Nucleoside reverse transcriptase inhibitor resistance mutations associated with first-line stavudine-containing antiretroviral therapy: Programmatic implications for countries phasing out stavudine

Michele W. Tang, Soo Yon Rhee, Silvia Bertagnolio, Nathan Ford, Susan Holmes, Kim C. Sigaloff, Raph L. Hamers, Tobias F.Rinke De Wit, Herve J. Fleury, Phyllis J. Kanki, Kiat Ruxrungtham, Claudia A. Hawkins, Carole L. Wallis, Wendy Stevens, Gert U. Van Zyl, Weerawat Manosuthi, Mina C. Hosseinipour, Nicole Ngo-Giang-Huong, Laurent Belec, Martine PeetersAvelin Aghokeng, Torsak Bunupuradah, Sherri Burda, Patricia Cane, Giulia Cappelli, Charlotte Charpentier, Anoumou Y. Dagnra, Alaka K. Deshpande, Ziad El-Katib, Susan H. Eshleman, Joseph Fokam, Jean Chrysostome Gody, David Katzenstein, Donato D. Koyalta, Johnstone J. Kumwenda, Marc Lallemant, Lutgarde Lynen, Vincent C. Marconi, Nicolas A. Margot, Sandrine Moussa, Thumbi Ndung'U, Phillipe N. Nyambi, Catherine Orrell, Jonathan M. Schapiro, Rob Schuurman, Sunee Sirivichayakul, Davey Smith, Maria Zolfo, Michael R. Jordan, Robert W. Shafer

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31 Citations (Scopus)


Background The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure.MethodsWe analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance.ResultsMutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01-AE increased the risk of K65R, but only CRF01-AE increased the risk of K65R without Q151M.ConclusionsRegardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.

Original languageEnglish
Pages (from-to)S70-S77
JournalJournal of infectious diseases
Issue numberSUPPL.2
Publication statusPublished - 15 Jun 2013


  • AZT
  • HIV-1
  • NRTI
  • TDF
  • d4T
  • drug resistance
  • mutations
  • nucleoside reverse transcriptase inhibitor
  • stavudine
  • subtypes
  • tenofovir
  • zidovudine

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