Impact of Tamoxifen on Vorinostat-Induced HIV Expression in Women on Antiretroviral Therapy (ACTG A5366:The MOXIE trial)

Abstract Background Biological sex and the estrogen receptor (ESR1) modulate residual HIV activity. Few women have been 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 ACTG A5366 enrolled 31 virologically suppressed, postmenopausal women on antiretroviral therapy(ART). Participants were randomized 2:1 to receive tamoxifen(Arm A, TAMOX/VOR) or observation(Arm B, VOR) for five weeks followed by two doses of vorinostat. Primary endpoints 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% CI 0.2,2.4]). Induction of spliced HIV RNA transcripts was higher among the 18 participants with increases in H4Ac (fold increase 2.78 [95% CI 1.34,5.79]) versus the 9 who did not (fold increase 1.04 [95% CI 0.25,4.29]). HIV DNA and plasma viremia by SCA did not substantially change. Conclusions Tamoxifen did not augment vorinostat-induced HIV RNA expression in post-menopausal women. The modest latency reversal activity of vorinostat, postmenopausal status and HIV RNA near the limits of quantification limited assessment of the impact of tamoxifen. This study is the first HIV cure trial done exclusively in women, establishes both the feasibility and necessity of investigating novel HIV cure strategies in women living with HIV.