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Major studies rule out any benefit of Interleukin-2 (IL-2): results from ESPRIT and SILCAAT

26 April 2009. Related: Conference reports, .

Nathen Geffen, TAC

The results of two Interleukin-2 (IL-2) trials, ESPRIT and SILCAAT, were presented at CROI. Based on previous evidence that IL-2 raises CD4 counts, the objective of the trials was to determine whether this translated to greater clinical benefits than HAART alone. Patients were randomised to either HAART or HAART plus IL-2.

Both studies reported similar results, primarily that IL-2 provided no additional clinical benefit, even though it raised CD4 counts. Despite this disappointing finding, with over 5,800 patients followed for seven years this is a rich data set that will hopefully explain these unexpected results.

Marcelo Losso presented the ESPRIT study which included over 4,000 patients from over 250 sites in 25 countries with CD4 counts of 300 cells/mm3 or higher. [1]

The IL-2 regimen consisted of at least three 5-day cycles (7.5 MIU twice daily) at eight week intervals in the first year. Optional additional cycles were encouraged to meet predefined goals of a CD4 counts >1,000 cells/mm3 or double baseline levels. The primary endpoint was an opportunistic disease or death. Secondary endpoints included serious non-AIDS illnesses and grade 4 clinical events.

The study needed 320 primary events to detect a 27% difference between the two groups with 80% power. By November 2008, 323 primary events were observed with a median follow up of 7 years and the study was closed.

Baseline demographics included: mean age 41 years, 19% women, 76% Caucasian. Median and nadir CD4 counts were approximately 450 (IQR 372-584) and 200 (IQR 91-306) cells/mm3 respectively. Viral load was <500 copies/mL in 80% of patients. 26% had prior clinical AIDS. Average time on HAART was just over 4 years. Both groups were well balanced in all these characteristics.

Over all follow-up, the IL-2 group had an average CD4 count that was 160 cells/mm3 higher than the control group (95% CI 145-174, p<0.001). The difference in CD4 cells was maintained throughout the study, but decreased from year one (approximately +207cells/mm3 vs+21cells/mm3) over the seven-year period, as use of IL-2 cycles diminished. The IL-group spent 6% of their time at CD4 counts less than 300 and 57% of their time at CD4 counts greater than 600 versus 9% and 36% respectively for the control group. There were no significant differences in viral load between the two groups throughout the study period.

The rate of opportunistic disease or death in the IL-2 and control groups was 1.13 versus 1.21 per 100 patients-years respectively and this was not statistically significant. There were 107 versus 116 deaths respectively. The hazard ratio (HR) was 0.93 (95%CI: 0.75, 1.16). Yet, based on the difference in CD4 count, the predicted HR was 0.74 showing that it would be extremely unlikely not to find a difference, if one existed.

There was not a statistically significant difference in the rate of non-AIDS events, but the IL-2 group had 466 grade 4 events versus 383 in the control and this was significant (HR: 1.23; p=0.003). Of these, vascular events were the biggest contributor (HR: 2.81; p<0.001). The most common vascular event was deep vein thrombosis (>100 days after a cycle) with 13 in the IL-2 group versus 2 in the control. There was also a trend to more common psychiatric events relating to depression in the IL-2 arm (n=44 vs 29, HR 1.4, p=0.1).

Yves Levy presented results from the SILCAAT study, which had a similar study design to ESPRIT, but enrolled patients with lower CD4 counts (50 to 299 cells/mm3) and a lower IL-2 dose with more cycles (six 5-day cycles using 4.5 MIU twice-daily at eight-week intervals. [2] Additional cycles were used to maintain the CD4 count 150 cells/mm3 above baseline. Non-AIDS events were not categorised separately as in ESPRIT.

The trial included about 1,700 subjects in 139 sites in 11 countries. Median follow-up was just under 8 years. It was similarly powered to ESPRIT, but when it was closed on the same date only 227 endpoints had been seen. Baseline characteristics were similar to ESPRIT, except that median and nadir CD4 counts were approximately 200 (IQR 155 – 255) and 60 (IQR 25-108) cells/mm3 respectively.

Median number of cycles was 7 with 72% patients using at least 6 cycles. The average difference in CD4 cells between the IL-2 and control groups was 59 cells/mm3 over the period of the study (p<0.001). The difference was greater for patients with higher CD4 counts. As with ESPRIT, the differences were greatest at the end of year 1 (99 cells/mm3) dropping to a median difference of 38 cells/mm3 at the end of year 6. The IL-2 group spent 23% of their time with a CD4 count below 200 and 38% of their time with a CD4 count above 300 versus 29% and 28% respectively in the control group. Interestingly, the percentage of patients who started a new class of drugs was lower in the IL-2 group (31% versus 37%, p=0.02).

The rate of opportunistic disease or death in the IL-2 and control groups was 1.92 versus 2.12 per 100 patient-years, with 81 versus 77 deaths (1.38/100py vs 1.31/100py, respectively). As with ESPRIT, these results were not statistically significant. The biggest causes of death were non-AIDS related illnesses. Of these, cancers were the largest contributor.

There were 38 grade 4 events in the IL-2 arm in the first year versus 19 in the control (HR: 2.02; p=0.01). However, in contrast to ESPRIT, after the first year there were no differences. Grade 4 events for gastrointestinal tract disorders (HR 1.83, p=0.01) and psychiatric events (HR 2.52, p=0.03) were both significantly higher in the IL-2 arm.

Both studies demonstrated that CD4 cell count is not a reliable surrogate marker for clinical outcomes in the evaluation of IL-2. The pooled HR for the two studies was 0.93 (95%CI: 0.78, 1.09; p=0.33; events: 267 v. 283; deaths: 188 v. 193).

Comment

The consistency of the findings from both studies confidently rules out the possibility of even a modest clinical benefit from IL-2.

Both presenters suggested that the lack of clinical benefit from IL-2 can perhaps be explained either by the expanded CD4 cells lacking functional equivalence, and a planned analysis of events by CD4 count may confirm this, or that the higher rate of serious IL-2 related complications cancelled out any benefit.

They also concluded that absolute CD4 count may not be the an appropriate surrogate marker for immune-based therapy. Although future IL-2 studies are unlikelyl, some of the same researchers have been looking at IL-7.

References:

Both oral presentations are webcasts in the session ‘Recent Developments in Vaccines and Immune-based Therapies’. Feb 10, 2009 10:00AM.

  1. Losso M et al. Effect of Interleukin-2 on clinical outcomes in patients with a CD+ cell count of 300/mm3. Primary results of the ESPRIT study. 16th CROI, Montreal, 2009. Oral abstract 90aLB.
    http://www.retroconference.org/2009/Abstracts/36786.htm
  2. Levy Y et al. Effect of Interleukin-2 on clinical outcomes in patients with CD4+ cell count 50 to 299/mm3: Primary results of the SILCAAT study. 16th CROI, Montreal, 2009. Oral abstract 90bLB.
    http://www.retroconference.org/2009/Abstracts/36787.htm

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