Almost one third of HIV-infected individuals are co-infected with hepatitis C virus (HCV). Use of anti-HCV agents such as ledipasvir (LDV), a P-glycoprotein (Pgp) inhibitor, with HIV antiretrovirals (ARV) such as tenofovir alafenamide (TAF), a Pgp substrate, may be complicated by drug-drug interactions (DDIs). Two Phase 1 studies evaluated DDIs between TAF-based regimens rilpivirine (RPV; R)/emtricitabine (FTC; F)/TAF or elvitegravir/cobicistat/ FTC/TAF (E/C/F/TAF) and the fixed-dose combination anti-HCV LDV/sofusbuvir (SOF).
In two multiple-dose, randomized, crossover studies, healthy volunteers received R/F/TAF (25/200/25 mg) [Study 1] or E/C/F/TAF (150/150/200/10 mg) [Study 2]), alone or in combination with LDV/SOF, daily with food for 11 [Study 1] or 10 [Study 2] days.
Plasma concentrations of RPV, EVG, COBI, FTC, TAF and TFV (TAF metabolite), LDV, SOF and GS-331007 (SOF metabolite) were analyzed and PK parameters calculated via noncompartmental analysis. Geometric least squares mean ratio (GMR; combination vs. alone) and 90% confidence intervals (CI) for analytes' AUC, Cmax and Ctau were estimated by linear mixed effect modeling and compared to lack of alteration bounds (70-143% except RPV: 80-125%). Safety was assessed throughout the studies.
Forty of 42 subjects (Study 1) and 30/30 subjects (Study 2) completed study. Treatments were generally well tolerated.
The GMR and 90% CI for all analytes' PK parameters are:
GLSM and 90% CIs for all analytes were contained within the prespecified bounds except TFV when RPV/FTC/TAF was administered with LDV/SOF, COBI, when E/C/F/TAF was coadministered with LDV/SOV, and LDV and SOF when administered with E/C/F/TAF.
Despite increase in TFV exposure upon coadministration of R/F/TAF + LDV/SOF, the mean TFV AUCtau is ~ 5 times lower than TFV from TDF, and within the range of TFV that did not lead to renal AEs or bone loss (E/C/F/TAF Phase 3). There is no association between higher COBI exposure and incidence of AEs, renal function parameters (E/C/F/TAF Phase 2/3 data). Exposures of LDV and SOF, while higher, are in the exposure-safety range (data from LDV/SOF development program).
R/F/TAF or E/C/F/TAF may be coadministered with LDV/SOF without dose modification.
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P. S. Pang, Gilead Sciences, Inc.: Employee , Salary
M. Das, Gilead Sciences, Inc.: Employee and Shareholder , Salary
H. Cao, Gilead Sciences, Inc.: Employee , Salary
G. Ma, Gilead Sciences, Inc.: Employee , Salary
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J. Zack, Gilead Sciences, Inc.: Employee , Salary
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