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

Alison A. Motsinger, Marylyn Deriggi 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

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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 1 2006

Fingerprint

efavirenz
Acquired Immunodeficiency Syndrome
Clinical Trials
Cytochrome P-450 CYP3A
Genes
Multifactor Dimensionality Reduction
Nelfinavir
Pharmaceutical Preparations
Reverse Transcriptase Inhibitors

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Motsinger, A. A., Ritchie, M. D., Shafer, R. W., Robbins, G. K., Morse, G. D., Labbé, L., ... 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
Motsinger, Alison A. ; Ritchie, Marylyn Deriggi ; Shafer, Robert W. ; Robbins, Gregory K. ; Morse, Gene D. ; Labbé, Line ; Wilkinson, Grant R. ; Clifford, David B. ; D'Aquila, Richard T. ; Johnson, Victoria A. ; Pollard, Richard B. ; Merigan, Thomas C. ; Hirsch, Martin S. ; Donahue, John P. ; Kim, Richard B. ; Haas, David W. / Multilocus genetic interactions and response to efavirenz-containing regimens : An Adult AIDS Clinical Trials Group study. In: Pharmacogenetics and Genomics. 2006 ; Vol. 16, No. 11. pp. 837-845.
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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- na{\"i}ve 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.",
author = "Motsinger, {Alison A.} and Ritchie, {Marylyn Deriggi} and Shafer, {Robert W.} and Robbins, {Gregory K.} and Morse, {Gene D.} and Line Labb{\'e} and Wilkinson, {Grant R.} and Clifford, {David B.} and D'Aquila, {Richard T.} and Johnson, {Victoria A.} and Pollard, {Richard B.} and Merigan, {Thomas C.} and Hirsch, {Martin S.} and Donahue, {John P.} and Kim, {Richard B.} and Haas, {David W.}",
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Motsinger, AA, Ritchie, MD, Shafer, RW, Robbins, GK, Morse, GD, Labbé, L, Wilkinson, GR, Clifford, DB, D'Aquila, RT, Johnson, VA, Pollard, RB, Merigan, TC, Hirsch, MS, Donahue, JP, Kim, RB & Haas, DW 2006, 'Multilocus genetic interactions and response to efavirenz-containing regimens: An Adult AIDS Clinical Trials Group study', Pharmacogenetics and Genomics, vol. 16, no. 11, pp. 837-845. https://doi.org/10.1097/01.fpc.0000230413.97596.fa

Multilocus genetic interactions and response to efavirenz-containing regimens : An Adult AIDS Clinical Trials Group study. / Motsinger, Alison A.; Ritchie, Marylyn Deriggi; Shafer, Robert W.; Robbins, Gregory K.; Morse, Gene D.; Labbé, Line; Wilkinson, Grant R.; Clifford, David B.; D'Aquila, Richard T.; Johnson, Victoria A.; Pollard, Richard B.; Merigan, Thomas C.; Hirsch, Martin S.; Donahue, John P.; Kim, Richard B.; Haas, David W.

In: Pharmacogenetics and Genomics, Vol. 16, No. 11, 01.11.2006, p. 837-845.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Multilocus genetic interactions and response to efavirenz-containing regimens

T2 - An Adult AIDS Clinical Trials Group study

AU - Motsinger, Alison A.

AU - Ritchie, Marylyn Deriggi

AU - Shafer, Robert W.

AU - Robbins, Gregory K.

AU - Morse, Gene D.

AU - Labbé, Line

AU - Wilkinson, Grant R.

AU - Clifford, David B.

AU - D'Aquila, Richard T.

AU - Johnson, Victoria A.

AU - Pollard, Richard B.

AU - Merigan, Thomas C.

AU - Hirsch, Martin S.

AU - Donahue, John P.

AU - Kim, Richard B.

AU - Haas, David W.

PY - 2006/11/1

Y1 - 2006/11/1

N2 - 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.

AB - 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.

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