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

Vardhanabhuti 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, A5207 ACTG Study Team
J Infect Dis. 2013 208 (4): 662-71

PMID: 23687222 · PMCID: PMC3719905 · DOI:10.1093/infdis/jit223

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.

MeSH Terms (20)

Adult 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

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