Pharmacokinetics of Piperaquine and Safety Profile of Dihydroartemisinin-Piperaquine Coadministered with Antiretroviral Therapy in Malaria-Uninfected HIV-Positive Malawian Adults

<jats:title>ABSTRACT</jats:title> <jats:p>There are limited data on the pharmacokinetic and safety profiles of dihydroartemisinin-piperaquine (DHA-PQ) among human immunodeficiency virus-infected (HIV-positive [HIV<jats:sup>+</jats:sup>]) individuals taking antiretroviral therapy (ART). In a two-step (parallel-group) pharmacokinetic trial with intensive blood sampling, we compared the area under the concentration-time curve from days 0 to 28 (AUC<jats:sub>0–28 days</jats:sub>) and the safety outcomes of piperaquine among malaria-uninfected HIV<jats:sup>+</jats:sup> adults. In step 1, half the adult dose of DHA-PQ was administered for 3 days as an initial safety check to four groups (<jats:italic>n</jats:italic> = 6/group) of HIV<jats:sup>+</jats:sup> adults (age ≥18 years): (i) antiretroviral-naive individuals, (ii) individuals on nevirapine-based ART, (iii) individuals on efavirenz-based ART, and (iv) individuals on ritonavir-boosted lopinavir-based ART. In step 2, a full adult treatment course of DHA-PQ was administered to a different cohort of participants in three groups: (i) antiretroviral-naive individuals, (ii) individuals on efavirenz-based ART, and (iii) individuals on nevirapine-based ART (<jats:italic>n</jats:italic> = 10 to 15/group). The ritonavir-boosted lopinavir-based ART group was dropped in step 2 due to the limited number of participants who were on this second-line ART and were eligible for recruitment. Piperaquine's AUC<jats:sub>0–28 days</jats:sub> in both steps was 43% lower among participants on efavirenz-based ART than among ART-naive participants. There were no significant differences in AUC<jats:sub>0–28 days</jats:sub> between the other ART groups and the ART-naive group in each of the two steps. Furthermore, no differences in treatment-emergent clinical and laboratory adverse events were observed across the groups in steps 1 and 2. Although it was well tolerated at the half and full standard adult treatment courses, the efavirenz-based antiretroviral regimen was associated with reduced piperaquine exposure, which may compromise dihydroartemisinin-piperaquine's effectiveness in programmatic settings. (The clinical trials presented in this study have been registered at the WHO's International Clinical Trials Registry Platform under ID numbers PACTR2010030001871293 and PACTR2010030001971409.)</jats:p>