What is an investigational drug?
An investigational drug is one that is under study and is not approved by the U.S. Food and Drug Administration (FDA) for sale in the United States. Medical research studies are conducted to evaluate the safety and effectiveness of an investigational drug. These research studies are also called clinical trials. Once an investigational drug has been proven safe and effective in clinical trials, FDA may approve the drug for sale in the United States.
To learn more about investigational drugs, read the AIDSinfo What is an Investigational HIV Drug? fact sheet.
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
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 T cells) for many months or even years. While HIV is in this latent state, the immune system cannot recognize the virus, and antiretroviral therapy (ART) has no effect on it. (ART is the recommended treatment for HIV infection and involves using a combination of different antiretroviral [ARV] drugs to prevent HIV from replicating.)9,10
Vorinostat belongs to a general class (group) of HIV drugs called latency-reversing agents.3 Latency-reversing agents reactivate (turn back on) latent HIV within resting CD4 T cells.10,11 There are different types of latency-reversing agents. Vorinostat is a type of latency-reversing agent called a histone deacetylase (HDAC) inhibitor.11
How do latency-reversing agents work?
Latency-reversing agents reactivate (turn back on) latent HIV within resting CD4 T cells. When latent HIV is reactivated, it is once again able to produce new virus and multiply (replicate). It is hoped that after latent HIV is reactivated, the CD4 T cells in which the virus was hiding are more likely to die off on their own or be recognized and killed by the body’s immune system.10,11
In addition, any new virus that is produced during reactivation can then be prevented from infecting other cells with the use of ongoing ART.10,11 Recent research has shown that additional therapies, together with latency-reversing agents, may be needed to fully eliminate latent HIV from the body.11
How are clinical trials of investigational drugs conducted?
Clinical trials are conducted in phases. Each phase has a different purpose and helps researchers answer different questions.12
- Phase I trials: Researchers test an investigational drug in a small group of people (20–80) for the first time. The purpose is to evaluate its safety and identify side effects.
- Phase II trials: The investigational drug is administered to a larger group of people (100–300) to determine its effectiveness and to further evaluate its safety.
- Phase III trials: The investigational drug is administered to large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it with standard or equivalent treatments, and collect information that will allow the investigational drug to be used safely.12
In most cases, an investigational drug must be proven effective and must show continued safety in a Phase III clinical trial to be considered for approval by FDA for sale in the United States. Some drugs go through FDA’s accelerated approval process and are approved before a Phase III clinical trial is complete. After a drug is approved by FDA and made available to the public, researchers track its safety in Phase IV trials to seek more information about the drug’s risks, benefits, and optimal use.12
In what phase of testing is vorinostat?
Vorinostat is currently being studied in Phase II clinical trials.2
What are some studies on vorinostat?
Study Name: NCT01319383
Sponsor: University of North Carolina, Chapel Hill
Location: United States (North Carolina)
- The study involved HIV-infected adults who had taken HIV medicines before starting the study (called treatment-experienced) and who were on a stable regimen of HIV medicines for at least 18 months.
- The participants had a suppressed viral load (the amount of HIV in the blood) of less than 50 copies/mL.
- Participants also had CD4 counts greater than 300 cells/mm3 for at least 6 months before starting the study. (A CD4 count is a laboratory test that measures the number of CD4 cells in a sample of blood and is an important indicator of immune function. The CD4 count of a healthy person ranges from 500 to 1,600 cells/mm3.)
: The purpose of this study was to determine the effectiveness of vorinostat in activating latent HIV in resting CD4 T cells when given as a single, one-time dose
versus multiple doses.6,13
Study Names: SEARCH 019; NCT02475915
Sponsor: South East Asia Research Collaboration with Hawaii
- Participants were HIV-infected, treatment-experienced adults who started ART during the acute HIV infection stage. (Acute HIV infection is the early stage of HIV infection that extends approximately 1 to 4 weeks from the time of the initial infection.)
- Participants had viral load levels that were less than 50 copies/mL for more than 48 weeks and CD4 counts of at least 450 cells/mm3.
- Participants were recruited from another study called RV253/SEARCH 010.
: This study evaluated the safety and effectiveness of a treatment regimen that combined vorinostat, the drugs hydroxychloroquine
and maraviroc, and ART in controlling viral load during a treatment interruption that followed. (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
* An observational sub-study (SEARCH 026; NCT02470351
) looked at how the two treatments discussed above affected the central nervous system (CNS), latent HIV in the CNS, and viral load levels in the CNS in SEARCH 019 participants who agreed to take part in the sub-study.16
Study Name: NCT01365065
Sponsor: Bayside Health
Location: Australia (Victoria)
- The study involved HIV-infected, treatment-experienced adults who were receiving ART at the time of the study.
- Participants had a suppressed viral load of less than 50 copies/mL for at least 3 years before starting the study and had CD4 counts greater than 500 cells/mm3 in the last 6 months before starting the study.
: The purpose of this study was to determine whether vorinostat could activate latent HIV in resting CD4 T cells.5
Study Names: RIVER trial; NCT02336074
Sponsor: Imperial College London
Location: United Kingdom
- The study involves HIV-infected adults who have never taken HIV medicines (called treatment-naive).
- All participants will have been diagnosed with HIV within 4 weeks of entering the study.
: The purpose of this study is to determine the effectiveness of a combination strategy to reduce latent HIV in resting cells. The combination strategy will consist of (1) a 4-drug ART regimen (which will include the HIV medicine raltegravir
) (2) two anti-HIV vaccines, and (3) 10 doses of vorinostat. Researchers will compare this to a 4-drug ART regimen given alone.7
Additionally, a Phase I/IIa study (VORVAX trial, NCT02707900), will look at vorinostat combined with one other therapy as a way to reduce latent HIV in resting cells. Investigators will combine vorinostat with AGS-004, an investigational HIV immunotherapy designed to boost the immune system's response to eliminating HIV.8,17
For more details on the studies listed above, see the Health Professional version.
What side effects might vorinostat cause?
In the first Phase I/II study (NCT01319383) discussed under the previous question, side effects during multiple vorinostat dosing included mild, temporary gastrointestinal symptoms; headache; and low platelet counts.13
In the second Phase I/II study (NCT02475915), two participants in the group taking vorinostat experienced 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 from food poisoning. When compared to 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.)14,18
In the Phase II study conducted in Australia (NCT01365065), most of the side effects that occurred were not serious. The most common side effects were nausea, diarrhea, fatigue, and low platelet counts.19
Because vorinostat is still being studied, 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.
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.
How can I find more information about participating in a clinical trial?
Participating in a clinical trial can provide benefits. For example, a volunteer participant can benefit from new research treatments before they are widely available. Participants also receive regular and careful medical attention from a research team that includes doctors and other health professionals. However, clinical trials may also involve risks of varying degrees, such as unpleasant, serious, or even life-threatening side effects from the treatment being studied.12
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.
- United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/149647-78-9. Last accessed on August 19, 2016.
- National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on August 19, 2016.
- Treatment Action Group website. Research Toward a Cure Trials. Available at: http://www.treatmentactiongroup.org/cure/trials. Last accessed on August 19, 2016.
- Merck Sharp & Dohme Corp. Zolinza-vorinostat capsule: Full Prescribing Information, December 2015. DailyMed. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092. Last accessed on August 19, 2016.
- 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01365065. Last accessed on August 19, 2016.
- 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. Available at: https://www.clinicaltrials.gov/ct2/show/study/NCT01319383. Last accessed on August 19, 2016.
- 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02336074. Last accessed on August 19, 2016.
- 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. Available at: http://ir.argostherapeutics.com/releasedetail.cfm?ReleaseID=904466. Last accessed on August 19, 2016.
- National Institute of Allergy and Infectious Diseases (NIAID): Bulletin, dated June 16, 2009. NIAID Invites Applications to Conduct Basic Research on HIV Persistence: Studies Key to Search for a Cure. Available at: http://www.niaid.nih.gov/news/newsreleases/Archive/2009/Pages/HIV_persistence.aspx. Last accessed on August 19, 2016.
- Siliciano RF, Greene WC. HIV Latency. Cold Spring Harb Perspect Med. 2011 Sep;1(1):a007096. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234450/. Last accessed on August 19, 2016.
- Rasmussen TA, Tolstrup M, Winckelmann A, Ostergaard L, Søgaard OS. Eliminating the latent HIV reservoir by reactivation strategies. Hum Vaccin Immunother. 2013 Apr 1;9(4):790-799. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903897/. Last accessed on August 19, 2016.
- National Institutes of Health (NIH). NIH Clinical Research Trials and You. Available at: http://www.nih.gov/health-information/nih-clinical-research-trials-you. Last accessed on August 19, 2016.
- 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 Sep 1;210(5):728-35. Available from National AIDS Treatment Advocacy Project (NATAP): http://www.natap.org/2014/HIV/JInfectDis.2014Archin-728-35.pdf. Last accessed on August 19, 2016.
- 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. Available at: https://clinicaltrials.gov/ct2/show/study/NCT02475915. Last accessed on August 19, 2016.
- 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. Available at: http://programme.aids2016.org/Abstract/Abstract/10535. Last accessed on August 19, 2016.
- 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. Available at: https://clinicaltrials.gov/ct2/show/study/NCT02470351. Last accessed on August 19, 2016.
- Gay, MD. IGHID 11424 - Pilot Trial of the Effect of Vorinostat and AGS-004 on Persistent HIV-1 Infection (The VORVAX Study). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 3, 2016. NLM Identifier: NCT02707900. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02707900. Last accessed on August 19, 2016.
- 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. Available at: http://www.natap.org/2016/IAC/IAC_07.htm. Last accessed on August 19, 2016.
- Elliott J, Solomon A, Wightman F, et al. THE SAFETY AND EFFECT OF MULTIPLE DOSES OF VORINOSTAT ON HIV TRANSCRIPTION IN HIV-INFECTED PATIENTS RECEIVING COMBINATION ANTIRETROVIRAL THERAPY. Abstract presented at: 20th Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2013; Atlanta, GA. Abstract 50LB. Available at: http://napwha.org.au/sites/default/files/CROI%202013%20vorinostat%20final%202.pdf. Last accessed on August 19, 2016.
Last Reviewed: August 16, 2016