Pharmacokinetics and safety profile of artesunate-amodiaquine co-administered with antiretroviral therapy in malaria uninfected HIV-positive Malawian adults.

There are limited data on the pharmacokinetic and safety profiles of artesunate-amodiaquine in human immnunodeficiency virus infected (HIV+) individuals receiving antiretroviral therapy. In a two-step intensive sampling pharmacokinetic trial, we compared area under the concentration time curve from 0 to 28 days (AUC0-28 days) of an active metabolite of amodiaquine, desethylamodiaquine, and treatment-emergent adverse events between antiretroviral therapy naive HIV+ adults and those taking nevirapine and ritonavir-boosted lopinavir-based antiretroviral therapy. In step 1, malaria uninfected adults (n=6/arm) received half the standard adult treatment regimen of artesunate-amodiaquine. In step 2, another cohort (n=25/arm) received the full regimen. In step 1, there were no safety signals and significant differences in desethylamodiaquine AUC0-28 days among participants in the ritonavir-boosted lopinavir, nevirapine and antiretroviral therapy-naive arms. In step 2, compared with the antiretroviral therapy-naive arm, participants in the ritonavir-boosted lopinavir arm had 51% lower desethylamodiaquine AUC0-28 days, (geometric mean [95% CI]; 23,822 [17,458-32506] vs 48,617 [40,787-57,950] ng.hr/mL, p < 0.001). No significant differences in AUC0-28 days were observed

between nevirapine and antiretroviral therapy-naïve arms. Treatment-emergent transaminitis was higher in the nevirapine (20% [5/25]) than the antiretroviral therapy naïve (0.0% [0/25]) arm (risk difference 20% [95% CI:4.3-35.7] p=0.018). Ritonavir-boosted lopinavir antiretroviral

regimen was associated with reduced desethylamodiaquine exposure which may compromise artesunate-amodiaquine’s efficacy. Co-administration of nevirapine and artesunate amodiaquine may be associated with hepatoxicity.