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rhIL7 in HIV-1-infected Subjects with CD4 T-cell Count >100cells/µL and Viral Load <50,000 copies/mL: Results from a Randomized, Placebo-controlled, Double-blinded Study (ACTG5214)
Irini Sereti*1, E Aga2, J Spritzler2, A Landay3, S Pahwa4, M Fischl4, D Asmuth5, A Tenorio6, R Buffet7, M Lederman8, and ACTG 5214 team
1NIAID, NIH, Bethesda, MD, US; 2Statistical & Data Analysis Ctr, Harvard Sch of Publ Hlth, Boston, MA, US; 3Rush-Presbyterian Med Coll, Chicago, IL, US; 4Univ of Miami, Miller Sch of Med, FL, US; 5Univ of California, Davis Med Ctr, US; 6Rush-Presbyterian-St Luke's Med Ctr, Chicago, IL, US; 7Cytheris, Inc, Paris, France; and 8Case Western Reserve Univ, Cleveland, OH, US
Background: IL-7 plays a fundamental role in T-cell
homeostasis. Elevated plasma IL-7 levels have been described in patients with
advanced CD4 lymphopenia, induced by HIV or
chemotherapy. Administration of IL-7 to non-human primates (uninfected and simian
immunodeficiency virus [SIV] -infected) expanded CD4 and CD8 T lymphocytes
without significant changes in plasma SIV levels.
Methods: This is a phase I double-blinded,
placebo-controlled, randomized, dose-escalation study of rhIL7 (Cytheris) in HIV-1-infected persons. Participants were
stratified according to plasma HIV RNA levels (stratum 1, <50 copies/mL or stratum 2, 50 to 50,000 copies/mL)
and were randomized 3:1 (4 per dose level) to receive rhIL7 (at 3, 10, 30, and
60 µg/kg) or placebo. Participants received a single dose of subcutaneous IL-7
(day 0) and were evaluated on days 1 to 4, days 14, 28, and 56. Dose escalation
progressed independently in the 2 strata in the absence of dose-limiting
toxicities. We report the completed results from stratum 1. Changes were tested
by the Sign Test.
Results: We enrolled 16 (12 active, 4 placebo) patients
with median CD4 count of 601 cells/µL and viral load <50 copies/mL. We saw 2 dose-limiting toxicities (a grade 3 local
reaction and a grade 3 transient LFT elevation) in dose level 4 (60 µg/kg); the maximum tolerated dose was therefore 30 µg/kg.
No participant developed antibodies to IL7. Most common side effects (grade I
and II) included local reactions, LFT elevation, and fatigue. Biologic activity
data of the rhIL7 group are shown in the table; p-values refer to within-subject changes
from baseline that reached statistical significance in the combined (all
actively treated) rhIL7 group. No statistically significant changes were
observed in these indices in placebo recipients and there were no statistically
significant viral load changes in either group. For each index shown, there was
evidence of dose-dependent IL-7 activity in the tested dose levels.
|
|
Day 1
|
Day 4
|
Day 14
|
Day 28
|
|
CD4 (cells/µL)
|
–423 (p <0.001)
|
+64
|
+186 (p = 0.04)
|
+213
|
|
CD8 (cells/µL)
|
–612 (p <0.001)
|
+83
|
+359
|
+356
|
|
%CD4 Ki67+
|
+1.5 (p = 0.006)
|
+14.5 (p <0.001)
|
–0.25
|
–0.25
|
|
%CD8 Ki67+
|
+0.9 (p = 0.006)
|
+10.7 (p <0.001)
|
–0.45
|
–0.25
|
|
%CD4 IL-7Ra+
|
–65.4 (p <0.001)
|
–8.2
|
+1.9 (p = 0.04)
|
+2.5
|
|
%CD8 IL-7Ra+
|
–56.7 (p <0.001)
|
–9.3
|
+4.3
|
+7.9
|
Conclusions: Single-dose rhIL-7 induced T-cell
proliferation, down-regulation of IL-7Ra, and transient T-cell increases. The maximum
tolerated dose was 30 µg/kg. Biologic activity at all
tested doses suggests a favorable therapeutic index of this cytokine for
potential use in HIV infection.
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