CONFERENCE ON RETROVIRUSES
AND OPPORTUNISTIC INFECTIONS

Boston, Massachusetts
March 8–11, 2020

 

Conference Dates and Location: 
March 4–7, 2019 | Seattle, Washington
Abstract Number: 
131

SIROLIMUS REDUCES T-CELL CYCLING AND IMMUNE CHECKPOINT MARKER EXPRESSION, ACTG A5337

Author(s): 

Timothy J. Henrich1, Ronald Bosch2, Catherine Godfrey3, Hanna Mar2, Apsara Nair4, Elizabeth Hawkins5, Carl Fichtenbaum6, Michael Keefer7, Jonathan Z. Li8, Daniel R. Kuritzkes8, Michael M. Lederman9, Priscilla Hsue1, Steven G. Deeks1

1University of California San Francisco, San Francisco, CA, USA,2Harvard University, Boston, MA, USA,3National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA,4Frontier Science & Technology Research Foundation, Inc, Amherst, NY, USA,5Social & Scientific Systems, Silver Spring, MD, USA,6University of Cincinnati, Cincinnati, OH, USA,7University of Rochester, Rochester, NY, USA,8Brigham and Women's Hospital, Boston, MA, USA,9Case Western Reserve University, Cleveland, OH, USA

Abstract Body: 

Reversing immune dysfunction and inhibiting T-cell proliferation are critical to immune-based HIV cure strategies. A prior retrospective analysis of the use of sirolimus, an mTOR inhibitor, in HIV+ renal transplant recipients suggests that it may lead to lower CD4+ T cell HIV DNA, but prospective studies are lacking. Therefore, we sought to evaluate the safety of sirolimus in ART-suppressed HIV-infected individuals and its effect on immune function and HIV-1 reservoir size.

 

A5337 was an open-label, single-arm, pilot study of 20 weeks of oral sirolimus treatment for HIV-infected individuals on ART with HIV RNA <40 cps/mL. Eligibility criteria included at least 24 months on ART, HIV RNA < assay limit and CD4+ cell count ≥ 350 cells/mm3. Measures of T-cell activation and cycling, immune exhuastion and CCR5 expression (secondary efficacy outcomes) were compared by paired t-tests prior to vs after continuous oral sirolimus.

 

32 participants enrolled in the study. Participants had a median age of 52 years, 28% were female and 56% were black non-Hispanic. The median baseline CD4+ cell count was 813 cells/mm3. Two participants did not start study drug, 14 completed less than 20 weeks of sirolimus, and 16 completed 20 weeks of therapy. Twenty weeks after initiating sirolimus, CD4+ cell counts declined by a mean of 118 cells/mm3 (p=0.04; n=16). Three participants had a grade 3 adverse event (stomatitis and perturbations of fasting glucose in a known diabetic) or a decrease in CD4+ cell count to <300 cells/mm3. Two participants stopped sirolimus because of assympomatic transient Epstein Barr viremia. Other individuals discontinued because of lower grade toxicities or minor, clinically insignificant laboratory abnormalities. Twenty weeks of sirolimus was associated with significant decreases in the percentages of cycling Ki67+ CD4+ and CD8+ T cells (mean change -0.5%, p=0.031, and -0.5%, p=0.005, respectively), PD-1+ CD8+ T cells (-2.9%, p=0.008), and CCR5+ CD8+ T cells (-3.9%, p=0.001).

 

Sirolimus use was associated with significant reductions in CCR5 expression and T-cell markers of cell cycling and immune exhaustion. There was a relatively high rate of treatment discontinuation, in part because of protocol-defined stopping criteria.

 

Session Number: 
O-12
Session Title: 
HIV/SIV AND THE IMMUNE SYSTEM: AN INTIMATE DANCE
Presenting Author: 
Timothy Henrich
Presenter Institution: 
UCSF