Extended Treatment Duration of Artemether-Lumefantrine in Ugandan Children with HIV on Efavirenz-Based Antiretroviral Therapy: A Randomized Controlled Pharmacokinetic and Pharmacodynamic Trial.

Malaria and HIV co-infection are prevalent in sub-Saharan Africa causing significant drug interactions with co-treatment. We previously reported a 30%-70% reduction in exposure to the standard 3-day (6-dose) artemether-lumefantrine (AL) treatment for malaria when given with efavirenz-based HIV therapy, impacting malaria reinfection risk. We conducted a prospective, randomized study comparing the 3-day regimen to an extended 5-day (10-dose) regimen with pharmacokinetic sampling for artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine (DBL) over 42 days. The primary outcome was comparative pharmacokinetics between regimens compared among children with HIV and among children without HIV receiving a 3-day regimen as controls (median age 5.3 years [range 1.4-13.9]; median weight 17.3 kg [range 8.7-39.1]). Children with HIV (n = 57; median age 10.8 years [range 3.4-17.1]; median weight 26.6 kg [range 14.6-54.5]) contributed 76 malaria episodes, with 71 included in the analysis. Another 97 children without HIV (median age 5.3 years [range 1.4-13.9]; median weight 17.3 kg [range 8.7-39.1]) contributed 114 episodes of malaria, with 109 included in the analysis. In the setting of efavirenz, artemether, dihydroartemisinin, lumefantrine, and DBL cumulative exposure was 2.09, 2.31, 1.90, and 1.65 fold higher with 5-day versus 3-day AL (all P < .001), and comparable to 3-day AL in children without HIV. The extended regimen in children with HIV did not result in a statistically significant reduction in recurrence risk at 28 or 42 days. Extending the duration of AL to 5 days compensated for a clinically significant reduction in all components of AL in the context of EFV-based antiretroviral therapy in young children.