Pharmacokinetic Interactions Between the HCV Inhibitors Elbasvir and Grazoprevir and HIV Protease Inhibitors Ritonavir, Atazanavir, Lopinavir, or Darunavir in Healthy Participants [Antiviral Agents]

The combination of the hepatitis C virus (HCV) NS5A inhibitor elbasvir and NS3/4A protease inhibitor grazoprevir is a potent, once-daily therapy indicated for the treatment of chronic HCV infection in individuals coinfected with human immunodeficiency virus-1 (HIV). We explored the pharmacokinetic interactions of elbasvir and grazoprevir with ritonavir and ritonavir–boosted HIV protease inhibitors in three phase 1 trials. Drug–drug interaction trials in healthy participants were conducted to evaluate the effect of ritonavir on the pharmacokinetics of grazoprevir (N = 10) and the potential 2-way pharmacokinetic interaction of elbasvir (N = 30) or grazoprevir (N = 39) when coadministered with ritonavir-boosted atazanavir, lopinavir, or darunavir. Coadministration of ritonavir with grazoprevir increased grazoprevir exposure: geometric mean ratio (GMR) for grazoprevir + ritonavir versus grazoprevir alone area under the concentration-time curve from 0 to 24 h (AUC_0-24) was 1.91 (90% confidence interval [CI]; 1.31 to 2.79). Grazoprevir exposure was markedly increased with coadministration of atazanavir/ritonavir, lopinavir/ritonavir, and darunavir/ritonavir, with GMRs for grazoprevir AUC_0-24 of 10.58 (7.78 to 14.39), 12.86 (10.25 to 16.13), and 7.50 (5.92 to 9.51), respectively. Elbasvir exposure was increased with coadministration of atazanavir/ritonavir, lopinavir/ritonavir, and darunavir/ritonavir, with GMRs for elbasvir AUC_0-24 of 4.76 (4.07 to 5.56), 3.71 (3.05 to 4.53), and 1.66 (1.35 to 2.05), respectively. Grazoprevir and elbasvir had little effect on atazanavir, lopinavir, and darunavir pharmacokinetics. Coadministration of elbasvir/grazoprevir with atazanavir/ritonavir, lopinavir/ritonavir, or darunavir/ritonavir is contraindicated owing to an increase in grazoprevir exposure. As such, HIV treatment regimens without HIV protease inhibitors should be considered in HCV/HIV-coinfected individuals who are treated with elbasvir/grazoprevir.

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