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Although the kinetics of CD4+ cell counts have been extensively studied in antiretroviral-naive HIV-infected patients, data on individuals who have failed combination antiretroviral therapy (cART) are lacking.This analysis was based on the ICONA Foundation Study. Subjects with ≥1 episode of viral suppression after starting first-line cART were included (n = 3537). Following a viral rebound, patients who achieved another episode of viral suppression could reenter the analysis. The percentage of patients with an increase in CD4+ cell count >300 cells/mm3 was estimated using Kaplan-Meier techniques; the rate of CD4+ cell count increase per year was estimated using a multivariable, multilevel linear model with fixed effects of intercept and slope. Multivariable models were also fitted to include several covariates.The median time to reach a CD4+ cell count increase >300 cells/mm3 from baseline was significantly associated with the number of failed regimens: 34 months, 41 months, 51 months, and 45 months in subjects without evidence of previous virological failure, or 1, 2, or ≥3 previous virologically failed regimens, respectively (P < .001, by log-rank test). The annual estimated increases in CD4+ cell count were 36 cells/mm3 (95% confidence interval [CI], 34-38 cells/mm3), 28 cells/mm3 (95% CI, 11-21 cells/mm3), 31 cells/mm3 (95% CI, 26-36 cells/ mm3), and 26 cells/mm3 (95% CI, 18-33 cells/mm3), respectively. Differences in the annual CD4+ cell count increase were observed between specific antiretrovirals.Subjects with ≥1 virological failure took a longer time to reach a CD4+ cell count >300 cell/ mm3 and had a slower annual increase than those without virological failure. Efforts should be made to optimize first-line cART, because this represents the best chance of achieving an effective CD4+ response.