Drug Database: Vorinostat

What is vorinostat?

Vorinostat is a drug that has been approved by the U.S. Food and Drug Administration (FDA) under the brand name Zolinza for the treatment of a certain type of cancer.⁴  Vorinostat is also being studied as an investigational drug as part of a strategy to cure HIV infection. As an investigational HIV drug, vorinostat belongs to a group of drugs called latency-reversing agents.³

To learn about how investigational drugs are tested during clinical trials, read the HIVinfo What is an Investigational HIV Drug? and HIV and AIDS Clinical Trials fact sheets.

How do latency-reversing agents work?

Currently, there is no cure for HIV infection. One of the main obstacles to curing HIV infection is that the virus can remain hidden and inactive (latent) inside certain cells of the immune system (such as resting CD4 cells) for many months or even years. The cells where latent HIV hides are known as the latent HIV reservoir. Because HIV in this latent state is inactive, the immune system cannot detect the virus, and the antiretroviral (ARV) drugs that are used to treat HIV have no effect on it.^5-7

Latency-reversing agents work by drawing HIV out of its latent state within resting CD4 cells. Once the latent HIV is reactivated, the CD4 cells that harbor the virus are more likely to be recognized and killed by the body’s immune system or may be killed by certain HIV therapies, such as those that can enhance the body's immune response to HIV. Researchers hope that the combined use of vorinostat and other HIV-fighting strategies, including ongoing antiretroviral therapy (ART), may fully eliminate HIV from the body.^5-7 To learn more, see the HIVinfo What is a Latent HIV Reservoir? fact sheet.

Select clinical trials of vorinostat

Study Name: NCT01319383

Phase: 1/2
Status: This study has been completed.
Location: United States
Purpose: The purpose of this study was to determine the effectiveness of vorinostat in activating latent HIV in resting CD4 cells after single and multiple vorinostat doses.⁸
Selected Study Results: Results published in Nature (2012), The Journal of Infectious Diseases (2014), and The Journal of Clinical Investigation (2017) showed that both a single dose of vorinostat and paired doses of vorinostat (with each dose separated by 72 hours) was capable of activating latent HIV in a majority of the participants studied. Multiple cycles of daily dosing with vorinostat, however, had only a minimal effect on reactivating HIV latency.^9–11

Study Names: SEARCH 019; NCT02475915 and SEARCH 026; NCT02470351

Phase: 1/2
Status: These studies have been completed.
Location: Thailand
Purpose: The SEARCH 019 study evaluated the safety and effectiveness of a treatment regimen that combined vorinostat, the drugs hydroxychloroquine and maraviroc, and ART in controlling viral load levels during an analytical treatment interruption that followed.

SEARCH 026 was a substudy that was conducted at the same time as SEARCH 019 and included some of the SEARCH 019 participants. The substudy evaluated how the treatment regimens used in SEARCH 019 affected the central nervous system (CNS), latent HIV in the CNS, and viral load levels in the CNS of the participants.^12-14
Selected Study Results: Results from the main study (SEARCH 019) published in the Journal of Virus Eradication (2020) showed that vorinostat, hydroxychloroquine, and maraviroc added to ART was not more effective in controlling viral load levels during a treatment interruption than ART given alone.¹⁵
Additional Published Material:

• AIDS, 2016: Central nervous system impact of vorinostat, hydroxychloroquine and maraviroc combination therapy followed by treatment interruption in individuals treated during acute HIV infection (SEARCH 026)

Study Name: NCT01365065

Phase: 2
Status: This study has been completed.
Location: Australia
Purpose: The purpose of this study was to determine whether vorinostat could activate latent HIV in resting CD4 cells of adults whose HIV was well controlled by ART.^3,16
Selected Study Results: Results published in the journal PLoS Pathogens (2014) demonstrated that vorinostat given once daily for 14 days was able to significantly activate latent HIV in the majority of participants studied.¹⁷

Study Names: RIVER trial; NCT02336074

Phase: 2
Status: This study has been completed.
Location: United Kingdom
Purpose: The purpose of this study was to determine whether a combination of drugs could effectively reduce the latent HIV reservoir in participants with newly diagnosed HIV infection. The combination strategy included ART, two therapeutic HIV vaccines, and vorinostat.^3,18
Selected Study Results: Results published in Lancet (2020) showed that this combination approach of ART, therapeutic HIV vaccines, and vorinostat did not prove to be any more beneficial than ART given alone in reducing latent HIV reservoir size.¹⁹

Study Names: MOXIE trial; ACTG A5366; NCT03382834

Phase: 2
Status: This study is ongoing, but not recruiting participants.
Location: United States and Puerto Rico
Purpose: The purpose of this study is to evaluate whether the hormone therapy tamoxifen can enhance vorinostat’s ability to activate latent HIV in post-menopausal women with HIV.²⁰
Selected Study Results: Results presented at CROI 2020 and published in Clinical Infectious Diseases (2022) showed that treatment with tamoxifen and vorinostat was not associated with any severe or life-threatening side effects. Tamoxifen did not enhance the magnitude of latent HIV activation with vorinostat in postmenopausal women.^21,22

For more details on the studies listed above, see the Health Professional version of this drug summary.

Other early-phase studies investigating vorinostat for HIV treatment have been conducted or are planned, including:

• XTRA trial (NCT03212989): A Phase 1 study that evaluated the effects of vorinostat used with a type of cell therapy (called HIV-1 antigen expanded specific T-cell therapy) on HIV infection in adults. This study has been completed, and results were presented at IAS 2023.²³ 
• VOR-07 study (NCT03803605): A Phase 1 study that evaluated the effects of vorinostat and the investigational broadly neutralizing antibody VRC07-523LS on persistent HIV infection in individuals with HIV on suppressive ART. This study has been completed, and results are available from IAS 2021 and The Journal of Infectious Diseases (2022).²⁴
• NCT05700630: A Phase 1 study evaluating an investigational NK cell therapy (called FT538) with and without vorinostat for the treatment of persistent low-level viremia. See the ClinicalTrials.gov record for this study’s status.²⁵

What side effects might vorinostat cause?

One goal of HIV research is to identify new drugs that have fewer side effects. The following side effects were observed in some of the studies of vorinostat listed above.

NCT01319383

In this study, side effects reported by participants who received vorinostat included mild, temporary gastrointestinal symptoms, headache, and low platelet counts.^10,11

SEARCH 019 (NCT02475915) and SEARCH 026 (NCT02470351)

In this Phase 1/2 study, two participants in the group taking vorinostat had serious side effects. One participant stopped the study because of poor kidney function and low platelet levels. The other participant had diarrhea that may have been caused by the study drugs or by food poisoning. When compared to participants in the ART-only group, more participants in the group taking vorinostat had low platelet levels and high creatinine levels. (High creatinine levels can mean that the kidneys are not working well.)^12,26

In the central nervous system (CNS) substudy, treatment with vorinostat did not result in the presence of HIV in cerebrospinal fluid or lead to other lasting side effects.^14,27

NCT01365065

In this Phase 2 study, 90% of the study participants experienced a mild or moderate side effect, with the most common side effects being nausea, diarrhea, fatigue, and low platelet counts.^16,28

RIVER trial (NCT02336074)

In this Phase 2 study, 97% of the participants who received ART plus two therapeutic HIV vaccines plus vorinostat had a side effect. Seventy percent of these side effects were mild and 23% were moderate in intensity. In comparison, 73% of participants receiving ART only had a side effect; 33% were mild and 20% were moderate. No treatment-related serious side effects were reported.^18,29,30

A substudy evaluating the CNS impacts of trial interventions found no evidence of increased CNS damage with ART, therapeutic vaccination, and vorinostat compared to ART alone.³¹

MOXIE trial (NCT03382834)

In this Phase 2 study, 21 women were assigned to receive vorinostat plus tamoxifen and 10 women were assigned to receive vorinostat alone. No severe or life-threatening drug-related side effects were reported during the study.^20,21

Because vorinostat is still being studied as an HIV drug, information on possible side effects of the drug is not complete. As testing of vorinostat continues, additional information on possible side effects will be gathered.

Additional information on side effects known to be associated with vorinostat can be found in the FDA-approved Full Prescribing Information for Zolinza.⁴

Where can I get more information about clinical trials studying vorinostat?

More information about vorinostat-related research studies is available from ClinicalTrials.gov. (The ClinicalTrials.gov search can be modified so that you can get results that better match your interests.)

Some clinical trials may be looking for volunteer participants. Your health care provider can help you decide whether participating in a clinical trial is right for you. For more information, visit NIH Clinical Research Trials and You.

References

1. National Center for Biotechnology Information. PubChem Compound Summary for CID 5311, vorinostat. Accessed October 17, 2023
2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Accessed October 17, 2023
3. Treatment Action Group website. Research toward a cure trials. Accessed October 17, 2023
4. Merck Sharp & Dohme Corp. Zolinza: full prescribing information, August 2022. DailyMed. Accessed October 17, 2023
5. Siliciano RF, Greene WC. HIV latency. Cold Spring Harb Perspect Med. 2011;1(1):a007096. Accessed October 17, 2023
6. Rasmussen TA, Tolstrup M, Winckelmann A, Østergaard L, Søgaard OS. Eliminating the latent HIV reservoir by reactivation strategies. Hum Vaccines Immunother. 2013;9(4):790–799. Accessed October 17, 2023
7. National Institute of Allergy and Infectious Diseases (NIAID). HIV viral eradication. Accessed October 17, 2023
8. University of North Carolina, Chapel Hill. A Phase I/II investigation of the effect of vorinostat (VOR) on HIV RNA expression in the resting CD4+ T cells of HIV-infected patients receiving stable antiretroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 17, 2011. NLM Identifier: NCT01319383. Accessed October 17, 2023
9. Archin NM, Liberty AL, Kashuba AD, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012;487(7408):482-485. doi:10.1038/nature11286. Accessed October 17, 2023
10. Archin NM, Bateson R, Tripathy M, et al. HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat. J Infect Dis. 2014;210(5):728-735. doi:10.1093/infdis/jiu155. Accessed October 17, 2023
11. Archin NM, Kirchherr JL, Sung JAM, et al. Interval dosing with the HDAC inhibitor vorinostat effectively reverses HIV latency. J Clin Invest. 127(8):3126-3135. doi:10.1172/JCI92684. Accessed October 17, 2023
12. SEARCH Research Foundation. A randomized study to compare the efficacy of vorinostat/hydroxychloroquine/maraviroc (VHM) in controlling HIV after treatment interruption in subjects who initiated ART during acute HIV infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 3, 2015. NLM Identifier: NCT02475915. Accessed October 17, 2023
13. Kroon E, Ananworanich J, Eubanks K, et al. Effect of vorinostat, hydroxychloroquine and maraviroc combination therapy on viremia following treatment interruption in individuals initiating ART during acute HIV infection. Abstract presented at: 21st International AIDS Conference (AIDS 2016); July 18-22, 2016; Durban, South Africa. Abstract TUAX0101LB. Accessed October 17, 2023
14. SEARCH Research Foundation. Study SEARCH 026Assessment of the HIV CNS reservoir, neurological and neuro-cognitive effects, and source of rebound HIV in CNS in subjects participating in Study SEARCH 019. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 2, 2015. NLM Identifier: NCT02470351. Accessed October 17, 2023
15. Kroon EDMB, Ananworanich J, Pagliuzza A, et al. A randomized trial of vorinostat with treatment interruption after initiating antiretroviral therapy during acute HIV-1 infection. J Virus Erad. 2020;6(3):100004. doi:10.1016/j.jve.2020.100004. Accessed October 17, 2023
16. Bayside Health. A pilot study to assess the safety and effect on HIV transcription of vorinostat in patients receiving suppressive combination anti-retroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 1, 2011. NLM Identifier: NCT01365065. Accessed October 17, 2023
17. Elliott JH, Wightman F, Solomon A, et al. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog. 2014;10(11). doi:10.1371/journal.ppat.1004473. Accessed October 17, 2023
18. Imperial College London. Research in viral eradication of HIV reservoirs. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 23, 2014. NLM Identifier: NCT02336074. Accessed October 17, 2023
19. Fidler S, Stöhr W, Pace M, et al. Antiretroviral therapy alone versus antiretroviral therapy with a kick and kill approach, on measures of the HIV reservoir in participants with recent HIV infection (the RIVER trial): a phase 2, randomised trial. Lancet Lond Engl. 2020;395(10227):888-898. doi:10.1016/S0140-6736(19)32990-3. Accessed October 17, 2023
20. National Institute of Allergy and Infectious Diseases (NIAID). Selective estrogen receptor modulators to enhance the efficacy of viral reactivation with histone deacetylase inhibitors. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 19, 2017. NLM Identifier: NCT03382834. Accessed October 17, 2023
21. Scully E, Tsibris A, Aga E, et al. Effect of tamoxifen on vorinostat-induced HIV RNA expression in women on ART (ACTG A5366): the MOXIE trial. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 8-11, 2020; Boston, MA. Poster 333. Accessed October 17, 2023
22. Scully EP, Aga E, Tsibris A, et al. Impact of tamoxifen on vorinostat-induced HIV expression in women on antiretroviral therapy (ACTG A5366:The MOXIE trial). Clin Infect Dis. Published online February 17, 2022:ciac136. doi:10.1093/cid/ciac136. Accessed October 17, 2023
23. University of North Carolina, Chapel Hill. IGHID 11627 - A Phase I study to evaluate the effects of vorinostat and HIV-1 antigen expanded specific T cell therapy (HXTC) on persistent HIV-1 infection in HIV-infected individuals started on antiretroviral therapy (The XTRA Study). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 11, 2018. NLM Identifier: NCT03212989. Accessed October 17, 2023
24. University of North Carolina, Chapel Hill. IGHID 11802 - Combination Therapy With the Novel Clearance Modality (VRC07-523LS) and the Latency Reversal Agent (Vorinostat) to Reduce the Frequency of Latent, Resting CD4+ T Cell Infection (The VOR-07 Study). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on: January 10, 2019. NLM Identifier: NCT03803605. Accessed October 17, 2023
25. Masonic Cancer Center, University of Minnesota. MT2022-06: Phase I study of FT538 monotherapy and in combination with vorinostat for the treatment of persistent low-level HIV viremia. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 9, 2022. NLM Identifier: NCT05700630. Accessed October 17, 2023
26. Kroon E, Ananworanich J, Eubanks K, et al. Effect of vorinostat, hydroxychloroquine and maraviroc combination therapy on viremia following treatment interruption in individuals treated during acute HIV infection. 21st International AIDS Conference (AIDS 2016); July 18-22, 2016; Durban, South Africa. Mascolini: Vorinostat, HCQ, Maraviroc Do Not Delay Time to Rebound After Interruption. Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2016. Accessed October 17, 2023
27. Kroon E, Ananworanich J, Le LT, et al. Central nervous system impact of vorinostat, hydroxychloroquine and maraviroc combination therapy followed by treatment interruption in individuals treated during acute HIV infection (SEARCH 026). International AIDS Conference; July 18-22, 2016; Durban, South Africa. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2016. Accessed October 17, 2023
28. Elliott J, Solomon A, Wightman F, et al. The safety and effect of multiple doses of vorinostat in HIV-infected patients receiving combination antiretroviral therapy. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2013; Atlanta, GA. Abstract 50LB. Accessed October 17, 2023
29. Fidler S. RIVER research in viral eradication of HIV reservoirs: a two-arm (proof of concept) randomised Phase II trial vorinostat plus a prime boost vaccine. Slides presented at: International AIDS Conference (AIDS 2018): July 23-27, 2018; Amsterdam, the Netherlands. Accessed October 17, 2023
30. Fidler S, Stohr W, Pace M, et al. A randomised controlled trial comparing the impact of antiretroviral therapy (ART) with a “Kick-and-Kill” approach to ART alone on HIV reservoirs in individuals with primary HIV infection (PHI); RIVER trial. Abstract presented at: International AIDS Conference (AIDS 2018); July 23-27, 2018; Amsterdam, the Netherlands. Abstract TUAA0202LB. Accessed October 17, 2023
31. Alagaratnam J, Stöhr W, Toombs J, et al. No evidence of neuronal damage as measured by neurofilament light chain in a HIV cure study utilising a kick-and-kill approach. J Virus Erad. 2021;7(3):100056. doi:10.1016/j.jve.2021.100056. Accessed October 17, 2023