Drugs

Vorinostat

Vorinostat

Other Names: MK-0683, VOR, Zolinza, suberoylanilide hydroxamic acid (SAHA) Drug Class: Latency-Reversing Agents Molecular Formula: C14 H20 N2 O3 Registry Number: 149647-78-9 (CAS) Chemical Name: 8-(hydroxyamino)-8-oxo-N-phenyl-octanamide Chemical Class: Other Carboxylic Acid Derivatives Organization: Merck & Co., Inc. Phase of Development: Vorinostat is in Phase II development as a latency-reversing agent for HIV.

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and Treatment Action Group website3)

What is vorinostat?

What is vorinostat?

Vorinostat (brand name: Zolinza) is a drug that has been approved by FDA for the treatment of cancer and is currently being studied as part of a possible strategy to cure HIV infection.4-8 As an HIV drug, vorinostat belongs to a general group of drugs called latency-reversing agents.3

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

How do latency-reversing agents work?

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.9,10

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 by ARV drugs. 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.10–12 To learn more, see the AIDSinfo What is a Latent HIV Reservoir? fact sheet.

Which clinical trials are studying vorinostat?

Which clinical trials are studying vorinostat?

Study Name: NCT01319383
Phase: I/II
Status: This study has been completed.
Location: United States
Purpose: The purpose of this study was to determine the effectiveness of a single dose of vorinostat in activating latent HIV in resting CD4 cells versus when given as multiple doses in a follow-on study.7,13

Study Names: SEARCH 019; NCT02475915 and SEARCH 026; NCT02470351
Phase: I/II
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 a treatment interruption. (A treatment interruption is a planned break from HIV medicines to evaluate how well an investigational drug can maintain control of a participant’s viral load during a clinical trial.) The researchers compared this combination to ART alone.14,15

SEARCH 026 was an observational sub-study that was conducted at the same time as SEARCH 019 and included some of the SEARCH 019 participants. The sub-study evaluated how the treatment regimens used in SEARCH 026 affected the central nervous system (CNS), latent HIV in the CNS, and viral load levels in the CNS of the participants in the sub-study before, during, and after they received the treatments.16

Study Name: NCT01365065
Phase: II
Status: This study is ongoing, but not recruiting participants.
Location: Australia
Purpose: The purpose of this study is to determine whether vorinostat can activate latent HIV in resting CD4 cells of adults whose HIV is well controlled by ART.6

Study Names: RIVER trial; NCT02336074
Phase: II
Status: This study is ongoing, but not recruiting participants.
Location: United Kingdom
Purpose: The purpose of this study in participants with newly diagnosed HIV is to determine whether a combination of drugs can effectively reduce latent HIV in resting CD4 cells. The combination will include (1) a 4-drug ART regimen (which will include the HIV medicine raltegravir) (2) 2 anti-HIV vaccines, and (3) 10 doses of vorinostat. Researchers will compare this to a 4-drug ART regimen given alone.4

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

Other HIV-related trials involving vorinostat include:

  • VORVAX trial (NCT02707900): This Phase I/IIa study will look at the effect of a combination of vorinostat and AGS-004 on latent HIV. AGS-004 is an investigational HIV immunotherapy designed to boost the immune system's response to reactivated latent HIV. This study is currently recruiting participants.8,17
  • NCT03198559: This Phase I/II study that will evaluate whether a combination of 2 latency-reversing agents – disulfiram and vorinostat – can effectively reactivate latent HIV. This study has been suspended for review of side effects reported by study participants.18
  • XTRA trial (NCT03212989): This Phase I study will evaluate the effect of vorinostat used with specific types of immune cells (called HIV-1 antigen expanded specific T-cell therapy) on reactivated latent HIV in adults whose HIV is well controlled by ART. This study is currently recruiting participants.19
  • ACTG A5366 (NCT03382834): This is an early Phase I study that will study whether tamoxifen (a drug that acts on the hormone estrogen) can boost vorinostat’s ability to reactivate latent HIV in post-menopausal women whose HIV is well controlled by ART. This study is currently recruiting participants.20

What side effects might vorinostat cause?

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 both the initial study and the follow-on study conducted under this study protocol, side effects reported by participants who received vorinostat included mild, temporary gastrointestinal symptoms, headache, and low platelet counts.13,21

SEARCH 019 (NCT02475915):
In this Phase I/II study, 2 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 aren’t working well.)14,15

NCT01365065:
In this Phase II study, most of the side effects that occurred were not serious. The most common side effects were nausea, diarrhea, fatigue, and low platelet counts.22

RIVER trial (NCT02336074):
In this Phase II study, 97% of the participants who received ART plus 2 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.4,23,24

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.

The FDA-approved Full Prescribing Information for Zolinza includes additional information on known side effects of vorinostat.5

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

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

More information about vorinostat-related research studies is available from the AIDSinfo database of ClinicalTrials.gov study summaries. Click on the title of any trial in the list to see the ClinicalTrials.gov trial summary and more information about the study.

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

References

  1. United States National Library of Medicine. ChemIDplus Advanced: Vorinostat. https://chem.nlm.nih.gov/chemidplus/rn/149647-78-9. Accessed August 15, 2018.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed August 15, 2018.
  3. Treatment Action Group website. Research toward a cure trials. http://www.treatmentactiongroup.org/cure/trials. Accessed August 15, 2018.
  4. 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. https://www.clinicaltrials.gov/ct2/show/NCT02336074. Accessed August 15, 2018.
  5. Merck Sharp & Dohme Corp. Zolinza: full prescribing information, December 2015. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092. Accessed August 15, 2018.
  6. 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. https://www.clinicaltrials.gov/ct2/show/NCT01365065. Accessed August 15, 2018.
  7. 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. https://www.clinicaltrials.gov/ct2/show/NCT01319383. Accessed August 15, 2018.
  8. Argos Therapeutics. Press Release, dated April 1, 2015. NIH funds study of fully personalized immunotherapy AGS-004 combined with a latency reversing therapy for the treatment of HIV. http://ir.argostherapeutics.com/releasedetail.cfm?ReleaseID=904466. Accessed August 15, 2018.
  9. National Institute of Allergy and Infectious Diseases (NIAID) Bulletin. NIAID invites applications to conduct basic research on HIV persistence: studies key to search for a cure.https://wayback.archive-it.org/7761/20160907080510/http://www.niaid.nih.gov/news/newsreleases/Archive/2009/Pages/HIV_persistence.aspx. Published June 16, 2009. Accessed August 15, 2018.
  10. Shattock RJ, Rosenberg Z. Microbicides: Topical prevention against HIV. Cold Spring Harb Perspect Med. 2012;2(2):a007385.
  11. 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.
  12. National Institute of Allergy and Infectious Diseases (NIAID). Fact Sheet, dated March 20, 2017. HIV Viral Eradication. https://www.niaid.nih.gov/diseases-conditions/hiv-viral-eradication. Accessed August 15, 2018.
  13. 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
  14. South East Asia Research Collaboration with Hawaii. 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. https://clinicaltrials.gov/ct2/show/NCT02475915. Accessed August 15, 2018.
  15. 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. http://programme.aids2016.org/Abstract/Abstract/10535. Accessed August 15, 2018.
  16. South East Asia Research Collaboration with Hawaii. 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. https://clinicaltrials.gov/ct2/show/NCT02470351. Accessed August 15, 2018.
  17. Cynthia L Gay, MD. IGHID 11424 - A Pilot Trial of the Effect of Vorinostat and AGS-004 on Persistent HIV-1 Infection (The VOR VAX Study). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 3, 2016. NLM Identifier: NCT02707900. https://clinicaltrials.gov/ct2/show/NCT02707900. Accessed August 15, 2018.
  18. The Peter Doherty Institute for Infection and Immunity. Combination latency reversal with high dose disulfiram plus vorinostat in HIV-infected individuals on ART (DIVA): a single arm clinical trial. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 14, 2017. NLM Identifier: NCT03198559. https://clinicaltrials.gov/ct2/show/NCT03198559. Accessed August 15, 2018.
  19. 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. https://clinicaltrials.gov/ct2/show/study/NCT03212989. Accessed August 15, 2018.
  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. https://clinicaltrials.gov/ct2/show/record/NCT03382834. Accessed August 15, 2018.
  21. 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
  22. Elliott J, Solomon A, Wightman F, et al. The safety and effect of multiple doses of vorinostat on 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. Available from National Association of People with HIV Australia (NAPWHA): http://napwha.org.au/sites/default/files/CROI%202013%20vorinostat%20final%202.pdf. Accessed August 15, 2018.
  23. 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. https://programme.aids2018.org/PAGMaterial/PPT/6106_3214/RIVER%20presentation%20at%20IAS%2024.7.2018%20final%20draft.pptx. Accessed August 15, 2018.
  24. 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. http://programme.aids2018.org/Abstract/Abstract/12977. Accessed August 15, 2018.

Last Reviewed: August 15, 2018