Mechanism of Action: Histone deacetylase (HDAC) inhibitor or HDACi. 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.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 promotes histone acetylation (hyperacetylation) of lysine residues by histone acetyltransferases (HATs), leading to chromatin relaxation and transcriptional activation.3,4 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 proteins, such as release of free positive transcription elongation factor b (P-TEFb) from the inhibitory 7SK small nuclear ribonucleoprotein (snRNP).5,6
Half-life (T½): As an FDA-approved treatment for acute manic or mixed episodes of bipolar disorder, some types of seizures, and migraine headache prophylaxis, valproate properties have been previously described. (Both valproic acid and divalproex sodium dissociate to the valproate ion in the gastrointestinal tract.) Following oral administration of valproate monotherapy (250 to 1000 mg), the mean terminal half-life ranged from 9 hours to 16 hours.7,8
Metabolism/Elimination: Valproate is metabolized primarily in the liver. In adult patients on valproate monotherapy, 30% to 50% of an administered dose appears 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. Less than 3% of a dose is excreted as unchanged drug in the urine.7,8
Resistance: Resistance to valproic acid in the context of HIV infection has not been described.
Dosing in Clinical Trials
: NCT00289952; CTN-205
: Study to determine if co-administration of valproic acid with ART can reduce the size of latent HIV reservoirs in CD4 T cells.
: HIV-infected, treatment-experienced adults receiving ART for at least 12 months, with viral load <50 copies/mL for at least 12 months, and with CD4 cell count ≥200 cells/mm3
: Participants were randomly assigned to one of the following two groups:
- Group 1: Oral valproic acid (Epival) 500 mg administered twice daily (adjusted to therapeutic range) together with ART for 16 weeks, followed by ART alone for 32 weeks.
- Group 2: ART alone for 16 weeks, followed by oral valproic acid (Epival) 500 mg administered twice daily (adjusted to therapeutic range) together with ART for 32 weeks.9,10
(See references cited above for information on study results.)
Study Identifier: NCT00614458
Study Purpose: Study to determine if adding raltegravir and valproic acid to ART can decrease the amount of latent HIV.
Study Population: HIV-infected, treatment-experienced adults receiving stable ART, with viral load <50 copies/mL for at least 6 months, and with CD4 cell count >300 cells/mm3
Dosing: Raltegravir 400 mg and valproic acid (Depakote ER) 500 mg to 750 mg, both administered twice daily, together with ART.11,12
(See references cited above for information on study results.)
In CTN-205, study withdrawals due to adverse events (AEs) were common during valproic acid treatment and increased with treatment duration.13
In the study investigating whether adding raltegravir and valproic acid to ART could reduce the size of HIV latent reservoirs in CD4 T cells (NCT00614458), no significant AEs were noted. Minor AEs were reported, but these were not clearly related to valproic acid.12
As an FDA-approved treatment for acute manic or mixed episodes of bipolar disorder, some types of seizures, and migraine headache prophylaxis, valproic acid drug interactions have been previously described. Co-administration of drugs that affect hepatic enzyme levels, particularly glucuronosyltransferases, may increase the clearance of valproic acid. Inhibitors of cytochrome P450 isoenzymes are expected to have little effect on valproic acid clearance.7
In a study of six HIV-infected patients, 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.7,14
The pharmacokinetic effects of valproic acid (250 mg twice daily) co-administered with efavirenz (600 mg once daily) and lopinavir/ritonavir (400/100 mg twice daily) have been studied in HIV-infected adults. Study results indicate that co-administration of valproic acid with either efavirenz or lopinavir/ritonavir decreases plasma concentrations of efavirenz or lopinavir. Trough concentrations of valproic acid are not significantly affected by efavirenz or lopinavir.15
- United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/99-66-1. Last accessed on July 31, 2015.
- 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 July 31, 2015.
- Matalon S, Rasmussen TA, Dinarello CA. Histone Deacetylase Inhibitors for Purging HIV-1 from the Latent Reservoir. Mol Med. 2011 May-Jun;17(5-6):466-72. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3105138/. Last accessed on July 31, 2015.
- Rasmussen TA, Tolstrup M, Winckelmann A, Østergaard L, Søgaard OS. Eliminating the latent HIV reservoir by reactivation strategies: Advancing to clinical trials. Hum Vaccin Immunother. 2013 Apr;9(4):790-9. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903897/. Last accessed on July 31, 2015.
- 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 May 17;288(20):14400-7. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656295/. Last accessed on July 31, 2015.
- 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 Nov 13;10(11):e1004473. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231123/. Last accessed on July 31, 2015.
- AbbVie Inc. Depakote ER: Full Prescribing Information, March 2015. DailyMed. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dc024ce-efc8-4690-7cb5-639c728fccac. Last accessed on July 31, 2015.
- AbbVie Inc. Depakene: Full Prescribing Information, March 2015. DailyMed. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b4331f5-4475-417a-6a9d-09c2f8334235. Last accessed on July 31, 2015.
- 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00289952. Last accessed on July 31, 2015.
- 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. Available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1468-1293.2011.00975.x/full. Last accessed on July 31, 2015.
- 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00614458. Last accessed on July 31, 2015.
- 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826423/. Last accessed on July 31, 2015.
- 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815453/. Last accessed on July 31, 2015.
- 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 Sep;56(3):272-8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7924122. Last accessed on July 31, 2015.
- 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 Nov;48(11):4328-31. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC525398/. Last accessed on July 31, 2015.
Last Reviewed: July 31, 2015