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Pharmacogenomics of HAART Metabolism and Transport: The Women's Interagency HIV Study
Celeste Pearce*1, M Gandhi2, S Gange3, K Anastos4, N Kono1, M Augenbraun5, C Liu6, R Greenblatt2, and A Levine1
1Keck Sch of Med, Univ of Southern California, Los Angeles, US; 2Univ of California, San Francisco, US; 3Johns Hopkins Univ Bloomberg Sch of Publ Hlth, Baltimore, MD, US; 4Montefiore Med Ctr, Bronx, NY, US; 5State Univ of New York Downstate Med Ctr, Brooklyn, US; and 6Georgetown Univ Med Ctr, Washington, DC, US
Background: Although the introduction of HAART for the
treatment of HIV has resulted in significantly improved prognoses, virologic and immunologic success on therapy is not
universal. Reasons for non-response to HAART include medication non-adherence,
viral resistance, and host genetics.
Methods: We investigated the role of host genetics in
determining response to HAART by studying 10 common genetic variants in 6 key
genes involved in the metabolism and transport of ART in participants of the
Women’s Interagency HIV Study (WIHS). The WIHS is a multi-ethnic national cohort
study where HIV+ women have been followed biannually since 1994. Response
to therapy was defined as achieving an undetectable viral load within 12 months
of initiating HAART. We studied 537 WIHS women who initiated HAART between 1995
and 2004 of whom 322 were responders and 215 were non-responders. Genotyping
was carried out using the TaqMan Allelic
Discrimination Assay and the Sequenom MassARRAY system. Data were analyzed using logistic
regression. Genotype was examined using a log additive model as well as
assuming no mode of inheritance.
Results: The 10 variants available for analysis were in
ADH1B, CYP2B6, CYP2D6, CYP2E1, MDR1, and UGT1A. The minor allele frequencies of
the variants ranged from 9.3% to 49.1%, with substantial ethnic differences. The
2 variants that have been studied fairly extensively with response to HIV
therapy are: rs3745274 (G516T) in CYP2B6
and rs1045642 (C3435T) in MDR1. After adjusting for ethnicity, we found no
association between CYP2B6 G516T and response to therapy (p = 0.88) in the WIHS. After adjusting for ethnicity, peak CD4+
cell count, and peak viral load prior to HAART initiation, there was a
marginally statistically significant association between response to therapy
and MDR1 C3435T (OR = 0.74, 95%CI 0.55 to 1.01, p = 0.057). Some evidence indicates that this association may be
restricted to protease-inhibitor-based regimens (OR = 0.67, 95%CI 0.47 to 0.96,
p <0.05), but there was no
statistically significant interaction between type of HAART and MDR1 C3435T. Analysis
of the remaining eight variants has also been conducted and will be reported.
Conclusions: This is the first large-scale pharmacogenomics study in HIV+ women. Among protease inhibitor-based HAART users,
C3435T in MDR1 may be associated with failure to respond—a result counter to
the associations currently published.
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