Multilocus genetic interactions and response to efavirenz-containing regimens: An Adult AIDS Clinical Trials Group study

Alison A. Motsinger, Marylyn D. Ritchie, Robert W. Shafer, Gregory K. Robbins, Gene D. Morse, Line Labbé, Grant R. Wilkinson, David B. Clifford, Richard T. D'Aquila, Victoria A. Johnson, Richard B Pollard, Thomas C. Merigan, Martin S. Hirsch, John P. Donahue, Richard B. Kim, David W. Haas

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

OBJECTIVE: For the HIV-1 reverse transcriptase inhibitor efavirenz, variant drug transporter gene ABCB1 may predict virologic response but not plasma efavirenz exposure. Conversely, variant drug metabolizing enzyme gene CYP2B6 predicts greater plasma efavirenz exposure but not virologic response. We examined whether long-term responses to efavirenz, and/or plasma efavirenz exposure, are better predicted by multilocus genetic interactions than by individual polymorphisms. MATERIALS AND METHODS: We studied antiretroviral- naïve study participants randomized to receive efavirenz (with or without nelfinavir) plus two nucleoside analogues in study ACTG 384, and who had DNA available for analysis. Participants were followed up for up to 3 years. Nine single nucleotide polymorphisms in ABCB1, CYP2B6, CYP3A4, CYP3A5 and CYP2C19 were identified. Gene-gene interactions were identified using multifactor dimensionality reduction. RESULTS: Among 340 efavirenz recipients, higher efavirenz AUC24 h values were associated with a single locus model involving CYP2B6 516G>T (73% accuracy; P<0.001). This was also the best model among blacks (69% accuracy; P<0.001), whereas among whites the best model involved a gene-gene interaction between CYP2B6 516G>T and ABCB1 2677G>T (82% accuracy, P<0.001). Among 155 participants who received efavirenz without nelfinavir, virologic failure was associated with a two-locus interaction between ABCB1 2677G>T and CYP2B6 516G>T (65% accuracy, P<0.001). Toxicity failure was best predicted by an interaction between ABCB1 2677G>T and ABCB1 3435C>T (71% accuracy, P<0.001). CONCLUSIONS: Multilocus genetic interactions between variant drug metabolism and transporter genes may predict efavirenz pharmacokinetics and treatment responses. This finding may have implications for better individualizing antiretroviral therapy.

Original languageEnglish (US)
Pages (from-to)837-845
Number of pages9
JournalPharmacogenetics and Genomics
Volume16
Issue number11
DOIs
StatePublished - Nov 2006

Keywords

  • HIV therapy-efavirenz
  • Multifactor dimensionality reduction
  • Pharmacogenomics

ASJC Scopus subject areas

  • Genetics
  • Pharmacology

Fingerprint Dive into the research topics of 'Multilocus genetic interactions and response to efavirenz-containing regimens: An Adult AIDS Clinical Trials Group study'. Together they form a unique fingerprint.

  • Cite this

    Motsinger, A. A., Ritchie, M. D., Shafer, R. W., Robbins, G. K., Morse, G. D., Labbé, L., Wilkinson, G. R., Clifford, D. B., D'Aquila, R. T., Johnson, V. A., Pollard, R. B., Merigan, T. C., Hirsch, M. S., Donahue, J. P., Kim, R. B., & Haas, D. W. (2006). Multilocus genetic interactions and response to efavirenz-containing regimens: An Adult AIDS Clinical Trials Group study. Pharmacogenetics and Genomics, 16(11), 837-845. https://doi.org/10.1097/01.fpc.0000230413.97596.fa