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Inadequate and/or inappropriate host immune responses, are mainly responsible for the liver disease of chronic hepatitis B. Infection of the hepatocyte with the hepatitis B virus (HBV) results in very high levels of viral replication without actually killing the infected cell directly. The HBV uses reverse transcription to copy its DNA genome and because of a lack of proof-reading capability, mutant viral genomes or quasi species, emerge continually. All the selection pressures, both endogenous (host immune clearance) and exogenous (vaccines and antiviral drugs), readily select particular quasispecies with increased replication fitness, which then emerge as the new dominant population. The specific viral mutations or combination of mutations that play a role in the final clinical outcome of HBV infection are not fully known, but certain patterns and associations are starting to emerge. In particular, the expression of a novel protein, the hepatitis B splice protein (HBSP), has been linked to liver fibrosis and liver disease progression. Further studies are needed to identify the molecular pathological basis and subsequent clinical sequelae arising from the selection of these quasispecies in infected individuals.

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Hepatitis B virus (HBV) infection is caused by a small enveloped DNA virus that infects the liver. Approximately 2 billion people of the world have been infected by HBV and 300-350 million of them are chronically infected with the virus. The annual global mortality rate from HBV infection and its sequelae is 1-2 million people. Control of HBV infection is a major challenge of contemporary virology, hepatology, immunology, and vaccinology. There are two important aspects of this problem. The first is the prevention of new HBV infection. Transmission of HBV from HBV-infected persons to uninfected healthy individuals can be blocked by interrupting the transmission cycle of the virus. But, this is extremely hard and time-consuming, especially in view of the socio-economic status and health care delivery system of most of the developing nations, where HBV carrier rate is high. Another practical solution to this problem is by immunoprophylaxis using vaccines against hepatitis B. Commercially available hepatitis B vaccines induce protective antibody against HBV in more than 90% of apparently healthy individuals. However, these vaccines are ineffective in about 5-10% of normal individuals, most immunosuppressed subjects and also in liver transplanted patients with HBV background. Accordingly, a more potent prophylactic vaccine against HBV is needed. The concept of using vaccine for treatment of chronic diseases (vaccine therapy) has existed for quite a long time, but very few clinical trials with vaccine therapy have been conducted to assess their efficacy and clinical usage. During the last decade, some studies have reported the use of hepatitis B vaccine to treat patients with chronic hepatitis B. The present regimen of vaccine therapy for patients with chronic hepatitis B is safe, but is not very effective as an independent therapeutic tool. This article reviews the development of more potent prophylactic vaccines against HBV and better regimens of therapeutic vaccines for patients with chronic hepatitis B with special reference to the recent developments in the relevant fields.

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Nucleot(s)ide analogues are making milestones in the treatment of chronic hepatitis B (CHB). Lamivudine was approved by FDA for the treatment of chronic hepatitis B in adult patients n 1998 (Zeffix^TM Heptodin^TM Heptovir^TM Epivir-HBV^TM Glaxo Wellcome). Adefovir dipivoxil was approved by FDA in 2002 (Hepsera, Gilead). Both were licensed and available in many countries. A comparison of their efficacy in the treatment of various subgroups of CHB patients will facilitate management decision and choice between these two agents. Lamivudine suppresses viral replication and reduces serum HBV DNA level by 3-4 log ₁₀ after one year of therapy, associated with normalization of serum alanine aminotansferase and significant improvement in histologic activity index. In HBeAg positive CHB, HBeAg loss/seroconversion rate at the end of one year of therapy is 18-30%; higher pretreatment serum alanine aminotransferase (ALT) level is associated with higher HBeAg loss/ seroconversion. HBeAg loss/seroconversion increases on extended therapy. The durability of response off therapy declines with time. Clinical efficacy in HBeAg negative CHB is similar. However, the drawback of Lamivudine therapy is increasingly being recognized. The endpoint for therapy is difficult to define and viral response is often not durable. Long-term therapy runs the risk of emergence of lamivudine resistant mutants (YMDDm) at the rate of around 15-30% each year, with a cumulative 70% at the end of year 4. YMDDm viraemia is eventually associated with relapse of hepatitis and occasionally hepatic decompensation. In patients with maintained or sustained response, there was significant improvement in necroinflammatory activity. Reversion of fibrosis has also been observed. In patients with advanced fibrosis and cirrhosis, three years of Lamivudine therapy reduced disease progression and possibly reduced occurrence of hepatocellular carcinoma. Lamivudine has also established its role for patients with hepatic decompensation pending liver transplantation, HBsAg positive patients receiving chemotherapy or organ transplantation. Its role in CHB children and viraemic CHB pregnant mothers is less certain. The clinical benefit of Adefovir dipivoxil was initially recognized in patients with Lamivudine resistant YMDD mutants. Subsequent pivotal phase 3 placebo-controlled trials showed significant antiviral activity against both wild type and HBeAg negative HBV. Adefovir dipivoxil 10 mg daily showed significant clinical benefit in normalization of serum ALT and histologic improvement in both HBeAg positive and HBeAg negative CHB. One important advantage of Adefovir dipivoxil over Lamivudine in long term therapy is the much lower rate of emergence of drug resistant mutants. No resistant mutation was detected at the end of first year of therapy and around 15% at the end of four years. It has good safety profile except for possible reversible renal toxicity which has been reported in isolated patients on the 10mg dosage. Data and clinical experience in other patient subgroups are pending.

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