Genotypic resistance to zidovudine as a predictor of failure of subsequenttherapy with human immunodeficiency virus type-1 nucleoside reverse-transcriptase inhibitors

To define factors predictive of failure to respond to nucleoside reverse-tr anscriptase inhibitors in human immunodeficiency virus type-1 (HIV-1)-infec ted subjects pretreated with zidovudine (ZDV), three groups of subjects shi fted to double therapy with ZDV plus didanosine (ddI, n = 13), zalcitabine (ddC, n = 14), or lamivudine (3TC, n = 12) were retrospectively evaluated, with respect to addition of the second NRTI, at week 0 and week 24. Factors considered included duration of ZDV pretreatment, CD4(+) cell counts, plas ma HIV-1 RNA load, peripheral blood mononuclear cell HIV-1 DNA load, and HI V-1 DNA genotypic resistance to nucleoside reverse-transcriptase inhibitors . The three groups were well matched for baseline characteristics and did n ot differ significantly in virological and immunological response to the di fferent combination treatments. Drug-specific resistance mutations were sel ected in more than half the cases by 3TC, but not by ddI and ddC. Low-level and substantial genotypic resistance to ZDV was detected 13 (33.3%) and in 19 (48.7%) patients at baseline, respectively, and evolved through week 24 in several patients. When subjects were divided into responders and nonres ponders to the second nucleoside reverse-transcriptase inhibitor on the bas is of a decrease of more than 0.5 log(10) (n = 15) or less than 0.5 log(10) (n = 21) in HIV-1 RNA, respectively, baseline genotypic ZDV resistance was the only independent predictor of failure in a logistic regression model ( P = 0.003 or P = 0.024, depending on whether low-level resistance was consi dered or not, respectively). Thus, selection of ZDV resistance mutations ma y impair subsequent use of different nucleoside reverse-transcriptase inhib itor compounds.