Correspondence Address:
Deepak N Amarapurkar
Ameya Society, New Prabhadevi Road, Prabhadevi, Mumbai 400 025
India

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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 phases [4]



Immune tolerantImmune clearanceResidual - nonreplicativeReactivaton 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 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.

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],[6],[7]

Differential progression rate with HBV infection may be related to various clinical, serological and histological markers. [8],[9],[10],[11],[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, 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],[20],[21]

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/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 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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