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

J Infect Dis. 2013 Jun 15;207 Suppl 2(Suppl 2):S70-7. doi: 10.1093/infdis/jit114.


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.

Methods: We 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.

Results: Mutations 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.

Conclusions: Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.

Keywords: AZT; HIV-1; NRTI; TDF; d4T; drug resistance; mutations; nucleoside reverse transcriptase inhibitor; stavudine; subtypes; tenofovir; zidovudine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / administration & dosage
  • Adenine / analogs & derivatives
  • Anti-Retroviral Agents / administration & dosage*
  • Benzoxazines / administration & dosage
  • Databases, Factual
  • Drug Resistance, Viral* / genetics
  • Drug Therapy, Combination
  • Genotype
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV-1 / drug effects
  • HIV-1 / genetics*
  • HIV-1 / physiology
  • Humans
  • Mutation, Missense
  • Nevirapine / administration & dosage
  • Organophosphonates / administration & dosage
  • RNA, Viral / analysis*
  • RNA, Viral / genetics
  • Reverse Transcriptase Inhibitors / administration & dosage*
  • Stavudine / administration & dosage
  • Tenofovir
  • Zidovudine / administration & dosage


  • Anti-Retroviral Agents
  • Benzoxazines
  • Organophosphonates
  • RNA, Viral
  • Reverse Transcriptase Inhibitors
  • Zidovudine
  • Nevirapine
  • Tenofovir
  • Stavudine
  • Adenine
  • efavirenz