Association of efavirenz hypersusceptibility with virologic response in ACTG 368, a randomized trial of abacavir (ABC) in combination with efavirenz (EFV) and indinavir (IDV) in HIV-infected subjects with prior nucleoside analog experience

Lisa M. Demeter, Victor DeGruttola, Stephanie Lustgarten, Daniel Bettendorf, Margaret Fischl, Susan Eshleman, William Spreen, Bach Yen Nguyen, Christine E. Koval, Joseph J. Eron, Scott Hammer, Kathleen Squires

Research output: Contribution to journalArticle

Abstract

Purpose: To evaluate the association of efavirenz hypersusceptibility (EFV-HS) with clinical outcome in a double-blind, placebo-controlled, randomized trial of EFV plus indinavir (EFV+IDV) vs. EFV+IDV plus abacavir (ABC) in 283 nucleoside-experienced HIV-infected patients. Method and Results: Rates of virologic failure were similar in the 2 arms at week 16 (p = .509). Treatment discontinuations were more common in the ABC arm (p = .001). Using logistic regression, there was no association between virologic failure and either baseline ABC resistance or regimen sensitivity score. Using 3 different genotypic scoring systems, EFV-HS was significantly associated with reduced virologic failure at week 16, independent of treatment assignment. In some patients on the nucleoside-sparing arm, the nucleoside-resistance mutation L74V was selected for in combination with the uncommonly occurring EFV-resistance mutations K103N+L100I; L74V was not detected as a minority variant, using clonal sequence analysis, when the nucleoside-sparing regimen was initiated. Conclusion: Premature treatment discontinuations in the ABC arm and the presence of EFV-HS HIV variants in this patient population likely made it difficult to detect a benefit of adding ABC to EFV+IDV. In addition, L74V, when combined with K103N+L100I, may confer a selective advantage to the virus that is independent of its effects on nucleoside resistance.

Original languageEnglish (US)
Pages (from-to)11-25
Number of pages15
JournalHIV Clinical Trials
Volume9
Issue number1
DOIs
StatePublished - Jan 2008

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efavirenz
Indinavir
Nucleosides
HIV
Mutation
abacavir

Keywords

  • Efavirenz hypersusceptibility
  • HIV drug resistance
  • NNRTI resistance
  • Nucleoside resistance

ASJC Scopus subject areas

  • Virology
  • Immunology

Cite this

Association of efavirenz hypersusceptibility with virologic response in ACTG 368, a randomized trial of abacavir (ABC) in combination with efavirenz (EFV) and indinavir (IDV) in HIV-infected subjects with prior nucleoside analog experience. / Demeter, Lisa M.; DeGruttola, Victor; Lustgarten, Stephanie; Bettendorf, Daniel; Fischl, Margaret; Eshleman, Susan; Spreen, William; Nguyen, Bach Yen; Koval, Christine E.; Eron, Joseph J.; Hammer, Scott; Squires, Kathleen.

In: HIV Clinical Trials, Vol. 9, No. 1, 01.2008, p. 11-25.

Research output: Contribution to journalArticle

Demeter, Lisa M. ; DeGruttola, Victor ; Lustgarten, Stephanie ; Bettendorf, Daniel ; Fischl, Margaret ; Eshleman, Susan ; Spreen, William ; Nguyen, Bach Yen ; Koval, Christine E. ; Eron, Joseph J. ; Hammer, Scott ; Squires, Kathleen. / Association of efavirenz hypersusceptibility with virologic response in ACTG 368, a randomized trial of abacavir (ABC) in combination with efavirenz (EFV) and indinavir (IDV) in HIV-infected subjects with prior nucleoside analog experience. In: HIV Clinical Trials. 2008 ; Vol. 9, No. 1. pp. 11-25.
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abstract = "Purpose: To evaluate the association of efavirenz hypersusceptibility (EFV-HS) with clinical outcome in a double-blind, placebo-controlled, randomized trial of EFV plus indinavir (EFV+IDV) vs. EFV+IDV plus abacavir (ABC) in 283 nucleoside-experienced HIV-infected patients. Method and Results: Rates of virologic failure were similar in the 2 arms at week 16 (p = .509). Treatment discontinuations were more common in the ABC arm (p = .001). Using logistic regression, there was no association between virologic failure and either baseline ABC resistance or regimen sensitivity score. Using 3 different genotypic scoring systems, EFV-HS was significantly associated with reduced virologic failure at week 16, independent of treatment assignment. In some patients on the nucleoside-sparing arm, the nucleoside-resistance mutation L74V was selected for in combination with the uncommonly occurring EFV-resistance mutations K103N+L100I; L74V was not detected as a minority variant, using clonal sequence analysis, when the nucleoside-sparing regimen was initiated. Conclusion: Premature treatment discontinuations in the ABC arm and the presence of EFV-HS HIV variants in this patient population likely made it difficult to detect a benefit of adding ABC to EFV+IDV. In addition, L74V, when combined with K103N+L100I, may confer a selective advantage to the virus that is independent of its effects on nucleoside resistance.",
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author = "Demeter, {Lisa M.} and Victor DeGruttola and Stephanie Lustgarten and Daniel Bettendorf and Margaret Fischl and Susan Eshleman and William Spreen and Nguyen, {Bach Yen} and Koval, {Christine E.} and Eron, {Joseph J.} and Scott Hammer and Kathleen Squires",
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T1 - Association of efavirenz hypersusceptibility with virologic response in ACTG 368, a randomized trial of abacavir (ABC) in combination with efavirenz (EFV) and indinavir (IDV) in HIV-infected subjects with prior nucleoside analog experience

AU - Demeter, Lisa M.

AU - DeGruttola, Victor

AU - Lustgarten, Stephanie

AU - Bettendorf, Daniel

AU - Fischl, Margaret

AU - Eshleman, Susan

AU - Spreen, William

AU - Nguyen, Bach Yen

AU - Koval, Christine E.

AU - Eron, Joseph J.

AU - Hammer, Scott

AU - Squires, Kathleen

PY - 2008/1

Y1 - 2008/1

N2 - Purpose: To evaluate the association of efavirenz hypersusceptibility (EFV-HS) with clinical outcome in a double-blind, placebo-controlled, randomized trial of EFV plus indinavir (EFV+IDV) vs. EFV+IDV plus abacavir (ABC) in 283 nucleoside-experienced HIV-infected patients. Method and Results: Rates of virologic failure were similar in the 2 arms at week 16 (p = .509). Treatment discontinuations were more common in the ABC arm (p = .001). Using logistic regression, there was no association between virologic failure and either baseline ABC resistance or regimen sensitivity score. Using 3 different genotypic scoring systems, EFV-HS was significantly associated with reduced virologic failure at week 16, independent of treatment assignment. In some patients on the nucleoside-sparing arm, the nucleoside-resistance mutation L74V was selected for in combination with the uncommonly occurring EFV-resistance mutations K103N+L100I; L74V was not detected as a minority variant, using clonal sequence analysis, when the nucleoside-sparing regimen was initiated. Conclusion: Premature treatment discontinuations in the ABC arm and the presence of EFV-HS HIV variants in this patient population likely made it difficult to detect a benefit of adding ABC to EFV+IDV. In addition, L74V, when combined with K103N+L100I, may confer a selective advantage to the virus that is independent of its effects on nucleoside resistance.

AB - Purpose: To evaluate the association of efavirenz hypersusceptibility (EFV-HS) with clinical outcome in a double-blind, placebo-controlled, randomized trial of EFV plus indinavir (EFV+IDV) vs. EFV+IDV plus abacavir (ABC) in 283 nucleoside-experienced HIV-infected patients. Method and Results: Rates of virologic failure were similar in the 2 arms at week 16 (p = .509). Treatment discontinuations were more common in the ABC arm (p = .001). Using logistic regression, there was no association between virologic failure and either baseline ABC resistance or regimen sensitivity score. Using 3 different genotypic scoring systems, EFV-HS was significantly associated with reduced virologic failure at week 16, independent of treatment assignment. In some patients on the nucleoside-sparing arm, the nucleoside-resistance mutation L74V was selected for in combination with the uncommonly occurring EFV-resistance mutations K103N+L100I; L74V was not detected as a minority variant, using clonal sequence analysis, when the nucleoside-sparing regimen was initiated. Conclusion: Premature treatment discontinuations in the ABC arm and the presence of EFV-HS HIV variants in this patient population likely made it difficult to detect a benefit of adding ABC to EFV+IDV. In addition, L74V, when combined with K103N+L100I, may confer a selective advantage to the virus that is independent of its effects on nucleoside resistance.

KW - Efavirenz hypersusceptibility

KW - HIV drug resistance

KW - NNRTI resistance

KW - Nucleoside resistance

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DO - 10.1310/hct0901-11

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