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.
Vorinostat (brand name: Zolinza) is a drug that has been approved by FDA for the treatment of cancer and is currently being studied to see if it can be effective as part of a strategy to cure HIV infection.3,4,5
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.)6,7,8
Vorinostat belongs to a class (group) of HIV drugs called histone deacetylase (HDAC) inhibitors.2 HDAC inhibitors reactivate (turn back on) latent HIV within resting CD4 T cells.8,9
When latent HIV is reactivated, it is once again able to produce new virus and multiply (replicate). This replication can be prevented with the use of ongoing ART.
In addition, when latent HIV becomes reactivated by HDAC inhibitors, 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.8,9 Recent research has shown that additional therapies, together with HDAC inhibitors, may be needed to fully eliminate latent HIV from the body.9
Clinical trials are conducted in phases. Each phase has a different purpose and helps researchers answer different questions.10
In most cases, an investigational drug must be proven safe and effective 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.10
Vorinostat is currently being studied in Phase II clinical trials.2
A Phase II study looked at whether vorinostat could activate latent HIV in resting CD4 T cells. Twenty HIV-infected participants were given vorinostat once daily for 14 days, in combination with ART. This study accepted only participants who had been on a stable ART regimen, had a suppressed viral load (viral load is the amount of HIV in the blood) for at least 3 years before the study, and had a normal immune system (as measured by CD4 count). A placebo was not used for comparison in this study. (A placebo is an inactive drug that is identical in appearance to the active drug being studied.)4,11
This study showed that vorinostat can reactivate HIV in latently infected resting CD4 T cells. However, the amount of latent HIV in the body did not appear to decrease. Therefore, additional therapies together with HDAC inhibitors may be needed to fully eliminate latent HIV in the body.4,11
A Phase I/II study looked at whether once-daily vorinostat given a few days per week for a total of 8 weeks could repeatedly activate latent HIV in resting CD4 T cells. Each of the five participants in this study was on a stable ART regimen, had a suppressed viral load, and had a normal immune system. Each participant had also previously shown increased activation of latent HIV after receiving a single, one-time dose of vorinostat.5,12
In this study, increased activation of latent HIV in resting CD4 T cells after multiple repeat dosing of vorinostat was seen in three of the five participants at two specific time points. The study found that multiple repeat dosing of vorinostat did not have as much of an effect on activating latent HIV as a single, one-time dose of vorinostat.5,12
In the 14-day Phase II study discussed under the previous question, most of the side effects that occurred were not serious. The most common side effects were nausea, diarrhea, fatigue, and low platelet counts.4
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.
More information about vorinostat-related research studies is available from the AIDSinfo database of HIV/AIDS-related 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.
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.10
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.
1. United States National Library of Medicine. ChemIDplus Advanced. Last accessed on April 7, 2014.
2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Last accessed on April 7, 2014.
3. Merck Sharp & Dohme Corp. Zolinza: Full Prescribing Information, April 2013. DailyMed. Last accessed on April 7, 2014.
4. 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. Last accessed on April 7, 2014.
5. 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. Last accessed on April 7, 2014.
6. 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. Last accessed on April 7, 2014.
7. National Institute of Allergy and Infectious Diseases (NIAID). HIV Hides From the Immune System. Last accessed on April 7, 2014.
8. Siliciano RF, Greene WC. HIV Latency. Cold Spring Harb Perspect Med. 2011 Sep;1(1):a007096. Last accessed on April 7, 2014.
9. 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. Last accessed on April 7, 2014.
10. National Institutes of Health (NIH). NIH Clinical Research Trials and You. Last accessed on April 7, 2014.
11. 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. Last accessed on April 7, 2014.
12. Archin NM, Bateson R, Tripathy M, et al. HIV-1 Expression within Resting CD4 T-Cells Following Multiple Doses of Vorinostat. J Infect Dis. 2014 Mar 11. [Epub ahead of print]. Last accessed on April 7, 2014.
Last Reviewed: April 7, 2014
Last Updated: April 25, 2014