Repeated Cycles of Recombinant Human Interleukin 7 in HIV-Infected Patients With Low CD4 T-Cell Reconstitution on Antiretroviral Therapy: Results of 2 Phase II Multicenter Studies

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).

Keywords: CD4; HIV; T-cell recovery; immune restoration; interleukin-7.

© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Figures

Figure 1.

Flow chart for INSPIRE 2 and INSPIRE 3 studies.

Figure 2.

Detailed immune response in INSPIRE 2 patients for total CD4+ T cells, CD4+ regulatory T cells (Tregs), CD4+CD31+ T cells, and CD4+ naive, central memory (TCM), and effector memory (TEM) T cells, from baseline (week 0) to week 12. Abbreviation: IQR, interquartile range.

Figure 3.

CD4 T-cell dynamics after recombinant human interleukin 7 injections: INSPIRE 2 (top left); INSPIRE 3 (top right); according to the first or second cycle, where week 0 is the beginning of the first or second cycle (bottom left); and according to the number of injections within cycles performed after a complete initial one (bottom right). Abbreviation: IQR, interquartile range.