1. Sofosbuvir (SOF) Suppresses Ledipasvir (LDV)-resistant Mutants during SOF/LDV Combination Therapy against Genotype 1b Hepatitis C Virus (HCV)
- Author
-
Michael Neely, Lisa Zhao, Walter M. Yamada, Gary P. Wang, Layla Schuster, Jaime L. Rodriquez, Ashley N. Brown, George L. Drusano, Eric Li, and Lin Liu
- Subjects
0301 basic medicine ,Ledipasvir ,Combination therapy ,Sofosbuvir ,Genotype ,Hepatitis C virus ,030106 microbiology ,Population ,lcsh:Medicine ,Hepacivirus ,Biology ,medicine.disease_cause ,Antiviral Agents ,Article ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Resistance, Viral ,medicine ,Humans ,Drug Interactions ,030212 general & internal medicine ,Replicon ,education ,lcsh:Science ,education.field_of_study ,Fluorenes ,Multidisciplinary ,lcsh:R ,Hepatitis C ,Hepatitis C, Chronic ,Models, Theoretical ,medicine.disease ,Virology ,Combined Modality Therapy ,3. Good health ,chemistry ,lcsh:Q ,Benzimidazoles ,Drug Therapy, Combination ,Uridine Monophosphate ,medicine.drug - Abstract
Our objective was to identify drug interactions between ledipasvir (LDV) and sofosbuvir (SOF) against a genotype 1b replicon to determine optimal exposures for each agent that will maximize antiviral activity against susceptible and drug-resistant subpopulations. LDV and SOF were evaluated using a fully factorial experimental design in the BelloCell system. Replicon levels and drug-resistant variants were quantified at various times post-therapy for 14 days and a high-dimensional mathematical model was fit to the data. Mutations associated with SOF resistance were not detected; but LDV-resistant mutants were selected and mutant subpopulations increased as exposure intensity increased. Combination therapy was additive for the total replicon population and the LDV-resistant population, but a threshold concentration of 100 ng/ml of SOF must be attained to suppress LDV-resistant subpopulations. These novel findings hold important implications for not only improving therapeutic outcomes, but also maximizing the clinical utility of LDV and SOF combination regimens.
- Published
- 2017