Parasite Clearance and Artemether Pharmacokinetics Parameters Over the Course of Artemether-Lumefantrine Treatment for Malaria in Human Immunodeficiency Virus (HIV)-Infected and HIV-Uninfected Ugandan Children

Abstract

Background.Artemisinins are primarily responsible for initial parasite clearance. Antimalarial pharmacokinetics (PK), human immunodeficiency virus (HIV) infection, and antiretroviral therapy have been shown to impact treatment outcomes, although their impact on early parasite clearance in children has not been well characterized.Methods.Parasite clearance parameters were generated from twice-daily blood smears in HIV-infected and HIV-uninfected Ugandan children treated with artemether-lumefantrine (AL). Artemether and dihydroartemisinin (DHA) area-under-the-curve from 0–8 hours (AUC0-8hr) after the 1st AL dose was compared with AUC0-8hr after the last (6th) dose in a concurrently enrolled cohort. The association between post-1st dose artemisinin AUC0-8hr and parasite clearance was assessed.Results.Parasite clearance was longer in HIV-infected versus HIV-uninfected children (median, 3.5 vs 2.8 hours; P = .003). Artemether AUC0-8hr was 3- to 4-fold lower after the 6th dose versus the 1st dose of AL in HIV-infected children on nevirapine- or lopinavir/ritionavir-based regimens and in HIV-uninfected children (P ≤ .002, 1st vs 6th-dose comparisons). Children on efavirenz exhibited combined post-1st dose artemether/DHA exposure that was significantly lower than those on lopinavir/ritonavir and HIV-uninfected children. Multiple regression analysis supported that the effect of artemether/DHA exposure on parasite clearance was significantly moderated by HIV status.Conclusions.Parasite clearance rates remain rapid in Uganda and were not found to associate with PK exposure. However, significant decreases in artemisinin PK with repeated dosing in nearly all children, coupled with small, but significant increase in parasite clearance half-life in those with HIV, may have important implications for AL efficacy, particularly because reports of artemisinin resistance are increasing.

The Impact of Extended Treatment With Artemether-lumefantrine on Antimalarial Exposure and Reinfection Risks in Ugandan Children With Uncomplicated Malaria: A Randomized Controlled Trial

“…We also observed a notable decrease in artemisinin PK with repeated dosing. This aligns with previous studies and has been thought to be caused by CYP3A4 autoinduction (likely an intestinal first-pass effect) by artemether and/or recovery from malaria leading to improved bioavailability and absorption [ 35–40 ]. The clinical impact of declining artemisinin exposure with each dose is unclear.…”

Concomitant nevirapine impacts pharmacokinetic exposure to the antimalarial artemether-lumefantrine in African children

“…However, the reductions in the artemisinins with NVP as reported here may of concern and warrant further study to determine the correct dose in young children. Alteration of AL exposure may alter clinical outcomes[ 33 ]. A recent meta-analysis found a higher ARM dose was associated with a lower gametocyte presence within 14 days of treatment and authors suggested a higher AL dose should be accessed in young children[ 34 ].…”

Strong correlation of lumefantrine concentrations in capillary and venous plasma from malaria patients

“…HIV-uninfected non-pregnant adults were enrolled as the control group. Major findings from the parent study were published elsewhere, including clinical parameters relating to study drug administration and tolerance [ 9 – 11 ]. Here we report, for the first time, LF concentrations from simultaneously collected venous and capillary plasma samples at 2, 24, and 120hr post last dose in 152 children, 44 pregnant women, 32 non-pregnant adults.…”

“…Our study was part of a larger study evaluating the impact of antiretrovirals for HIV, age and pregnancy on AL pharmacokinetics and pharmacodynamics. The study was registered at clinicaltrials.gov as NCT01717885 [ 8 ] and reported previously [ 9 – 11 ].…”