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

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A randomized trial of vorinostat with treatment interruption after initiating antiretroviral therapy during acute HIV-1 infection
Journal of Virus Eradication ( IF 3.5 ) Pub Date : 2020-07-18 , DOI: 10.1016/j.jve.2020.100004
Eugène D M B Kroon ₁ , Jintanat Ananworanich _{1,

2,

3,

4} , Amélie Pagliuzza ₅ , Ajantha Rhodes _{6,

7} , Nittaya Phanuphak ₁ , Lydie Trautmann _{2,

3} , Julie L Mitchell _{2,

3} , Michelle Chintanaphol _{1,

8} , Jintana Intasan ₁ , Suteeraporn Pinyakorn _{1,

2,

3} , Khuntalee Benjapornpong ₁ , J Judy Chang _{6,

7} , Donn J Colby ₁ , Nitiya Chomchey ₁ , James L K Fletcher ₁ , Keith Eubanks ₉ , Hua Yang ₉ , John Kapson ₉ , Ashanti Dantanarayana _{6,

7} , Surekha Tennakoon _{6,

7} , Robert J Gorelick ₁₀ , Frank Maldarelli ₁₁ , Merlin L Robb _{2,

3} , Jerome H Kim ₁₂ , Serena Spudich ₈ , Nicolas Chomont ₅ , Praphan Phanuphak ₁ , Sharon R Lewin _{6,

7,

13} , Mark S de Souza ₁ ,

Affiliation

SEARCH, Thai Red Cross AIDS Research Centre, Bangkok, Thailand.
The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
United States Military HIV Research Program, Bethesda, MD, USA.
Bill and Melinda Gates Medical Research Institute, Cambridge, MA, USA.
Centre de Recherche du CHUM and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Canada.
The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia.
Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Center, Melbourne, Australia.
Department of Neurology, Yale University School of Medicine, Yale University, New Haven, CT, USA.
Cooper Human Systems, Nashua, NH, USA.
AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
International Vaccine Initiative, Seoul, Republic of Korea.
Department of Infectious Diseases, Alfred Health and Monash University, Melbourne, Australia.

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.

中文翻译：

急性 HIV-1 感染期间开始抗逆转录病毒治疗后中断治疗的伏立诺他随机试验

目标与设计

一项随机、开放标签的试点研究，受试者为急性 HIV 感染 (AHI) 后接受抗逆转录病毒治疗 (ART) 的个体，治疗方案包括组蛋白脱乙酰酶抑制剂，以诱导 HIV 潜伏并在随后的治疗中断 (TI) 期间控制 HIV 复制。

方法

在 AHI 开始 ART 的 15 名参与者被随机分配至伏立诺他/羟氯喹/马拉韦罗 (VHM) 加 ART (n = 10) 或单独 ART (n = 5)。VHM 组在 TI 前 10 周内接受了 3 个为期 14 天的伏立诺他周期。当血浆病毒载量 (VL)>1,000 HIV RNA 拷贝/mL 时，恢复 ART。主要结局是 TI 后 24 周内接受 VHM + ART 的参与者与仅接受 ART 且 VL < 50 拷贝/mL 的参与者的比例。

结果

15 名 ART 参与者（中位：178 周：范围 79-295）入组。两名接受 VHM+ART 的患者经历了严重的不良事件。14 名参与者接受了 TI；所有患者都经历过 VL 反弹，两组之间的时间没有差异：VHM + ART (n = 9) 中位数：4 周，仅 ART (n = 5) 中位数：5 周。在第一个周期后，通过单拷贝 HIV RNA 检测，VHM 诱导 VL 增加 2.2 倍（p = 0.008）。前两个周期后新蝶呤水平显着增加。VHM 治疗后，外周血单核细胞中携带 HIV 总 DNA 和细胞相关 RNA 的频率没有变化。所有参与者在重新开始 ART 后均实现了 VL 抑制。