NDLI: Characterization of Hepatitis C Virus (HCV) Quasispecies Dynamics upon Short-Term Dual Therapy with the HCV NS5B Nucleoside Polymerase Inhibitor Mericitabine and the NS3/4 Protease Inhibitor Danoprevir

Content Provider	PubMed Central
Author	Le, Pogam S. Yan, J. M. Chhabra, M. Ilnicka, M. Kang, H. Kosaka, A. Ali, S. Chin, D. J. Shulman, N. S. Smith, P. Klumpp, K. Nájera, I.
Copyright Year	2012
Abstract	In the INFORM-1 study, 73 patients with chronic hepatitis C virus infection received mericitabine plus danoprevir for up to 13 days. Seventy-two patients experienced a continuous decline in HCV RNA levels during treatment, and of these patients, 14 had viral loads that remained >1,000 IU/ml by day 13 and 1 met the definition for viral breakthrough. In-depth NS5B and NS3/4A population and clonal sequencing studies and mericitabine and danoprevir drug susceptibility testing were performed to assess the variability and quasispecies dynamics before and upon monotherapy or dual therapy. Sequence analysis of the viral quasispecies indicated that the mericitabine resistance mutation S282T was not present at baseline, nor was it selected (even at a low level) during treatment. Protease inhibitor resistance mutations, either as predominant or as minority species, were detected in 18 patients at baseline. No enrichment of minority protease inhibitor-resistant variants present at baseline was observed during treatment; viral population samples were fully susceptible to mericitabine and/or danoprevir, despite the presence within their quasispecies of minority variants confirmed to have reduced susceptibility to danoprevir or other protease inhibitors. It was also observed that certain NS3 amino acid substitutions affected protease inhibitor drug susceptibility in a compound-specific manner and varied with the genetic context. In summary, the slower kinetics of viral load decline observed in some patients was not due to the selection of danoprevir or mericitabine resistance during treatment. Over 2 weeks' therapy, mericitabine suppressed the selection of danoprevir resistance, results that could differ upon longer treatment periods.
Related Links	http://dx.doi.org/10.1128/aac.01035-12
Ending Page	5502
Page Count	9
Starting Page	5494
File Format	PDF
ISSN	00664804
e-ISSN	10986596
Journal	Antimicrobial Agents and Chemotherapy
Issue Number	11
Volume Number	56
Language	English
Publisher	American Society for Microbiology
Publisher Date	2012-11-01
Access Restriction	Open
Rights Holder	American Society for Microbiology
Subject Keyword	Pharmacology (medical) Pharmacology Infectious Diseases Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Infectious Diseases Pharmacology Pharmacology (medical)

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Characterization of Hepatitis C Virus (HCV) Quasispecies Dynamics upon Short-Term Dual Therapy with the HCV NS5B Nucleoside Polymerase Inhibitor Mericitabine and the NS3/4 Protease Inhibitor Danoprevir

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