Rodolphe Thiébaut1, Ana Jarne1, Jean-Pierre Routy2, Irini Sereti3, Margaret Fischl4, Prudence Ive5, Roberto F Speck6, Gianpiero D'Offizi7, Salvatore Casari8, Daniel Commenges1, Sharne Foulkes9, Ven Natarajan10, Thérèse Croughs11, Jean-François Delfraissy11, Guiseppe Tambussi12, Yves Levy13, Michael M Lederman14. 1. INSERM U1219, INRIA SISTM, Bordeaux University. 2. McGill University Health Centre, Montreal, Quebec, Canada. 3. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda. 4. University of Miami Miller School of Medicine, Florida. 5. Clinical HIV Research Unit, Johannesburg. 6. Division of Infectious Diseases, University of Zurich, University Hospital of Zurich, Switzerland. 7. Institute for Infectious Diseases Lazzaro Spallanzani, Rome. 8. Infectious and Tropical Diseases Unit, Brescia. 9. JOSHA Research, Bloemfontein, South Africa. 10. Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Maryland. 11. INSERM/ANRS, Paris. 12. San Raffaele Scientific Institute, Milan, Italy. 13. INSERM U955, Université Paris Est, Faculté de Médecine, Créteil, Vaccine Research Institute Créteil, AP-HP, Hôpital H. Mondor-A. Chenevier, Service d'Immunologie Clinique et Maladies Infectieuses, Créteil, France. 14. Case Western Reserve University, Cleveland, Ohio.
Abstract
BACKGROUND: Phase I/II studies in human immunodeficiency virus (HIV)-infected patients receiving antiretroviral therapy have shown that a single cycle of 3 weekly subcutaneous (s/c) injections of recombinant human interleukin 7 (r-hIL-7) is safe and improves immune CD4 T-cell restoration. Herein, we report data from 2 phase II trials evaluating the effect of repeated cycles of r-hIL-7 (20 µg/kg) with the objective of restoring a sustained CD4 T-cell count >500 cells/µL. METHODS: INSPIRE 2 was a single-arm trial conducted in the United States and Canada. INSPIRE 3 was a 2 arm trial with 3:1 randomization to r-hIL-7 versus control conducted in Europe and South Africa. Participants with plasma HIV RNA levels <50 copies/mL during antiretroviral therapy and with CD4 T-cell counts between 101 and 400 cells/µL were eligible. A repeat cycle was administered when CD4 T-cell counts fell to <550 cells/µL. RESULTS: A total of 107 patients were treated and received 1 (n = 107), 2 (n = 74), 3 (n = 14), or 4 (n = 1) r-hIL-7 cycles during a median follow-up of 23 months. r-hIL-7 was well tolerated. Four grade 4 events were observed, including 1 case of asymptomatic alanine aminotransferase elevation. After the second cycle, anti-r-hIL-7 binding antibodies developed in 82% and 77% of patients in INSPIRE 2 and 3, respectively (neutralizing antibodies in 38% and 37%), without impact on the CD4 T-cell response. Half of the patients spent >63% of their follow-up time with a CD4 T-cell count >500 cells/µL. CONCLUSIONS: Repeated cycles of r-hIL-7 were well tolerated and achieved sustained CD4 T-cell restoration to >500 cells/µL in the majority of study participants. CLINICAL TRIALS REGISTRATION: INSPIRE II: clinicaltrials.gov (NCT01190111) and INSPIRE III: EudraCT (No. 2010-019773-15) and clinicaltrials.gov (NCT01241643).
BACKGROUND: Phase I/II studies in humanimmunodeficiency virus (HIV)-infectedpatients receiving antiretroviral therapy have shown that a single cycle of 3 weekly subcutaneous (s/c) injections of recombinant humaninterleukin 7 (r-hIL-7) is safe and improves immune CD4 T-cell restoration. Herein, we report data from 2 phase II trials evaluating the effect of repeated cycles of r-hIL-7 (20 µg/kg) with the objective of restoring a sustained CD4 T-cell count >500 cells/µL. METHODS: INSPIRE 2 was a single-arm trial conducted in the United States and Canada. INSPIRE 3 was a 2 arm trial with 3:1 randomization to r-hIL-7 versus control conducted in Europe and South Africa. Participants with plasma HIV RNA levels <50 copies/mL during antiretroviral therapy and with CD4 T-cell counts between 101 and 400 cells/µL were eligible. A repeat cycle was administered when CD4 T-cell counts fell to <550 cells/µL. RESULTS: A total of 107 patients were treated and received 1 (n = 107), 2 (n = 74), 3 (n = 14), or 4 (n = 1) r-hIL-7 cycles during a median follow-up of 23 months. r-hIL-7 was well tolerated. Four grade 4 events were observed, including 1 case of asymptomatic alanine aminotransferase elevation. After the second cycle, anti-r-hIL-7 binding antibodies developed in 82% and 77% of patients in INSPIRE 2 and 3, respectively (neutralizing antibodies in 38% and 37%), without impact on the CD4 T-cell response. Half of the patients spent >63% of their follow-up time with a CD4 T-cell count >500 cells/µL. CONCLUSIONS: Repeated cycles of r-hIL-7 were well tolerated and achieved sustained CD4 T-cell restoration to >500 cells/µL in the majority of study participants. CLINICAL TRIALS REGISTRATION: INSPIRE II: clinicaltrials.gov (NCT01190111) and INSPIRE III: EudraCT (No. 2010-019773-15) and clinicaltrials.gov (NCT01241643).
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