A Pilot Study Evaluating Time to CD4 T-cell Count <350 cells/mm3 After Treatment Interruption Following Antiretroviral Therapy ± Interleukin 2: Results of ACTG A5102

Abstract

IL-2 before TI did not prolong time to CD4 of less than 350 cells/mm. A TI strategy utilizing a CD4 T-cell threshold of less than 350 cells/mm for restarting ART appears generally safe with most subjects in both arms remaining off ART for more than 1 year. Implications of our results for TI strategies include the potential advantage of starting ART at higher CD4 T-cell levels while avoiding any drug resistance and evaluating immunomodulators or drugs to reduce T-cell activation and HIV-1 RNA rebound during the TI.

Factors predicting the time for CD4 T‐cell count to return to nadir in the course of CD4‐guided therapy interruption in chronic HIV infection*

“…Many studies have shown that the slope of the decrease in CD4 cell count after TI is biphasic, there being an initial fast drop, followed by a slower decrease [9][10][11]16,18,19,28,29]. This observation was confirmed by our findings.…”

“…Attempts have been made in numerous studies to evaluate possible differences in the evolution of HIV infection in men compared with women. However, according to a recent review [27], none of the studies demonstrated a statistically significant effect of sex on disease progression, but most found somewhat slower rates of progression to AIDS and death in women than in men.Many studies have shown that the slope of the decrease in CD4 cell count after TI is biphasic, there being an initial fast drop, followed by a slower decrease [9][10][11]16,18,19,28,29]. This observation was confirmed by our findings.…”

“…In brief, interruption of therapy recreates the same situation that occurs during an acute infection by HIV; that is, a biphasic fall in the number of CD4 lymphocytes, HIV RNA levels that peak and then fall spontaneously in most patients [14], and the achievement of a virological setpoint after about 4 months [10]. The factors predicting the loss of CD4 cells are the same as those for the natural infection and, for similar CD4 cell counts, the same clinical events already observed prior to ART recur.…”

“…There is, in fact, no doubt that the diversity of the results of studies on TI is related to the different study designs. A CD4 lymphocyte count of 350 cells/mL was considered an indication for interrupting therapy in the SMART [1] The efficacy and safety of the new therapeutic strategies must be evaluated in randomised studies, but, in order to plan such studies, it is important that the immunological, virological and clinical events related to the TI are fully understood so that appropriate patients are selected and the criteria for resuming therapy are correct.It has been demonstrated that, after TI, the viral load rebounds to pre-ART levels [8][9][10][11][12][13][14][15], and several studies on CD4-guided TI have evaluated the predictive factors for the duration of the first TI, with the nadir CD4 lymphocyte count emerging as the most constant and influential of these factors [8][9][10][16][17][18][19].In previous studies on the cohort of patients presented here, we noted that, during TI, the time taken to lose the CD4 cells recovered during ART was independent of the nadir CD4 count [19] and that the correlation between the duration of the first TI and the nadir CD4 count was a result of the fact that the resumption of ART started at CD4 cell counts different from the nadir counts. According to the criteria for resuming treatment that we adopted, patients with a CD4 nadir count o200 cells/mL had to restart treatment at a CD4 cell count above their nadir count and had a short TI.…”

“…It has been demonstrated that, after TI, the viral load rebounds to pre-ART levels [8][9][10][11][12][13][14][15], and several studies on CD4-guided TI have evaluated the predictive factors for the duration of the first TI, with the nadir CD4 lymphocyte count emerging as the most constant and influential of these factors [8][9][10][16][17][18][19].…”