Valproic Acid

Other Names: Depakene, Depakote, Depakote ER, Epival, VPA, Valproate, divalproex sodium Drug Class: Latency-Reversing Agents
Molecular Formula: CH16 O2
Registry Number: 99-66-1 (CAS) Chemical Name: 2-propylpentanoic acid Chemical Class: Other Carboxylic Acid Derivatives Organization: AbbVie Inc.; Abbott Laboratories Phase of Development: Valproic acid is in Phase 2 development as a latency-reversing agent for HIV.

Chemical Image:

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valproic acid

valproic acid

Molecular Weight: 144.2124

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 Treatment Action Group website,3 and Depakote ER full prescribing information4)


Mechanism of Action: Latency-reversing agent, specifically a histone deacetylase inhibitor (HDACi).3 Valproic acid is a carboxylate-based non-specific HDACi that does not specifically target HDAC-1 or HDAC-2. HDAC-1 and HDAC-2 are two of the primary HDACs that, along with HDAC-3, are thought to prevent HIV-1 expression.Valproic acid is an FDA-approved drug indicated for the treatment of mania associated with bipolar disorder and epilepsy. It is also approved for the prevention of migraine headaches.4,6 As an HIV therapeutic, valproic acid is being investigated as an agent for reactivating latent HIV expression.3

In HIV-1 latency, HDACs are recruited to the proviral 5' long terminal repeat (LTR), where they catalyze deacetylation of lysine residues on histones, resulting in chromatin condensation on nucleosome 1 (nuc-1) and preventing HIV transcription. Inhibition of HDAC activity, however, causes histone acetylation (hyperacetylation) of lysine residues by histone acetyltransferases (HATs). This leads to chromatin relaxation and transcriptional activation of HIV.5,7 Some research suggests that the activity of HDACis in inducing HIV transcription may not be caused by direct effects on histone acetylation, but may be caused by effects on other nonhistone proteins.8-10

Half-life (T½): Both valproic acid and divalproex sodium dissociate to the valproate ion in the gastrointestinal tract. Following oral administration of valproate monotherapy (250–1,000 mg), the mean terminal half-life ranged from 9 hours to 16 hours.4,6

Metabolism/Elimination: Valproate is metabolized primarily in the liver. Thirty percent to 50% of an administered valproate dose is excreted in urine as a glucuronide conjugate. Typically, over 40% of the dose is eliminated by the other major metabolic pathway—mitochondrial β-oxidation—and less than 15% to 20% of a dose is eliminated by other oxidative mechanisms. Unchanged drug in the urine accounts for less than 3% of a dose.4,6

Select Clinical Trials

Study Identifiers: CTN-205; NCT00289952
Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Phase: 2
Status: This study has been completed.
Study Purpose: The purpose of this study was to determine if coadministration of valproic acid with ART could reduce the size of the latent HIV reservoir.
Study Population:
  • Participants were adults with HIV who were receiving a stable ART regimen for at least the past 12 months.
  • Participants had HIV RNA <50 copies/mL for at least 12 months and CD4 counts ≥200 cells/mm3.11-13

Selected Study Results:

Study Identifier:
Sponsor: University of North Carolina, Chapel Hill
Phase: 2
Status: This study has been completed.
Study Purpose: The purpose of this study was to determine if adding raltegravir and valproic acid to ART could decrease the amount of latent HIV.
Study Population:

  • Participants were adults with HIV who were receiving a stable ART regimen.
  • Participants had HIV RNA <50 copies/mL for at least 6 months and CD4 counts >300 cells/mm3.14,15
Selected Study Results:
Study Identifiers: LUNA; NCT03525730
Sponsor: Erasmus Medical Center
Phase: 1/2
Status: The recruitment status of this study is unknown.
Study Purpose: The purpose of this study is to examine whether valproic acid and the BAF inhibitor pyrimethamine can reactivate latent HIV and reduce the size of the latent HIV reservoir.
Study Population:
  • Participants are adults with HIV who are currently receiving ART.
  • Participants have had HIV RNA <50 copies/mL for at least 1 year prior to study entry and have CD4 counts ≥200 cells/mm3 at study entry. Before initiating ART, participants had HIV RNA ≥10,000 copies/mL.16

Adverse Events

CTN-205 (NCT00289952):
In this Phase 2 study, withdrawals due to adverse events (AEs) were common during valproic acid treatment and increased with treatment duration.13

In this Phase 2 study investigating whether adding raltegravir and valproic acid to ART could reduce the size of the latent HIV reservoir, no significant AEs were noted. Minor or transient AEs were reported, but these were not clearly related to valproic acid.14,15

Additional AEs known to be associated with valproic acid are described in the FDA-approved Full Prescribing Information for valproic acid and Full Prescribing Information for Depakote ER.4,6

Drug Interactions

Coadministration of drugs that affect hepatic enzyme levels, particularly glucuronosyltransferases, may increase the clearance of valproic acid. Inhibitors of CYP450 isoenzymes are expected to have little effect on valproic acid clearance.4

In a study of six patients with HIV, valproic acid (250 or 500 mg administered every 8 hours) was shown to inhibit glucuronidation of zidovudine (100 mg administered every 8 hours) and decrease the clearance of zidovudine by 38%. The half-life of zidovudine was unaffected.4,17

The pharmacokinetic effects of valproic acid (250 mg twice daily) coadministered with efavirenz (600 mg once daily) and lopinavir/ritonavir (400/100 mg twice daily) have been studied in adults with HIV. Study results indicate that valproic acid coadministered with either efavirenz or lopinavir/ritonavir does not cause a decrease in plasma concentrations of efavirenz or lopinavir. Trough concentrations of valproic acid are not significantly affected by efavirenz or lopinavir.18

In a pharmacokinetic substudy involving participants from the LUNA trial (NCT03525730), researchers assessed a previously reported drug-drug interaction between dolutegravir and valproic acid. Results confirmed that total dolutegravir plasma concentrations rapidly decreased when valproic acid was coadministered with dolutegravir; however, a concomitant increase in the free fraction of dolutegravir was also observed. Investigators concluded that the interaction between dolutegravir and valproic acid was due to protein binding competition and unlikely to have any clinical significance.19

Additional known interactions between valproic acid and coadministered drugs are described in the FDA-approved Full Prescribing Information for valproic acid and Full Prescribing Information for Depakote ER.4,6


  1. United States National Library of Medicine. ChemIDplus Advanced: valproic acid. https://chem.nlm.nih.gov/chemidplus/rn/99-66-1. Accessed June 9, 2020
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed June 9, 2020
  3. Treatment Action Group website. Research toward a cure trials. http://www.treatmentactiongroup.org/cure/trials. Accessed June 9, 2020
  4. AbbVie Inc. Depakote ER: full prescribing information, May 27, 2020. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dc024ce-efc8-4690-7cb5-639c728fccac. Accessed June 9, 2020
  5. Matalon S, Rasmussen TA, Dinarello CA. Histone deacetylase inhibitors for purging HIV-1 from the latent reservoir. Mol Med. 2011;17(5-6):466-472.
  6. Bionpharma Inc. Valproic acid capsules: full prescribing information, March 5, 2019. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ceb52870-76d0-4108-a1d4-ba7096fbacdd. Accessed June 9, 2020
  7. 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.
  8. Bartholomeeusen K, Fujinaga K, Xiang Y, Peterlin BM. Histone deacetylase inhibitors (HDACis) that release the positive transcription elongation factor b (P-TEFb) from its inhibitory complex also activate HIV transcription. J Biol Chem. 2013;288(20):14400-14407.
  9. Elliott JH, Wightman F, Solomon A, et al. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog. 2014;10(11). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231123/. Accessed June 9, 2020
  10. Shirakawa K, Chavez L, Hakre S, Calvanese V, Verdin E. Reactivation of latent HIV by histone deacetylase inhibitors. Trends Microbiol. 2013;21(6):277-285.
  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. https://clinicaltrials.gov/ct2/show/NCT00289952. Accessed June 9, 2020
  12. 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. 13(5):291-296.
  13. Routy J, Angel J, Spaans J, 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;13(6). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815453/. Accessed June 9, 2020
  14. 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. https://clinicaltrials.gov/ct2/show/NCT00614458. Accessed June 9, 2020
  15. 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;5(2). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826423/. Accessed June 9, 2020
  16. Erasmus Medical Center. LRAs united as a novel anti-HIV strategy (LUNA): a randomized controlled trial. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 23, 2018. NLM Identifier: NCT03525730. https://clinicaltrials.gov/ct2/show/NCT03525730. Accessed June 9, 2020
  17. Lertora JJ, Rege AB, Greenspan DL, et al. Pharmacokinetic interaction between zidovudine and valproic acid in patients infected with human immunodeficiency virus. Clin Pharmacol Ther. 1994;56(3):272-278.
  18. DiCenzo R, Peterson D, Cruttenden K, et al. Effects of valproic acid coadministration on plasma efavirenz and lopinavir concentrations in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2004;48(11):4328-4331.
  19. Bollen P, Prins H, Velthoven K, et al. The valproic acid - dolutegravir drug-drug interaction is based on displacement of protein binding and unlikely to be clinically relevant. Abstract presented at: International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs; May 14-16, 2019; Noordwijk, Netherlands. Abstract 44. http://regist2.virology-education.com/abstractbook/2019/abstractbook_20ANTIVIRAL.pdf. Accessed June 9, 2020

Last Reviewed: June 9, 2020