Virologic Resistance Analysis From a Phase 2 Study of MK-5172 Combined With Pegylated Interferon/Ribavirin in Treatment-Naive Patients With Hepatitis C Virus Genotype 1 Infection

• Published in: Clinical infectious diseases 2014-12, Vol.59 (12), p.1657-1665
• Main Authors: Howe, Anita Y. M., Black, Stuart, Curry, Stephanie, Ludmerer, Steven W., Liu, Rong, Barnard, Richard J. O., Newhard, William, Hwang, Peggy M. T., Nickle, David, Gilbert, Christopher, Caro, Luzelena, DiNubile, Mark J., Mobashery, Niloufar
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antivirals; ARTICLES AND COMMENTARIES; Biological and medical sciences; Drug resistance; Drug Resistance, Viral; Genotype; Genotype & phenotype; Genotypes; Hepacivirus; Hepatitis; Hepatitis C; Hepatitis C - drug therapy; Human viral diseases; Humans; Infections; Infectious diseases; Interferon; Interferons - therapeutic use; Medical sciences; Pharmacology. Drug treatments; Protease inhibitors; Quinoxalines - therapeutic use; Replicon; Ribavirin - therapeutic use; Ribonucleic acid; RNA; Sequencing; Viral diseases; Viral hepatitis; Virology; Viruses
• ISSN: 1058-4838; 1537-6591
• DOI: 10.1093/cid/ciu696

Background. Virologic failure following treatment of hepatitis C virus (HCV) genotype 1 with direct-acting antiviral agents is often accompanied by the emergence of resistant variants. MK-5172 is an investigational once-daily protease inhibitor. We analyzed variants in treatment-naive noncirrhotic patients with virologic failure on MK-5172 (100–800 mg/day) plus pegylated interferon alfa/ribavirin (peg-IFN/RBV) during a phase 2 trial. Methods. Population and selective clonal sequencing were performed at baseline and at virologic failure in the 4 MK-5172 dosing arms. MK-5172 activity was determined using a mutant replicon assay. Results. Six of 266 (2.3%) MK-5172 recipients satisfied prespecified criteria for virologic failure, all with genotype 1a infection. Five patients with virologic failure were in the MK-5172 100-mg arm, including 4 patients with low plasma MK-5172 levels documented during triple therapy. Variants associated with >4-fold loss of potency were detected in 3 of the 4 patients with genotype 1a breakthrough while on MK-5172. The fifth patient had undetectable HCV-RNA levels at the end of triple therapy but subsequently broke through during the peg-IFN/RBV tail 16 weeks after completion of MK-5172. Three patients had D168 variants at virologic failure, including 2 with the D168A variant associated with a 95-fold loss of potency. The sole apparent relapse was actually a genotype 3a reinfection in the MK-5172 200-mg group. Conclusions. Virologic failure occurred uncommonly (6/266 [2.3%]) in MK-5172/peg-IFN/RBV recipients. The most prevalent treatment-emergent variants were detected at the D168 locus. D168A variants conferring approximately 2-log reduction in MK-5172 susceptibility emerged in 2 of the 4 evaluable patients with genotype 1a breakthrough.