HIV reservoirs differ between men and women but few women have been enrolled in HIV cure trials to date. In vitro and ex vivo data have identified a suppressive role for the estrogen receptor in HIV transcriptional control. ACTG A5366 investigated whether the selective estrogen receptor modulator tamoxifen enhances HIV transcription in vivo after vorinostat exposure.
Postmenopausal women with HIV suppression for >1 yr and continuous ART for >=2 yrs were randomized 2:1 to 5 wks of tamoxifen (ArmA) vs observation (ArmB); both groups then received 2 doses of 400mg of vorinostat separated by 72 hrs. Primary outcomes were safety in all treated women and change in HIV RNA expression from baseline to 5 hrs after second vorinostat dose in those receiving full study treatment (efficacy group). Total HIV DNA and unspliced cell-associated RNA(caRNA) were measured in 5×106 CD4 T cells by qPCR, and spliced HIV envelope transcripts were measured in 106 resting memory CD4 cells by EDITS assay. Single copy assay(SCA) of plasma viremia and histone acetylation by ELISA were measured. Arms were compared by t-tests.
31 women enrolled in 3 months; median age 57, 58% African American, median CD4 count 688 cells/mm3. No >=Grade 3 adverse events related to study drugs were seen. 27 women comprised the efficacy group (19 ArmA, 8 ArmB). There was no difference between the groups in the change in HIV expression by caRNA (mean fold change: ArmA 1.2, ArmB 1.5, p=0.6) or in EDITS (mean fold change ArmA 1.5, ArmB 4.3, p=0.12). Following vorinostat, 18 participants had increased histone acetylation; in these women, HIV expression by EDITS also increased (mean fold increase: Overall 2.8; ArmA 1.7; ArmB 7.4; Table 1). There were no changes in HIV DNA or SCA. Targeted plasma concentrations of tamoxifen and vorinostat were achieved.
In post-menopausal women receiving vorinostat, ESR1 antagonism with tamoxifen was not associated with a significant change in the magnitude of HIV RNA induction by qPCR or EDITS. Induction of HIV RNA after vorinostat by the EDITS assay was primarily seen in women with increases in histone acetylation which was only observed in 67% of trial participants; this may have limited the ability to detect an effect of tamoxifen. This clinical trial, the first to study HIV latency reversal exclusively in women, was rapidly enrolled and completed, supporting the feasibility of future efforts to investigate sex-specific features of the HIV reservoir.