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Sustained elevations in CD4 cell counts commonly occur despite incomplete viral suppression with protease inhibitor-based antiretroviral therapy.To determine the incidence and risk factors associated with return of CD4 cell count to pre-therapy levels in patients experiencing virologic failure of protease inhibitor therapy.This is a clinic-based cohort study of HIV-infected adults who failed to maintain durable viral suppression on a protease inhibitor-based regimen.Virologic failure was defined as persistent plasma HIV RNA level > 500 copies/ml. Immunologic failure was defined as return of CD4 cell count to pre-therapy levels.A total of 291 patients experienced virologic failure on a protease inhibitor-based regimen and had a treatment-mediated CD4 cell increase above pre-therapy levels at the time of virologic failure. If patient data were censored at the time a successful salvage regimen was initiated, then the median time to immunologic failure after the onset of virologic failure was 3 years. If patient data were also censored at the time therapy was discontinued, then 36.8% of the cohort experienced immunologic failure after 3 years of continuous virologic failure. The change in viral load from a pre-treatment baseline, and not the absolute level of viremia achieved, was a strong and independent predictor of immunologic failure. Discontinuing therapy was associated with immunologic failure independent of viral load changes.Reduction in T CD4+ cell numbers may eventually occur during prolonged virologic failure of a protease inhibitor-based regimen and is predicted by the degree of virologic suppression below a pre-therapy ‘set-point'.