A randomized trial of vorinostat with treatment interruption after initiating antiretroviral therapy during acute HIV-1 infection

Abstract

Objective and design: A randomized, open-label pilot study in individuals treated with antiretroviral therapy (ART) since acute HIV infection (AHI) with a regimen including a histone deacetylase inhibitor to induce HIV from latency and control HIV replication during subsequent treatment interruption (TI).

Methods: Fifteen participants who initiated ART at AHI were randomized to vorinostat/hydroxychloroquine/maraviroc (VHM) plus ART (n ​= ​10) or ART alone (n ​= ​5). The VHM arm received three 14-day vorinostat cycles within 10 weeks before TI. ART was resumed for plasma viral load (VL) ​> ​1,000 HIV RNA copies/mL. Primary outcome was proportion of participants on VHM ​+ ​ART versus ART only with VL ​< ​50 copies/mL for 24 weeks after TI.

Results: Fifteen participants on ART (median: 178 weeks: range 79-295) enrolled. Two on VHM ​+ ​ART experienced serious adverse events. Fourteen participants underwent TI; all experienced VL rebound with no difference in time between arms: VHM ​+ ​ART (n ​= ​9) median: 4 weeks and ART only (n ​= ​5) median: 5 weeks. VHM induced a 2.2-fold increase in VL (p ​= ​0.008) by single-copy HIV RNA assay after the first cycle. Neopterin levels increased significantly following the first two cycles. After VHM treatment, the frequencies of peripheral blood mononuclear cells harboring total HIV DNA and cell-associated RNA were unchanged. All participants achieved VL suppression following ART re-initiation.

Conclusions: Administration of VHM increased HIV VL in plasma, but this was not sustained. VHM did not impact time to viral rebound following TI and had no impact on the size of the HIV reservoir, suggesting that HIV reservoir elimination will require alternative treatment strategies.

Keywords: Acute HIV infection; HIV remission; Latency reversal; Maraviroc; Vorinostat.

Fig. 1

Protocol schema for multiple cycles of vorinostat/hydroxychloroquine/maraviroc (VHM). Vorinostat was administered at 400 ​mg/day, hydroxychloroquine at 400 ​mg/day and maraviroc at 300–1,200mg/day. Antiretroviral therapy (ART) was interrupted at week 10.

Fig. 2

Plasma viral load during 10 weeks of treatment with vorinostat/hydroxychloroquine/maraviroc (VHM) ​+ ​ART (left panel) and ART only (right panel) measured by the single-copy HIV RNA assay. The horizontal bars above the left panel show the times of administration of vorinostat. ∗: p ​= ​0.008 relative to study entry. C: Cycle.

Fig. 3

Change in CA-US HIV RNA in the vorinostat/hydroxychloroquine/maraviroc (VHM) ​+ ​ART treatment arm (left panel) versus ART only (right panel). Grey shaded area represents the VHM treatment period. Treatment in both study arms was interrupted at week 10. The vertical dashed lines represent the minimum and maximum times following treatment interruption at which viral rebound occurred (2–7 weeks in the VHM ​+ ​ART group and 4–16 weeks in the ART only group). Horizontal bars at the top of the left panel show the timing of vorinostat administration. The color schema used in Fig. 2 for each participant is retained. C: Cycle.

Fig. 4

Total HIV DNA during the 34-week study period in the vorinostat/hydroxychloroquine/maraviroc treatment arm (left panel) versus ART only (right panel). Grey shaded area represents the VHM treatment period. Treatment in both arms was interrupted at week 10. The vertical dashed lines represent the minimum and maximum times following treatment interruption at which viral rebound occurred (2–7 weeks in the VHM ​+ ​ART group and 4–16 weeks in the ART only group). Horizontal bars at the top of the left panel show the timing of vorinostat administration. Horizontal dashed line shows the limit of detection of the assay. The color schema used in Fig. 2 for each participant is retained. C: Cycle.