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

Figure 1

Pooled incidence and distribution of preexisting primary and secondary reverse transcriptase mutations compiled using data from 50 previous studies. The distribution and overall incidence of RT region is presented; numbers indicate the pooled incidence rate of the RT mutation in a total of 8,435 treatment-naïve patients. ^aPre-existing RT mutation associated with the progression of HCC in treatment-naïve patients.

Figure 2

Pooled incidence and distribution of preexisting putative and pretreatment reverse transcriptase mutations compiled using data from 50 previous studies. The distribution and overall incidence of RT region is presented; numbers indicate the pooled incidence rate of the RT mutation in a total of 8435 treatment-naïve patients. ^aPre-existing RT mutation associated with the progression of HCC in treatment-naïve patients; ^bA-B interdomain region.

Figure 3

Schematic representation indicating the role of preexisting hepatitis B virus reverse transcriptase mutations in liver disease progression and treatment outcomes. HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; ASC: Asymptomatic carriers; CHB: Chronic hepatitis B; HIV: Human immunodeficiency virus.