February 28, 2007
Most antiretroviral treatment guidelines utilize a CD4+ cell count threshold for the initiation of therapy. Interventions that increase CD4+ cell counts may not only be clinically beneficial, they may also be able to prolong the time off of antiretroviral therapy in treatment-naive patients as well as patients in studies of CD4+ cell count-guided treatment interruptions.
The administration of interleukin-2 (IL-2) has been shown to increase CD4+ cell counts. As such, the TILT (Therapy Interruption With and Without Use of InterLeukin-Two) trial1 was designed to assess whether the use of IL-2 affects CD4+ cell count-guided treatment interruption. This randomized pilot trial enrolled HIV-infected individuals on stable antiretroviral therapy with HIV RNA levels below 50 copies/mL, a CD4+ cell count above 300 cells/mm3, and a nadir CD4+ cell count above 100 cells/mm3.
Patients were randomly assigned to one of three treatment arms:
For Arm B, antiretroviral therapy was restarted when the CD4+ cell count fell below 200 cells/mm3. For Arm C, another cycle of IL-2 was administered if the CD4+ cell count fell below 300 cells/mm3. Antiretroviral therapy was also restarted for individuals in Arm C when their CD4+ cell count dropped below 200 cells/mm3. Another treatment interruption was considered for patients in Arm B when their viral load was suppressed below 50 copies/mL for more than 12 weeks and their CD4+ cell count remained at or above the baseline level. Similarly, patients in Arm C could undergo another treatment interruption if their viral load remained below 50 copies/mL for at least 12 weeks and their CD4+ cell count was below the baseline value, so long as they had received two cycles of IL-2. Patients were evaluated for a total of 105 weeks.
The study opened in March 2001 and closed in June 2006. Eighty-six individuals were enrolled. Their mean age was 40 (+7.8) years, their median nadir CD4+ cell count was 268 cells/mm3 and their median baseline CD4+ cell count was 754 cells/mm3.
For individuals in Arm A (n = 27), there were nine nonprotocol-related treatment interruptions, with seven individuals restarting antiretroviral therapy. All individuals in Arm B (n = 28) except one underwent treatment interruption. All individuals in Arm C (n = 31) received at least one cycle of IL-2; 13 received two cycles, nine received three cycles and seven received four or five cycles. There were six IL-2 dose modifications and two IL-2 cycle interruptions.
The median CD4+ cell count in Arm C jumped from 748 to 1,100 cells/mm3 after the first IL-2 cycle. However, this dramatic CD4+ cell count increase waned, and at week 96, the median CD4+ cell count in Arm C was less than the count seen in either of the other arms.
At the end of the study, the proportion of individuals on antiretroviral therapy was 96% for Arm A, 61% for Arm B and 35% for Arm C, suggesting that IL-2 produced an antiretroviral therapy-sparing effect. For individuals in Arm B and Arm C who had to restart antiretroviral therapy due to a CD4+ cell count below 200 cells/mm3, 94% and 91%, respectively, were able to resuppress viral replication to undetectable levels (i.e., less than 50 copies/mL).
No individuals died, experienced an AIDS event or had their CD4+ cell count fall below 100 cells/mm3 during the study. Grade 3/4 adverse events occurred in 12, five and 21 individuals in Arm A, Arm B and Arm C, respectively.
The uninterrupted antiretroviral therapy control arm of the study, Arm A, showed superior continuous viral suppression and maintenance of CD4+ cell count levels compared with the two treatment interruption arms. This pilot trial was too underpowered to show any clinical advantage by one antiretroviral therapy strategy over another, and thus would likely miss any infrequent, but serious, AIDS-related or non-AIDS-related clinical events like those seen in the treatment interruption arm of the SMART study. More adverse events occurred in the IL-2 arm, although it is worth noting that the dose of IL-2 used was lower and thus better tolerated than has been seen with standard IL-2 dosing in two large, ongoing clinical trials of IL-2 (i.e., ESPRIT and SILCAAT).
Using a CD4+ cell count of 200 cells/mm3 as the threshold to restart antiretroviral therapy would be considered unwise in light of the results from several treatment interruption studies, such as SMART and Trivacan,2,3 utilizing a CD4+ cell count threshold below 250 cells/mm3. The modestly positive results regarding treatment interruption from this pilot study are not very persuasive and do not support further studies utilizing a similar trial design, especially given the steadily improving tolerability and efficacy of modern antiretroviral therapy regimens.
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