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.
Valproic acid is a drug that has been approved by FDA for the treatment of certain symptoms of bipolar disorder (a type of mental illness), the treatment of seizures, and the prevention of migraine headaches.5 It has been studied to see if it could be effective as part of a strategy to cure HIV infection.
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.)6-8
Valproic acid belongs to a class (group) of 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.8
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
The use of valproic acid to reduce latent HIV has been studied in Phase II clinical trials.2
A Phase II study (known as CTN-205) looked at whether valproic acid in combination with ART could reduce the amount of latent HIV in resting CD4 T cells. Fifty-six HIV-infected participants were given either: 1) valproic acid plus ART for 16 weeks, followed by ART alone for 32 weeks or 2) ART alone for 16 weeks, followed by valproic acid plus ART for 32 weeks. All participants were required to have been on ART and have a suppressed viral load (viral load is the amount of HIV in the blood) for at least 1 year before starting the study. In this study, adding valproic acid to ART did not reduce the amount of latent HIV in HIV-infected participants.3,11,12
Another Phase II study looked at whether adding valproic acid and the ARV drug raltegravir to ART could reduce the amount of latent HIV in resting CD4 T cells in seven HIV-infected adults. All study participants were taking ART and had a suppressed viral load for at least 6 months before starting the study. In this study, adding valproic acid and raltegravir to ART did not reduce the amount of latent HIV in the study participants.4,13
During the study that looked at adding valproic acid to ART, some participants dropped out of the study because of side effects they experienced during the period that they were receiving valproic acid. As the length of time on valproic acid increased, the number of participants dropping out of the study also increased. During the study that looked at adding valproic acid and raltegravir to ART, no significant side effects related to valproic acid were reported.4
Information on possible side effects of the drug is not complete. If testing of valproic acid continues, additional information on possible side effects will be gathered.
More information about valproic acid-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.
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 30, 2014.
2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Last accessed on April 30, 2014.
3. Routy JP, Tremblay CL, Angel JB, et al. Valproic acid in association with highly active antiretroviral therapy for reducing systemic HIV-1 reservoirs: results from a multicentre randomized clinical study. HIV Med. 2012 May;13(5):291-6. Last accessed on April 30, 2014.
4. Archin NM, Cheema M, Parker D, et al. Antiretroviral Intensification and Valproic Acid Lack Sustained Effect on Residual HIV-1 Viremia or Resting CD4+ Cell Infection. PLoS One. 2010 Feb 23;5(2):e9390. Last accessed on April 30, 2014.
5. AbbVie Inc. Depakote ER: Full Prescribing Information, 2014. DailyMed. Last accessed on April 30, 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 30, 2014.
7. National Institute of Allergy and Infectious Diseases (NIAID). HIV Hides From the Immune System. Last accessed on April 30, 2014.
8. Siliciano RF, Greene WC. HIV Latency. Cold Spring Harb Perspect Med. 2011 Sep;1(1):a007096. Last accessed on April 30, 2014.
9. Rasmussen TA, Tolstrup M, Winckelmann A, Østergaard L, Søgaard OS. Eliminating the latent HIV reservoir by reactivation strategies. Hum Vaccin Immunother. 2013 Apr;9(4):790-9. Last accessed on April 30, 2014.
10. National Institutes of Health (NIH). NIH Clinical Research Trials and You. Last accessed on April 30, 2014.
11. McGill University Health Center. Use of Valproic Acid to Purge HIV From Resting CD4+ Memory Cells/ A Proof-of-Concept Study. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 8, 2006. NLM Identifier: NCT00289952. Last accessed on April 30, 2014.
12. Routy JP, Angel JB, Spaans JN, et al. Design and Implementation of a Randomized Crossover Study of Valproic Acid and Antiretroviral Therapy to Reduce the HIV Reservoir. HIV Clin Trials. 2012 Nov-Dec;13(6):301-7. Last accessed on April 30, 2014.
13. University of North Carolina, Chapel Hill. 10493 - MK-0518 Intensification and HDAC Inhibition in Depletion of Resting CD4+ T Cell HIV Infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 31, 2008. NLM Identifier: NCT00614458. Last accessed on April 30, 2014.
Last Reviewed: April 30, 2014