Sequencing of protease inhibitor therapy

Insights from an analysis of HIV phenotypic resistance in patients failing protease inhibitors

Carol A. Kemper, Mallory D. Witt, Philip Keiser, Michael P. Dubé, Donald N. Forthal, Matthew Leibowitz, D. Scott Smith, Andrew Rigby, Nicholas S. Hellmann, Yolanda S. Lie, John Leedom, Douglas Richman, J. Allen McCutchan, Richard Haubrich

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Objective: To characterize the pattern of HIV-1 susceptibility to protease inhibitors in patients failing an initial protease inhibitor-containing regimen. Design: A cross-sectional analysis of antiretroviral susceptibility. Setting: HIV clinics in six metropolitan areas. Patients: Eighty-eight HIV-infected adults with HIV RNA > 400 copies/ml after ≥ 6 months of antiretroviral therapy, including the use of one protease inhibitor for ≥ 3 months. Measurements: The frequency and magnitude of decreased susceptibility, measured with a phenotypic assay using recombinant constructs, to five protease inhibitors. Decreased susceptibility was defined as > 2.5-fold increase in the 50% inhibitory concentration (IC 50) compared with drug sensitive control virus. Results: At study entry, patients were being treated with nelfinavir (63%), indinavir (25%), or another protease inhibitor (11%). HIV isolates from these patients were susceptible (fold change < 2.5) to all five protease inhibitors in 18% of patients and to none in 8%. Isolates from patients receiving nelfinavir were less likely to have reduced susceptibility to other protease inhibitors than isolates from patients treated with indinavir (P < 0.001) or one of the other three agents (P < 0.001), even after adjustment for the duration of prior protease inhibitor use. Reduced susceptibility to saquinavir and amprenavir was observed significantly less frequently than for the other protease inhibitors. Conclusion: The frequency of protease inhibitor cross-resistance and the magnitude of changes in susceptibility varied according to the initial protease inhibitor used in the failing treatment regimen. Significantly less protease inhibitor cross-resistance was demonstrated for isolates from patients failing a nelfinavir-containing regimen compared with those from patients receiving other protease inhibitors.

Original languageEnglish (US)
Pages (from-to)609-615
Number of pages7
JournalAIDS
Volume15
Issue number5
DOIs
StatePublished - Mar 30 2001
Externally publishedYes

Fingerprint

Protease Inhibitors
HIV
Nelfinavir
Therapeutics
Indinavir
Saquinavir
Drug and Narcotic Control
Inhibitory Concentration 50
HIV-1
Cross-Sectional Studies
RNA
Viruses

Keywords

  • Antiretroviral resistance
  • HIV-1
  • Phenotypic assay
  • Protease inhibitor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Sequencing of protease inhibitor therapy : Insights from an analysis of HIV phenotypic resistance in patients failing protease inhibitors. / Kemper, Carol A.; Witt, Mallory D.; Keiser, Philip; Dubé, Michael P.; Forthal, Donald N.; Leibowitz, Matthew; Smith, D. Scott; Rigby, Andrew; Hellmann, Nicholas S.; Lie, Yolanda S.; Leedom, John; Richman, Douglas; McCutchan, J. Allen; Haubrich, Richard.

In: AIDS, Vol. 15, No. 5, 30.03.2001, p. 609-615.

Research output: Contribution to journalArticle

Kemper, CA, Witt, MD, Keiser, P, Dubé, MP, Forthal, DN, Leibowitz, M, Smith, DS, Rigby, A, Hellmann, NS, Lie, YS, Leedom, J, Richman, D, McCutchan, JA & Haubrich, R 2001, 'Sequencing of protease inhibitor therapy: Insights from an analysis of HIV phenotypic resistance in patients failing protease inhibitors', AIDS, vol. 15, no. 5, pp. 609-615. https://doi.org/10.1097/00002030-200103300-00010
Kemper, Carol A. ; Witt, Mallory D. ; Keiser, Philip ; Dubé, Michael P. ; Forthal, Donald N. ; Leibowitz, Matthew ; Smith, D. Scott ; Rigby, Andrew ; Hellmann, Nicholas S. ; Lie, Yolanda S. ; Leedom, John ; Richman, Douglas ; McCutchan, J. Allen ; Haubrich, Richard. / Sequencing of protease inhibitor therapy : Insights from an analysis of HIV phenotypic resistance in patients failing protease inhibitors. In: AIDS. 2001 ; Vol. 15, No. 5. pp. 609-615.
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abstract = "Objective: To characterize the pattern of HIV-1 susceptibility to protease inhibitors in patients failing an initial protease inhibitor-containing regimen. Design: A cross-sectional analysis of antiretroviral susceptibility. Setting: HIV clinics in six metropolitan areas. Patients: Eighty-eight HIV-infected adults with HIV RNA > 400 copies/ml after ≥ 6 months of antiretroviral therapy, including the use of one protease inhibitor for ≥ 3 months. Measurements: The frequency and magnitude of decreased susceptibility, measured with a phenotypic assay using recombinant constructs, to five protease inhibitors. Decreased susceptibility was defined as > 2.5-fold increase in the 50{\%} inhibitory concentration (IC 50) compared with drug sensitive control virus. Results: At study entry, patients were being treated with nelfinavir (63{\%}), indinavir (25{\%}), or another protease inhibitor (11{\%}). HIV isolates from these patients were susceptible (fold change < 2.5) to all five protease inhibitors in 18{\%} of patients and to none in 8{\%}. Isolates from patients receiving nelfinavir were less likely to have reduced susceptibility to other protease inhibitors than isolates from patients treated with indinavir (P < 0.001) or one of the other three agents (P < 0.001), even after adjustment for the duration of prior protease inhibitor use. Reduced susceptibility to saquinavir and amprenavir was observed significantly less frequently than for the other protease inhibitors. Conclusion: The frequency of protease inhibitor cross-resistance and the magnitude of changes in susceptibility varied according to the initial protease inhibitor used in the failing treatment regimen. Significantly less protease inhibitor cross-resistance was demonstrated for isolates from patients failing a nelfinavir-containing regimen compared with those from patients receiving other protease inhibitors.",
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AU - Kemper, Carol A.

AU - Witt, Mallory D.

AU - Keiser, Philip

AU - Dubé, Michael P.

AU - Forthal, Donald N.

AU - Leibowitz, Matthew

AU - Smith, D. Scott

AU - Rigby, Andrew

AU - Hellmann, Nicholas S.

AU - Lie, Yolanda S.

AU - Leedom, John

AU - Richman, Douglas

AU - McCutchan, J. Allen

AU - Haubrich, Richard

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N2 - Objective: To characterize the pattern of HIV-1 susceptibility to protease inhibitors in patients failing an initial protease inhibitor-containing regimen. Design: A cross-sectional analysis of antiretroviral susceptibility. Setting: HIV clinics in six metropolitan areas. Patients: Eighty-eight HIV-infected adults with HIV RNA > 400 copies/ml after ≥ 6 months of antiretroviral therapy, including the use of one protease inhibitor for ≥ 3 months. Measurements: The frequency and magnitude of decreased susceptibility, measured with a phenotypic assay using recombinant constructs, to five protease inhibitors. Decreased susceptibility was defined as > 2.5-fold increase in the 50% inhibitory concentration (IC 50) compared with drug sensitive control virus. Results: At study entry, patients were being treated with nelfinavir (63%), indinavir (25%), or another protease inhibitor (11%). HIV isolates from these patients were susceptible (fold change < 2.5) to all five protease inhibitors in 18% of patients and to none in 8%. Isolates from patients receiving nelfinavir were less likely to have reduced susceptibility to other protease inhibitors than isolates from patients treated with indinavir (P < 0.001) or one of the other three agents (P < 0.001), even after adjustment for the duration of prior protease inhibitor use. Reduced susceptibility to saquinavir and amprenavir was observed significantly less frequently than for the other protease inhibitors. Conclusion: The frequency of protease inhibitor cross-resistance and the magnitude of changes in susceptibility varied according to the initial protease inhibitor used in the failing treatment regimen. Significantly less protease inhibitor cross-resistance was demonstrated for isolates from patients failing a nelfinavir-containing regimen compared with those from patients receiving other protease inhibitors.

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