February 10, 2009

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The ESPRIT HIV Treatment Study

The SILCAAT HIV Treatment Study

8.		What is the SILCAAT study?
		The study called “Subcutaneous, Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts Under Active Antiretroviral Therapy” (SILCAAT) was an international, multicenter, Phase III clinical trial that examined whether IL-2 plus combination antiretroviral therapy in adults with advanced HIV infection would reduce the risk of AIDS-associated opportunistic diseases or death more effectively than combination antiretroviral therapy alone. Previous studies had shown that giving IL-2 to HIV-infected individuals taking antiretroviral drug regimens increased the number of CD4+ T cells in their blood. SILCAAT investigated whether these IL-2-induced increases in CD4+ T cells translated into better health outcomes.
9.		Who participated in the SILCAAT study?
		The SILCAAT study team enrolled 1,971 HIV-infected men and women ages 18 and older. To be eligible to participate, all volunteers needed documentation of their HIV diagnosis, a CD4+ T cell count between 50 and 299 cells/mm³ and a detectable viral load under 10,000 copies/mL. Participants also were required to have been taking at least two antiretroviral drugs for at least four months before they were assigned to a study group. For participants taking exactly two antiretrovirals, one had to be a protease inhibitor. In addition, participants could not have a recent history of an AIDS-defining illness, evidence of active infection, any significant medical condition; or be currently pregnant, breastfeeding, or using corticosteroids or immunosuppressants. After a change in study management (see #11 below), the SILCAAT study protocol was amended; subsequently, some of the original volunteers chose not to continue participating in the study and some sites were no longer able to participate for administrative reasons. A number of volunteers from sites that discontinued participation were transferred to other sites for the remainder of the trial, but for many volunteers, this was not feasible. To determine without bias which of the original volunteers would be included when the study staff finally analyzed their data (i.e., who would be in the “primary analysis cohort’), the SILCAAT leadership had to balance two factors: 1) include enough volunteers in the cohort to get meaningful results; and 2) consider that the people who dropped out of the study may have had something in common that skewed some characteristic(s) of the population of remaining participants either overall or differentially between the control and treatment groups. Consequently, the SILCAAT leadership decided to include in the primary analysis cohort all participants at sites where at least two-thirds of the volunteers had consented to the amended protocol or had died (randomization was carried out within site). This left 1,695 participants in the primary analysis cohort.
10.		When and where did the SILCAAT study take place?
		SILCAAT began in April 1999 and ended in November 15, 2008. It originally took place at 139 sites, but after the change in management in 2003 (see #11 below), 25 sites could no longer participate for administrative reasons, so the trial continued at 114 sites in the following 11 countries: Argentina Australia Belgium Brazil Canada France Germany Italy Spain The Netherlands United States
11.		Who conducted, funded and sponsored the SILCAAT study?
		The SILCAAT study was overseen by a scientific committee and coordinated by the Medical Research Council Clinical Trials Unit in London; the Copenhagen HIV Program in Denmark; the National Centre in HIV Epidemiology and Clinical Research at the University of New South Wales in Sydney, Australia; and the University of Minnesota in Minneapolis. SILCAAT was funded primarily by Chiron Corp. of Emeryville, Calif. (since 2006 part of Novartis), which was also the trial’s initial sponsor. In November 2002, Chiron announced it would no longer support the trial because it did not receive accelerated approval from the U.S. Food and Drug Administration to use IL-2 in patients with HIV infection.  In February 2003, NIAID assumed regulatory sponsorship of the trial under a cooperative agreement with Chiron. The SILCAAT Scientific Committee and the investigators conducting ESPRIT undertook the management and administration of SILCAAT, and the data and safety monitoring board for ESPRIT assumed oversight of the study.
12.		What was the design of the SILCAAT study?
		Like ESPRIT, the primary objective of SILCAAT was to compare the effects of IL-2 with no IL-2 on disease progression and death in HIV-infected individuals on antiretroviral therapy.  HIV-infected volunteers on antiretroviral therapy who had a CD4+ T cell count between 50 and 299 cells/mm³ were assigned at random to receive either combination antiretroviral therapy alone (the control group) or combination antiretrovirals plus injections of Proleukin (the IL-2 group). Participants assigned to the IL-2 group received injections of 4.5 MIUs of the drug twice a day for five consecutive days every eight weeks for 49 weeks. From that point on, the participants could receive five-day cycles of IL-2 injections every four months as needed to maintain their CD4+ T cell counts at 125 to 175 cells/mm3 above baseline. All volunteers were followed up every four months for about seven years. During follow-up, study staff measured participants’ HIV RNA levels, CD4+ T cell counts and percentage of CD4+ T cells relative to all T cells. Staff also performed clinical evaluations and recorded volunteers’ medical histories and changes to antiretroviral therapy or other treatments.
13.		What are the results of SILCAAT?
		The study investigators found that the CD4+ T cell counts of participants who received IL-2 rose an average of 59 cells/mm3 higher than those of participants in the control group, a statistically significant difference. Yet the investigators determined that treatment with IL-2 in conjunction with antiretroviral therapy offered no health advantages to HIV-infected individuals compared with antiretroviral therapy alone. The rate of death and HIV-associated opportunistic diseases did not differ significantly between participants who received IL-2 plus combination antiretrovirals and those who received combination antiretrovirals alone. Among volunteers taking IL-2 plus antiretrovirals, there were 109 cases of HIV-associated opportunistic diseases or death, and among volunteers taking only antiretrovirals, there were 118 cases of HIV-associated opportunistic diseases or death. Looking at deaths from all causes, there were 81 deaths in the IL-2 group and 77 deaths in the control group. In addition, the percentage of participants with 500 or fewer copies of HIV/mL of blood—a sign of successful treatment—was similar in the two groups.
14.		How were the two studies and the safety of volunteers monitored?
		A data and safety monitoring board (DSMB), an independent committee of clinical research experts, statisticians, ethicists and community representatives, provided continuous oversight of both the ESPRIT and SILCAAT studies and their participants. DSMBs provide additional oversight of some Phase II and all Phase III clinical research studies and regularly review unblinded study data while a clinical trial is in progress to ensure the safety of study participants and to ensure that any benefits found in the study are quickly made available to all participants. A DSMB may recommend that a trial, or part of a trial, be stopped if there are safety concerns or if the trial objectives have either been achieved or are unlikely to be achieved. The DSMB met nine times to review the ESPRIT study data and five times to review the SILCAAT study data. After each meeting, the DSMB recommended that the trials continue.
15.		What will happen to the ESPRIT and SILCAAT study participants?
		The participants in both clinical trials were promptly informed of the study results and are no longer receiving IL-2. They will continue to receive HIV treatment through their personal physicians.
16.		What impact do the ESPRIT and SILCAAT results have on other clinical trials?
		NIAID has discontinued IL-2 therapy in a separate clinical trial known as STALWART, which stands for “Study of Aldesleukin with and without Antiretroviral Therapy.” Beginning in November 2005, STALWART examined the effects of providing intermittent cycles of IL-2 either alone or in concert with short cycles of antiretrovirals to individuals at an early stage of HIV infection. The goal was to try to delay disease progression and, therefore, the need for continuous antiretroviral therapy. STALWART was being conducted in 20 countries in patients who do not yet meet the criteria to begin highly active antiretroviral therapy.

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NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

The National Institutes of Health (NIH)—The Nation's Medical Research Agency—includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

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