February 10, 2009
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The ESPRIT HIV Treatment Study
The “Evaluation of Subcutaneous Proleukin® in a Randomized International Trial” (ESPRIT) was an international, multicenter, Phase III clinical trial that tested the hypothesis that giving interleukin-2 (IL-2) to HIV-infected individuals already on combination antiretroviral therapy would reduce the rate of AIDS-related opportunistic diseases and death more than combination antiretrovirals alone. This hypothesis was based on prior studies in HIV-infected individuals that showed that treatment with IL-2 plus antiretrovirals increases the number of CD4+ T cells substantially more than antiretrovirals alone. CD4+ T cells are the white blood cells that play an important role in protecting the body from infections and the development of certain cancers. HIV invades CD4+ T cells and replicates there; as a result, the number of CD4+ T cells declines over time in untreated HIV-infected individuals.
IL-2 is a protein produced naturally by the immune system. Normally, IL-2 boosts the quantity and activity of several immune system components, including CD4+ T cells.
Proleukin is a synthetic, recombinant form of IL-2 made by Novartis Pharmaceuticals of Basel, Switzerland. Proleukin is approved in the United States to treat metastatic melanoma and metastatic kidney cell carcinoma in adults. It was used in the ESPRIT and SILCAAT clinical trials under an investigational new drug application to test it as HIV treatment in combination with antiretroviral therapy.
As a cancer treatment in the United States, Proleukin is administered to hospitalized patients for a shorter duration and at a higher dosage than in the ESPRIT and SILCAAT clinical trials.
The ESPRIT study was preceded by four Phase II clinical trials known as “vanguard studies,” which were also examining IL-2 in HIV-infected individuals, but used CD4+ T cell counts rather than clinical disease progression as a primary study endpoint. The vanguard studies involved 729 volunteers who were invited to participate in the ESPRIT study.
ESPRIT and the preceding vanguard studies collectively enrolled 4,241 HIV-infected men and women ages 18 and older. To be eligible to participate, volunteers needed a confirmed diagnosis of HIV infection; a CD4+ T cell count at or above 300 cells per cubic millimeter (mm³); to be free of active clinical disease for at least one year; and to be taking or beginning to take combination antiretroviral therapy as prescribed by a physician.
Sites where fewer than 90 percent of the vanguard participants consented to participate in ESPRIT were excluded from the primary data analyses. As a result, the ESPRIT primary analyses are based on 4,111 study participants.
The vanguard studies began in October 1997. The ESPRIT study began in March 2000 and ended as scheduled in November 2008. It took place at 252 clinical trial sites in the following 25 countries:
The ESPRIT study was overseen by an executive committee and coordinated by the centers of the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT). These centers are 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 Community Programs for Clinical Research on AIDS (CPCRA) unit in Washington, D.C. The study’s statistical and data management center was based at the University of Minnesota in Minneapolis.
The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), funds INSIGHT and sponsored ESPRIT.
The primary objective of ESPRIT 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 and with at least 300 CD4+ T cells/mm³ were assigned at random to receive either combination antiretroviral therapy alone (the control group) or combination antiretroviral therapy plus injections of Proleukin (the IL-2 group). Participants in the IL-2 group received injections of 7.5 million international units (MIUs) of IL-2 twice a day for five consecutive days every eight weeks for at least six months. After that time, the volunteers’ physicians decided whether to continue prescribing IL-2 based on whether the drug was helping boost the participants’ CD4+ T cell counts. The goal was to maintain a CD4+ T cell count at least twice as high as the level where the participant began or at or above 1,000 cells/mm³. On average, the volunteers in the treatment group had 4.8 cycles of IL-2 therapy.
ESPRIT was designed to stop once study staff had identified 320 cases of clinical disease progression, or “primary endpoints,” in the participants during routine follow-up visits. All volunteers were followed every 4 months for a median of 6.9 years for the study to reach the required number of primary endpoints. During follow-up, study staff measured participants’ CD4+ T cell counts and HIV RNA levels (viral load), and assessed whether participants showed new or recurrent signs of disease or of health abnormalities.
The study investigators found that the CD4+ T-cell counts of participants who received IL-2 rose an average of 160 cells/mm³ higher than those of participants in the control group, a significant difference.
Yet the investigators also determined that treatment with IL-2 offered no health advantage to the individuals who received it. The incidence of HIV-associated opportunistic diseases and death was not significantly different for participants who received IL-2 plus combination antiretroviral therapy compared with those who received combination antiretroviral therapy alone. Among volunteers taking IL-2 plus antiretroviral therapy, there were 158 cases of HIV-associated opportunistic diseases and death; among volunteers taking only antiretroviral therapy, there were 165 cases of HIV-associated opportunistic diseases and death. In analyzing deaths from any cause, there were 107 in the IL-2 group and 116 in the control group.
In addition, participants in the IL-2 group had significantly more “grade 4” health events—events that are severe or life-threatening—than participants in the control group. There were 466 grade 4 events in the IL-2 group and 383 in the control group. Further analysis is required to determine why this happened.
Finally, the study also found that the rates of serious non-AIDS health events did not differ significantly between the two study groups. There were 188 serious non-AIDS health events in the IL-2 group and 185 in the control group.
The percentage of participants with 500 or fewer copies of HIV per milliliter (mL) of blood—a sign of treatment success—was similar for the two groups throughout the study (between 75 and 85 percent).
The SILCAAT HIV Treatment 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.
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.
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:
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.
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.
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.
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.
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.
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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Last Updated February 09, 2009