Efavirenz but Not Atazanavir/Ritonavir Significantly Reduces Atovaquone Concentrations in HIV-Infected Subjects

Background. The current study was conducted to determine if efavirenz (EFV) or atazanavir/ritonavir (ATV/r)-based combination antiretroviral therapy (cART) impacted steady-state atovaquone plasma concentrations in human immunodeficiency virus (HIV)-infected patients receiving treatment doses of atovaquone. Methods. Thirty HIV-infected volunteers were recruited, 10 taking no cART and 10 each taking cART that included EFV or ATV/r. Subjects were randomly assigned to atovaquone 750 mg twice daily (BID) for 14 days followed by atovaquone 1500 mg BID for 14 days, or vice-versa, with a washout period in between. On day 14 of each phase, blood was sampled for pharmacokinetic studies, and the area under the concentration-time curve (AUC_τ) and average concentration (C_avg) were calculated and compared using an unpaired t test. Results. Twenty-nine subjects completed both dosing cohorts. Subjects receiving EFV-based cART had 47% and 44% lower atovaquone AUC_τ than subjects not receiving cART at atovaquone doses of 750 mg BID and 1500 mg BID, respectively (P ≤. 01). Only 5 of 10 subjects receiving EFV-based cART plus atovaquone 750 mg BID had an atovaquone C_avg >15 μg/mL, which has previously been associated with successful treatment of Pneumocystis jiroveci pneumonia. AUC_τ and C_avg did not significantly differ for concurrent ATV/r for 750 mg BID or 1500 mg BID when compared to the group not receiving cART. Nine of 10 subjects not receiving cART, 8 of 10 subjects receiving ATV/r, and 2 of 10 subjects receiving EFV in combination with atovaquone 750 mg BID achieved an atovaquone C_avg >18.5 μg/mL, a concentration that has previously been associated with successful treatment of Toxoplasma encephalitis (TE). Conclusions. These data suggest that the currently recommended dose of atovaquone 750 mg BID for treatment of mild to moderate PCP may not be adequate in patients receiving concurrent EFV. Furthermore, doses lower than the currently recommended dose of 1500 mg BID may achieve plasma concentrations adequate to treat TE in HIV-infected patients not receiving EFV.