Clinical and genetic determinants of plasma nevirapine exposure following an intrapartum dose to prevent mother-to-child HIV transmission.

TitleClinical and genetic determinants of plasma nevirapine exposure following an intrapartum dose to prevent mother-to-child HIV transmission.
Publication TypeJournal Article
Year of Publication2013
AuthorsVardhanabhuti S, Acosta EP, Ribaudo HJ, Severe P, Lalloo U, Kumarasamy N, Taulo F, Kabanda J, Oneko O, Ive P, Sambarey P, Chan ES, Hitti J, Hong F, McMahon D, Haas DW
Corporate AuthorsA5207 ACTG Study Team
JournalJ Infect Dis
Volume208
Issue4
Pagination662-71
Date Published2013 Aug 15
ISSN1537-6613
KeywordsAdult, Anti-HIV Agents, Aryl Hydrocarbon Hydroxylases, Chemoprevention, Cytochrome P-450 CYP2B6, Female, HIV Infections, Humans, Infant, Newborn, Infectious Disease Transmission, Vertical, Inhibitory Concentration 50, Male, Metabolic Clearance Rate, Nevirapine, Oxidoreductases, N-Demethylating, Plasma, Polymorphism, Genetic, Pregnancy, Time Factors, Young Adult
Abstract

OBJECTIVE: Nevirapine is metabolized by cytochrome P450 (CYP) 2B6 and CYP3A4. We characterized relationships between clinical parameters, human genetics, pharmacokinetics, and human immunodeficiency virus type 1 (HIV-1) drug resistance mutations in pregnant women following single-dose intrapartum nevirapine.

METHODS: In AIDS Clinical Trials Group study A5207, women received nevirapine at onset of labor and were randomly assigned to receive lamivudine/zidovudine, emtricitabine/tenofovir, or lopinavir/ritonavir for 7 or 21 days. Plasma nevirapine level was quantified on postpartum day 1 and on weeks 1, 3, and 5. We assayed 214 polymorphisms in CYP2B6 and other genes and evaluated associations with pharmacokinetic parameters, including elimination constant, time to protein-adjusted 50% inhibitory concentration (IC50), and week 5 nevirapine level below the quantification limit.

RESULTS: Among 301 women with evaluable pharmacokinetic and genotype data, lower body mass index and random assignment to receive lopinavir/ritonavir were associated with more rapid nevirapine elimination. Among those of African ancestry, longer time to IC50 was associated with CYP2B6 983T → C (P = .004) but not with CYP2B6 516G → T (P = .8). Among Indians, slower nevirapine elimination was associated with CYP2B6 516G → T (P = .04). Emergent resistance was infrequent and not associated with pharmacokinetics or CYP2B6 genotype.

CONCLUSIONS: The effects on plasma drug exposure following single-dose nevirapine may be greater for CYP2B6 983T → C than for 516G → T and are less pronounced than at steady state.

DOI10.1093/infdis/jit223
Alternate JournalJ. Infect. Dis.
PubMed ID23687222
PubMed Central IDPMC3719905
Grant ListP30 AI54999 / AI / NIAID NIH HHS / United States
R01 AI077505 / AI / NIAID NIH HHS / United States
U01 AI068634 / AI / NIAID NIH HHS / United States
U01 AI068634 / AI / NIAID NIH HHS / United States
U01 AI068636 / AI / NIAID NIH HHS / United States
U01 AI068636 / AI / NIAID NIH HHS / United States
U01 AI069417 / AI / NIAID NIH HHS / United States
U01 AI069421 / AI / NIAID NIH HHS / United States
U01 AI069426 / AI / NIAID NIH HHS / United States
U01 AI069432 / AI / NIAID NIH HHS / United States
U01 AI069439 / AI / NIAID NIH HHS / United States
U01 AI069484 / AI / NIAID NIH HHS / United States
U01 AI069494 / AI / NIAID NIH HHS / United States
U01 AI069501 / AI / NIAID NIH HHS / United States
U01 AI069518 / AI / NIAID NIH HHS / United States
U01 AI38858 / AI / NIAID NIH HHS / United States
U01 AI69463 / AI / NIAID NIH HHS / United States
UM1 AI069421 / AI / NIAID NIH HHS / United States
UM1 AI069432 / AI / NIAID NIH HHS / United States
UM1 AI069494 / AI / NIAID NIH HHS / United States
UM1 AI106701 / AI / NIAID NIH HHS / United States