Impact of Drug Exposure on Resistance Selection Following Artemether‐Lumefantrine Treatment for Malaria in Children With and Without HIV in Uganda

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.

Trends ofPlasmodium falciparummolecular markers associated with resistance to artemisinins and reduced susceptibility to lumefantrine in Mainland Tanzania from 2016 to 2021

“…to AL selecting the N86 allele [30][31][32]. There was a significant increase in both the 184F and NFD haplotypes over the years, and this might be linked to selection caused by lumefantr ine.…”

Persistent and multiclonal malaria parasite dynamics despite extended artemether-lumefantrine treatment in children

“…Our study consisted of an HIV-infected cohort of children on efavirenz-based antiretroviral therapy and daily TS prophylaxis, which is known to have antimalarial activity 2 . We previously described how HIV-infected children on efavirenz were at lower risk of recurrent malaria compared to HIV-uninfected children, despite significantly lower lumefantrine exposure, which we largely attributed to the protective effects of TS [59][60][61] . Surprisingly, we did not find an impact of HIVinfection (and thus TS prophylaxis) on parasite recurrence rates or densities throughout follow-up using 18S or SBP1-determined densities.…”

Diversity, Equity, and Inclusion: Translating Clinical Pharmacology for All

“…Equally important to appreciate for successful personalization of therapeutics and dosing across diverse populations is the multiplicity of intrinsic and extrinsic determinants of benefit/risk of drugs and our often incomplete understanding of the role of these factors, particularly in under-represented racial groups, as reviewed for direct oral anticoagulants by Thompson et al 13 With the exponential increase in our ability to harness multi-modal data and digital technologies, translation of our understanding of population sources of variability to precision dosing solutions for all patients is an opportunity for intelligent clinical decision support systems, as reviewed by Hughes et al 14 We are witnessing substantial progress in the science and technology required to develop EDITORIAL intelligent, continuously learning precision dosing systems driven by population pharmacology models built from clinical trial and real-world data in diverse populations. [14][15][16] Translating scientific and medical advances to equity in health care will, however, need to consider and address the critically important extrinsic factor of Social Determinants of Health through innovative health system, public health, and policylevel interventions, as eloquently discussed by Golden 17 -reflecting her compelling State of the Art lecture at the ASCPT 2022 Annual Meeting.…”