Antiretroviral Choice for HIV Impacts Antimalarial Exposure and Treatment Outcomes in Ugandan Children

Sunil Parikh, Richard Kajubi, Liusheng Huang, Joshua Ssebuliba, Sylvia Kiconco, Qin Gao, Fangyong Li, Moses Were, Abel Kakuru, Jane Achan, Norah Mwebaza, Francesca T Aweeka, Sunil Parikh, Richard Kajubi, Liusheng Huang, Joshua Ssebuliba, Sylvia Kiconco, Qin Gao, Fangyong Li, Moses Were, Abel Kakuru, Jane Achan, Norah Mwebaza, Francesca T Aweeka

Abstract

Background: The optimal treatment of malaria in human immunodeficiency virus (HIV)-infected children requires consideration of critical drug-drug interactions in coinfected children, as these may significantly impact drug exposure and clinical outcomes.

Methods: We conducted an intensive and sparse pharmacokinetic/pharmacodynamic study in Uganda of the most widely adopted artemisinin-based combination therapy, artemether-lumefantrine. HIV-infected children on 3 different first-line antiretroviral therapy (ART) regimens were compared to HIV-uninfected children not on ART, all of whom required treatment for Plasmodium falciparum malaria. Pharmacokinetic sampling for artemether, dihydroartemisinin, and lumefantrine exposure was conducted through day 21, and associations between drug exposure and outcomes through day 42 were investigated.

Results: One hundred forty-five and 225 children were included in the intensive and sparse pharmacokinetic analyses, respectively. Compared with no ART, efavirenz (EFV) reduced exposure to all antimalarial components by 2.1- to 3.4-fold; lopinavir/ritonavir (LPV/r) increased lumefantrine exposure by 2.1-fold; and nevirapine reduced artemether exposure only. Day 7 concentrations of lumefantrine were 10-fold lower in children on EFV vs LPV/r-based ART, changes that were associated with an approximate 4-fold higher odds of recurrent malaria by day 28 in those on EFV vs LPV/r-based ART.

Conclusions: The choice of ART in children living in a malaria-endemic region has highly significant impacts on the pharmacokinetics and pharmacodynamics of artemether-lumefantrine treatment. EFV-based ART reduces all antimalarial components and is associated with the highest risk of recurrent malaria following treatment. For those on EFV, close clinical follow-up for recurrent malaria following artemether-lumefantrine treatment, along with the study of modified dosing regimens that provide higher exposure, is warranted.

Keywords: HIV; antimalarial; antiretroviral; malaria; pharmacokinetics.

© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Plasma concentration-time profile of artemether (A), dihydroartemisinin (DHA) (B), and lumefantrine (C) in human immunodeficiency virus (HIV)-uninfected (no antiretroviral therapy [ART]) and HIV-infected children (stabilized on either an efavirenz [EFV]-, nevirapine [NVP]-, or lopinavair/ritonavir [LPV/r]–based regimen). Data are represented as median, and values below the limit of quantitation (BLQ) are shown.
Figure 2.
Figure 2.
Cumulative risk of recurrent malaria by day 42 following treatment with artemether-lumefantrine stratified by human immunodeficiency virus (HIV) status and antiretroviral therapy regimen. Includes children from intensive and sparse cohorts. Risk-adjusted for repeated measures, age, parasite density, and hemoglobin on day 0. Abbreviations: EFV, efavirenz; LPV/r, lopinavir/ritonavir; NVP, nevirapine.
Figure 3.
Figure 3.
Cumulative risk of recurrent malaria by day 42 following treatment with artemether-lumefantrine stratified by human immunodeficiency virus (HIV) status and a day 7 lumefantrine concentration of 200 ng/mL. Includes children from intensive and sparse cohorts. Risk-adjusted for repeated measures, age, parasite density, and hemoglobin on day 0.

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