A Study to Evaluate the Effects of Genetic Factors on the Pharmacokinetics of Antiretroviral Drugs During Pregnancy and Lactation

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Total Enrollment

460 participants

Study Classification

OBSERVATIONAL

Study Start Date

2012-12-31

Study Completion Date

2013-11-30

Brief Summary

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Mother-to-child transmission of HIV (MTCT) during pregnancy and breastfeeding is prevented with maternal antiretroviral drugs (ARV) and infant nevirapine post-exposure prophylaxis (PEP). However, the pharmacokinetics of certain ARVs is associated with marked inter-individual variability. This variability has been associated with single nucleotide polymorphisms (SNPs) in genes encoding metabolising enzymes, transporters and transcriptional regulators. Pregnancy is also associated with additional changes in pharmacokinetics. The resulting sub-therapeutic or supra-therapeutic drug exposures may have serious consequences for virological control, MTCT, emergence of drug resistance, and toxicity. Foetal and infant exposure to maternal ARV during pregnancy and breastfeeding is believed to play a role in the prevention of mother-to-child transmission of HIV (PMTCT). However, such exposures may also result in toxicity. For example, efavirenz is contraindicated in children less than 3 years old or 10kg but transferred to breastfed babies through breast milk. On the other hand, double exposure to nevirapine from breast milk and PEP may also predispose breastfed infants to nevirapine-associated toxicity.

In the proposed study, the influence of selected SNPs in certain drug disposition genes on the pharmacokinetics of efavirenz and nevirapine during pregnancy and lactation, as well as the level of infant exposure to both drugs through breast milk, will be studied. Mathematical models will be developed to predict potential dose optimisation strategies during pregnancy, and to predict infant exposure to maternal drugs through breast milk.

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Detailed Description

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Study design: This is an observational study that will be conducted in two phases. In the preliminary phase, associations between selected SNPs in drug disposition genes and mid-dose plasma and breast milk efavirenz and nevirapine concentrations will be explored in an unselected cohort of HIV positive pregnant women and nursing mothers and their breastfed infants taking either drug as part of combination antiretroviral therapy for PMTCT. In the second phase, the SNP independently associated with the highest predictive power will be used to stratify pregnant women and mother-infant pairs into three groups: non-carriers, heterozygotes, and homozygotes. Randomly selected pregnant women or mother-infant pairs from each group were re-recruited and invited for the intensive pharmacokinetic phase.

Samples collection: In the preliminary phase, mid-dose paired dried blood spots (DBS) (and dried breast milk spots in nursing mothers) samples will be collected at a single, recorded time point post dose. In the intensive pharmacokinetic phase, DBS (and dried breast milk spots in nursing mothers) samples will be collected at multiple time points after an observed dose of efavirenz or nevirapine. Samples will be shipped at room temperature to the Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom for analysis.

DNA extraction and SNP genotyping: Genomic DNA will be extracted using available commercial kits in accordance with the manufacture's protocol and genotyping will be performed by allelic discrimination real-time polymerase chain reaction using TaqMan® chemistry-based assays.

Drug quantification and pharmacokinetic analysis: Liquid chromatography-mass spectrometry methods will be developed for the quantification of efavirenz and nevirapine in DBS and dried breast milk spots. Pharmacokinetic parameters will be determined using standard procedures.

Conditions

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HIV Pregnancy Breastfeeding

Study Design

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Observational Model Type

COHORT

Study Time Perspective

PROSPECTIVE

Study Groups

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Pregnant women - efavirenz

Pregnant women taking 600 mg efavirenz daily as part of combination antiretroviral therapy for PMTCT and for their own health

Efavirenz

Intervention Type DRUG

600 mg once daily in combination with other drugs (e.g. tenofovir and emtricitabine)

Nursing mothers - efavirenz

Nursing mothers taking 600 mg efavirenz daily as part of combination antiretroviral therapy for PMTCT and for their own health and their breastfed babies

Efavirenz

Intervention Type DRUG

600 mg once daily in combination with other drugs (e.g. tenofovir and emtricitabine)

Pregnant women - nevirapine

Pregnant women taking 200 mg nevirapine twice daily as part of combination antiretroviral therapy for PMTCT and for their own health

Nevirapine

Intervention Type DRUG

200 mg twice daily in combination with other drugs (e.g. tenofovir and emtricitabine)

Nursing mothers - nevirapine

Nursing mothers taking 200 mg nevirapine twice daily as part of combination antiretroviral therapy for PMTCT and for their own health and their breastfed babies

Nevirapine

Intervention Type DRUG

200 mg twice daily in combination with other drugs (e.g. tenofovir and emtricitabine)

Interventions

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Efavirenz

600 mg once daily in combination with other drugs (e.g. tenofovir and emtricitabine)

Intervention Type DRUG

Nevirapine

200 mg twice daily in combination with other drugs (e.g. tenofovir and emtricitabine)

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

* HIV positive
* breastfeeding
* enrolled in PMTCT programme
* started efavirenz- or nevirapine-containing regimen during pregnancy

Exclusion Criteria

* exclusive replacement feeding
* mixed feeding before 6 months
* severe maternal or infant illness
* maternal or infant treatment with other drugs or herbal medication with known or uncertain interaction with study drug

Minimum Eligible Age

18 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No