Journal Article

Nadir CD4 T Cell Count as Predictor and High CD4 T Cell Intrinsic Apoptosis as Final Mechanism of Poor CD4 T Cell Recovery in Virologically Suppressed HIV-Infected Patients: Clinical Implications

Eugènia Negredo, Marta Massanella, Jordi Puig, Núria Pérez-Álvarez, José Miguel Gallego-Escuredo, Joan Villarroya, Francesc Villarroya, José Molto, Jose Ramón Santos, Bonaventura Clotet and Julià Blanco

in Clinical Infectious Diseases

Published on behalf of Infectious Diseases Society of America

Volume 50, issue 9, pages 1300-1308
Published in print May 2010 | ISSN: 1058-4838
Published online May 2010 | e-ISSN: 1537-6591 | DOI: http://dx.doi.org/10.1086/651689
Nadir CD4 T Cell Count as Predictor and High CD4 T Cell Intrinsic Apoptosis as Final Mechanism of Poor CD4 T Cell Recovery in Virologically Suppressed HIV-Infected Patients: Clinical Implications

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Background. Although antiretroviral therapy improves immune response, some human immunodeficiency virus-infected patients present unsatisfactory CD4 T cell recovery despite achieving viral suppression, resulting in increased morbidity and mortality.

Methods. Cross-sectional, case-control study to characterize the mechanism and to identify predictive factors of poor immune response. We included 230 patients who were receiving highly active antiretroviral therapy and who had a viral load <50 copies/mL for >2 years; 95 were “discordant” (case patients; CD4 T cell count always <350 cells/µL), and 135 were “concordant” (control subjects). Activation markers, CD4 T cell death (necrosis, intrinsic apoptosis, and extrinsic apoptosis), and caspase-3 were measured. Clinical parameters, particularly antiretroviral combinations, were correlated with immune recovery.

Results. Discordant patients showed higher levels of activation markers, mainly in CD4 T cells (P < .001), and higher rates of spontaneous cell death (P < .001). Rates of activation and rates of CD4 T cell death (mainly by intrinsic apoptosis) were the best predictive factors for immune recovery, along with nadir CD4 T cell count. Patients who were receiving a protease inhibitor-based regimen were more likely to be discordant and showed higher rates of activation (P=.011), higher rates of CD4 T cell death (P=.033), and a lower nadir CD4 T cell count (P < .001). Multivariate analysis, however, ruled out any effect of protease inhibitors on immune recovery. No differences were observed between the use of tenofovir-emtricitabine (Truvada) and the use of abacavirlamivudine (Kivexa).

Conclusions. CD4 T cell apoptosis by the intrinsic pathway represents the determinant mechanism of the unsatisfactory immune recovery and should be targeted to manage therapy for discordant patients. The predictive value of low nadir CD4 T cell count for a poor immune recovery led us to consider starting antiretroviral therapy earlier. No differences were observed among antiretrovirals in terms of immune recovery.

Journal Article.  4887 words.  Illustrated.

Subjects: Infectious Diseases ; Immunology ; Public Health and Epidemiology ; Microbiology

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