Eileen P Scully1, Evgenia Aga2, Athe Tsibris3, Nancie Archin4, Kate Starr5, Qing Ma6, Gene D Morse6, Kathleen E Squires7, Bonnie J Howell8, Guoxin Wu8, Lara Hosey9, Scott F Sieg10, Lynsay Ehui11, Francoise Giguel3, Kendyll Coxen3, Curtis Dobrowolski10, Monica Gandhi12, Steve Deeks12, Nicolas Chomont13, Elizabeth Connick14, Catherine Godfrey15, Jonathan Karn10, Daniel R Kuritzkes3, Ronald J Bosch2, Rajesh T Gandhi16. 1. Departement of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. 2. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. 3. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 4. University of North Carolina, Chapel Hill, North Carolina, USA. 5. ACTG Clinical Research Site, Ohio State University, Hilliard, Ohio, USA. 6. Translational Pharmacology Research Core, University at Buffalo, Buffalo, New York, USA. 7. Merck Research Labs, Upper Gwynned, Pennsylvania, USA. 8. Department of Infectious Disease and Vaccines, Merck and Co, West Point, Pennsylvania, USA. 9. ACTG Network Coordinating Center, Silver Spring, Maryland, USA. 10. Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA. 11. Whitman-Walker Health, Washington, D.C., USA. 12. Department of Medicine, University of California, San Francisco, California, USA. 13. Department of Microbiology, Infectiology and Immunology, Université de Montréal, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Canada. 14. Department of Medicine, University of Arizona, Tucson, Arizona, USA. 15. Office of the Global AIDS Coordinator, Department of State, Washington D.C., USA. 16. Department of Medicine, Massachusetts General Hospital, Harvard University, Boston, Massachusetts, USA.
Abstract
BACKGROUND: Biological sex and the estrogen receptor alpha (ESR1) modulate human immunodeficiency virus (HIV) activity. Few women have enrolled in clinical trials of latency reversal agents (LRAs); their effectiveness in women is unknown. We hypothesized that ESR1 antagonism would augment induction of HIV expression by the LRA vorinostat. METHODS: AIDS Clinical Trials Group A5366 enrolled 31 virologically suppressed, postmenopausal women on antiretroviral therapy. Participants were randomized 2:1 to receive tamoxifen (arm A, TAMOX/VOR) or observation (arm B, VOR) for 5 weeks followed by 2 doses of vorinostat. Primary end points were safety and the difference between arms in HIV RNA induction after vorinostat. Secondary analyses included histone 4 acetylation, HIV DNA, and plasma viremia by single copy assay (SCA). RESULTS: No significant adverse events were attributed to study treatments. Tamoxifen did not enhance vorinostat-induced HIV transcription (between-arm ratio, 0.8; 95% confidence interval [CI], .2-2.4). Vorinostat-induced HIV transcription was higher in participants with increases in H4Ac (fold increase, 2.78; 95% CI, 1.34-5.79) vs those 9 who did not (fold increase, 1.04; 95% CI, .25-4.29). HIV DNA and SCA plasma viremia did not substantially change. CONCLUSIONS: Tamoxifen did not augment vorinostat-induced HIV RNA expression in postmenopausal women. The modest latency reversal activity of vorinostat, postmenopausal status, and low level of HIV RNA expression near the limits of quantification limited assessment of the impact of tamoxifen. This study is the first HIV cure trial done exclusively in women and establishes both the feasibility and necessity of investigating novel HIV cure strategies in women living with HIV. CLINICAL TRIALS REGISTRATION: NCT03382834.
BACKGROUND: Biological sex and the estrogen receptor alpha (ESR1) modulate human immunodeficiency virus (HIV) activity. Few women have enrolled in clinical trials of latency reversal agents (LRAs); their effectiveness in women is unknown. We hypothesized that ESR1 antagonism would augment induction of HIV expression by the LRA vorinostat. METHODS: AIDS Clinical Trials Group A5366 enrolled 31 virologically suppressed, postmenopausal women on antiretroviral therapy. Participants were randomized 2:1 to receive tamoxifen (arm A, TAMOX/VOR) or observation (arm B, VOR) for 5 weeks followed by 2 doses of vorinostat. Primary end points were safety and the difference between arms in HIV RNA induction after vorinostat. Secondary analyses included histone 4 acetylation, HIV DNA, and plasma viremia by single copy assay (SCA). RESULTS: No significant adverse events were attributed to study treatments. Tamoxifen did not enhance vorinostat-induced HIV transcription (between-arm ratio, 0.8; 95% confidence interval [CI], .2-2.4). Vorinostat-induced HIV transcription was higher in participants with increases in H4Ac (fold increase, 2.78; 95% CI, 1.34-5.79) vs those 9 who did not (fold increase, 1.04; 95% CI, .25-4.29). HIV DNA and SCA plasma viremia did not substantially change. CONCLUSIONS: Tamoxifen did not augment vorinostat-induced HIV RNA expression in postmenopausal women. The modest latency reversal activity of vorinostat, postmenopausal status, and low level of HIV RNA expression near the limits of quantification limited assessment of the impact of tamoxifen. This study is the first HIV cure trial done exclusively in women and establishes both the feasibility and necessity of investigating novel HIV cure strategies in women living with HIV. CLINICAL TRIALS REGISTRATION: NCT03382834.
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