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Can IL-7 Succeed Where IL-2 Failed in People With HIV?
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49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy), September 12-15, 2009, San Francisco
Mark Mascolini
After 7 years and many millions of dollars, two clinical endpoint studies established beyond doubt that CD4 cells gained with interleukin 2 (IL-2) plus antiretrovirals did nothing to slow HIV disease progression when compared with standard antiretroviral therapy alone [1,2]. Less than a year later, some of the same investigators offered more data on another immune-stimulating candidate--recombinant human IL-2 (r-hIL-7)--in people with HIV [3]. As in the IL-2 trials, r-hIL-7 significantly boosted CD4 counts in people taking antiretrovirals. Whether that jump translates into better health will take more study.
Yves Levy of Creteil, France, a long-time IL-2 proponent and investigator, presented results of this trial conducted with collaborators in Canada, France, Italy, and the United States [3]. Two earlier studies found that IL-7 hoists CD4 counts in people with chronic HIV infection [4,5]. This trial sought to confirm that finding, map traits of the added CD4 cells, and determine how r-hIL-7 affects thymic output of T cells.
Study participants had taken a potent antiretroviral combination for at least 1 year, had a viral load below 50 copies, and had 101 to 400 CD4 cells. No one had HBV or HCV infection. Levy and coworkers randomized participants to placebo or r-hIL-7 at one of three doses: 10, 20, or 30 micrograms/kg. Plans called for 10 people in each dosage group, 8 taking r-hIL-7 and 2 taking placebo. Study participants took the immune modulator by subcutaneous injection on days 0, 7, and 14.
Levy had results for the 10- and 20-microgram groups. As can happen in a trial this small, some baseline characteristics were not balanced between people taking r-hIL-7 and those taking placebo. The 4 placebo recipients were older (median 53 years versus 43 with 10 micrograms and 42 with 20 micrograms), had been infected with HIV longer (median 14 years versus 5 years in the r-hIL-7 groups), and had taken antiretrovirals longer (median 13 years versus 4 in with 10 micrograms and 1 with 20 micrograms).
Lowest-ever CD4 count was lower in the 4 placebo recipients (45 versus 100 in the 10-microgram group and 98 in the 20-microgram group), but starting CD4 counts were similar (278 on placebo, 261 on 10 micrograms, and 230 on 20 micrograms). CD4-to-CD8 ratio was higher in the placebo group (0.50) than in the 10- and 20-microgram groups (0.35 and 0.39).
No one taking r-hIL-7 was lost to follow-up, and no clinical or laboratory side effects were rated higher than grade 2. Injection site reactions were mild to moderate. Four people taking r-hIL-7 had transient increases in plasma viremia above 50 copies (the highest to 1023 copies). No neutralizing anti-IL-7 antibodies became detectable during the study.
One person in the 10-microgrm group and 2 in the 20-microgram group did not receive all 3 injections. By week 12, median CD4 counts rose from 268 to 419 in the 10-microgram group and from 240 to 563 in the 20-microgram group (P = 0.006 and P = 0.004). CD8 counts also rose significantly in both groups. Median naive CD4 counts rose from 41 to 93 at week 12 with the lower dose (P = 0.016) and from 66 to 136 with the higher dose (P = 0.016). There was a trend toward increased thymic output with the higher dose (P = 0.062). Five of 8 people taking the 20-microgram dose had a CD4 count above 500 at week 12 (P < 0.05).
When asked if it would take 7 years and millions of dollars to learn whether r-hIL-7 has any clinical value, Levy argued that this immune modulator cannot be compared with IL-2 because it produces CD4 cells of an entirely different phenotype. Specifically, r-hIL-7 stimulated recent thymic emigrant (CD45RA+ CCR7+ CD31[high]) CD4 cells, naive (CD45RA+ CCR7+) CD4 cells, central memory (CD45RA- CCR7+) CD4 cells, and effector memory (CD45RA- CCR7-) CD4 cells.
Levy suggested that massive clinical endpoint studies would not be necessary to prove the value of r-hIL-7. Although he did not spell out a comprehensive trial strategy, Levy proposed that the next step will be to test several cycles of r-hIL-7, instead of the single cycle tested in this trial, to see if longer treatment sustains T-cell benefits.
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.
3. Levy Y, Sereti I, Tambussi G, et al. Effects of r-hIL-7 on T cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: interim analysis of a phase I/IIa multicenter study. 49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy). September 12-15, 2009. San Francisco. Abstract H-1230a.
4. Levy Y, Lacabaratz C, Weiss L, et al. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest. 2009;119:997-1007.
5. Sereti I, Dunham RM, Spritzler J, et al. IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection. Blood. 2009;113:6304-6314.
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