The Body Covers: The 9th Conference on Retroviruses and Opportunistic Infections
IL-2 and Other Forms of Immunotherapy (Poster Session 71)
February 25, 2002
To date, ESPRIT has enrolled 2,560 subjects who achieved CD4 counts >300 on suppressive ART, with a total of 4,000 subjects planned. One thousand three hundred and seven subjects have been randomized to receive IL-2 in combination with their ART in an attempt to determine if IL-2 reduces the risk of AIDS or death.
Preliminary analyses of ESPRIT have shown 43% of patients reaching the endpoint of doubling baseline CD4 count or reaching 1,000 cells. Three hundred and ninety-six subjects underwent 3 cycles of IL-2 starting at 7.5 MIU BID for 5 days and have completed eight months of follow-up, forming the group described in this abstract.
The subjects were grouped into tertiles, based on month eight change from baseline CD4 count. The boundaries for these three groups were <212 cells, 212-426 cells, and >426. A number of baseline factors were compared across these tertiles, including age, gender, injected drug use, hepatitis B/C co-infection, nadir and baseline CD4, HIV RNA, body mass index, ART drug class exposure and duration of prior ART.
In univariate analyses, baseline CD4 (534 vs. 510 vs. 596, p=0.0002), nadir CD4 (231 vs. 255 vs. 333, p<0.0001), age (p=0.02), and duration of prior ART (5.3 years vs. 5.0 years vs. 3.9 years, p<0.0001) varied significantly across the three groups.
In multivariate modeling, nadir CD4 was significantly associated with CD4 change from baseline, with each 100 cells that the nadir was higher translating into a 46 greater cell increase with IL-2 after eight months (p<0.0001). Subjects with <1 year of prior ART had a 112 cell greater CD4 response than other subjects with more ART experience.
Although this analysis indicates that subjects with lower nadir CD4 counts prior to starting ART had less CD4 gain after IL-2, those with the lowest nadir (<100 CD4 cells) still gained a respectable mean of 256 cells from their baseline with the use of IL-2. Furthermore, although those subjects with the shortest duration of ART had the greatest CD4 increases, those with the longest prior therapy, >6 years, gained an average of 282 cells from baseline.
Since IL-2 is an injected therapy that requires substantial patient commitment and is often complicated by adverse reactions that limit its tolerability and continued use, it will be necessary to determine who are the best candidates for IL-2. SILCAAT will examine its use in patients who have suppressed HIV with ART but failed to gain substantial CD4 cells. ESPRIT will examine its use in patients who have rebounded to at least 300 CD4 cells. This study further explores the role of a number of potentially influential factors in determining the magnitude of CD4 responses among a small group of subjects who received IL-2 in ESPRIT.
Notably, nadir CD4 count and duration of prior ART seemed to be independent baseline determinants of CD4 gains. This would suggest that in the context of the ESPRIT cohort, the effect of IL-2 might be best in those who get it earlier in their disease and treatment course. However, that is not to say that the gains seen in those with the lowest nadirs and most extensive prior ART do not experience good gains in CD4 with IL-2. Whether any of these additional CD4 cell gains with IL-2 are clinically significant in terms of decreased rate of AIDS or death is yet to be seen, however. Whether these gains might allow for later safe periods of ART interruption is also yet to be seen in other trials.
Although the reasons for the significance of these factors are not entirely clear, it seems likely that patients with the lowest CD4 nadirs may have lost some capacity for greater CD4 gains. It also seems possible that patients with the longest prior ART may have already experienced CD4 gains so that IL-2 does not add as much as it does for those with shorter time on ART. This type of exploratory analysis illustrates a very useful approach to determining the factors that will ultimately help to plan strategies for initiating immune-based therapies such as IL-2. For now, the jury is still out on the clinical benefits of the CD4 gains seen in trials of IL-2. Since IL-2 is not generally available in routine clinical care, for patients interested in participating in these trials, recruitment is ongoing at many centers.
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