Comparison of the Mechanisms of Drug Resistance among HIV, Hepatitis B, and Hepatitis C

Abstract

Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) are the most prevalent deadly chronic viral diseases. HIV is treated by small molecule inhibitors. HBV is treated by immunomodulation and small molecule inhibitors. HCV is currently treated primarily by immunomodulation but many small molecules are in clinical development. Although HIV is a retrovirus, HBV is a double-stranded DNA virus, and HCV is a single-stranded RNA virus, antiviral drug resistance complicates the development of drugs and the successful treatment of each of these viruses. Although their replication cycles, therapeutic targets, and evolutionary mechanisms are different, the fundamental approaches to identifying and characterizing HIV, HBV, and HCV drug resistance are similar. This review describes the evolution of HIV, HBV, and HCV within individuals and populations and the genetic mechanisms associated with drug resistance to each of the antiviral drug classes used for their treatment.

Keywords: HBV; HCV; HIV; antiviral therapy; drug resistance; evolution; quasispecies.

Figure 1

Phylogenetic Trees Created from HIV-1 Group M RT, HBV RT, and HCV Polymerase Sequences. The trees demonstrate the greater distances separating the HCV genotypes compared with those separating the HIV-1 group M subtypes and the HBV genotypes. Distances were calculated using the HKY85 substitution model with rate variation conforming to a gamma distribution. Trees were constructed using the neighbor-joining algorithm.

Figure 2

HCV NS3 Protease Variability and Protease Inhibitor (PI) Resistance Mutations. Alignment of NS3 residues 36 to 170 showing: (i) The consensus genotype 1a sequence and common variants in genotype 1 (GT1) and genotypes 2 to 6 (GT2–6) according to [277]; (ii) The active site residues are shaded blue-grey; (iii) The substrate binding site positions are shaded grey. The subsite numbering was derived from the following references: [–282]; (iv) Mutations selected by specific PIs and/or associated with decreased PI susceptibility are indicated beneath the alignment. Underlined positions have been reported to decrease susceptibility >10-fold. PI abbreviations: Telaprevir (TVR), boceprevir (BVR), danoprevir (R7227), and vaniprevir (MK-7009). TMC435 does not have a generic name.