Functional CYP2B6 variants and virologic response to an efavirenz-containing regimen in Port-au-Prince, Haiti

Abstract

Objectives: Efavirenz is widely prescribed for HIV-1 infection. Three polymorphisms in CYP2B6 define plasma efavirenz trough concentration strata that vary across an ∼10-fold range. We characterized associations between human genetic polymorphisms and virologic response among participants who received efavirenz-containing regimens in a prospective clinical trial.

Methods: We genotyped 76 polymorphisms in CYP2B6 (including those that define efavirenz concentration strata), CYP2A6, CYP3A4, CYP3A5 and ABCB1 and week 48 virologic responses in 360 Haitians who initiated efavirenz-containing regimens in protocol HT 001. Associations were characterized by logistic regression analysis and Fisher's exact test.

Results: Proportions with HIV-1 RNA <50 or <200 copies/mL did not differ across 10 CYP2B6 metabolizer strata. In analyses that combined strata into three metabolizer levels (extensive, intermediate and slow), the respective proportions were 0.79, 0.79 and 0.81 (<50 copies/mL cut-off) and 0.84, 0.86 and 0.87 (<200 copies/mL cut-off). Genetic associations were not identified after controlling for baseline variables or with other polymorphisms after adjusting for multiple comparisons.

Conclusions: Virologic failures in HT 001 were not explained by genetic polymorphisms known to define the lowest plasma efavirenz concentration stratum.

Trial registration: ClinicalTrials.gov NCT00120510.

Keywords: AIDS; HIV; antiretroviral therapy; pharmacogenomics.

© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Proportions of efavirenz recipients with plasma HIV-1 RNA below limits of quantification at 48 weeks. Graphs represent subjects who initiated 600 mg of efavirenz once daily, had no change in their antiretroviral therapy regimen before week 48 and had HIV-1 RNA data available at both week 0 and week 48. (a) Week 48 HIV-1 RNA CYP2B6 metabolizer strata, defined by C15582T, G516T and T983C. (b) Week 48 HIV-1 RNA <200 copies/mL for each of 10 CYP2B6 metabolizer strata, defined by C15582T, G516T and T983C. Predicted median efavirenz Cmin concentrations are from the study by Holzinger et al. (c, left half) Week 48 HIV-1 RNA <50 copies/mL for each of three combined CYP2B6 metabolizer strata. (c, right half) Week 48 HIV-1 RNA <200 copies/mL for each of three combined CYP2B6 metabolizer strata. Combined CYP2B6 metabolizer strata are defined as follows: EXT. (extensive) = left two strata in (a) and (b); Figure 1; INT. (intermediate) = middle five strata in (a) and (b); and SLO. (slow) = right three strata in (a) and (b). Error bars represent 95% CI by the modified Wald method. BLQ, below the limit of quantification.