By Liz Highleyman

Despite effective ART, some people with full viral load suppression do not achieve robust CD4 cell gains (known as discordant response). Furthermore, the cells that do return may not have the same function as those lost. Several recent studies indicate that spending more time with lower CD4 counts increases the risk of not only AIDS-defining opportunistic illness, but also non-AIDS-related diseases such as cancer, well before reaching the "danger zone" below 200 cells/mm3.

Yves Levy and an international team of colleagues aimed to determine whether recombinant human IL-7 would have a positive effect on T-cell recovery and thymic function in HIV patients on ART with undetectable viral load.

IL-7 is among the many cytokines, or chemical messengers, that influence immune system activity. Two recently completed large trials, ESPRIT AND SILCAAT, looked at another cytokine, interleukin 2 (IL-2). Other such messengers are also under study.

Past research by Levy and others has shown that IL-7 stimulates T-cell maturation and release from the thymus, as well as inhibiting spontaneous CD4 and CD8 cell death. The thymus is a gland in the upper chest where T-cells mature; it typically shrinks and becomes less active as people age.

The INSPIRE study included 22 participants randomly assigned to receive weekly injections of 10 or 20 mcg/kg of IL-7 (using a preparation called CYT107) or placebo for 12 weeks. The study also has a 30 mcg/kg dose cohort, but Levy only reported interim results from the 2 lower-dose groups.

All study participants were men. Those receiving IL-7 had a median age of about 40 years; placebo recipients were on average about age 50. All had a viral load below 50 copies/mL. At the time of enrollment, CD4 count ranged from 101 to 400 cells/mm3 (median of about 270 cells/mm3), but the median nadir (lowest-ever) level was 100 cells/mm3, indicating advanced immune deficiency. The median CD8 count was about 750 cells/mm3 and the median CD4/CD8 ratio was 0.35.

Results

	Overall, IL-7 appeared generally safe and well tolerated in the 10 and 20 mcg/kg dose cohorts over 12 weeks.
	No serious adverse events or dose-limiting toxicities were reported.
	Some patients experienced mild-to-moderate local injection site reactions, but no systemic reactions.
	Viral load generally remained suppressed, although 4 patients in the 20 mcg/kg group experienced low-level transient "blips" (3 with 500 copies/mL or less, 1 with around 1000 copies/mL).
	Participants experienced significant increases in both CD4 and CD8 cell counts:
	CD4 cells:   10 mcg/kg group: 152% increase from baseline (median 268 cells/mm3) to week 4 (median 643 cells/mm3), falling back to 87% by week 12 (median 419 cells/mm3).   20 mcg/kg group: 205% increase from baseline (median 240 cells/mm3) to week 4 (median 709 cells/mm3), falling back to 135% by week 12 (median 563 cells/mm3). CD8 cells:   10 mcg/kg group: 91% increase from baseline (median 761 cells/mm3) to week 4 (median 1434 cells/mm3), falling back to 42% by week 12 (median 1081 cells/mm3).   20 mcg/kg group: 131% increase from baseline (median 659 cells/mm3) to week 4 (median 1695 cells/mm3), falling back to 65% by week 12 (median 1210 cells/mm3).
	1 of 7 participants (14%) in the 10 mcg/kg group and 5 of 8 (63%) in the 20 mcg/kg group reached a CD4 cell level above 500 cells/mm3, which took a median of 14 days.
	There were gains in both naive T-cells (not yet committed to fighting specific pathogens) and central memory cells (which "remember" past invaders), but more mature effector memory cells did not increase.
	Patients' thymus glands appeared to release more cells, leading to increased numbers of "recent thymic emigrants."

Larger and longer studies will be needed to determine whether these promising increases in CD4 and CD8 cell levels translate into clinical benefits. As reported earlier this year, ESPRIT AND SILCAAT showed that IL-2 did not lead to improved long-term clinical outcomes or survival, even though it did produce CD4 cell increases.

Levy noted that the types of CD4 T-cells expanded by IL-7 are completely different from those expanded by IL-2, and rather than looking at progression to AIDS or death, as done in ESPRIT and SILCAAT, it may be possible to see beneficial clinical outcomes sooner using different types of endpoints.

Hosp. H. Mondor, Créteil, France; NIAID/NIH, Bethesda, MD; San Raffaele Scientific Inst., Milano, Italy; MUHC, Montreal, Canada; Hosp K. Bicêtre, Kremlin Bicêtre, France; Hosp St Louis, Paris, France; Univ. of Miami Sch. of Medecine, Miami, FL; Cytheris, Issy-Les-Moulineaux, France; NIML, Montreal, Canada; Case Western Reserve Univ., Cleveland, OH.

9/18/09

Reference
Y Levy, I Sereti, G Tambussi, and others. INSPIRE Study: Effects of r-hIL-7 on T cell recovery and thymic output in HIV-infected patients receiving c-ART - interim analysis of a phase I/IIa multicenter study. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2009). San Francisco. September 12-15, 2009. Abstract H-1230a.