A CYP2B6 haplotype influences nevirapine plasma concentrations following a single dose to reduce mother to child transmission

Tim Cressey from the Program for HIV Prevention and Treatment (PHPT), Chaing Mai, Thailand and Harvard School of Public Health, Boston, USA presented data from an evaluation of the association between single nucleotide polymorphisms (SNP) and haplotypes within CYP2B6, CYP3A4 and ABCB1, and nevirapine (NVP) plasma concentrations in Thai women following single dose NVP as part of HIV mother to child transmission prophylaxis. [1]

Currently, pregnant HIV-positive women that do not reach eligibility criteria for antiretroviral treatment in Thailand receive AZT from 28 weeks gestation and intrapartum single dose NVP to reduce mother to child transmission. Persistence of NVP in plasma following a single dose has been demonstrated to select for NNRTI mutations, which, in turn, can compromise subsequent NNRTI containing HAART.

In this study, investigators from Thailand and the USA, used plasma and DNA samples from 330 women who had received single dose NVP in the PHPT-2 trial. [2] Nine SNPs within CYP2B6, CYP3A4 and ABCB1 were genotyped using real time PCR. Data from 640 plasma samples taken between delivery and 21 days post partum were available.

Nevirapine plasma concentrations were determined by high-performance liquid chromatography and used in a population pharmacokinetic analysis.

For the CYP2B6 516G>T polymorphism, the investigators found, 43.0% (n=142), 46.7% (n=154) and 10.3% (n=34) of women had G/G, G/T and T/T genotypes, respectively. Nevirapine exposure was higher in women carrying the CYP2B6 516G>T polymorphism but this was not statistically significant, p=0.054.

Two tag-SNPs in CYP2B6: g.18492T>C and g.21563C>T, were significantly associated with NVP AUC, p=0.041 p=0.019 respectively.

The mean (SD) NVP AUC was 154.7 (33.7), 160.9 (33.3) and 17.7 (34.4) mcg.hr/mL in women with g.21563C/C C/T and T/T genotypes, respectively, p=0.27.

When they performed a haplotype analysis of CYP2B6 at 5 loci they found that the TGATC haplotype (g.3003T>C, 516G>T, 785A>G, g.18492T.C and g.21563C>T) was significantly associated with NVP AUC, p=0.00061.

The mean (SD) NVP AUC was 164.5 (33.8, n=197), 152.7 (33.9, n=114) and 146.1 (23.9, n=19) mcg.hr/mL for women with non-TGATC, TGATC-heterozygous and TGATC-homozygous genotypes respectively, p=0.0029.

The median time for NVP concentrations to reach 10 ng/mL postpartum was 18 (IQR 14-21) days, 16 (IQR 13-20) days and 14 (IQR 14-19) days for women with non-TGATC, TGATC-heterozygous and TGATC-homozygous genotypes respectively, p=0.02. No other genetic polymorphisms evaluated in this analysis were significantly associated with NVP AUC.

CYP2B6 516G>T has previously been shown to affect NVP oral clearance during chronic treatment. The investigators observed that CYP2B6 516G>T seems to have a more modest impact on single dose NVP than on NVP used in chronic treatment. They suggest that the physiological changes experienced during pregnancy and/or the minimal autoinduction of CYP3A4 and 2B6 enzymes following a single dose compared to steady state (1.5 to 2-fold increase in NVP CL/F during first two weeks of treatment) may explain this observation.

They concluded that CYP2B6 polymorphisms following single dose NVP may account for some of the interpatient variability observed in post partum NVP concentrations but that the clinical significance of this finding may be relatively small.

Chantarangsu S et al. A CYP2B6 haplotype influences nevirapine plasma concentrations postpartum following a single intrapartum dose for the prevention of mother to child transmission of HIV in Thai women. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Abstract O_02.