ESPRIT and SILCAAT Studies Find No Long-term Benefits of IL-2

By Liz Highleyman

Effective antiretroviral therapy (ART) that suppress HIV replication typically leads to increased CD4 cell counts, and ample data clearly shows that it reduces the risk of AIDS-related illness and death.

Some individuals do not experience adequate CD4 T-cell recovery, however, and researchers have therefore explored other potential methods of restoring immune function. One such candidate is interleukin-2 (IL-2, Proleukin), a natural cytokine (chemical messenger) produced by immune cells that stimulates CD4 cell production and maturation. Treatment activists were early champions of IL-2, and urged researchers to conduct more research.

The result was 2 large international Phase 3 studies dubbed ESPRIT and SILCAAT. Long-term findings from both studies were presented this week at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) in Montreal.

ESPRIT (Evaluation of Subcutaneous Proleukin in a Randomized International Trial) included 4111 participants without severe immune deficiency who had a CD4 count of at least 300 cells/mm3 (mean 457 cells/mm3 at entry; nadir 197 cells/mm3). Half the participants received subcutaneous injections of IL-2 in addition to HAART, while half received HAART alone. In this study, IL-2 was administered as 3 x 5-day cycles every 8 weeks, plus additional injections if needed to keep the CD4 count above a pre-set level (2 x baseline or > 1000 cells/mm3). The average duration of follow-up was 6.9 years.

SILCAAT (Subcutaneous IL-2 in patients with Low CD4 Counts under Active Antiretroviral Therapy) enrolled 1695 patients with more advanced immune suppression and a lower CD4 count between 50 and 299 cells/mm3 despite HAART (mean 202 cells/mm3 at entry; nadir 60 cells/mm3). In this trial, all participants received HAART, and half also received IL-2 given as 6 x 5-day cycles at 8-week intervals, again with additional cycles as needed to keep the CD4 count at least 150 cells/mm3 above the baseline level. The average duration of follow-up was 7.6 years at the time the study's Data Safety Monitoring Board prematurely halted the trial.

In both trials, participants had well-controlled HIV, with 80% having undetectable viral load. Even though the ESPRIT participants had a higher CD4 count, about 30% in both trials had a history of opportunistic illnesses.

Both studies showed that regular IL-2 injections taken in addition to an effective antiretroviral regimen did indeed raise CD4 T-cell levels above those of patients receiving HAART alone. In ESPRIT, patients in the IL-2 group had on average 153 cell/mm3 more than the HAART-only arm, while in SILCAAT, IL-2 recipients gained 57 more cells. In both studies, while patients on HAART only experienced a slow and steady CD4 cell increase, those taking IL-2 experienced a faster rise during the first year, but then reached a plateau.

The increases in CD4 count did not translate into clinical benefits, however. Rates of AIDS-defining illnesses, serious illness not traditionally classified as HIV-related, and death due to any causes were similar in the IL-2 and HAART-only arms. These results are consistent with interim data from the studies reported previously.

Furthermore, IL-2 often caused adverse side effects including gastrointestinal symptoms and psychiatric problems, In ESPRIT, patients in the IL-2 arm were 23% more likely to experience severe (grade 4) adverse events than those treated with HAART only. In SILCAAT, rates of severe side effects were similar in both arms over the entire course of the study, but IL-2 recipients had twice as many during the first year. The most frequent life-threatening adverse event in both trials was deep vein thrombosis.

Summing up the findings in a media statement, National Institute of Allergy and Infectious Diseases director Anthony Fauci said, "In both studies, the volunteers who received IL-2 and antiretrovirals experienced notable, sustained increases in CD4 T cell counts, as anticipated. 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."
In a press conference discussing the results, Yves Levy, who presented the SILCAAT data, said that "a potential clinical benefit of IL-2, even moderate, can be definitively ruled out."

Explaining the outcome, he suggested that the additional CD4 cells that result from IL-2 stimulation may not be functionally equivalent to CD4 cells that arise naturally. Another possibility is that adding IL-2 may disrupt the complex set of feedback loops necessary for effective immune response, not all of which are fully understood. Finally, among patients with HIV suppressed on HAART, gaining an additional 60-160 CD4 cells may not be enough to appreciably affect clinical outcomes.

2/13/09

References

M Losso, D Abrams, and the INSIGHT ESPRIT Study Group. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 90aLB.

Y Levy and the SILCAAT Scientific Committee. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 90bLB.

Other source

NIH/National Institute of Allergy and Infectious Diseases. IL-2 Immunotherapy Fails to Benefit HIV-Infected Individuals Already Taking Antiretrovirals. Press release. February 10, 2009.