Resistance characterization of ledipasvir and velpatasvir in hepatitis C virus genotype 4

J Viral Hepat. 2018 Feb;25(2):134-143. doi: 10.1111/jvh.12795. Epub 2017 Nov 7.

Abstract

HCV genotype 4 (GT4) has often been overlooked in drug development, even though it infects ~20 million people worldwide. Ledipasvir/sofosbuvir and sofosbuvir/velpatasvir were highly efficacious in GT4 HCV-infected patients from GS-US-337-1119 and GS-US-342-1138. Here, we characterize the resistance profile of ledipasvir (LDV) and velpatasvir (VEL) in patients with GT4 HCV infection. NS5A deep-sequencing was performed for 454 patients infected with HCV GT4 at baseline, including 44 patients enrolled in GS-US-337-1119 and 116 patients enrolled in GS-US-342-1138, and at relapse for patients with virologic failure. LDV and VEL susceptibilities of 56 patient isolates were determined. In GS-US-337-1119, SVR12 rates were 100% for all subtypes except 4b and 4r. Phenotypic assessment of 56 HCV NS5A patient isolates from various GT4 subtypes indicated that LDV had high potency for the common subtypes 4a/d, and subtypes 4c/f/k/l/m/n/o/p/r/t despite the presence of resistance-associated substitutions (RASs). For the rare GT4b, LDV median EC50 was higher, but with a broad range of individual values. Importantly, all GT4b isolates tested had 2-4 NS5A RASs, some including Y93H. Similarly, the 2 GT4r infected patients who had virologic relapse had rare triple RASs. Reversion of these substitutions to the consensus residue significantly increased LDV susceptibility. In GS-US-342-1138, all patients achieved SVR12, regardless of their subtype or presence of RASs. In vitro data confirmed that VEL is potent against all GT4 isolates tested. LDV and VEL are potent antiviral drugs, estimated to be effective against >95% and >99%, respectively, of GT4 HCV isolates.

Keywords: direct-acting antiviral; hepatitis C virus; ledipasvir; resistance; sofosbuvir; velpatasvir.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Antiviral Agents / pharmacology*
  • Benzimidazoles / pharmacology*
  • Carbamates / pharmacology*
  • Drug Resistance, Multiple, Viral / genetics*
  • Drug Therapy, Combination
  • Fluorenes / pharmacology*
  • Genotype
  • Hepacivirus / drug effects*
  • Hepacivirus / genetics*
  • Hepatitis C, Chronic / drug therapy
  • Hepatitis C, Chronic / virology
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Sequence Analysis, DNA
  • Sofosbuvir
  • Sustained Virologic Response
  • Uridine Monophosphate / analogs & derivatives*
  • Uridine Monophosphate / pharmacology
  • Viral Nonstructural Proteins / genetics

Substances

  • Antiviral Agents
  • Benzimidazoles
  • Carbamates
  • Fluorenes
  • Heterocyclic Compounds, 4 or More Rings
  • NS-5 protein, hepatitis C virus
  • Viral Nonstructural Proteins
  • ledipasvir, sofosbuvir drug combination
  • Uridine Monophosphate
  • velpatasvir
  • Sofosbuvir