Interaction between artemether-lumefantrine and nevirapine-based antiretroviral therapy in HIV-1-infected patients

Abstract

Artemether-lumefantrine and nevirapine-based antiretroviral therapy (ART) are the most commonly recommended first-line treatments for malaria and HIV, respectively, in Africa. Artemether, lumefantrine, and nevirapine are metabolized by the cytochrome P450 3A4 enzyme system, which nevirapine induces, creating potential for important drug interactions. In a parallel-design pharmacokinetic study, concentration-time profiles were obtained in two groups of HIV-infected patients: ART-naïve patients and those stable on nevirapine-based therapy. Both groups received the recommended artemether-lumefantrine dose. Patients were admitted for intense pharmacokinetic sampling (0 to 72 h) with outpatient sampling until 21 days. Concentrations of lumefantrine, artemether, dihydroartemisinin, and nevirapine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The primary outcome was observed day 7 lumefantrine concentrations, as these are associated with therapeutic response in malaria. We enrolled 36 patients (32 females). Median (range) day 7 lumefantrine concentrations were 622 ng/ml (185 to 2,040 ng/ml) and 336 ng/ml (29 to 934 ng/ml) in the nevirapine and ART-naïve groups, respectively (P = 0.0002). The median artemether area under the plasma concentration-time curve from 0 to 8 h [AUC((0-8 h))] (P < 0.0001) and dihydroartemisinin AUC((60-68 h)) (P = 0.01) were lower in the nevirapine group. Combined artemether and dihydroartemisinin exposure decreased over time only in the nevirapine group (geometric mean ratio [GMR], 0.76 [95% confidence interval {CI}, 0.65 to 0.90]; P < 0.0001) and increased with the weight-adjusted artemether dose (GMR, 2.12 [95% CI, 1.31 to 3.45]; P = 0.002). Adverse events were similar between groups, with no difference in electrocardiographic Fridericia corrected QT and P-R intervals at the expected time of maximum lumefantrine concentration (T(max)). Nevirapine-based ART decreased artemether and dihydroartemisinin AUCs but unexpectedly increased lumefantrine exposure. The mechanism of the lumefantrine interaction remains to be elucidated. Studies investigating the interaction of nevirapine and artemether-lumefantrine in HIV-infected patients with malaria are urgently needed.

Trial registration: ClinicalTrials.gov NCT00790881.

Figures

Fig. 1.

Lumefantrine plasma concentrations (μg/ml) over time in HIV-1-infected patients who are antiretroviral naïve or on nevirapine-based antiretroviral therapy. ART, antiretroviral therapy. The time (in hours) after the first dose of artemether-lumefantrine is shown.

Fig. 2.

Artemether and dihydroartemisinin plasma concentrations (ng/ml) over time after the first (0 to 8 h) and last (60 to 68 h) dosing occasion in HIV-1-infected patients who are antiretroviral naïve or on nevirapine-based antiretroviral therapy. ART, antiretroviral therapy; DHA, dihydroartemisinin. The time (in hours) after the first dose of artemether-lumefantrine is shown. (A) Points indicating concentration over time of artemether from 0 to 8 h after the initial dose of artemether-lumefantrine. (B) Points indicating concentration over time of artemether from 60 to 68 h after the initial dose of artemether-lumefantrine. (C) Points indicating concentration over time of dihydroartemisinin from 0 to 8 h after the initial dose of artemether-lumefantrine. (D) Points indicating concentration over time of dihydroartemisinin from 60 to 68 h after the initial dose of artemether-lumefantrine.