Providing a synthetic form of the immune system protein interleukin-2 (IL-2) to HIV-infected individuals already taking combination antiretroviral therapy boosts their numbers of CD4+ T cells, the key white blood cells destroyed by HIV, but fails to reduce their risk of HIV-associated opportunistic diseases or death compared with combination antiretroviral therapy alone.

These are the findings of two large international clinical trials presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in Montreal.

The phase-III trials, known as the Esprit and Silcaat studies, were sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and funded respectively by NIAID and Chiron Corp of Emeryville, Calif (since 2006 part of Novartis Pharmaceuticals).

Marcelo H Losso, MD of Hospital José María Ramos Mejía, Buenos Aires, Argentina, presented the results of ESPRIT, and Yves Levy, MD of Hôpital Henri Mondor, Créteil, France, presented the results of Silcaat.

IL-2 is produced naturally in the body and plays an important role in regulating CD4+ T cell production and survival. As their CD4+ T cell levels drop, people infected with HIV become more vulnerable to AIDS-related opportunistic diseases and death. Earlier research established that giving synthetic IL-2 plus antiretroviral therapy to people with HIV infection boosts their CD4+ T cell counts more than does antiretroviral therapy alone, but it was unknown whether this boost translated into better health. Esprit and Silcaat were designed to test whether giving IL-2 to HIV-infected individuals already on antiretroviral therapy would keep them healthier longer than HIV-infected individuals taking only antiretrovirals.

Together, the Esprit and Silcaat studies involved more than 5,800 HIV-infected volunteers in 25 countries. Participants were assigned at random to receive either combination antiretroviral therapy alone or combination antiretrovirals plus injections of Proleukin (Novartis Pharmaceuticals, Basel, Switzerland), a synthetic form of IL-2, over several five-day cycles. To evaluate the effects of IL-2 treatment at different stages of HIV infection, the Esprit study enrolled people with early-stage infection (CD4+ T cell counts at or above 300 cells per cubic millimeter, or mm3), while the Silcaat study enrolled volunteers with later-stage HIV infection (CD4+ T cell counts between 50 and 299 cells/ mm3).

"In both studies, the volunteers who received IL-2 and antiretrovirals experienced notable, sustained increases in CD4+ T cell counts, as anticipated," notes NIAID director Anthony S Fauci, MD. "Unfortunately, these increases did not translate into reduced risks of HIV-associated opportunistic diseases or death when compared with the risks in volunteers who were taking only antiretrovirals. Although further analyses may help us better understand these findings, the two studies clearly demonstrated that the use of IL-2 did not improve health outcomes for HIV-infected people."

It is unclear why increased CD4+ T cell counts did not translate into better health outcomes. James D Neaton, of the University of Minnesota, principal investigator of the global clinical trials network that conducted Esprit, offers two possible explanations. "It could be that the types of CD4+ T cells induced by IL-2 play no role in protecting the HIV-infected patient, and therefore the administration of IL-2 has no benefit," says Dr Neaton. "A second possibility is that the CD4+ T cells are at least somewhat functional or that IL-2 has some modest benefit, but that the side effects of IL-2 may neutralize any possible benefit."

"In the end, the results of these two studies indicate that although a person's number of CD4+ T cells is a key measure of success in the treatment of HIV with antiretroviral drugs, we can't rely on CD4+ T cell counts to predict whether immune-based therapies such as IL-2 will improve the health of HIV-infected individuals," concludes Dr Levy, the principal investigator of Silcaat.

"The purpose of clinical research is to clearly state and accurately test hypotheses with an ultimate goal of improving patient care," notes H Clifford Lane, director of clinical research at NIAID and a member of the executive committee of Esprit. "These two clinical trials successfully reached a definitive answer about the utility of IL-2 therapy for treating HIV infection. NIAID thanks the thousands of dedicated volunteers and investigators who made these studies possible. The results will have significant implications for the future development of immune-based therapies for HIV and studies of HIV pathogenesis."

The Esprit study -- which stands for 'Evaluation of Subcutaneous Proleukin in a Randomized International Trial' -- began in March 2000 and ended as scheduled in November 2008.