Functional CYP2B6 variants and virologic response to an efavirenz-containing regimen in Port-au-Prince, Haiti.
OBJECTIVE
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.
Vanderbilt University School of Medicine, Nashville, TN, USA david.haas@vanderbilt.edu.
David W
DW
Haas
GHESKIO Centers, Port-au-Prince, Haiti.
Patrice
P
Severe
GHESKIO Centers, Port-au-Prince, Haiti.
Marc Antoine
MA
Jean Juste
GHESKIO Centers, Port-au-Prince, Haiti Weill Cornell Medical College, New York, NY, USA.
Jean William
JW
Pape
GHESKIO Centers, Port-au-Prince, Haiti Weill Cornell Medical College, New York, NY, USA.
Daniel W
DW
Fitzgerald
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use; D048588:Benzoxazines / Q000097:blood* / Q000627:therapeutic use*; D003521:Cyclopropanes; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D065695:Cytochrome P-450 CYP2B6 Inducers / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006205:Haiti; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D064210:Secondary Metabolism; D016896:Treatment Outcome
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D065695:Cytochrome P-450 CYP2B6 Inducers; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; C585710:CYP2A6 protein, human; C510164:CYP3A5 protein, human; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C098320:efavirenz
AIDS; HIV; antiretroviral therapy; pharmacogenomics