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 2 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 the U.S. Food and Drug Administration (FDA) for the treatment of cancer. It is also being studied as an investigational drug as part of a strategy to cure HIV infection.3,4 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 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.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 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: 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

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 a treatment interruption.9,10

SEARCH 026 was a 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 019 affected the central nervous system (CNS), latent HIV in the CNS, and viral load levels in the CNS of the participants.9,11

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.3,12

Study Names: RIVER trial; NCT02336074
Phase: 2
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 strategy will include ART, two therapeutic HIV vaccines, and vorinostat.13

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.14

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

Other HIV-related trials investigating vorinostat include:

  • XTRA trial (NCT03212989): A Phase 1 study that will evaluate the effect of vorinostat used with specific types of immune cells (called HIV-1 antigen expanded specific T-cell therapy) on HIV infection in adults. This study is currently recruiting participants.15
  • VOR-07 study (NCT03803605): A Phase 1 study that will evaluate the effects of vorinostat and the investigational broadly neutralizing antibody VRC07-523LS on HIV infection in adults. This study is ongoing, but not recruiting participants.16

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 this study, side effects reported by participants who received vorinostat included mild, temporary gastrointestinal symptoms, headache, and low platelet counts.17,18

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 aren’t working well.)9,19

In the sub-study, treatment with vorinostat did not result in the presence of HIV in cerebrospinal fluid or other lasting side effects.11,20

NCT01365065:
In this Phase 2 study, most of the side effects that occurred were not serious. The most common side effects were nausea, diarrhea, fatigue, and low platelet counts.21

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.13,22,23

MOXIE trial (NCT03382834):
In this Phase 2 study, 21 women were assigned to receive vorinostat plus tamoxifen and 10 women were assigned to receive voirnostat alone. No severe or life-threatening drug-related side effects were reported during the study.14,24

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.

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?

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 May 29, 2020
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed May 29, 2020
  3. Treatment Action Group website. Research toward a cure trials. http://www.treatmentactiongroup.org/cure/trials. Accessed May 29, 2020
  4. Merck Sharp & Dohme Corp. Zolinza: full prescribing information, January 2020. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092. Accessed May 29, 2020
  5. Siliciano RF, Greene WC. HIV latency. Cold Spring Harb Perspect Med. 2011;1(1):a007096.
  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.
  7. National Institute of Allergy and Infectious Diseases (NIAID). HIV viral eradication. https://www.niaid.nih.gov/diseases-conditions/hiv-viral-eradication. Accessed May 29, 2020
  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. https://www.clinicaltrials.gov/ct2/show/NCT01319383. Accessed May 29, 2020
  9. 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 May 29, 2020
  10. 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 May 29, 2020
  11. 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 May 29, 2020
  12. 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 May 29, 2020
  13. 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 May 29, 2020
  14. 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 May 29, 2020
  15. 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 May 29, 2020
  16. 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. https://clinicaltrials.gov/ct2/show/NCT03803605. Accessed May 29, 2020
  17. 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
  18. 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
  19. 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. http://www.natap.org/2016/IAC/IAC_07.htm. Accessed May 29, 2020
  20. 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). Poster presented at: International AIDS Conference (AIDS 2016); July 18-22, 2016; Durban, South Africa. Poster LBPE005. http://programme.aids2016.org/PAGMaterial/eposters/0_10588.pdf. Accessed May 29, 2020
  21. Mota TM, Rasmussen TA, Rhodes A, et al. No adverse safety or virological changes 2 years following vorinostat in HIV-infected individuals on antiretroviral therapy. AIDS. 2017;31(8):1137-1141. doi:10.1097/QAD.0000000000001442
  22. 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 May 29, 2020
  23. 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 May 29, 2020
  24. 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. https://www.croiconference.org/wp-content/uploads/sites/2/posters/2020/1430_1_Scully_00333.pdf. Accessed May 29, 2020

Last Reviewed: May 29, 2020

Print