title: Nucleoside reverse transcriptase inhibitor resistance mutations associated with first-line stavudine-containing antiretroviral therapy: programmatic implications for countries phasing out stavudine.
abstract: 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.
authors.affiliation: Division Infectious Diseases, Department of Medicine, Stanford University, California 94305, USA. micheletang@gmail.com
authors.forename: Michele W
authors.initials: MW
authors.lastname: Tang
authors.forename: Soo-Yon
authors.initials: SY
authors.lastname: Rhee
authors.forename: Silvia
authors.initials: S
authors.lastname: Bertagnolio
authors.forename: Nathan
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authors.lastname: Ford
authors.forename: Susan
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authors.lastname: Holmes
authors.forename: Kim C
authors.initials: KC
authors.lastname: Sigaloff
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authors.lastname: Hamers
authors.forename: Tobias F Rinke
authors.initials: TF
authors.lastname: de Wit
authors.forename: Herve J
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authors.lastname: Fleury
authors.forename: Phyllis J
authors.initials: PJ
authors.lastname: Kanki
authors.forename: Kiat
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authors.lastname: Ruxrungtham
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Hawkins
authors.forename: Carole L
authors.initials: CL
authors.lastname: Wallis
authors.forename: Wendy
authors.initials: W
authors.lastname: Stevens
authors.forename: Gert U
authors.initials: GU
authors.lastname: van Zyl
authors.forename: Weerawat
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authors.lastname: Manosuthi
authors.forename: Mina C
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authors.lastname: Hosseinipour
authors.forename: Nicole
authors.initials: N
authors.lastname: Ngo-Giang-Huong
authors.forename: Laurent
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authors.lastname: Belec
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authors.lastname: Peeters
authors.forename: Avelin
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authors.lastname: Aghokeng
authors.forename: Torsak
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authors.lastname: Bunupuradah
authors.forename: Sherri
authors.initials: S
authors.lastname: Burda
authors.forename: Patricia
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authors.lastname: Cane
authors.forename: Giulia
authors.initials: G
authors.lastname: Cappelli
authors.forename: Charlotte
authors.initials: C
authors.lastname: Charpentier
authors.forename: Anoumou Y
authors.initials: AY
authors.lastname: Dagnra
authors.forename: Alaka K
authors.initials: AK
authors.lastname: Deshpande
authors.forename: Ziad
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authors.lastname: El-Katib
authors.forename: Susan H
authors.initials: SH
authors.lastname: Eshleman
authors.forename: Joseph
authors.initials: J
authors.lastname: Fokam
authors.forename: Jean-Chrysostome
authors.initials: JC
authors.lastname: Gody
authors.forename: David
authors.initials: D
authors.lastname: Katzenstein
authors.forename: Donato D
authors.initials: DD
authors.lastname: Koyalta
authors.forename: Johnstone J
authors.initials: JJ
authors.lastname: Kumwenda
authors.forename: Marc
authors.initials: M
authors.lastname: Lallemant
authors.forename: Lutgarde
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authors.lastname: Lynen
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Marconi
authors.forename: Nicolas A
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authors.lastname: Margot
authors.forename: Sandrine
authors.initials: S
authors.lastname: Moussa
authors.forename: Thumbi
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authors.lastname: Ndung'u
authors.forename: Phillipe N
authors.initials: PN
authors.lastname: Nyambi
authors.forename: Catherine
authors.initials: C
authors.lastname: Orrell
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schapiro
authors.forename: Rob
authors.initials: R
authors.lastname: Schuurman
authors.forename: Sunee
authors.initials: S
authors.lastname: Sirivichayakul
authors.forename: Davey
authors.initials: D
authors.lastname: Smith
authors.forename: Maria
authors.initials: M
authors.lastname: Zolfo
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jordan
authors.forename: Robert W
authors.initials: RW
authors.lastname: Shafer
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000480:Alkynes; D044966:Anti-Retroviral Agents / Q000008:administration & dosage*; D048588:Benzoxazines / Q000008:administration & dosage; D003521:Cyclopropanes; D016208:Databases, Factual; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D006801:Humans; D020125:Mutation, Missense; D019829:Nevirapine / Q000008:administration & dosage; D063065:Organophosphonates / Q000008:administration & dosage; D012367:RNA, Viral / Q000032:analysis* / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage*; D018119:Stavudine / Q000008:administration & dosage; D000068698:Tenofovir; D015215:Zidovudine / Q000008:administration & dosage
chemical_list: D000480:Alkynes; D044966:Anti-Retroviral Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D063065:Organophosphonates; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D019829:Nevirapine; D000068698:Tenofovir; D018119:Stavudine; D000225:Adenine; C098320:efavirenz
keywords: AZT; HIV-1; NRTI; TDF; d4T; drug resistance; mutations; nucleoside reverse transcriptase inhibitor; stavudine; subtypes; tenofovir; zidovudine