No Clinical Benefit from Adding IL-2 to ART

Several small studies have suggested that patients with suboptimal CD4-cell recovery on antiretroviral therapy (ART) might benefit clinically from boosting their CD4-cell counts with interleukin (IL)-2. However, preliminary results from two large clinical trials described at this year’s Retrovirus Conference failed to show any such benefit.

In the SILCAAT trial, presented by Yves Levy [Abstract 90bLB], 1695 patients who had CD4 counts <300 cells/mm³ while receiving ART were randomized either to continue ART alone or to also receive IL-2 (4.5 million IU, delivered subcutaneously twice daily in at least 6 cycles of 5 days each, separated by 8-week intervals). The median nadir CD4 count was 60 cells/mm³, and the median entry CD4 count was 202 cells/mm³; 81% of patients had viral loads ≤500 copies/mL. The two treatment groups were well matched at baseline. During follow-up (median, 7.6 years), the IL-2 group averaged 57 more CD4 cells/mm³ than did the ART-alone group, but the rate of opportunistic disease or death was similar between the groups. Adverse event rates were also similar, except in the first year, when the IL-2 group had a higher rate of grade 4 events (mostly psychiatric and gastrointestinal).

The ESPRIT trial, presented by Marcelo Losso [Abstract 90aLB], had the same study design as SILCAAT, but the 4111 patients had baseline CD4 counts ≥300 cells/mm³, and the IL-2 was dosed differently (7.5 million IU, delivered subcutaneously twice daily in at least 3 cycles of 5 days each, separated by 8-week intervals). The overall median nadir CD4 count was 197 cells/mm³, and the mean enrollment CD4 count was 457 cells/mm³; 80% of patients had viral loads ≤500 copies/mL. Results were similar to those of the SILCAAT study: The IL-2 group gained more CD4 cells than did the ART-alone group (average difference, 153 cells/mm³) but did not have a lower rate of opportunistic disease or death. Again, the IL-2 group had an excess of grade 4 adverse events (this time, mostly vascular complications).

Why didn’t IL-2 protect against clinical events in these studies when it clearly boosted CD4-cell counts? Several explanations have been offered. First, CD4 cells generated by IL-2 might not function as well as those recovered during ART. Second, IL-2 might cause some harm that has not yet been defined but that counterbalances any beneficial effect. Finally, the clinical benefit seen with effective ART might simply overwhelm any modest effect afforded by IL-2–related CD4-cell boosting. We hope that final results from these studies will eventually provide some explanation and help guide future efforts at immune-based therapy.