HIV-Positive Nigerian Adults Harbor Significantly Higher Serum Lumefantrine Levels than HIV-Negative Individuals Seven Days after Treatment for Plasmodium falciparum Infection

Abstract

e Management of coinfection with malaria and HIV is a major challenge to public health in developing countries, and yet potential drug-drug interactions between antimalarial and antiviral regimens have not been adequately investigated in people with both infections. Each of the constituent components of artemether-lumefantrine, the first-line regimen for malaria treatment in Nigeria, and nevirapine, a major component of highly active antiretroviral therapy, are drugs metabolized by the cytochrome P450 3A4 isoenzyme system, which is also known to be induced by nevirapine. We examined potential interactions between lumefantrine and nevirapine in 68 HIV-positive adults, all of whom were diagnosed with asymptomatic Plasmodium falciparum infections by microscopy. Post hoc PCR analysis confirmed the presence of P. falciparum in only a minority of participants. Day 7 capillary blood levels of lumefantrine were significantly higher in HIV-positive participants than in 99 HIV-negative controls (P ‫؍‬ 0.0011). Associations between day 7 levels of lumefantrine and risk of persistent parasitemia could not be evaluated due to inadequate power. Further investigations of the impact of nevirapine on in vivo malaria treatment outcomes in HIV-infected patients are thus needed.

Differential Impact of Nevirapine on Artemether-Lumefantrine Pharmacokinetics in Individuals Stratified by CYP2B6 c.516G>T Genotypes

“…influenced by CYP2B6 polymorphisms (14,20,36). The overall 30% higher exposure to lumefantrine when not stratified to CYP2B6 c.516GϾT genotypes is consistent with data from previous similar parallel design studies (29,(32)(33)(34). Kredo et al (29) recruited ART-naive patients as control and reported 56% significantly higher lumefantrine exposure.…”

“…Kredo et al (29) recruited ART-naive patients as control and reported 56% significantly higher lumefantrine exposure. Chijioke-Nwauche et al (32) recruited HIV-negative subjects as controls and obtained 29% higher day 7 plasma lumefantrine levels versus the observed 37% rise in the present study's day 6 plasma lumefantrine levels (C day 6 ). The Maganda et al (33) study in HIV-and malaria-coinfected patients recruited ART naive patients as control and reported 25% nonsignificantly higher lumefantrine exposure compared to the 30% rise obtained in this study.…”

“…In addition, data on the pharmacokinetic drug interactions between nevirapine and artemether-lumefantrine in HIV-infected patients have been inconsistent and conflicting, especially with respect to lumefantrine exposure (29)(30)(31)(32)(33)(34). While South African (29), Nigerian (32), and Tanzanian (33) studies and, recently, a Malawian-Ugandan (34) study reported increased lumefantrine exposures, a Ugandan study (30) and another Nigerian study (31) reported decreased exposures. Moreover, data on the impact of genetic polymorphisms on the drug-drug interactions between artemether-lumefantrine and nevirapine are sparse (35).…”

An Individual Participant Data Population Pharmacokinetic Meta-analysis of Drug-Drug Interactions between Lumefantrine and Commonly Used Antiretroviral Treatment

“…(8)(9)(10)(11)(12) Results are inconsistent in the few studies on October 5, 2020 by guest http://aac.asm.org/ Downloaded from investigating the effect of nevirapine-based ART on lumefantrine exposure, showing increased, decreased or no effect on lumefantrine exposure. (13)(14)(15)(16)(17)(18) Dolutegravir-based ART is being rapidly adopted as first-line HIV treatment; Dolutegravir is an HIV-integrase inhibitor reported to have minimal effects on CYP3A4 and a study has shown that DTGbased ART did not alter lumefantrine exposure significantly. (19,20) Additionally, no information is available on whether malaria or HIV disease may affect lumefantrine pharmacokinetics.…”

Development of an evidence evaluation and synthesis system for drug-drug interactions, and its application to a systematic review of HIV and malaria co-infection

“…Etravirine decreased lumefantrine AUC by 13%. [28] Unexpectedly, nevirapine was found to significantly increase exposure to lumefantrine in some studies, [31, 35, 38, 39]…”