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.

• Authors: David W Haas, Patrice Severe, Marc Antoine Jean Juste, Jean William Pape, Daniel W Fitzgerald
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 69 Issue 8 Pg. 2187-90 (Aug 2014) ISSN: 1460-2091 [Electronic] England
• PMID: 24695352 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 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: [email protected].

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• Alkynes
• Anti-HIV Agents
• Benzoxazines
• Cyclopropanes
• Cytochrome P-450 CYP2B6 Inducers
• RNA, Viral
• Reverse Transcriptase Inhibitors
• CYP2A6 protein, human
• CYP3A5 protein, human
• Cytochrome P-450 CYP2A6
• Cytochrome P-450 CYP2B6
• Cytochrome P-450 CYP3A
• efavirenz

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics)
• Adult
• Alkynes
• Anti-HIV Agents (therapeutic use)
• Benzoxazines (blood, therapeutic use)
• Cyclopropanes
• Cytochrome P-450 CYP2A6 (genetics)
• Cytochrome P-450 CYP2B6 (genetics)
• Cytochrome P-450 CYP2B6 Inducers (therapeutic use)
• Cytochrome P-450 CYP3A (genetics)
• Female
• Genetic Association Studies
• HIV Infections (drug therapy)
• HIV-1 (drug effects)
• Haiti
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Prospective Studies
• RNA, Viral (blood)
• Reverse Transcriptase Inhibitors (therapeutic use)
• Secondary Metabolism
• Treatment Outcome