title: Thymidine analog and multinucleoside resistance mutations are associated with decreased phenotypic susceptibility to stavudine in HIV type 1 isolated from zidovudine-naive patients experiencing viremia on stavudine-containing regimens.
abstract: Studies have demonstrated that HIV-1 isolated from subjects experiencing virologic failure on stavudine (d4T)-containing regimens often contains thymidine analog mutations (TAMs), consisting of reverse transcriptase (RT) mutations M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E, previously associated only with zidovudine (ZDV) resistance. In clinical study NZT40012, HIV-1 was isolated from 86 ZDV-naive subjects experiencing viremia on d4T-based therapies (plasma HIV-1 RNA > or =1000 copies/ml) and analyzed to examine the association between RT mutations and phenotypic resistance to d4T. Resistance-associated mutations were analyzed from HIV-1 isolated from 85 subjects. Of these, 24 samples (28%) had TAMs, and 30 samples (35%) had either TAMs and/or the Q151M multinucleoside resistance (MNR) mutation. Phenotypic susceptibility to d4T was determined by two commercially available methods. Statistically significant increases (p < 0.001) in phenotypic fold resistance to d4T were observed in virus with at least one TAM or MNR mutation. However, the mean increases in phenotypic resistance were 4-fold for the Antivirogram assay and 3-fold for the Phenosense HIV assay, only slightly above the levels used to designate decreased susceptibility to d4T. Subjects can experience viremia on d4T-containing regimens with virus exhibiting only small increases in IC(50), suggesting that relatively small changes in viral susceptibility to d4T may influence drug efficacy.
authors.affiliation: Department of Virology, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. llr8156@gsk.com
authors.forename: L
authors.initials: L
authors.lastname: Ross
authors.forename: A
authors.initials: A
authors.lastname: Scarsella
authors.forename: S
authors.initials: S
authors.lastname: Raffanti
authors.forename: K
authors.initials: K
authors.lastname: Henry
authors.forename: S
authors.initials: S
authors.lastname: Becker
authors.forename: R
authors.initials: R
authors.lastname: Fisher
authors.forename: Q
authors.initials: Q
authors.lastname: Liao
authors.forename: A
authors.initials: A
authors.lastname: Hirani
authors.forename: N
authors.initials: N
authors.lastname: Graham
authors.forename: M
authors.initials: M
authors.lastname: St  Clair
authors.forename: J
authors.initials: J
authors.lastname: Hernandez
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004352:Drug Resistance, Microbial / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D016333:HIV Protease / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D008969:Molecular Sequence Data; D009154:Mutation; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D018119:Stavudine / Q000494:pharmacology* / Q000627:therapeutic use; D013936:Thymidine / Q000031:analogs & derivatives* / Q000235:genetics; D014766:Viremia / Q000821:virology; D015215:Zidovudine / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D018119:Stavudine; D054303:HIV Reverse Transcriptase; D016333:HIV Protease; D013936:Thymidine