Thymidine analog and multinucleoside resistance mutations are associated with decreased phenotypic susceptibility to stavudine in HIV type 1 isolatedfrom zidovudine-naive patients experiencing viremia on stavudine-containing regimens

Studies have demonstrated that HIV-1 isolated from subjects experiencing vi rologic failure on stavudine (d4T)containing regimens often contains thymid ine analog mutations (TAMs), consisting of reverse transcriptase (RT) mutat ions M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E, previously associated o nly with zidovudine (ZDV) resistance. In clinical study NZT40012, HIV-1 was isolated from 86 ZDV-naive subjects experiencing viremia on d4T-based ther apies (plasma HIV-1 RNA greater than or equal to 1000 copies/ml) and analyz ed to examine the association between RT mutations and phenotypic resistanc e 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) mutatio n. Phenotypic susceptibility to d4T was determined by two commercially avai lable methods. Statistically significant increases (p < 0.001) in phenotypi c fold resistance to d4T were observed in virus with at least one TAM or MN R mutation. However, the mean increases in phenotypic resistance were 4-fol d 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 exh ibiting only small increases in IC50, suggesting that relatively small chan ges in viral susceptibility to d4T may influence drug efficacy.