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.
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/microL), 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 abacavir-lamivudine (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.
Negredo
Eugènia
E
Lluita contra SIDA Foundation, Institut de Recerca en Ciències de Salut Germans Trias i Pujol, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain. enegredo@flsida.org
Massanella
Marta
M
Puig
Jordi
J
Pérez-Alvarez
Núria
N
Gallego-Escuredo
José Miguel
JM
Villarroya
Joan
J
Villarroya
Francesc
F
Moltó
José
J
Santos
José Ramón
JR
Clotet
Bonaventura
B
Blanco
Julià
J
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D017209:Apoptosis; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D016022:Case-Control Studies; D053148:Caspase 3 / Q000032:analysis; D003430:Cross-Sectional Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D014481:United States; D019562:Viral Load
D019380:Anti-HIV Agents; D053148:Caspase 3