Antiviral therapies: Focus on hepatitis B reverse transcriptase

Abstract

Hepatitis B virus (HBV) is the etiologic agent of mankind’s most serious liver disease. While the availability of a vaccine has reduced the number of new HBV infections, the vaccine does not benefit the approximately 350 million people already chronically infected by the virus. Most of the drugs approved by the FDA for the treatment of hepatitis B target the reverse transcriptase (RT or P gene product) and are nucleoside RT inhibitors (NRTIs) that suppress viral replication. However, prolonged monotherapies directed against a single target result in the emergence of viral resistance. HBV genotypic differences affect NRTI resistance, and because the reading frames of the S (surface antigen) and P genes partially overlap, genomic differences that affect the surface of the virus may also alter the viral polymerase sequence, function and drug susceptibility. The scope of this review is to assess the effects of HBV genotypic variation on the development of drug resistance to NRTIs. Some RT residues that vary among different genotypes are in the vicinity of residues that mutate and give rise to NRTI resistance. Interactions between these amino acids can help explain the effect of HBV genotype on the development of NRTI resistance during antiviral therapies, and might help in the design of improved therapeutic strategies.

Profile of Mutations in the Reverse Transcriptase and Overlapping Surface Genes of Hepatitis B Virus (HBV) in Treatment-Naïve Indonesian HBV Carriers

“…These RT domains are responsible for drug binding. The primary and secondary mutations have been shown to ensure that an antiviral drug would not work effectively because the mutations is associated with a change in the structure of the drug-binding region (33). Prolonged NA therapy favors the selection of putative NAr mutations that are associated with NAr or replication compensation.…”

Resistance mutations of hepatitis B virus in entecavir‐refractory patients

“…Hepatitis B virus (HBV), a member of the Hepadnaviridae family, has a partially double‐stranded 3.2‐kb DNA genome and comprises four open reading frames coding for hepatitis B surface antigen (HBsAg), core protein/hepatitis B e antigen (HBeAg), viral polymerase, and X protein 1, 2. Infection with this virus causes severe liver diseases, including acute, chronic, and fulminant hepatitis; cirrhosis; and hepatocellular carcinoma (HCC) 3.…”

Structural basis of HIV inhibition by translocation-defective RT inhibitor 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA)

“…Entecavir is the most potent anti-hepatitis B NRTI drug, and sofosbuvir is the most successful anti-hepatitis C virus nucleotide drug (1)(2)(3)(4)(5). 4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) extends this concept as an anti-HIV agent.…”