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Extra CD4s With IL-2 Confer No Clinical Benefit in Two Randomized Trials
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16th Conference on Retroviruses and Opportunistic Infections,
February 8-11, 2009, Montreal
Mark Mascolini
"A potential clinical benefit of IL-2, even [a] moderate [benefit], can be definitively ruled out."
Interleukin 2 (IL-2) investigator Yves Levy pronounced that verdict in summarizing a combined analysis of two clinical endpoint trials that randomized people to combination antiretroviral therapy alone or to antiretrovirals plus IL-2. The massive studies, ESPRIT and SILCAAT, involved nearly 6000 people monitored for over 7 years [1,2] (from Jules: and cost up to $150 million). The two trials yielded remarkably consistent results that can be summarized in three points:
• People taking IL-2 gained significantly more CD4 cells than those taking antiretrovirals alone.
• The extra T cells with IL-2 did not protect people from disease progression or death.
• In ESPRIT, taking IL-2 posed a significantly greater risk of life-threatening grade 4 events, including deep venous thrombosis and depression. In the first year of SILCAAT, grade 4 events were significantly more frequent with IL-2.
Why didn't IL-2 work? Marcello Losso, who spelled out the ESPRIT findings, suggested two possibilities: First, CD4 cells resulting from IL-2 expansion are not functionally equivalent to CD4 cells that arise through antiretroviral-induced suppression of HIV replication. Second, IL-2 may have harmful effects that counterbalance any CD4 benefit (from Jules: one theory offered is that IL-2 disregulates cytokines). Harvard's Daniel Kuritzkes, who was not involved in either trial, offered a third possibility after Losso's talk: In a population with well-controlled viral replication, like ESPRIT and SILCAAT participants, the CD4 difference afforded by IL-2 is not enough to make a clinical difference.
The two trials had similar designs, differing primarily in the CD4 counts of people recruited and in IL-2 dosing. ESPRIT enrolled HIV-infected patients with counts above 299, while SILCAAT signed up patients with 50 to 299 CD4s. ESPRIT enrollees took three cycles of subcutaneous IL-2 (7.5 MIU twice daily for 5 days separated by 8 weeks), then additional cycles needed to maintain a CD4 count above 1000 or a tally twice higher than the prestudy count. SILCAAT participants took six cycles of subcutaneous IL-2 (4.5 MIU twice daily for 5 days separated by 8 weeks), then additional cycles to maintain at least a 150-cell CD4 increase. The primary endpoint of both trials was opportunistic disease or death from any cause, and secondary endpoints included serious non-AIDS events and life-threatening (grade 4) clinical events.
ESPRIT randomized 2071 people to IL-2 plus antiretrovirals and 2040 to antiretrovirals alone. The study plan called for 320 clinical events to detect a 27% difference between arms, and investigator recorded 323 events in 7 years of follow-up. Study participants lived in Europe (40%), North America (27%), South America (16%), Asia (12%), Australia (5%), and Africa (1%). The IL-2 and control arms were similar in age (average 41 overall), median CD4 count (457), lowest-ever CD4 count (197), proportion with a viral load under 500 (80%), a clinical AIDS diagnosis (26%), and years of antiretroviral therapy (4.2).
The IL-2 group rapidly outpaced the control group in CD4 gains and averaged 150 more CD4s through 6.9 years of follow-up, a highly significant difference (P < 0.001). But at the 7-year mark, the ESPRIT team counted 158 opportunistic diseases or deaths in the IL-2 group (1.13 per 100 person-years) and 165 in the antiretroviral-only group (1.21 per 100 person-years), a nonsignificant difference (P = 0.52).
The groups did not differ in rates of death or serious non-AIDS events. But people taking IL-2 suffered significantly more grade 4 clinical events than those not taking IL-2 (466 versus 383), which translated into a 23% higher risk with IL-2 (P = 0.003). Vascular complications, usually deep venous thrombosis, were significantly more common with IL-2 (P < 0.001).
SILCAAT randomized 849 people to IL-2 and 846 to antiretrovirals only. The study plan called for 300 primary endpoints, but the trial stopped with 227 to close in conjunction with ESPRIT. Study participants lived in Europe (46%), North America (32%), South America (14%), and Australia (7%). The treatment arms were similar in age (40 years overall), median CD4 count (202), nadir CD4 count (60), proportion with a viral load under 500 (81.4%), an AIDS diagnosis (32.5%), and years of antiretroviral therapy (3.9).
Through 7.6 years of follow-up, IL-2 yielded an extra 59 CD4s on average, a highly significant difference from the antiretroviral-only group (P < 0.001). People taking IL-2 spent 23% of trial time with fewer than 200 CD4s and 38% of the time with more than 350. Respective time proportions in the control group were 29% and 28%.
But clinical events did not differ significantly between the two study arms, with 109 in the IL-2 group (1.92 per 100 person-years) and 118 in the control group (2.12 per 100 person-years) (P = 0.47). The grade 4 event rate was significantly higher with IL-2 in the trial's first year (4.69 versus 2.32 per 100 person-years, hazard ratio 2.02, P = 0.01), but not overall for the trial's 7 years. People taking IL-2 endured significantly more gastrointestinal and psychiatric complications than people taking only antiretrovirals.
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. 16th Conference on Retroviruses and Opportunistic Infections, February 8-11, 2009, Montreal. Abstract 90aLB.
2. Levy Y and SILCAAT Scientific Committee. Effect of interleukin-2 on clinical outcomes in patients with CD4+ cell count 50 to 299/mm3: primary results of the SILCAAT study. 16th Conference on Retroviruses and Opportunistic Infections, February 8-11, 2009, Montreal. Abstract 90bLB.
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