Characterization of Hepatitis B Viral Drug Resistance inIndian Subcontinent Patients with Chronic Liver Disease.

Globally, an estimated two billion people are infected with hepatitis B virus (HBV) and around 350 million live with chronic infection. Approximately 75% of these patients reside in the Asia-Pacific region, India harbouring the second largest pool of about 50 million chronic HBV carriers. About 15% to 40% of HBV infected subjects develop complications leading to cirrhosis, decompensated cirrhosis and hepatocellular carcinoma (HCC) contributing to over 1 million deaths per year. Thus HBV associated liver diseases is considered to be of public health importance, emphasizing the need for the prevention and control of disease progression. Hepatitis B virus is a circular, partially double-stranded DNA virus of the family Hepadnaviridae. The virus is classified into 8 major genotypes and several subgenotypes with an intergenotypic diversity of 8% and intra-genotypic diversity of 4% respectively. These genotypes have known to show a geographical pattern in their distribution and have been used to trace the migration of populations from geographically distant regions. The HBV strains are also distinguished into nine major subtypes based on their antigenic determinants in the major hydrophilic region. Hepatitis B virus genotypes and subtypes have been reported to influence disease progression and treatment response. Therefore, determination of HBV genotypes and subtypes is important for disease monitoring and clinical outcome. The study aimed to characterize the antiviral resistance mutations in Indian subcontinent subjects with chronic hepatitis B. It was also aimed to identify the association between HBV genotypes, subgenotypes, subtypes and treatment outcome in these subjects. The antiviral efficacies of three widely used drugs in this country i.e., lamivudine, adefovir and entecavir were studied. In view of the limited potency and high resistance rates to lamivudine, our study emphasises the use of more potent drugs in the treatment of chronic hepatitis B to ensure an optimum virological response and prevent the progression of disease. Though the frequencies of adefovir resistance mutations are low, there is paucity in the proportion of subjects who showed virological response. Therefore, adefovir in the management of HBV should be used judiciously. Among the three drugs studied, entecavir seems to be a suitable drug of choice in the management of HBV. However, due to cost constraints long-term use of entecavir is implausible in resource limited countries like India. Our study has identified some baseline and on-treatment predictive factors of response and non-response. Our study has also revealed valuable information that would widen the scope of testing antiviral resistance mutations for appropriate tailoring of therapy. The absence of resistance mutations in most of the non-responders for all three drugs in our study subjects is contradictory to the expectation. We also show that HBV genotypes and subtypes do not influence treatment outcome to all three antiviral drugs studied. Further, based on the findings of this study we hypothesize that high viral genetic diversity, elevated baseline serum aminotransferases and spontaneous anti-HBe seroconversion (suggesting a high immune response) coupled with antiviral action play an effective role in clearing the viral infection. We also propose that future studies be directed towards extending the combination therapy approach to HBV, as currently practiced in the management of HIV infection.