Non-nucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance: Implications for preclinical evaluation of novel NNRTIs and clinical genotypic resistance testing

George L. Melikian, Soo Yon Rhee, Vici Varghese, Danielle Porter, Kirsten White, Jonathan Taylor, William Towner, Paolo Troia-Cancio, Jeffrey Burack, Edwin DeJesus, Gregory K. Robbins, Kristin Razzeca, Ron Kagan, Tommy F. Liu, W. Jeffrey Fessel, Dennis Israelski, Robert W. Shafer

    Research output: Contribution to journalArticle

    44 Citations (Scopus)

    Abstract

    Objectives: The introduction of two new non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the past 5 years and the identification of novel NNRTI-associated mutations have made it necessary to reassess the extent of phenotypic NNRTI cross-resistance. Methods:We analysed a dataset containing 1975, 1967, 519 and 187 genotype-phenotype correlations for nevirapine, efavirenz, etravirineandrilpivirine, respectively. We used linear regression to estimatethe effects of RTmutations on susceptibility to each of these NNRTIs. Results: Sixteen mutations at 10 positions were significantly associated with the greatest contribution to reduced phenotypic susceptibility (≥10-fold) to one or more NNRTIs, including: 14 mutations at six positions for nevirapine (K101P, K103N/S, V106A/M, Y181C/I/V, Y188C/L and G190A/E/Q/S); 10 mutations at six positions for efavirenz (L100I, K101P, K103N, V106M, Y188C/L and G190A/E/Q/S); 5 mutations at four positions for etravirine (K101P, Y181I/V, G190E and F227C); and 6 mutations at five positions for rilpivirine (L100I, K101P, Y181I/V, G190E and F227C). G190E, amutation that causes high-level nevirapine and efavirenz resistance, also markedly reduced susceptibility to etravirineand rilpivirine. K101H, E138G, V179FandM230Lmutations, associated with reduced susceptibility to etravirine and rilpivirine, were also associated with reduced susceptibility to nevirapine and/or efavirenz. Conclusions: The identification of novel cross-resistance patternsamong approved NNRTIs illustrates the need fora systematic approach for testing novel NNRTIs against clinical virus isolates with major NNRTI-resistancemutations and for testing older NNRTIs against virus isolates withmutations identified during the evaluation of a novel NNRTI.

    Original languageEnglish (US)
    Article numberdkt316
    Pages (from-to)12-20
    Number of pages9
    JournalJournal of Antimicrobial Chemotherapy
    Volume69
    Issue number1
    DOIs
    StatePublished - Jan 1 2014

    Fingerprint

    Reverse Transcriptase Inhibitors
    efavirenz
    Rilpivirine
    Nevirapine
    etravirine
    Mutation
    Viruses
    Genetic Association Studies
    Linear Models

    Keywords

    • Drug resistance
    • Etravirine
    • HIV-1
    • Linear regression
    • Rilpivirine

    ASJC Scopus subject areas

    • Pharmacology
    • Pharmacology (medical)
    • Infectious Diseases

    Cite this

    Non-nucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance : Implications for preclinical evaluation of novel NNRTIs and clinical genotypic resistance testing. / Melikian, George L.; Rhee, Soo Yon; Varghese, Vici; Porter, Danielle; White, Kirsten; Taylor, Jonathan; Towner, William; Troia-Cancio, Paolo; Burack, Jeffrey; DeJesus, Edwin; Robbins, Gregory K.; Razzeca, Kristin; Kagan, Ron; Liu, Tommy F.; Jeffrey Fessel, W.; Israelski, Dennis; Shafer, Robert W.

    In: Journal of Antimicrobial Chemotherapy, Vol. 69, No. 1, dkt316, 01.01.2014, p. 12-20.

    Research output: Contribution to journalArticle

    Melikian, GL, Rhee, SY, Varghese, V, Porter, D, White, K, Taylor, J, Towner, W, Troia-Cancio, P, Burack, J, DeJesus, E, Robbins, GK, Razzeca, K, Kagan, R, Liu, TF, Jeffrey Fessel, W, Israelski, D & Shafer, RW 2014, 'Non-nucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance: Implications for preclinical evaluation of novel NNRTIs and clinical genotypic resistance testing', Journal of Antimicrobial Chemotherapy, vol. 69, no. 1, dkt316, pp. 12-20. https://doi.org/10.1093/jac/dkt316
    Melikian, George L. ; Rhee, Soo Yon ; Varghese, Vici ; Porter, Danielle ; White, Kirsten ; Taylor, Jonathan ; Towner, William ; Troia-Cancio, Paolo ; Burack, Jeffrey ; DeJesus, Edwin ; Robbins, Gregory K. ; Razzeca, Kristin ; Kagan, Ron ; Liu, Tommy F. ; Jeffrey Fessel, W. ; Israelski, Dennis ; Shafer, Robert W. / Non-nucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance : Implications for preclinical evaluation of novel NNRTIs and clinical genotypic resistance testing. In: Journal of Antimicrobial Chemotherapy. 2014 ; Vol. 69, No. 1. pp. 12-20.
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    abstract = "Objectives: The introduction of two new non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the past 5 years and the identification of novel NNRTI-associated mutations have made it necessary to reassess the extent of phenotypic NNRTI cross-resistance. Methods:We analysed a dataset containing 1975, 1967, 519 and 187 genotype-phenotype correlations for nevirapine, efavirenz, etravirineandrilpivirine, respectively. We used linear regression to estimatethe effects of RTmutations on susceptibility to each of these NNRTIs. Results: Sixteen mutations at 10 positions were significantly associated with the greatest contribution to reduced phenotypic susceptibility (≥10-fold) to one or more NNRTIs, including: 14 mutations at six positions for nevirapine (K101P, K103N/S, V106A/M, Y181C/I/V, Y188C/L and G190A/E/Q/S); 10 mutations at six positions for efavirenz (L100I, K101P, K103N, V106M, Y188C/L and G190A/E/Q/S); 5 mutations at four positions for etravirine (K101P, Y181I/V, G190E and F227C); and 6 mutations at five positions for rilpivirine (L100I, K101P, Y181I/V, G190E and F227C). G190E, amutation that causes high-level nevirapine and efavirenz resistance, also markedly reduced susceptibility to etravirineand rilpivirine. K101H, E138G, V179FandM230Lmutations, associated with reduced susceptibility to etravirine and rilpivirine, were also associated with reduced susceptibility to nevirapine and/or efavirenz. Conclusions: The identification of novel cross-resistance patternsamong approved NNRTIs illustrates the need fora systematic approach for testing novel NNRTIs against clinical virus isolates with major NNRTI-resistancemutations and for testing older NNRTIs against virus isolates withmutations identified during the evaluation of a novel NNRTI.",
    keywords = "Drug resistance, Etravirine, HIV-1, Linear regression, Rilpivirine",
    author = "Melikian, {George L.} and Rhee, {Soo Yon} and Vici Varghese and Danielle Porter and Kirsten White and Jonathan Taylor and William Towner and Paolo Troia-Cancio and Jeffrey Burack and Edwin DeJesus and Robbins, {Gregory K.} and Kristin Razzeca and Ron Kagan and Liu, {Tommy F.} and {Jeffrey Fessel}, W. and Dennis Israelski and Shafer, {Robert W.}",
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    T2 - Implications for preclinical evaluation of novel NNRTIs and clinical genotypic resistance testing

    AU - Melikian, George L.

    AU - Rhee, Soo Yon

    AU - Varghese, Vici

    AU - Porter, Danielle

    AU - White, Kirsten

    AU - Taylor, Jonathan

    AU - Towner, William

    AU - Troia-Cancio, Paolo

    AU - Burack, Jeffrey

    AU - DeJesus, Edwin

    AU - Robbins, Gregory K.

    AU - Razzeca, Kristin

    AU - Kagan, Ron

    AU - Liu, Tommy F.

    AU - Jeffrey Fessel, W.

    AU - Israelski, Dennis

    AU - Shafer, Robert W.

    PY - 2014/1/1

    Y1 - 2014/1/1

    N2 - Objectives: The introduction of two new non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the past 5 years and the identification of novel NNRTI-associated mutations have made it necessary to reassess the extent of phenotypic NNRTI cross-resistance. Methods:We analysed a dataset containing 1975, 1967, 519 and 187 genotype-phenotype correlations for nevirapine, efavirenz, etravirineandrilpivirine, respectively. We used linear regression to estimatethe effects of RTmutations on susceptibility to each of these NNRTIs. Results: Sixteen mutations at 10 positions were significantly associated with the greatest contribution to reduced phenotypic susceptibility (≥10-fold) to one or more NNRTIs, including: 14 mutations at six positions for nevirapine (K101P, K103N/S, V106A/M, Y181C/I/V, Y188C/L and G190A/E/Q/S); 10 mutations at six positions for efavirenz (L100I, K101P, K103N, V106M, Y188C/L and G190A/E/Q/S); 5 mutations at four positions for etravirine (K101P, Y181I/V, G190E and F227C); and 6 mutations at five positions for rilpivirine (L100I, K101P, Y181I/V, G190E and F227C). G190E, amutation that causes high-level nevirapine and efavirenz resistance, also markedly reduced susceptibility to etravirineand rilpivirine. K101H, E138G, V179FandM230Lmutations, associated with reduced susceptibility to etravirine and rilpivirine, were also associated with reduced susceptibility to nevirapine and/or efavirenz. Conclusions: The identification of novel cross-resistance patternsamong approved NNRTIs illustrates the need fora systematic approach for testing novel NNRTIs against clinical virus isolates with major NNRTI-resistancemutations and for testing older NNRTIs against virus isolates withmutations identified during the evaluation of a novel NNRTI.

    AB - Objectives: The introduction of two new non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the past 5 years and the identification of novel NNRTI-associated mutations have made it necessary to reassess the extent of phenotypic NNRTI cross-resistance. Methods:We analysed a dataset containing 1975, 1967, 519 and 187 genotype-phenotype correlations for nevirapine, efavirenz, etravirineandrilpivirine, respectively. We used linear regression to estimatethe effects of RTmutations on susceptibility to each of these NNRTIs. Results: Sixteen mutations at 10 positions were significantly associated with the greatest contribution to reduced phenotypic susceptibility (≥10-fold) to one or more NNRTIs, including: 14 mutations at six positions for nevirapine (K101P, K103N/S, V106A/M, Y181C/I/V, Y188C/L and G190A/E/Q/S); 10 mutations at six positions for efavirenz (L100I, K101P, K103N, V106M, Y188C/L and G190A/E/Q/S); 5 mutations at four positions for etravirine (K101P, Y181I/V, G190E and F227C); and 6 mutations at five positions for rilpivirine (L100I, K101P, Y181I/V, G190E and F227C). G190E, amutation that causes high-level nevirapine and efavirenz resistance, also markedly reduced susceptibility to etravirineand rilpivirine. K101H, E138G, V179FandM230Lmutations, associated with reduced susceptibility to etravirine and rilpivirine, were also associated with reduced susceptibility to nevirapine and/or efavirenz. Conclusions: The identification of novel cross-resistance patternsamong approved NNRTIs illustrates the need fora systematic approach for testing novel NNRTIs against clinical virus isolates with major NNRTI-resistancemutations and for testing older NNRTIs against virus isolates withmutations identified during the evaluation of a novel NNRTI.

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    KW - HIV-1

    KW - Linear regression

    KW - Rilpivirine

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