cytopathic for the hepatocytes but abnormal expression of
viral gene products and cellular immune response to the infected
hepatocytes may result in cytotoxicity of hepatocytes. Viral clearance
may result from killing the hepatocytes by NK cells and T cells.
The mechanism of hepatocellular injury is predominantly immune
mediated, activation of which occurs by both virus specific and
non-specific immune responses leading to hepatocellular injury. The
natural history of HBV depends on the host’s antiviral responses
in eliminating the HBV infection. In fulminant hepatitis immune
response is hyper acute leading to massive hepatocellular necrosis
and elimination of virus. In acute viral hepatitis appropriate immune
response leads to icteric hepatitis with elimination of virus within
six months. Chronic HBV infections result from inability of host
antiviral mechanisms to eliminate the persistent viral infection.3
Chronic Hepatitis B infection evolves in 4 different phases4
1. Immune tolerant
2. Immune clearance
3. Residual - nonreplicative
4. Reactivaton
Immune tolerant phase: HBsAg and HBeAg are detectable,
HBVDNA levels are high, but aminotransferase levels are normal
or minimally elevated and mostly asymptomatic. It is during the
replication of the virus that the liver suffers injury; usually it lasts
for 20-30 years with very low spontaneous HBsAg clearance rate
of 2-3% per year and annual risk for HCC 0.5%.
Immune clearance phase - during the second or third decades

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of chronic infection, HBVDNA levels decrease and aminotransferase

levels increase, the patient becomes symptomatic and experiences
flares of aminotransferase.
In some this is followed by HBeAg seroconversion and
very low HBVDNA levels that are suppressed by the host immune
reaction. This state may then evolve into either inactive carrier or
may lead to resolution of HBV infection with a spontaneous HBeAg
clearance rate of up to 10-20% per year.
Residual phase - inactive carrier stage with HBeAg negativity,
antiHBe positivity, undetectable HBVDNA and normal ALT. Histology
depends on duration of disease prior to seroconversion.
In reactivation phase, a proportion of HBeAg negative
patients may later develop higher levels of HBV replication and
progress to HBeAg negative chronic hepatitis. There are two types
of chronic hepatitis B differing in their HBeAg or anti-HBe status.
The course of HBeAg positive chronic hepatitis depends on the
age at infection. Patients with perinatal infection develop moderate
to severe HBeAg positive chronic hepatitis with elevated ALT levels
only after 10 to 30 years of infection. In contrast patients infected
later in life usually present with moderate or severe liver disease
after a shorter duration of infection. HBeAg positive chronic hepatitis
is more frequent in males. HBeAg seroconversion is followed by
resolution of biochemical and histological signs of inflammatory
activity. Spontaneous seroconversion occurs in 50-70% of patients
with elevated aminotransferases within 5-10 years of diagnosis.
Older age, female gender and high serum aminotransferase
levels are predictive of HBeAg seroconversion. In a majority of
cases HBeAg seroconversion masks the transition from chronic
hepatitis B to the inactive HBsAg carrier state. However in 1-5%
of patients biochemical and histological activity persists with high
serum HBV DNA levels. These patients constitute the group of
HBeAg negative chronic hepatitis in which HBsAg and anti-HBe are
present in serum, HBV DNA is detectable using non-PCR based
methods, serum aminotransferase levels are elevated and liver
biopsy shows necroinflammation. HBeAg is undetectable because of
predominance of mutant HBV strains that cannot express HBeAg.
These patients tend to be older males and to present with severe
necroinflammation and cirrhosis.

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The inactive HBsAg carrier state is characterized by HBsAg

and anti HBe in serum, undetectable HBeAg, low or undetectable
levels of HBV DNA and normal serum aminotransferases with little
or no necroinflammation and mild or no fibrosis. The prognosis
of carrier state without cirrhosis is usually benign but 20-30% of
patients may undergo reactivation of hepatitis B.5-7
Differential progression rate with HBV infection may be
related to various clinical, serological and histological markers.8-12
Recognized risk factors for progression are presence of hepatitis
B e-antigen, advanced stage, increased alanine transaminase
levels (ALT), co-infection with other hepatitis viruses and diabetes
mellitus.
Natural history of HBV and on-treatment responses to HBV
are punctuated by rises in transaminases during the course of
chronic infection which are termed as flares or acute exacerbation of
chronic HBV infection. ALT flare is classically defined as intermittent
elevation of aminotransferase activity to more than 10 times the
upper limit of normal or more than twice the base line value.13 More
than 80% of the ALT flares in chronic HBV infection are related to
HBV induced factors or host related factors which may be on or
off treatment. Twenty percent of the acute flares may be due to
other hepatitis viruses, HIV infection, concurrent bacterial infection,
surgery, emotional or physical stress, or pregnancy.14 Etiological
classification of ALT flares is as shown in Table 1.
Immuno pathogenesis of ALT flares in chronic HBV infection
is related to cytotoxic T cell recognition of viral antigens presented
by HLA class I antigens and tumor necrosis factor (TNF) or fas
ligands produced by inflammatory cells leading hepatocellular injury.
Up regulation of T cell responses may represent reaction to various
events like 1) increased levels of wild type virus 2) mutant virus 3)
responses to withdrawal of immunologically modifying drugs e.g.
interferon, corticosteroids, cancer chemotherapy 4) independent
effects brought about by other hepatitis viruses, HIV infection or
bacterial infection. The initiating event that leads to spontaneous
flares is not clear.15
Spontaneous ALT flares occur in both HBeAg positive as
well as HBeAg negative, chronic CHB. The frequency of ALT flares
in e positive patients is 27% while it is 10% in e native? patients.
There is no difference in clinical features, biochemical characteristics,

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Table 1: Etiologic classification of acute flares in chronic HBV

Spontaneous reactivation of chronic hepatitis B
Reactivated hepatitis due to immunosuppressive medications
Cancer chemotherapy
Antirejection drugs
Corticosteroids
Resulting from antiviral therapy
Interferon
Nucleoside analogues
Corticosteroid withdrawal
Induced by HBV genotypic variation
Precore mutant
Core promoter mutant
HBV DNA polymerase mutant
Due to superimposed infections with other hepatotropic viruses
Hepatitis A virus
Hepatitis C virus
Hepatitis delta virus
Caused by interaction with HIV infection
Reactivated hepatitis
Effect of immune reconstitution therapy
Concurrent bacterial infection
Surgery
Emotional or physical stress
Pregnancy

ALT, serum bilirubin, alpha feto protein and histological findings

in patients of acute exacerbation in HBe positive and anti HBe
positive patients.16
The predictors of flares in chronic HBV infection are 1) male,
2) Age > 20, 3) HBeAg +ve 4) Base line ALT > 200.17
Twenty percent of patients have ALT flares in chronic HBV
infection due to super added viral infections. In India we found
25% acute viral hepatitis in HBsAg positive patients is due to
other hepatitis viruses.18 Mortality due to acute hepatitis A or
superimposed delta infection or hepatitis B and C co-infection is
significantly higher than monoinfected patients.19-21

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In our experience acute flares in chronic HBV infections

were seen in 45 patients over a period of six years. (N = 45,
M: F 4:1. Age range: 7-65 years with a mean of 38.5 years.)
The clinical presentations were jaundice, ascites, encephalopathy
and asymptomatic in 16, 10, 4 and 19 patients respectively. Half
of the patients with acute flares had underlying cirrhosis. Acute
flares were associated with spontaneous seroconversion in 15,
spontaneous sero-reversion in one, associated HEV infection in
six, HAV one, HCV three, two due to development of YMDD
mutation on lamivudine treatment, two due to interferon, two deaths
occurred during ALT flares.19 Details of the patients are shown in
Table 2: lamuvidine was successful in patients with acute flares of
chronic HBV infection when used in the early phase. It prevented
decompensation and fatality. When serum bilirubin levels rise over
20 mg/dl, antiviral treatment may not be useful.22
Acute flare is a well-known phenomenon during antiviral
therapy. Interferon induced flares are seen in 25 to 40% patients
with interferon treatment. Flares occur due to the stimulatory effect
of interferon, which is capable of increasing T cell cytolytic activity
and natural killer cell function. The flares occurred as? increased
numbers of CD8 +ve specific T lymphocytes. Predictors of flares
during the interferon treatment are 1) pre existing cirrhosis 2) initial
low levels of ALT. Thirty-six percent of flares are host induced,
36% are virus induced and 26% are indeterminate. Fifty-eight
percent of host-induced flares are seen in treatment responders
while 20% of the virus induced flares are seen in the treatment
responders.23
Flares in oral nucleotide/nucleoside analog treatment are
generally seen of treatment? due to viral rebound (10-20%),
emergence of viral strain resistant mutants to drugs, pre-core
mutant, and drug toxicity.24
While evaluating data on extended lamivudine treatment
in 85 patients (m:f 66:19, age range 5-85 years, HBeAg +ve 50,
HBeAg-ve 32, lamivudine treatment for 12-60 months), in the
long term hepatitis flares were seen in 8 out of 25 patients with
lamivudine resistance. These patients were successfully managed
with addition of adefovir.
For the management of HBV infection, in addition to interferon/

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Table 2: Acute flares in chronic HBV infection

Demographic features Clinical features
n = 45 (over 6 years) n = 45
Age = 38.35 years (mean) Jaundice: 16
(7 to 65 years range) Ascites: 10
M: F ratio = 4.06: 1 Encephalopathy: 4
Presence of cirrhosis: 22/45 Non specific symptoms: 19
or asymptomatic
Cause of flare n = 45
Spontaneous seroconversion 15
Spontaneous sero-reversion 1
Associated HEV 6
HAV 1
HCV 3
Development of SBP 2
Alcohol consumption 1
Surgery 1
YMDD mutant (on lamivudine) 2
On interferon 2
Drug related (AKT, antiepileptic, steroid) 6
No cause found (delta –ve) 5
Result of flare n = 45
Cleared HBsAg 1
Seroconversion (became HBeAg –ve) 17
Sero-reversion (became HBeAg +ve) 3
Same Serology 24
Death 2

Peg Interferon/Thymosin alpha, four oral antivirals like lamivudine,

adefovir, entecavir, Telbuvidine are licensed and Tenofovir and
emcetarabine are licensed for HIV and HBV co-infection. The
success rate of these antiviral agents does not exceed 30 to 40%;
in long term treatment and with prolonged therapy the menace
of antiviral resistance exists. The rate of mutations varies from
drug to drug and duration of treatment, and drug resistance is
a universal problem. Clinical consequences of resistance are (1)
decreased HBeAg clearance 2) reversal of histological improvement
3) increased rate of disease progression 4) exacerbation, clinical
decompensation or even death in patients with cirrhosis 5) risk of

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graft loss and death in liver transplant recipients 6) transmission

of drug resistance strain 7) vaccine failure mutation.
Antiviral drug resistance is a major problem in management
of chronic HBNV infection. Combining a second drug with no
cross-resistance at appropriate times seems to be the best policy
currently. A combination of two drugs with different resistance
profile looks ideal but clinical trials need to be done to confirm
the safety and efficacy of this approach.
Management of drug resistance: In compensated liver disease
either add a second drug to continued therapy with first drug or
switch to a second drug with a 1-2 month overlap. Stopping therapy
may be considered in patients if it appears that the original therapy
should not have been started e.g. in patients with very mild disease
careful monitoring is required. In cirrhosis, HIV/HBV co-infection,
liver transplant, continue first drug and add a second drug.25
In managing ALT flares in chronic HBV infection the following
precautions should be taken to identify flares at the earliest. All
patients with chronic HBV infection should be followed at periodical
intervals with liver function tests and HBV DNA levels. All patients
with chronic HBV infection should be tested and vaccinated for
hepatitis A. Potential hepatotoxic drugs should be avoided. To
avoid fatal flares due to interferon, this treatment should not be
given to patients with advanced liver disease. Oral nucleoside/
nucleotide treatment related flares can be effectively managed as
stated above. Flares occurring with immunosuppressive regimes can
be managed with concurrent administration of oral antiviral drugs
and continuing them for more than six months after withdrawal of
immune suppression.
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Source of Support: Nil, Conflict of Interest: None declared.

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