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It is essential to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ACTs in vulnerable populations at risk of suboptimal dosing. We developed a population PK\/PD model using data from our previous study of artemether\u2010lumefantrine in HIV\u2010uninfected and HIV\u2010infected children living in a high\u2010transmission region of Uganda. HIV\u2010infected children were on efavirenz\u2010, nevirapine\u2010, or lopinavir\u2010ritonavir\u2010based antiretroviral regimens, with daily trimethoprim\u2010sulfamethoxazole prophylaxis. We assessed selection for resistance in two key parasite transporters, <jats:italic>pfcrt<\/jats:italic> and <jats:italic>pfmdr1<\/jats:italic>, over 42\u2010day follow\u2010up and incorporated genotyping into a time\u2010to\u2010event model to ascertain how resistance genotype in relation to drug exposure impacts recurrence risk. Two hundred seventy\u2010seven children contributed 364 episodes to the model (186 HIV\u2010uninfected and 178 HIV\u2010infected), with recurrent microscopy\u2010detectable parasitemia detected in 176 episodes by day 42. The final model was a two\u2010compartment model with first\u2010order absorption and an estimated age effect on bioavailability. Systemic lumefantrine exposure was highest with lopinavir\u2010ritonavir, lowest with efavirenz, and equivalent with nevirapine and HIV\u2010uninfected children. HIV status and lumefantrine concentration were significant factors associated with recurrence risk. Significant selection was demonstrated for <jats:italic>pfmdr1<\/jats:italic> N86 and <jats:italic>pfcrt<\/jats:italic> K76 in recurrent infections, with no evidence of selection for <jats:italic>pfmdr1<\/jats:italic> Y184F. Less sensitive parasites were able to tolerate lumefantrine concentrations ~\u20093.5\u2010fold higher than more sensitive parasites. This is the first population PK model of lumefantrine in HIV\u2010infected children and demonstrates selection for reduced lumefantrine susceptibility, a concern as we confront the threat to ACTs posed by emerging artemisinin resistance in Africa.<\/jats:p>","DOI":"10.1002\/cpt.2768","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T15:33:59Z","timestamp":1666193639000},"page":"660-669","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Impact of Drug Exposure on Resistance Selection Following Artemether\u2010Lumefantrine Treatment for Malaria in Children With and Without <scp>HIV<\/scp> in Uganda"],"prefix":"10.1111","volume":"113","author":[{"given":"Katherine","family":"Kay","sequence":"first","affiliation":[{"name":"Metrum Research Group  Tariffville Connecticut 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