Institute For Therapeutic Innovation, Department of Medicine, University of Florida, 6550 Sanger Road, Orlando, FL, 32827, United States. Ashley.Brown@medicine.ufl.edu.
Infectious Diseases and Global Medicine, University of Florida, Gainesville, FL, United States.
Institute For Therapeutic Innovation, Department of Medicine, University of Florida, 6550 Sanger Road, Orlando, FL, 32827, United States.
Medical Service, North Florida/South Georgia Veterans Health System, Gainesville, FL, United States.
Laboratory of Applied Pharmacokinetics and Bioinformatics (LAPKB), Children's Hospital Los Angeles Saban Research Institute, Los Angeles, CA, United States.
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.