Activation of HIV Transcription with Short-Course Vorinostat in HIV-Infected Patients on Suppressive Antiretroviral Therapy

<div><p></p><p>Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/show/NCT01365065" target="_blank">NCT01365065</a></p></div

Baseline characteristics of study participants.

a<p>Values represent n (% with characteristic) or median (interquartile range).</p>b<p>Patient had a single HIV RNA viral load to <200 copies/mL during period of suppression.</p>c<p>Antiretroviral agents separated by “/” were fixed dose combination.</p><p>“+r” denotes administration of ritonavir.</p><p>NOTE: TDF, Tenofovir; 3TC, Lamivudine; FTC, Emtricitabine; EFV, Efavirenz; NVP, Nevirapine; ABC, Abacavir; 3TC, Lamivudine; DRV, Darunavir; RTV, Ritonavir; AZT, Zidovudine; LPV, Lopinavir; RAL, Raltegravir; ATV, Atazanavir; NVP SR Nevirapine (slow release).</p><p>Baseline characteristics of study participants.</p

Changes in virological and immunological parameters from one patient with viral rebound on study.

<p>Changes in (A) CA-US HIV RNA (red), (B) plasma HIV RNA (green) and (C) CA-HIV DNA (blue) are shown as the mean± SD for replicates of CA-US HIV RNA and HIV DNA. Programmed death-1 (PD1) expression on CD4+ and CD8+ CD45RA- T-cells is shown. Grey shaded box represents the time on vorinostat. (D) Dot plot analysis of flow cytometry for co-expression of PD-1 and CD45RA on CD4+ (top panel) and CD8+ (lower panel) T-cells at baseline, after 7 days of vorinostat and at day 84 of follow up.</p

Individual changes in CA-US HIV RNA in blood and tissue.

<p>A) Fold change in CA-US HIV RNA following vorinostat in CD4+ T-cells from blood (left panel) and rectal tissue (right panel) compared to baseline. The maximum fold change in CA-US HIV RNA on study (solid column) and change at day 84 (open column) is shown for CD4+ T-cells from blood; and change at day 14 for rectal tissue is shown for each participant (upper panel) and the median (IQR) change for all participants (lower panel). The grey dashed line indicates 1-fold change. B) Time to reach maximum fold increase in CA-US HIV RNA for each participant. Grey shaded box represents the time on vorinostat. (C) Correlation between baseline CA-US HIV RNA and peak CA-US HIV RNA (left panel) and day 84 CA-US HIV RNA (right panel).</p