title: CYP2B6*6 genotype and high efavirenz plasma concentration but not nevirapine are associated with low lumefantrine plasma exposure and poor treatment response in HIV-malaria-coinfected patients.
abstract: We investigated the influence of efavirenz (EFV)- or nevirapine (NVP)-based antiretroviral therapy (ART) on lumefantrine plasma exposure in HIV-malaria-coinfected patients and implication of pharmacogenetic variations. A total of 269 HIV patients with uncomplicated falciparum malaria on NVP-based ART (NVP-arm), EFV-based ART (EFV-arm) or not receiving ART (control-arm) were enrolled and treated with artemether-lumefantrine. Day-7 lumefantrine, baseline EFV and NVP plasma concentrations, and CYP2B6*6,*18, CYP3A4*1B, CYP3A5*3,*6,*7, ABCB1 c.3435C>T and ABCB1 c.4036A>G genotypes were determined. The median day-7 lumefantrine plasma concentration was significantly lower in the EFV-arm compared with that in NVP- and control-arm. High EFV plasma concentrations and CYP2B6*6/*6 genotype significantly correlated with low lumefantrine plasma concentrations and high rate of recurrent parasitemia. No significant effect of NVP-based ART on lumefantrine exposure was observed. In conclusion, owing to long-term CYP3A induction, EFV-based ART cotreatment significantly reduces lumefantrine plasma exposure leading to poor malaria treatment response, which is more pronounced in CYP2B6 slow metabolizers.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
authors.forename: B A
authors.initials: BA
authors.lastname: Maganda
authors.affiliation: Unit of Pharmacology and Therapeutics, School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
authors.forename: O M S
authors.initials: OM
authors.lastname: Minzi
authors.affiliation: Unit of Pharmacology and Therapeutics, School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
authors.forename: E
authors.initials: E
authors.lastname: Ngaimisi
authors.affiliation: Unit of Pharmacology and Therapeutics, School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
authors.forename: A A R
authors.initials: AA
authors.lastname: Kamuhabwa
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratory of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Aklillu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood* / Q000627:therapeutic use; D000962:Antimalarials / Q000097:blood* / Q000627:therapeutic use; D000077549:Artemether; D037621:Artemisinins / Q000097:blood / Q000627:therapeutic use; D048588:Benzoxazines / Q000097:blood* / Q000627:therapeutic use; D016022:Case-Control Studies; D060085:Coinfection; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004336:Drug Antagonism; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000097:blood* / Q000627:therapeutic use; D005449:Fluorenes / Q000097:blood* / Q000627:therapeutic use; D005838:Genotype; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D000078102:Lumefantrine; D008288:Malaria / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D019829:Nevirapine / Q000097:blood* / Q000627:therapeutic use; D011446:Prospective Studies
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000480:Alkynes; D019380:Anti-HIV Agents; D000962:Antimalarials; D037621:Artemisinins; D048588:Benzoxazines; D003521:Cyclopropanes; D004983:Ethanolamines; D005449:Fluorenes; D019829:Nevirapine; D000077549:Artemether; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D000078102:Lumefantrine; C098320:efavirenz