Exploratory trial of ombitasvir and ABT-450/r with or without ribavirin for HCV genotype 1, 2, and 3 infection

Abstract

In this study, ombitasvir and ABT-450/r ± RBV regimens were generally well-tolerated. Sustained virologic response was achieved in most patients with HCV genotype 1 or 2 infection, but low SVR rates were observed in HCV genotype 3-infected patients.

Substitutions at NS3 Residue 155, 156, or 168 of Hepatitis C Virus Genotypes 2 to 6 Induce Complex Patterns of Protease Inhibitor Resistance

“…Among substitutions at the highly conserved A156, A156G/S generally resulted in minor fitness impairment, whereas A156T/V resulted in strong fitness impairment. This is in line with previous studies, suggesting relatively high fitness of genotype 1a, 2a, and 6 A156S versus A156T/V variants in vitro and in vivo (13,(52)(53)(54), and the fact that A156G/S variants were frequently found in genotype 1 and, more recently, also in genotype 2 and 3 PI-treated patients (9,10,14,16,21,26). Changes at position 168, harboring a highly conserved glutamine in genotype 3 and aspartic acid in other genotypes, did not result in major fitness impairment for most genotypes, as was previously suggested for genotype 1 (52).…”

“…In line with our findings, a previous study suggested relatively high fitness of genotype 1a R155K/T versus R155G/Q variants in vitro (52). In addition, the fact that R155K was frequently found in genotype 1 and, more recently, also in genotype 2, 3, and 5 PI-treated patients indicates a relatively high fitness (9,10,14,16,18,21,26,53). Among substitutions at the highly conserved A156, A156G/S generally resulted in minor fitness impairment, whereas A156T/V resulted in strong fitness impairment.…”

“…However, efficient full-length recombinants currently are only available for genotypes 1a, 2a, and 2b (31,(44)(45)(46)(47)(48)(49). Recent reports indicate that HCV genotypes 2 to 6 acquire substitutions examined in this study de novo when subjected to PI treatment in vivo and in vitro (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). However, only a few studies have investigated the impact of such substitutions on PI resistance.…”

“…The likelihood with which a resistant variant is selected during treatment and persists following the end of treatment is determined by the degree of resistance and by the fitness of the specific variant (9). Recent reports suggest that genotypes 2 to 6 also acquire substitutions at NS3P positions 155, 156, and 168 during PI treatment; however, their impact on resistance to different PIs and on viral fitness has not been characterized systematically (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). In addition, substitutions at these positions are found at low frequency in treatment-naive HCVinfected patients (9,10,20,(27)(28)(29).…”

Hepatitis C Virus Genotype 1 to 6 Protease Inhibitor Escape Variants: In Vitro Selection, Fitness, and Resistance Patterns in the Context of the Infectious Viral Life Cycle

“…3) (28) are indicated by NA (not applicable). genotypes 2 to 6 (4,8), recent clinical and in vitro studies on selected genotypes and substitutions suggested that these patterns might be found across genotypes (50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65). Certain substitutions were preferentially acquired by specific recombinants, depending on the genetic barrier to resistance, as evidenced by the fact that the substitutions identified were encoded by a single nucleotide change.…”