Impact of Dolutegravir‐, Lopinavir/Ritonavir‐, and Efavirenz‐Based Antiretrovirals on Piperaquine Pharmacokinetics in Ugandan Children Living with <scp>HIV</scp>

Dihydroartemisinin–piperaquine is increasingly used for malaria treatment and chemoprevention in children with HIV co‐infection. Its efficacy and safety are associated with piperaquine exposure, which can be compromised by drug–drug interactions with antiretroviral therapy. In a prospective, open‐label study, we evaluated the pharmacokinetics of piperaquine following a 3‐day standard dihydroartemisinin–piperaquine regimen in malaria‐uninfected Ugandan children living with HIV receiving either dolutegravir‐, lopinavir/ritonavir‐, or efavirenz‐based antiretroviral therapies. Children without HIV aged 11–17 and 3–10 years were enrolled as control groups to match (a) the dolutegravir and (b) lopinavir/ritonavir and efavirenz groups, respectively ( n = 30 per group). Intensive pharmacokinetic sampling for piperaquine over 42 days was completed. Compared to controls, overall piperaquine exposure, as measured by area under the concentration–time curve from the 3 rd dihydroartemisinin–piperaquine dose to 42 days in the dolutegravir group was similar but terminal piperaquine concentrations were reduced by 32% on day 28 ( P = 0.02) and 64% on day 42 ( P &lt; 0.0001). In contrast, overall piperaquine exposure in the lopinavir/ritonavir group increased by 240% ( P &lt; 0.0001), with day 42 concentration increasing by 91% ( P &lt; 0.0001), while exposure with efavirenz was reduced by 69% ( P &lt; 0.0001), with day 42 concentration reducing by 92% ( P &lt; 0.0001). Electrocardiographic monitoring during co‐administration with lopinavir/ritonavir identified two transient grade 3 changes that resolved. Efavirenz and lopinavir/ritonavir have opposing effects on piperaquine exposure in children living with HIV, which may impact efficacy and toxicity, respectively, although co‐administration in this study did not yield concerning safety findings. Dolutegravir reduced only terminal concentrations significantly, which may shorten the duration of post‐treatment chemoprophylaxis.