ArticleClinical pharmacology and therapeutics2023
Impact of Drug Exposure on Resistance Selection Following Artemether-Lumefantrine Treatment for Malaria in Children With and Without HIV in Uganda.
Article in Clinical pharmacology and therapeutics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
8 citing papers in PubMed, 1 synthesis or guideline pooled it, 9 citations in OpenAlex.
- Unraveling the HIV-malaria interactions: a bibliometric analysis of global research trends and emerging insights.Frontiers in microbiology · 2025Pooled it
- Persistent and multiclonal malaria parasite dynamics despite extended artemether-lumefantrine treatment in children.Nature communications · 2024Trial
- Impact of Dolutegravir-, Lopinavir/Ritonavir-, and Efavirenz-Based Antiretrovirals on Piperaquine Pharmacokinetics in Ugandan Children Living with HIV.Clinical pharmacology and therapeutics · 2026Article
- Preparation, characterization and pre-clinical evaluation of artemether-lumefantrine-paracetamol (AL-P) loaded nanocarriers in the treatment of malaria.Malaria journal · 2026Article
- Influence of genetic factors of humans, mosquitoes and parasites, on the evolution of Plasmodium falciparum infections, malaria transmission and genetic control methods: a review of the literature.BMC medical genomics · 2025Review
- Artemisinin-resistant malaria.Clinical microbiology reviews · 2024Review
- Polymorphisms in the Pfcrt, Pfmdr1, and Pfk13 genes of Plasmodium falciparum isolates from southern Brazzaville, Republic of Congo.Scientific reports · 2024Article
- Trends of Plasmodium falciparum molecular markers associated with resistance to artemisinins and reduced susceptibility to lumefantrine in Mainland Tanzania from 2016 to 2021.Malaria journal · 2024Article
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 3 countries.
Funding
Abstract
Artemisinin-based combination therapies (ACTs) are the primary treatment for malaria. 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-lumefantrine in HIV-uninfected and HIV-infected children living in a high-transmission region of Uganda. HIV-infected children were on efavirenz-, nevirapine-, or lopinavir-ritonavir-based antiretroviral regimens, with daily trimethoprim-sulfamethoxazole prophylaxis. We assessed selection for resistance in two key parasite transporters, pfcrt and pfmdr1, over 42-day follow-up and incorporated genotyping into a time-to-event model to ascertain how resistance genotype in relation to drug exposure impacts recurrence risk. Two hundred seventy-seven children contributed 364 episodes to the model (186 HIV-uninfected and 178 HIV-infected), with recurrent microscopy-detectable parasitemia detected in 176 episodes by day 42. The final model was a two-compartment model with first-order absorption and an estimated age effect on bioavailability. Systemic lumefantrine exposure was highest with lopinavir-ritonavir, lowest with efavirenz, and equivalent with nevirapine and HIV-uninfected children. HIV status and lumefantrine concentration were significant factors associated with recurrence risk. Significant selection was demonstrated for pfmdr1 N86 and pfcrt K76 in recurrent infections, with no evidence of selection for pfmdr1 Y184F. Less sensitive parasites were able to tolerate lumefantrine concentrations ~ 3.5-fold higher than more sensitive parasites. This is the first population PK model of lumefantrine in HIV-infected children and demonstrates selection for reduced lumefantrine susceptibility, a concern as we confront the threat to ACTs posed by emerging artemisinin resistance in Africa.
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Registered trials
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