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

ABSTRACT: 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.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.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.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.

SUBMITTER: Vardhanabhuti S

PROVIDER: S-EPMC3719905 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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

Vardhanabhuti Saran S Acosta Edward P EP Ribaudo Heather J HJ Severe Patrice P Lalloo Umesh U Kumarasamy Nagalingeshwaran N Taulo Frank F Kabanda Joseph J Oneko Olola O Ive Prudence P Sambarey Pradeep P Chan Ellen S ES Hitti Jane J Hong Francis F McMahon Deborah D Haas David W DW

The Journal of infectious diseases 20130517 4

<h4>Objective</h4>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.<h4>Methods</h4>In AIDS Clinical Trials Group study A5207, women received nevirapine at onset of labor and were randomly assigned to receive lamivudine/zidovudine, emtricitabine/tenofo ...[more]

PMID: 23687222

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Project description:Intrapartum single-dose nevirapine plus third trimester maternal and infant zidovudine are essential components of programs to prevent mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings. The persistence of nevirapine in the plasma for 3 weeks postpartum risks selection of resistance mutations to nonnucleoside reverse-transcriptase inhibitors (NNRTIs). We hypothesized that a 1-month zidovudine-didanosine course initiated at the same time as single-dose nevirapine (sdNVP) would prevent the selection of nevirapine-resistance mutations.HIV-infected pregnant women in the PHPT-4 cohort with CD4 cell counts >250 cells/mm3 received antepartum zidovudine from the third trimester until delivery, sdNVP during labor, and a 1-month zidovudine-didanosine course after delivery. These women were matched on the basis of baseline HIV load, CD4 cell count, and duration of antepartum zidovudine to women who received sdNVP in the PHPT-2 trial (control subjects). Consensus sequencing and the more sensitive oligonucleotide ligation assay were performed on samples obtained on postpartum days 7-10, 37-45, and 120 (if the HIV load was >500 copies/mL) to detect K103N/Y181C/G190A mutations.The 222 PHPT-4 subjects did not differ from matched control subjects in baseline characteristics except for age. The combined group median CD4 cell count was 421 cells/mm3 (interquartile range [IQR], 322-549 cells/mm3), the median HIV load was 3.45 log10 copies/mL (IQR, 2.79-4.00 log10 copies/mL), and the median duration of zidovudine prophylaxis was 10.4 weeks (IQR, 9.1-11.4 weeks). Using consensus sequencing, major NNRTI resistance mutations were detected after delivery in 0% of PHPT-4 subjects and 10.4% of PHPT-2 controls. The oligonucleotide ligation assay detected resistance in 1.8% of PHPT-4 subjects and 18.9% of controls. Major NNRTI resistance mutations were detected by either method in 1.8% of PHPT-4 subjects and 20.7% of controls (P < .001).A 1-month postpartum course of zidovudine plus didanosine prevented the selection of the vast majority of NNRTI resistance mutations.

Dataset Information

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

Publications

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

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