Naturally occurring hepatitis B virus reverse transcriptase mutations related to potential antiviral drug resistance and liver disease progression

Abstract

The annual number of deaths caused by hepatitis B virus (HBV)-related disease, including cirrhosis and hepatocellular carcinoma (HCC), is estimated as 887000. The reported prevalence of HBV reverse transcriptase (RT) mutation prior to treatment is varied and the impact of preexisting mutations on the treatment of naïve patients remains controversial, and primarily depends on geographic factors, HBV genotypes, HBeAg serostatus, HBV viral loads, disease progression, intergenotypic recombination and co-infection with HIV. Different sensitivity of detection methodology used could also affect their prevalence results. Several genotype-dependent HBV RT positions that can affect the emergence of drug resistance have also been reported. Eight mutations in RT (rtL80I, rtD134N, rtN139K/T/H, rtY141F, rtM204I/V, rtF221Y, rtI224V, and rtM309K) are significantly associated with HCC progression. HBeAg-negative status, low viral load, and genotype C infection are significantly related to a higher frequency and prevalence of preexisting RT mutations. Preexisting mutations are most frequently found in the A-B interdomain of RT which overlaps with the HBsAg “a” determinant region, mutations of which can lead to simultaneous viral immune escape. In conclusion, the presence of baseline RT mutations can affect drug treatment outcomes and disease progression in HBV-infected populations via modulation of viral fitness and host-immune responses.

Keywords: Polymerase; Hepatocellular carcinoma; Reverse transcriptase; Preexisting mutations; Hepatitis B virus

Core tip: The prevalence of preexisting reverse transcriptase (RT) mutations in treatment-naïve patients largely depends on geographic factors, HBV genotypes, HBeAg serostatus, hepatitis B virus (HBV) viral loads, disease progression, intergenotypic recombination, co-infection with HIV and the method used for detecting the mutation. Genotype-dependent polymorphic amino acid substitutions in RT may affect the emergence of drug resistance, and genotype C exhibits relatively elevated spontaneous RT mutation rates. HBeAg-negative status and low viral loads are significantly associated with a higher frequency and prevalence of HBV preexisting RT mutations. Preexisting mutations are most frequently found in the A-B interdomain of RT, mutations of which can lead to simultaneous viral immune escape.