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Interleukin-2: Trials and Tribulations; IL-2 Fails Again, EDITORIAL COMMENTARY
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The Journal of Infectious Diseases July 15 2009;200:164-165
Daniel R. Kuritzkes
Section of Retroviral Therapeutics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
Received 3 April 2009; accepted 7 April 2009; electronically published 9 June 2009.
(See the article by Molina et al., on pages 206-15.)
"At the fourth planned interim review of the study by an independent data and safety monitoring board, the board recommended discontinuing IL-2 therapy and extending follow-up for an additional year because of the occurrence of 4 cases of lymphoma (3 in the IL-2 arm and 1 in the control arm)...Of note, post-hoc analyses showed that the benefit of IL-2 appeared to be limited to those with a plasma HIV-1 RNA level <4.5 log10 copies/mL at study entry. At week 96, the median change in CD4 cell count from baseline was +51 cells/µL among subjects in the IL-2 arm and -64 cells/µL among subjects in the control arm"
"Accumulating evidence suggests that uncontrolled HIV-1 replication and the attendant generalized immune activation may have deleterious consequences independent of their effects on CD4 cell count [10-13]. In addition, data from the North American AIDS Cohort Collaboration on Research and Design suggest that earlier initiation of ART provides a significant clinical benefit [14]. These findings pose significant challenges for the development and validation of immune-based therapies designed to delay the initiation of ART. Exploring immune-based therapies as adjuncts to ART in order to maximize immunologic recovery and minimize inappropriate immune activation may be a more fruitful avenue of research."
Depletion of CD4 T lymphocytes is the hallmark of human immunodeficiency virus type 1 (HIV-1) infection. Identification of the precise mechanisms by which HIV-1 causes CD4 cell depletion remains controversial, but viral replication clearly plays a central role. Efforts to prevent or reverse the decline in CD4 cell numbers have, therefore, focused on blocking viral replication, with impressive results. AIDS-related morbidity and mortality have decreased dramatically in the developed world, where combination antiretroviral therapy (ART) has been the standard of care for nearly 15 years [1, 2]. As ART is made more available, similar benefits are beginning to be seen in resource-limited countries.
Enormous strides have been made in HIV-1 therapeutics since zidovudine was approved as the first antiretroviral agent >20 years ago. The advent of more-potent drugs with improved safety and pharmacokinetic properties allows clinicians and patients to choose from among a range of once-daily regimens for initial ART. Clinical trials of these regimens show that 75%-80% of patients can achieve and maintain suppression of plasma HIV-1 RNA levels to <50 copies/mL, the virologic goal of treatment [3-5]. In most patients, virologic suppression is associated with a substantial increase in CD4 cell count and clinically significant restoration of immune function.
Despite these advances, ART still imposes the burden of regular adherence, the risk of drug resistance, the threat of toxicity with long-term exposure, and cost. Therapeutic approaches that preserve CD4 cell number and function and that defer the need to initiate treatment with antiretroviral drugs could offer an attractive alternative. The best studied of these approaches is intermittent administration of the cytokine interleukin (IL)-2. Intermittent treatment with high-dose IL-2 produces substantial and sustained increases in CD4 cell counts [6]. This observation led to 2 large phase 3 trials to determine the clinical benefit of IL-2 for HIV-infected patients, about which more later.
In this issue of the Journal, Molina et al. [7] report the results of a randomized, open-label, 96-week phase 2 trial sponsored by the Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS). The trial (ANRS 119) was designed to address the question of whether intermittent cycles of IL-2 administration could increase CD4 cell counts and delay the initiation of ART. Asymptomatic HIV-infected patients with CD4 cell counts of 300-500 cells/µL were eligible to enroll if they had never received ART or had received <6 months of ART and were not currently receiving therapy. A total of 130 subjects were randomized to the IL-2 or control arms. Subjects assigned to the IL-2 arm received 3 cycles of IL-2, given as 4.5 MIU subcutaneously twice a day for 5 consecutive days at weeks 0, 8, and 16; a fourth cycle was administered at week 24 if the CD4 cell count had not doubled by that time. Similarly, subjects could receive up to 2 additional cycles of IL-2 per year if the CD4 cell count was no more than 20% above baseline after week 48. The primary end point was time to first CD4 cell count <300 cells/µL, initiation of ART, occurrence of an AIDS-defining illness, or death. Safety end points included rates of grade 3 or 4 adverse events and laboratory abnormalities.
At the fourth planned interim review of the study by an independent data and safety monitoring board, the board recommended discontinuing IL-2 therapy and extending follow-up for an additional year because of the occurrence of 4 cases of lymphoma (3 in the IL-2 arm and 1 in the control arm). At the time of this decision, all subjects had already completed the first year of study, so its impact was limited to subjects who might have required "booster" doses of IL-2 during subsequent years of follow-up. No additional cases of lymphoma were diagnosed during the follow-up period.
Significantly more subjects in the control arm than in the IL-2 arm reached the primary study end point by week 96 (59% vs. 35%; p=.008). Immunologic failure and initiation of ART accounted for nearly all of the end points. Of note, post-hoc analyses showed that the benefit of IL-2 appeared to be limited to those with a plasma HIV-1 RNA level <4.5 log10 copies/mL at study entry. At week 96, the median change in CD4 cell count from baseline was +51 cells/µL among subjects in the IL-2 arm and -64 cells/µL among subjects in the control arm (p<.001). Adverse events were significantly more frequent in the IL-2 arm but were mostly mild to moderate in severity and comprised constitutional symptoms typically associated with IL-2 administration.
While this manuscript was under review, the results of 2 large clinical end-point trials of IL-2 became known. The ESPRIT (Evaluation of Subcutaneous Proleukin in a Randomized International Trial) study compared IL-2 plus ART with ART alone in patients with CD4 cell counts >350 cells/µL; 4111 subjects were randomized and followed up for a median of 7 years [8]. The SILCAAT (Subcutaneous, Recombinant, Human IL-2 in HIV-Infected Patients with Low CD4 Counts under Active Antiretroviral Therapy) study focused on patients with CD4 cell counts between 50 and 299 cells/µL; 1971 subjects were randomized to IL-2 plus ART or to ART alone and followed up for a median of 7.6 years [9]. The primary end point of both studies was the occurrence of opportunistic disease or death. Although the average CD4 cell count over time was significantly greater in the IL-2 arms of both studies than in the respective control arms (+153 cells/µL in ESPRIT and +57 cells/µL in SILCAAT), there was no benefit of IL-2 in either study.
In light of these results, how should the findings of Molina et al. be interpreted? In ANRS 119, the difference in primary end points was driven primarily by higher CD4 cell counts in the IL-2 arm, a difference that the ESPRIT and SILCAAT studies show does not translate into clinical benefit over the longer term. An important difference between these studies is that subjects in ESPRIT and SILCAAT were receiving ART, whereas those in the study by Molina et al. were not. It is conceivable that a clinical benefit not evident in ESPRIT or SILCAAT might be found in a clinical end-point study based on the current study design, but that seems unlikely.
Molina et al. argue that the lack of clinical benefit in ESPRIT and SILCAAT is not relevant to their study, because they were testing the hypothesis that treatment with IL-2 delays the time to initiation of ART, whereas ESPRIT and SILCAAT asked whether IL-2 treatment prevented the occurrence of opportunistic disease or death. The strategy tested in ANRS 119, however, rests on the assumption that avoiding ART for as long as possible is beneficial, so long as a stable CD4 cell count can be maintained. That assumption, in turn, rests on the validity of the CD4 cell count as a reliable surrogate marker of clinical benefit. This key assumption is challenged by the results of ESPRIT and SILCAAT, which suggest that IL-2-mediated increases in CD4 cell count do not have the same clinical significance as CD4 cell count increases associated with ART.
Accumulating evidence suggests that uncontrolled HIV-1 replication and the attendant generalized immune activation may have deleterious consequences independent of their effects on CD4 cell count [10-13]. In addition, data from the North American AIDS Cohort Collaboration on Research and Design suggest that earlier initiation of ART provides a significant clinical benefit [14]. These findings pose significant challenges for the development and validation of immune-based therapies designed to delay the initiation of ART. Exploring immune-based therapies as adjuncts to ART in order to maximize immunologic recovery and minimize inappropriate immune activation may be a more fruitful avenue of research.
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