Despite CD4+ Boost, Interleukin-2 Provides No Discernible Long-Term Health Benefits to Patients on HAART, ESPRIT/SILCAAT Studies Find

The use of interleukin-2 (IL-2) alongside antiretroviral therapy does not further reduce an HIV-infected patient's risk of developing an opportunistic infection or dying, according to findings from a pair of large, long-term, international studies. The findings provide a fresh -- and possibly final -- blow to the use of IL-2 as an immune-based therapy for HIV-infected patients receiving combination antiretroviral therapy.

The two clinical trials were sponsored by the U.S. National Institute of Allergy and Infectious Diseases (NIAID). They followed a total of 5,806 patients for an average of seven years at sites scattered throughout the world. One study, ESPRIT,¹ focused specifically on patients with a CD4+ cell count of 300 cells/mm³ or higher. The other study, SILCAAT,² involved patients with a CD4+ cell count between 50 and 299 cells/mm³. The ESPRIT findings were presented at CROI 2009 by Marcelo Losso, M.D., of Hospital José María Ramos Mejía in Buenos Aires, Argentina; the SILCAAT findings were presented by Yves Levy, M.D., of Hôpital Henri Mondor in Créteil, France.

Both studies ultimately reached similar conclusions despite the CD4+ cell count disparities between their patient populations. Supplementation of antiretroviral therapy with IL-2 resulted in a statistically significant increase in CD4+ cell count; in ESPRIT, for instance, patients receiving IL-2 achieved an average CD4+ cell count 160 cells/mm³ greater (P < .001) than patients who did not receive IL-2. However, both studies failed to find statistically significant differences in the primary study endpoints, which were the development of an opportunistic infection or death.

Slide from ESPRIT presentation; Marcelo Losso et al. CROI 2009; abstract 90aLB. Reprinted with permission. Click here to view the full presentation.

Dr. Losso, who presented the ESPRIT findings, offered two possible explanations for the failure of IL-2 to improve health outcomes despite the drug's obvious ability to boost CD4+ cell count. One hypothesis was that the CD4+ cells that are restored with IL-2 simply do not function as well, or in the same manner, as CD4+ cells that are restored with successful antiretroviral therapy. Another possibility was that IL-2 may have harmful effects of its own that offset whatever CD4+ cell benefit it may incur. (Grade 4, or serious, adverse events -- including fever, malaise, injection site reactions and deep-vein thrombosis -- were more likely to occur among patients receiving IL-2 in the ESPRIT study, but not in SILCAAT.)

The idea of finding a compound that can boost an HIV-infected person's immune system while -- or before -- using HIV medications has long attracted HIV researchers, activists and patients. IL-2 has been under study for years for its potential benefit in people with HIV, with no conclusive findings to either completely support or completely bury its continued development. However, at a press conference announcing the findings, both researchers suggested that these study results should effectively sound the death knell for IL-2 -- at least as an adjunct to antiretroviral therapy. "I think these trials provide a definite answer about the clinical value of the drug in HIV disease," said Dr. Losso. Dr. Levy promptly concurred: "I don’t see any possible development of IL-2 based on the results we have presented today."

Others interpreted the poor IL-2 findings even more broadly, calling into question the potential to develop similar immune-based therapies. "I think the results of these studies will make it difficult to develop an immunomodulator," said Pablo Tebas, M.D., an associate professor of medicine and head of the AIDS Clinical Trials Unit at the University of Pennsylvania, during a round-table discussion with The Body PRO following the conclusion of CROI 2009. "If you're a pharmaceutical company developing an immunomodulator, what do you have to do? Another 4,000-person trial with clinical endpoints that is going to last seven years? It's not a very attractive proposal for anybody."

Still, some are hopeful that these IL-2 studies will ultimately yield information that can be useful to researchers -- and to future developments in HIV treatment. Of particular interest may be teasing out the possible benefits of the CD4+ cell increase brought about by the use of IL-2. "The INSIGHT Trials Network that did these IL-2 trials does have an extensive collection of stored samples and they are going to be examining a large number of what they're calling biomarkers," pointed out Bob Munk, a prominent HIV activist and founder of AIDS InfoNet. "Hopefully, they will find some relevant correlations with some of them."

References

1. Losso M, Abrams D, and INSIGHT ESPRIT Study Group. Effect of interleukin-2 on clinical outcomes in patients with a CD4+ cell count of 300/mm³: primary results of the ESPRIT study. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montréal, Canada. Abstract 90aLB.
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2. Levy Y and SILCAAT Sci Committee. Effect of interleukin-2 on clinical outcomes in patients with CD4+ cell count 50 to 299/mm³: primary results of the SILCAAT study. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montréal, Canada. Abstract 90bLB.