Genotypic resistance to zidovudine as a predictor of failure of subsequent therapy with human immunodeficiency virus type-1 nucleoside reverse-transcriptase inhibitors.
To define factors predictive of failure to respond to nucleoside reverse-transcriptase inhibitors in human immunodeficiency virus type-1 (HIV-1)-infected subjects pretreated with zidovudine (ZDV), three groups of subjects shifted 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, plasma HIV-1 RNA load, peripheral blood mononuclear cell HIV-1 DNA load, and HIV-1 DNA genotypic resistance to nucleoside reverse-transcriptase inhibitors. The three groups were well matched for baseline characteristics and did not differ significantly in virological and immunological response to the different combination treatments. Drug-specific resistance mutations were selected 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 nonresponders to the second nucleoside reverse-transcriptase inhibitor on the basis of a decrease of more than 0.5 log10 (n = 15) or less than 0.5 log10 (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 considered or not, respectively). Thus, selection of ZDV resistance mutations may impair subsequent use of different nucleoside reverse-transcriptase inhibitor compounds.
Venturi
G
G
Dipartimento di Biologia Molecolare, Università di Siena, Italy.
Romano
L
L
Catucci
M
M
Riccio
M L
ML
De Milito
A
A
Gonnelli
A
A
Rubino
M
M
Valensin
P E
PE
Zazzi
M
M
D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D004279:DNA, Viral / Q000097:blood; D004352:Drug Resistance, Microbial / Q000235:genetics*; D004359:Drug Therapy, Combination; D015751:Genes, pol; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D011237:Predictive Value of Tests; D011533:Proviruses; D012367:RNA, Viral / Q000097:blood; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D017211:Treatment Failure; D019562:Viral Load; D015215:Zidovudine / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D004279:DNA, Viral; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine