Pharmacogenetics of long-term responses to antiretroviral regimens containing efavirenz and/or nelfinavir: An adult AIDS clinical trials group study

David W. Haas, Laura M. Smeaton, Robert W. Shafer, Gregory K. Robbins, Gene D. Morse, Line Labbé, Grant R. Wilkinson, David B. Clifford, Richard T. D'Aquila, Victor De Gruttola, Richard B Pollard, Thomas C. Merigan, Martin S. Hirsch, Alfred L. George, John P. Donahue, Richard B. Kim

Research output: Contribution to journalArticle

215 Citations (Scopus)

Abstract

Background. Efavirenz and nelfinavir are metabolized by cytochrome P-450 (CYP) 2B6 and CYP2C19, respectively, with some involvement by CYP3A. Nelfinavir is a substrate for P-glycoprotein, which is encoded by MDR1. The present study examined associations between genetic variants and long-term responses to treatment. Methods. Adult AIDS Clinical Trials Group study 384 randomized antiretroviral-naive subjects to receive efavirenz and/or nelfinavir plus 2 nucleoside analogues, with follow-up lasting up to 3 years. Population pharmacokinetics were estimated from a nonlinear mixed-effects model. Polymorphisms in CYP2B6, CYP2C19, CYP3A4, CYP3A5, and MDR1 were characterized. Results. The 504 participants in the genetic study included 340 efavirenz recipients and 348 nelfinavir recipients (184 of the 504 participants received both efavirenz and nelfinavir). Of the participants, 49% were white, 31% were black, and 19% were Hispanic. Plasma exposure to efavirenz and nelfinavir in each population was significantly associated with the polymorphisms CYP2B6 516G→T and CYP2C19 681G→A, respectively. Among efavirenz recipients, the MDR1 position 3435 TT genotype was associated with decreased likelihood of virologic failure and decreased emergence of efavirenz-resistant virus but not with plasma efavirenz exposure. Among nelfinavir recipients, a trend toward decreased virologic failure was associated with the polymorphism CYP2C19 681G→A. Conclusions. Genetic variants predict plasma exposure to efavirenz and nelfinavir, and they may predict virologic failure and/or emergence of drug-resistant virus. These associations with treatment responses must be validated in other studies.

Original languageEnglish (US)
Pages (from-to)1931-1942
Number of pages12
JournalJournal of Infectious Diseases
Volume192
Issue number11
DOIs
StatePublished - Dec 1 2005

Fingerprint

efavirenz
Nelfinavir
Pharmacogenetics
Acquired Immunodeficiency Syndrome
Clinical Trials
Cytochrome P-450 CYP3A
Viruses
P-Glycoprotein

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Immunology

Cite this

Pharmacogenetics of long-term responses to antiretroviral regimens containing efavirenz and/or nelfinavir : An adult AIDS clinical trials group study. / Haas, David W.; Smeaton, Laura M.; Shafer, Robert W.; Robbins, Gregory K.; Morse, Gene D.; Labbé, Line; Wilkinson, Grant R.; Clifford, David B.; D'Aquila, Richard T.; De Gruttola, Victor; Pollard, Richard B; Merigan, Thomas C.; Hirsch, Martin S.; George, Alfred L.; Donahue, John P.; Kim, Richard B.

In: Journal of Infectious Diseases, Vol. 192, No. 11, 01.12.2005, p. 1931-1942.

Research output: Contribution to journalArticle

Haas, DW, Smeaton, LM, Shafer, RW, Robbins, GK, Morse, GD, Labbé, L, Wilkinson, GR, Clifford, DB, D'Aquila, RT, De Gruttola, V, Pollard, RB, Merigan, TC, Hirsch, MS, George, AL, Donahue, JP & Kim, RB 2005, 'Pharmacogenetics of long-term responses to antiretroviral regimens containing efavirenz and/or nelfinavir: An adult AIDS clinical trials group study', Journal of Infectious Diseases, vol. 192, no. 11, pp. 1931-1942. https://doi.org/10.1086/497610
Haas, David W. ; Smeaton, Laura M. ; Shafer, Robert W. ; Robbins, Gregory K. ; Morse, Gene D. ; Labbé, Line ; Wilkinson, Grant R. ; Clifford, David B. ; D'Aquila, Richard T. ; De Gruttola, Victor ; Pollard, Richard B ; Merigan, Thomas C. ; Hirsch, Martin S. ; George, Alfred L. ; Donahue, John P. ; Kim, Richard B. / Pharmacogenetics of long-term responses to antiretroviral regimens containing efavirenz and/or nelfinavir : An adult AIDS clinical trials group study. In: Journal of Infectious Diseases. 2005 ; Vol. 192, No. 11. pp. 1931-1942.
@article{51a24c308b2b451495ad3caa5e2c132b,
title = "Pharmacogenetics of long-term responses to antiretroviral regimens containing efavirenz and/or nelfinavir: An adult AIDS clinical trials group study",
abstract = "Background. Efavirenz and nelfinavir are metabolized by cytochrome P-450 (CYP) 2B6 and CYP2C19, respectively, with some involvement by CYP3A. Nelfinavir is a substrate for P-glycoprotein, which is encoded by MDR1. The present study examined associations between genetic variants and long-term responses to treatment. Methods. Adult AIDS Clinical Trials Group study 384 randomized antiretroviral-naive subjects to receive efavirenz and/or nelfinavir plus 2 nucleoside analogues, with follow-up lasting up to 3 years. Population pharmacokinetics were estimated from a nonlinear mixed-effects model. Polymorphisms in CYP2B6, CYP2C19, CYP3A4, CYP3A5, and MDR1 were characterized. Results. The 504 participants in the genetic study included 340 efavirenz recipients and 348 nelfinavir recipients (184 of the 504 participants received both efavirenz and nelfinavir). Of the participants, 49{\%} were white, 31{\%} were black, and 19{\%} were Hispanic. Plasma exposure to efavirenz and nelfinavir in each population was significantly associated with the polymorphisms CYP2B6 516G→T and CYP2C19 681G→A, respectively. Among efavirenz recipients, the MDR1 position 3435 TT genotype was associated with decreased likelihood of virologic failure and decreased emergence of efavirenz-resistant virus but not with plasma efavirenz exposure. Among nelfinavir recipients, a trend toward decreased virologic failure was associated with the polymorphism CYP2C19 681G→A. Conclusions. Genetic variants predict plasma exposure to efavirenz and nelfinavir, and they may predict virologic failure and/or emergence of drug-resistant virus. These associations with treatment responses must be validated in other studies.",
author = "Haas, {David W.} and Smeaton, {Laura M.} 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 {De Gruttola}, Victor and Pollard, {Richard B} and Merigan, {Thomas C.} and Hirsch, {Martin S.} and George, {Alfred L.} and Donahue, {John P.} and Kim, {Richard B.}",
year = "2005",
month = "12",
day = "1",
doi = "10.1086/497610",
language = "English (US)",
volume = "192",
pages = "1931--1942",
journal = "Journal of Infectious Diseases",
issn = "0022-1899",
publisher = "Oxford University Press",
number = "11",

}

TY - JOUR

T1 - Pharmacogenetics of long-term responses to antiretroviral regimens containing efavirenz and/or nelfinavir

T2 - An adult AIDS clinical trials group study

AU - Haas, David W.

AU - Smeaton, Laura M.

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 - De Gruttola, Victor

AU - Pollard, Richard B

AU - Merigan, Thomas C.

AU - Hirsch, Martin S.

AU - George, Alfred L.

AU - Donahue, John P.

AU - Kim, Richard B.

PY - 2005/12/1

Y1 - 2005/12/1

N2 - Background. Efavirenz and nelfinavir are metabolized by cytochrome P-450 (CYP) 2B6 and CYP2C19, respectively, with some involvement by CYP3A. Nelfinavir is a substrate for P-glycoprotein, which is encoded by MDR1. The present study examined associations between genetic variants and long-term responses to treatment. Methods. Adult AIDS Clinical Trials Group study 384 randomized antiretroviral-naive subjects to receive efavirenz and/or nelfinavir plus 2 nucleoside analogues, with follow-up lasting up to 3 years. Population pharmacokinetics were estimated from a nonlinear mixed-effects model. Polymorphisms in CYP2B6, CYP2C19, CYP3A4, CYP3A5, and MDR1 were characterized. Results. The 504 participants in the genetic study included 340 efavirenz recipients and 348 nelfinavir recipients (184 of the 504 participants received both efavirenz and nelfinavir). Of the participants, 49% were white, 31% were black, and 19% were Hispanic. Plasma exposure to efavirenz and nelfinavir in each population was significantly associated with the polymorphisms CYP2B6 516G→T and CYP2C19 681G→A, respectively. Among efavirenz recipients, the MDR1 position 3435 TT genotype was associated with decreased likelihood of virologic failure and decreased emergence of efavirenz-resistant virus but not with plasma efavirenz exposure. Among nelfinavir recipients, a trend toward decreased virologic failure was associated with the polymorphism CYP2C19 681G→A. Conclusions. Genetic variants predict plasma exposure to efavirenz and nelfinavir, and they may predict virologic failure and/or emergence of drug-resistant virus. These associations with treatment responses must be validated in other studies.

AB - Background. Efavirenz and nelfinavir are metabolized by cytochrome P-450 (CYP) 2B6 and CYP2C19, respectively, with some involvement by CYP3A. Nelfinavir is a substrate for P-glycoprotein, which is encoded by MDR1. The present study examined associations between genetic variants and long-term responses to treatment. Methods. Adult AIDS Clinical Trials Group study 384 randomized antiretroviral-naive subjects to receive efavirenz and/or nelfinavir plus 2 nucleoside analogues, with follow-up lasting up to 3 years. Population pharmacokinetics were estimated from a nonlinear mixed-effects model. Polymorphisms in CYP2B6, CYP2C19, CYP3A4, CYP3A5, and MDR1 were characterized. Results. The 504 participants in the genetic study included 340 efavirenz recipients and 348 nelfinavir recipients (184 of the 504 participants received both efavirenz and nelfinavir). Of the participants, 49% were white, 31% were black, and 19% were Hispanic. Plasma exposure to efavirenz and nelfinavir in each population was significantly associated with the polymorphisms CYP2B6 516G→T and CYP2C19 681G→A, respectively. Among efavirenz recipients, the MDR1 position 3435 TT genotype was associated with decreased likelihood of virologic failure and decreased emergence of efavirenz-resistant virus but not with plasma efavirenz exposure. Among nelfinavir recipients, a trend toward decreased virologic failure was associated with the polymorphism CYP2C19 681G→A. Conclusions. Genetic variants predict plasma exposure to efavirenz and nelfinavir, and they may predict virologic failure and/or emergence of drug-resistant virus. These associations with treatment responses must be validated in other studies.

UR - http://www.scopus.com/inward/record.url?scp=27944460707&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=27944460707&partnerID=8YFLogxK

U2 - 10.1086/497610

DO - 10.1086/497610

M3 - Article

C2 - 16267764

AN - SCOPUS:27944460707

VL - 192

SP - 1931

EP - 1942

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

SN - 0022-1899

IS - 11

ER -