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Sofosbuvir (SOF) Suppresses Ledipasvir (LDV)-resistant Mutants during SOF/LDV Combination Therapy against Genotype 1b
Ashley N Brown1, Lin Liu2, Jaime L Rodriquez3
1Institute For Therapeutic Innovation, Department of Medicine, University of Florida, 6550 Sanger Road, Orlando, FL, 32827, United States. Ashley.Brown@medicine.ufl.edu.
Scientific Reports
|November 2, 2017
Summary
Ledipasvir and sofosbuvir combination therapy shows additive effects against HCV genotype 1b. A sofosbuvir threshold is needed to suppress ledipasvir-resistant mutants, optimizing treatment outcomes.
Area of Science:
- Hepatology
- Virology
- Pharmacology
Background:
- Hepatitis C virus (HCV) genotype 1b infection requires effective antiviral therapies.
- Ledipasvir (LDV) and sofosbuvir (SOF) are key components of direct-acting antiviral regimens.
- Understanding drug interactions and resistance is crucial for optimizing treatment efficacy.
Purpose of the Study:
- To investigate drug interactions between LDV and SOF against HCV genotype 1b.
- To determine optimal drug exposures for maximizing antiviral activity.
- To evaluate efficacy against susceptible and drug-resistant viral subpopulations.
Main Methods:
- Utilized a fully factorial experimental design in the BelloCell system.
- Quantified replicon levels and drug-resistant variants over 14 days.
- Applied a high-dimensional mathematical model to analyze treatment data.
Main Results:
- No sofosbuvir (SOF) resistance mutations were detected.
- Ledipasvir (LDV)-resistant mutants were selected and increased with higher exposure.
- Combination therapy demonstrated additive effects on total and LDV-resistant replicon populations.
- A SOF threshold concentration of 100 ng/ml is required to suppress LDV-resistant subpopulations.
Conclusions:
- Combination therapy with LDV and SOF is additive against HCV genotype 1b.
- Achieving a specific SOF concentration is critical for suppressing LDV-resistant variants.
- These findings can inform optimized dosing strategies for improved therapeutic outcomes and clinical utility.
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