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Chronic hepatitis in humans that is modulated by host immunity, might lead to development of liver cirrhosis and hepatocellular carcinoma. To understand virological basis of chronic hepatitis we studied HBV genetic diversity, drug resistance and immune escape mutations at different disease phases associated with Hepatitis B. We reported temporal changes in genetic composition of the HBV population using whole-genome sequences and identified recent introduction of HBV Genotype C, possibly linked with disease severity and HCC. We have characterized 4 subgenotypes of HBV/D (the predominant genotype in India) with differential mutation pattern and liver injury; identified a new subgenotype D5 by whole genome sequencing as well as establishing specific mutations as significant predictor of cirrhosis. Moreover we have also highlighted the significance of HBV genotypes vis-á-vis hepatocarcinogenesis. Our investigation has provided significant new information regarding the different disease phases of hepatitis B, established that differences exist between HBV variants found in peripheral blood mononuclear cells and plasma. We have also documented the compartmentalization of specific HBV variants in the peripheral blood mononuclear cells; indicating occurrence of HBV evolution in a compartment and disease phase-specific fashion as well as the possibility of independent evolution of HBV in PBL and liver. Another area of interest is Occult HBV infection, we found its high prevalence among blood donors & family points to the need for donor-screening by antiHBc-testing. We reported HBV to be the major co-infection among HIV infected, establishing HBeAg positivity as effective marker for starting anti-HBV treatment in resource-poor settings. Further our work has located the influx of HBV/D2 genotype from western to eastern India along with HIV. In HIV HBV co-infection, highly immune-suppressed patients infected with most prevalent HBV genotype were found to have lower rate of plasma-circulating HBV mutants compared to those with mild immunosuppression. The use of antiretroviral with a consequent immune restoration might therefore predispose the emergence of HBV immune/therapy escape mutants in them. Interestingly, the reverse was true for emergence of mutants in the next commons subgenotype; possibly associated with the differential expression pattern of innate/adaptive immune response genes with varying CD4 count. Our current study has established positive correlation of microRNA-155 with TLR7 in HBV infection and reported that onco and tumor suppressor microRNA are differentially modulated by hepatitis B virus X protein in malignant hepatocytes.