The Molecular and Structural Basis of HBV-resistance to Nucleos(t)ide Analogs

Abstract

Infection with hepatitis B virus (HBV) is a worldwide health problem. Chronic hepatitis B can lead to fibrosis, liver cirrhosis, and hepatocellular carcinoma (HCC). Management of the latter two conditions often requires liver transplantation. Treatment with conventional interferon or pegylated interferon alpha can clear the virus, but the rates are very low. The likelihood, however, of viral resistance to interferon is minimal. The main problems with this therapy are the frequency and severity of side effects. In contrast, nucleos(t)ide analogs (NAs) have significantly lower side effects, but require long term treatment as sustained virological response rates are extremely low. However, long term treatment with NAs increases the risk for the development of anti-viral drug resistance. Only by understanding the molecular basis of resistance and using agents with multiple sites of action can drugs be designed to optimally prevent the occurrence of HBV antiviral resistance.

Hepatitis B Virus Molecular Epidemiology, Host-Virus Interaction, Coinfection, and Laboratory Diagnosis in the MENA Region: An Update

“…The high prevalence of the HBV infection in the MENA region could be due to several factors (discussed below) including its genetic variability and heterogeneity. The genetic variability of HBV might be explained by its genome structure, which harbors a reverse transcriptase that facilitates the replication of the viral genomic DNA (Figure 1), due to the lack of proofreading mechanism of the HBV reverse transcriptase and high viral replication rate, which is around 1.4–3.6 × 10 −5 substitutions per nucleotide site per cell infection [53]. HBV mutation rates are 100 times higher than other DNA viruses (ranging from DNA 10 −8 to 10 −6 ) and almost similar to RNA viruses (ranging from 10 −6 and 10 −4 ) [54,55].…”

Mutational characterization of HBV reverse transcriptase gene and the genotype-phenotype correlation of antiviral resistance among Chinese chronic hepatitis B patients

“…ETV appears less likely to develop drug resistance due to its property of high barrier to resistance, which makes it be recommended as the first-line antiviral regimen at present. The classic ETV resistance mutations rtT184G/rtS202I/rtM250V will reduce susceptibility to ETV, only in conjunction with additional LMV resistance mutations, such as rtM204V/I [ 5 ].…”

Efficacy of hepatitis B virus ribonuclease H inhibitors, a new class of replication antagonists, in FRG human liver chimeric mice

“…However, these monotherapies very rarely eradicate the virus even though they greatly reduce HBV replication, hepatitis, and progression of fibrosis (Tong and Revill, 2016; Zeisel et al, 2015). Advantages of interferon α treatment include relatively frequent (~30%) seroconversion against the HBV e antigen (HBeAg) (Perrillo, 2009), limited treatment duration, negligible risk of development viral resistance, and slightly increased clearance of HBV with time (Gupta et al, 2014). However, side effects often limit its use.…”

“…Unfortunately, long-term treatment with NAs is required because viral titers almost always rebound upon drug removal (Tong and Revill, 2016). In addition, HBV’s high mutation rate (Caligiuri et al, 2016; Tong and Revill, 2016) can readily lead to drug resistance against the older NAs such as lamivudine (Gupta et al, 2014). Therefore, more efficient therapies are urgently needed.…”