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

B A Maganda; O M S Minzi; E Ngaimisi; A A R Kamuhabwa; E Aklillu

doi:10.1038/tpj.2015.37

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

Pharmacogenomics J. 2016 Feb;16(1):88-95. doi: 10.1038/tpj.2015.37. Epub 2015 May 12.

Authors

B A Maganda¹, O M S Minzi², E Ngaimisi², A A R Kamuhabwa², E Aklillu³

Affiliations

¹ Department of Pharmaceutics, School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
² Unit of Pharmacology and Therapeutics, School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
³ Division of Clinical Pharmacology, Department of Laboratory of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

PMID: 25963334
DOI: 10.1038/tpj.2015.37

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / genetics
ATP Binding Cassette Transporter, Subfamily B / metabolism
Alkynes
Anti-HIV Agents / blood*
Anti-HIV Agents / therapeutic use
Antimalarials / blood*
Antimalarials / therapeutic use
Artemether
Artemisinins / blood
Artemisinins / therapeutic use
Benzoxazines / blood*
Benzoxazines / therapeutic use
Case-Control Studies
Coinfection
Cyclopropanes
Cytochrome P-450 CYP2B6 / genetics*
Cytochrome P-450 CYP2B6 / metabolism
Cytochrome P-450 CYP3A / genetics
Cytochrome P-450 CYP3A / metabolism
Drug Antagonism
Drug Therapy, Combination
Ethanolamines / blood*
Ethanolamines / therapeutic use
Fluorenes / blood*
Fluorenes / therapeutic use
Genotype
HIV Infections / complications
HIV Infections / drug therapy*
HIV Infections / genetics
Humans
Lumefantrine
Malaria / complications
Malaria / drug therapy*
Malaria / genetics
Nevirapine / blood*
Nevirapine / therapeutic use
Prospective Studies

Substances

ABCB1 protein, human
ATP Binding Cassette Transporter, Subfamily B
Alkynes
Anti-HIV Agents
Antimalarials
Artemisinins
Benzoxazines
Cyclopropanes
Ethanolamines
Fluorenes
Nevirapine
Artemether
Cytochrome P-450 CYP2B6
Cytochrome P-450 CYP3A
Lumefantrine
efavirenz