127
Repeated r-hIL-7 Doses Improve T-cell Recovery in HIV-1-infected Patients Enrolled in a Phase I/II Multicentric Study
Y Levy1,2, Y Levy1,2, L Weiss1,3,4, L Weiss1,3,4, L Weiss1,3,4, J P Viard5, J Molina6, C Goujard7, F Boué8, S Delluc1, C Rouzioux5, M Morre9, and jean-François Delfraissy*7
1INSERM, Creteil, France; 2Henri Mondor Hosp, Creteil, France; 3Hosp Georges Pompidou, Paris, France; Rene-Descartes Univ and INSERM, Creteil, France; 4Rene-Descartes Univ, Paris, France; 5Necker Hosp, Paris, France; 6Hosp St Louis, Paris, France; 7Kremlin-Bicetre Hosp, France; 8Hosp Antoine Beclere, Clamart, France; and 9Cytheris, Issy, France
Background: Interleukin-7 (IL-7) is a critical cytokine for T-cell
development, thymopoiesis, peripheral homeostasis,
and T-cell maturation. Repeated doses of r-hIL-7 leads to a
dose-dependant expansion of T cells in cancer patients (26 patients). We
evaluated the safety and biological effects of escalating doses of r-hIL-7 in chronically HIV-infected patients.
Methods: Patients with CD4 between 100 and 400 cells/µL and plasma HIV RNA <50 copies/mL for at least 6 months, while on HAART for at least 12
months, were eligible. We included 6 patients in the first dose level (3 µg/kg); they received 8 subcutaneous injections (3
times/week; days 1 to 18) of r-hIL-7. Clinical, biological, and virological safeties, quantitative, phenotypic, and
functional changes of T cells were monitored until
week 12. Statistical analyses were performed using the Wilcoxon
rank test.
Results: All patients received the
8 planned doses. No clinical or biological side effects >grade 2 were
recorded. Plasma HIV RNA values remained <50 copies/mL
throughout the study. Median CD4 counts increased from 210/µL to 405/µL (+95%) at day 21 and remained significantly
above baseline at week 12: 300/µL (+47%)
(p <0.01).
The first 2 patients who completed the 10-µg/kg dose level experienced a higher
increase in CD4 counts suggesting a dose-dependent effect of rh-IL-7.
Phenotypic analyses showed an expansion of both naïve and memory CD4 and CD8 T
cells. At day 28, expression of CD127 increased on CD4+ and CD8 T
cells (p = 0.046 and 0.028, respectively
for comparisons to baseline). There was a trend to an increase of Ki67 on naive
CD4+CD45RA+CD27+ cells at day 14 (median 5.1% vs 0.9 at baseline, p
= 0.08). Expression of CD95 on CD3+CD4+ T cells
increased during r-hIL-7 treatment (p =
0.04) and returned to baseline at week 12. An increase of BCL-2 expression on
CD4 T cells was observed in 3 of 6 patients. An expansion of CD8+T
cells expressing CD28 (from a median of 43.2% to 59.2% at week, 12; p = 0.028) was noted suggesting that
IL-7 could promote CD8 maturation in vivo.
No patient experienced an increase in B cell progenitors.
Conclusions: A short cycle of r-hIL-7 leads to a significant expansion of T cells
in patients who maintained low CD4 counts while on HAART. This effect was
observed at the lowest dose (3 µg/kg) without
clinical or virological concerns. Results of the
whole study will be presented. These results encourage further trials
evaluating IL-7 as a novel strategy for improving immune reconstitution in
HIV-infected patients.
|
