In vitro resistance profile of hepatitis C virus NS5A inhibitor velpatasvir in genotypes 1 to 6

Abstract

Hepatitis C virus (HCV) is estimated to infect 1% of the world population, corresponding to 71.1 million individuals. 1,2 Chronic HCV infection can lead to cirrhosis, hepatocellular carcinoma and other complications. HCV is classified into eight recognized genotypes based on viral genome sequence, each differing at 30%-35% of nucleotide sites, and into at least 68 confirmed and 20 provisional subtypes, differing at <15% of nucleotide sites within genotype. [3][4][5][6][7] The diversity of the HCV genome is a result of its high replication rate and the intrinsically error-prone RNA-dependent RNA polymerase, NS5B, that lacks a proofreading activity and makes AbstractVelpatasvir is a pan-genotypic hepatitis C virus (HCV) NS5A inhibitor, which is used with sofosbuvir for treatment of infection with HCV genotypes 1-6. In vitro resistance studies were performed to characterize NS5A changes that might confer reduced velpatasvir susceptibility in vivo. Resistance selection studies using HCV replicon cells for subtypes 1a, 1b, 2a, 2b, 3a, 4a, 5a and 6a identified NS5A resistance-associated substitutions (RASs) at nine positions, most often 28M/S/T, 31F/I/M/P/V and 93D/H/N/S. In subtype 1a, RASs were selected at positions 31 and/or 93, while in subtype 1b, replicons with two or more RASs at positions 31, 54 or 93 were selected.Y93H was selected in subtypes 1a, 1b, 2a, 3a and 4a. In subtype 5a or 6a, L31P or P32L/Q was selected, respectively. Velpatasvir susceptibility of 358 replicons from genotypes 1 to 6 containing one or more NS5A RASs was also evaluated. The majority (63%) of subtypes 1a and 1b single RAS-containing replicons retained susceptibility to velpatasvir (<2.5-fold change in EC 50 ). High levels of resistance to velpatasvir were observed for six single mutants in subtype 1a, including M28G, A92K, Y93H/N/ R/W and for one mutant, A92K, in subtype 1b. Most single mutants in subtypes 2a, 2b, 3a, 4a and 5a displayed low levels of reduced velpatasvir susceptibility. High-level resistance was observed for C92T and Y93H/N in subtype 2b, Y93H/S in 3a, and L31V and P32A/L/Q/R in 6a, and several double mutants in these subtypes. Overall, velpatasvir maintained activity against most common RASs that are known to confer resistance to first-generation NS5A inhibitors. K E Y W O R D Sdirect-acting antiviral, HCV, NS5A inhibitor, resistance, velpatasvir

Real‐world efficacy of sofosbuvir plus velpatasvir therapy for patients with hepatitis C virus‐related decompensated cirrhosis

“…Although NS5A-L31M has similar susceptibility to VEL as wild-type HCV, NS5A-L31M+Y93H RASs have 44-fold increased resistance to VEL relative to wild-type, based on analysis using a genotype 1b HCV replicon system. 16 Case 3 had NS5A-Y93H RASs before the treatment and acquired an additional L31V substitution at the time of HCV relapse. The NS5A-Y93H RAS confers only 3.3-fold resistance, but NS5A-L31V+Y93H has 510-fold resistance to VEL relative to wild-type HCV.…”

“…Amino acid positions related to resistance to VEL are shown based on analysis using HCV subgenomic replicon systems. [15][16][17]…”

Impact of an Open Access Nationwide Treatment Model on Hepatitis C Virus Antiviral Drug Resistance

“…( 37 ) The very high prevalence of Y93H among treatment failures is clinically important as Y93H confers high levels of resistance against most NS5A inhibitors, with a 3,500‐fold reduction in half‐maximal effective concentration (EC50) for daclatasvir and over 700‐fold reduction in EC50 for velpatasvir. ( 38 )…”

Consensus recommendations for resistance testing in the management of chronic hepatitis C virus infection: Public Health England HCV Resistance Group

“…The combination of sofosbuvir with the second generation NS5A inhibitor, velpatasvir, is licensed for treating genotypes 1-6. In vitro, RAS conferring high (>100x EC50) fold changes to velpatasvir include L31V and Y93C/H/N/R/W in genotype 1a, and L31V and Y93H/S in genotype 3a (46,51,52).…”