CYP2B6 variants and plasma efavirenz concentrations during antiretroviral therapy in Port-au-Prince, Haiti.
BACKGROUND
Polymorphisms in CYP2B6 are known to predict increased steady-state plasma concentrations of efavirenz. We characterized relationships between genetic polymorphisms and plasma efavirenz concentrations among 45 Haitians who initiated antiretroviral therapy in Port-au-Prince.


METHODS
An observational study characterized relationships between clinical factors, pharmacokinetics, and treatment response among antiretroviral-naive patients initiating once-daily treatment with efavirenz plus twice-daily treatment with zidovudine and lamivudine. Plasma drug concentrations were determined at weeks 2 and 4. Drug doses were directly observed by field workers or designated family members. We retrospectively characterized relationships between efavirenz concentrations and 50 single-nucleotide polymorphisms in CYP2B6 and several polymorphisms in CYP2A6, CYP3A4, CYP3A5, and ABCB1.


RESULTS
Plasma specimens for efavirenz analysis were obtained from study participants a mean (+/- standard deviation) of 13.9 +/- 1.6 h after they received the dose. As expected, CYP2B6 516G-->T was associated with increased plasma efavirenz concentrations (Spearman rho = 0.71; P < .001), as were 10 polymorphisms in linkage disequilibrium with 516G-->T. Distinct CYP2B6 polymorphisms were associated with decreased plasma efavirenz concentrations (greatest absolute rho = 0.48; P = .001). Associations were replicated by results from a recent pharmacokinetic study involving 34 healthy, human immunodeficiency virus-negative African Americans.


CONCLUSIONS
Relatively frequent CYP2B6 polymorphisms may predict decreased plasma efavirenz exposure in patients of African descent. If replicated in other cohorts, the implications of these novel associations for treatment response warrant further study.
Leger
Paul
P
Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes, 33 Boulevard Harry Truman, Port-au-Prince, Haiti. pauldenisl@gheskio.org
Dillingham
Rebecca
R
Beauharnais
Carole Anne
CA
Kashuba
Angela D M
AD
Rezk
Naser L
NL
Fitzgerald
Daniel W
DW
Pape
Jean William
JW
Haas
David W
DW
D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D048588:Benzoxazines / Q000097:blood / Q000493:pharmacokinetics*; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics; D006205:Haiti / Q000453:epidemiology; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz