The Body Covers: The 35th Annual Meeting of the Infectious Diseases Society of America
Virologic Failure and Resistance with Triple Combination Antiretroviral Therapy (START Studies I and II)
November 19, 1999
Several recent studies have shown that resistance to 3TC emerges prior to protease inhibitor (PI) resistance in the setting of initial failure of AZT/3TC/PI regimens. Little is known, however, about the pattern of drug resistance that emerges in patients failing PI regimens that include d4T/3TC or d4T/ddI as the nucleoside RT inhibitors (NRTI). In this study, Gulick et al determined the resistance patterns of plasma virus in patients experiencing treatment failure in the START I or START II studies. START I compared the efficacy of AZT/3TC/indinavir (IDV) vs d4T/3TC/IDV, whereas START II compared the efficacy of AZT/3TC/IDV vs d4t/ddI/IDV. (Final results of the START II study were presented by Eron et al. [Abstract 14].) Genotypic and phenotypic resistance testing was performed on paired baseline and follow-up samples from 61 patients who had received at least 12 weeks of study medication, had at least one plasma HIV-1 RNA level <500 copies/mL and subsequently had a confirmed rise in plasma HIV-1 RNA to >500 copies/mL. For subjects assigned to ZDV/3TC/IDV, wild-type virus was recovered in samples from 10/34 (29%) patients at the time of failure. Evidence of 3TC resistance (M184V) was present in 20/34 (59%), whereas new mutations associated with PI resistance were detected in 3/34 (9%). Similar results were observed for subjects assigned to d4T/3TC/IDV: wild-type virus was found in 4/13 (31%), and 3TC resistance was found in 7/13 (54%). No new PI resistance mutations were found in samples from these patients. For patients assigned to d4T/ddI/IDV, wild-type virus was found in 9/14 (64%), and new PI-resistance mutations were found in 3/14 (21%). These results further extend previously reported findings of Havlir et al (from ACTG 343), Descamps et al (from the Trilege study), and D'Aquila et al (from ACTG 347), which showed that resistance to 3TC is the most common finding in samples from patients with initial treatment failure. The more rapid emergence of 3TC resistance in this setting most likely reflects the substantial growth advantage conferred by the M184V mutation in the setting of 3TC-containing regimens. It is still unresolved, however, whether 3TC resistance is the cause of treatment failure in these cases or merely serves as a marker of treatment failure. The emergence of IDV resistance mutations in the d4T/ddI/IDV arm suggests that these mutations confer a greater advantage to the virus than ddI resistance, since ddI resistance mutations were not observed.
Authored by: R.M. Gulick, J.J. Eron, J. Squires, R. Murphy, A.T. Pavia, E.M. Dale, N. Hellmann, W. Huang, N. Parkin, R.A. Grosso, M.R. Stevens, for the START I and II Protocol Teams
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