BACKGROUND: RATIONALE FOR THE SILCAAT AND ESPRIT TRIALS
The results of the SILCAAT and ESPRIT trials of interleukin-2 (IL-2), two of the largest and most costly trials of a potential HIV therapy, were presented in 2009. These studies involved over 5800 volunteers with HIV from 25 countries, and cost an estimated $100 million. In order to best understand the reasons why such an effort was undertaken, we shall briefly summarise the rationale that led to these studies, recap the trials themselves, and discuss the potential for HIV immunotherapy in the post-SILCAAT/ESPRIT era.
The first abnormality of cytokine function described in patients with HIV infection was a reduced production of IL-2 . Our understanding of the immunopathogenesis of HIV is still incomplete but it is evident that there is widespread immune dysregulation affecting not just T cells, but also B cells, NK cells and macrophages. The increased cell activation in HIV infection, in part controlled by CD4+CD25+ T regulatory cells, also helps drive infection of cells by HIV, and cell death . The common chain cytokines, in particular IL-2, IL-7, IL-12 and IL-15, help govern the process of T cell proliferation, function and cell death, and also HIV-specific immune responses. The production of these cytokines is markedly perturbed in HIV infection, with reductions in IL-2, IL-12 and IL-15, and increases in IL-7.
It was soon established that the functional deficit of IL-2 occurred even in the majority ofasymptomatic patients with HIV, and that the degree of reduced IL-2 production predicted the subsequent decline in CD4+ cell counts [3,4], and also predicted subsequent HIV-associated morbidity and mortality . Conversely, it has recently been shown that HIV controllers express higher levels of certain cytokines, including IL-2, than those who progress normally . These findings prompted investigation into the effect of IL-2 administration to patients on antiretroviral therapy (ART), and found that there was a marked rise in CD4 counts compared to the use of ART alone [7-9]. Other studies more closely defined the minimal likely effective dose, which was important in order to abrogate the considerable side effects of IL-2 therapy [10,11].
In the pre-HAART era, the predominant clinical phenotype was AIDS-associated disease and death in those with a CD4 count below 200 cell [mm.sup.2]. When HAART was introduced, it was thought that if treatment could raise the absolute CD4 count above this figure, or prevent it falling below 200, and help normalise the percentages, then almost all excess morbidity and mortality in HIV-infected individuals might be avoided. It was only after SILCAAT and ESPRIT were begun that strong evidence emerged for commencing HAART at higher CD4 counts.
THE SILCAAT AND ESPRIT TRIALS
Hence the stage was set for large (Phase 3) studies to determine the clinical utility of IL-2. The initial sponsor of SILCAAT, Chiron, failed to gain accelerated approval from the Food and Drug Administration (USA) for their subcutaneous recombinant human IL-2 product, Proleukin, on the basis of CD4 cell count changes alone. The NIAID took over the running of the trials. Participants were assigned at random to receive either HAART alone or HAART plus subcutaneous Proleukin over several 5-day cycles. The ESPRIT study enrolled people with early-stage infection (CD4+ T cell counts at or above 300 cells/[mm.sup.3]), and the SILCAAT study enrolled volunteers with later-stage HIV infection (CD4+ T cell counts between 50 and 299 cells/[mm.sup.3]). The primary endpoint of both trials was to compare the effects of IL-2 with no IL-2 on disease progression and death in HIV-infected individuals on combination antiretroviral therapy. These two trials confirmed that IL-2 infusions would increase the CD4 cell count number, and over the trial period of 7-8 years, the CD4 cell count rise was higher in the group receiving IL-2 compared to the controls (median rise of 53 and 159 cells/[mm.sup.3] in the SILCAAT and ESPRIT groups, respectively). In both the SILCAAT and ESPRIT studies, however, the incidence of HIV-associated opportunistic...