Overlooking these factors places children at greater risk of poor treatment outcomes, including increasing rates of reinfection in highly endemic regions, and of greater concern, the potential for treatment failure and ACT resistance. In addition, use of trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis further impacts one's risk of malaria. HIV infection impairs antimalarial immunity, and if untreated, increases malaria morbidity and mortality. Developmental changes in pharmacokinetics in children are often ignored, and concomitant ACT and ART results in drug–drug interactions that may have significant treatment effects. Optimally treating malaria and HIV in children requires consideration of complex biological and pharmacological factors that impact artemisinin-based combination therapy (ACT). Despite reduced mother-to-child transmission, an estimated 2 million HIV-infected children will reside in sub-Saharan Africa in 2020. For children aged ≥3 years, including adolescents, efavirenz (EFV) is preferred, and NVP is the alternative. Currently, a lopinavir/ritonavir (LPV/r)–based regimen is recommended as first-line in children <3 years, or, if this is not feasible, a nevirapine (NVP)–based regimen. Access to antiretroviral therapy (ART) has expanded, and the WHO recommends that all children receive ART. Sub-Saharan Africa is also home to 25 million people with HIV 2.9 million are children aged <15 years. Although malaria deaths have declined, a substantial burden remains, reflected in malaria infection rates of up to 6 episodes per person year in HIV-uninfected children in Eastern Uganda. The World Health Organization (WHO) estimated 198 million malaria cases and 584 000 malaria-related deaths in 2013, with 90% occurring in sub-Saharan Africa. Malaria and human immunodeficiency virus infection (HIV) impose extensive and overlapping burdens in sub-Saharan Africa. (See the Editorial Commentary by Fehintola, Adedeji, and Morse on pages 423–4.) Malaria, HIV, antimalarial, antiretroviral, pharmacokinetics 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. EFV-based ART reduces all antimalarial components and is associated with the highest risk of recurrent malaria following treatment. 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. 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.Ĭonclusions.
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. One hundred forty-five and 225 children were included in the intensive and sparse pharmacokinetic analyses, respectively.
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. 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. We conducted an intensive and sparse pharmacokinetic/pharmacodynamic study in Uganda of the most widely adopted artemisinin-based combination therapy, artemether-lumefantrine. 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.
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