Study of Valproic Acid to Treat HIV Infected Adults

NCT00312546 | Terminated Phase 1

• 5 other identifiers: U01AI067854-02CID 07037R01AI064074-01A17R01AI045297-08U01A125868
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

A histone deacetylase (HDAC) inhibitor is a class of drug that interferes with the function of HDAC, an enzyme that hides HIV within inactive CD4 cells. These drugs are normally used to treat seizures and other nervous system problems but have been found to work against HIV. The purpose of this study is to investigate the efficacy of valproic acid (VPA), an HDAC inhibitor, in treating HIV infected adults using anti-HIV drugs.

Conditions

HIV Infections

Keywords

Virus Latency; Valproic Acid; Histone Deacetylase

Outcome Measures

Primary Outcomes (1)

• Frequencies of replication-competent HIV detected in resting CD4 cells

  At pre-entry and Week 0 to Weeks 12 and 16

Secondary Outcomes (6)

• Change in integrated proviral genomes

  Throughout study

• Genital tract proviral DNA and viral load

  Throughout study

• Detectable viral load during VPA therapy and if it remains undetectable after VPA is discontinued

  Throughout study

• HIV-specific antibody changes and CTL responses

  From Week 0 to 16

• Change in replication-competent HIV detected in resting CD4 cells in study participants after intensified HAART, and after extended VPA therapy with or without intensified HAART

  Throughout study

Study Arms (4)

2A

EXPERIMENTAL

Discontinuation of VPA and enfuvirtide administered for 24 weeks. As of 05/20/08 this step was discontinued.

Drug: Enfuvirtide

2B

EXPERIMENTAL

Continuation of VPA for up to 96 weeks. As of 05/20/08 this step was discontinued.

Drug: Valproic acid

3A

EXPERIMENTAL

VPA may be added to enfuvirtide for 16 weeks. VPA and enfuvirtide will be continued for up to 96 weeks in responders, and the study will be discontinued in nonresponders.

Drug: Enfuvirtide; Drug: Valproic acid

3B

EXPERIMENTAL

Enfuvirtide may be continued for up to 96 weeks. As of 05/20/08 this step was discontinued.

Drug: Enfuvirtide

Interventions

Enfuvirtide DRUG

90 mg subcutaneously twice daily

Also known as: T-20

2A; 3A; 3B

Valproic acid DRUG

500 to 750 mg, taken orally twice daily

2B; 3A

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• HIV-1 infected
• Adherent to current HAART regimen
• Adequate vascular access for leukapheresis
• Receiving HAART, defined as at least two nucleoside reverse transcriptase inhibitors plus at least one protease inhibitor or non-nucleoside reverse transcriptase inhibitor, without changes to the regimen within 24 weeks of study entry
• Viral load more than 50 copies/ml on two consecutive occasions for more than 6 months, and less than 200 copies/ml on occasion for more than 6 months prior to study entry
• CD4 count more than 300 cells/mm3
• Willing and able to comply with all study requirements
• Willing to use acceptable forms of contraception

You may not qualify if:

• Currently receiving zidovudine or enfuvirtide
• Require certain medications known to interact with valproate (e.g., lamotrigine; barbiturates; carbamazepine; prescription dosages of salicylates, hydantoins, felbamate, and clonazepam)
• Any medical, psychiatric, or job-related responsibility that would interfere with the study. More information about this criterion can be found in the protocol.
• Contraindications to taking VPA (e.g., pregnancy, bleeding disorders, history of pancreatitis, history of hepatitis)
• Receiving interferon, other immunomodulators, or other experimental medications
• Abnormal liver enzyme tests
• Hepatitis B virus infected
• Symptoms of hepatic decompensation
• Blood transfusions or hematopoietic growth factors within 90 days prior to study entry
• Systemic cytotoxic chemotherapy, investigational agents, or immunomodulators within 90 days prior to study entry
• Current drug or alcohol abuse that, in the opinion of the site investigator, would interfere with the study
• Serious illness requiring systemic treatment or hospitalization within 90 days prior to study entry
• Treatment for a current AIDS-defining opportunistic infection within 90 days prior to screening
• Anemic
• Involuntarily incarcerated for treatment of either a psychiatric illness or physical illness (e.g., infectious disease)

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead

Study Sites (1)

University of North Carolina Memorial Hospital

Chapel Hill, North Carolina, 27599, United States

Location

Related Publications (3)

• Jiang G, Espeseth A, Hazuda DJ, Margolis DM. c-Myc and Sp1 contribute to proviral latency by recruiting histone deacetylase 1 to the human immunodeficiency virus type 1 promoter. J Virol. 2007 Oct;81(20):10914-23. doi: 10.1128/JVI.01208-07. Epub 2007 Aug 1.

  PMID: 17670825 BACKGROUND

• Siliciano JD, Lai J, Callender M, Pitt E, Zhang H, Margolick JB, Gallant JE, Cofrancesco J Jr, Moore RD, Gange SJ, Siliciano RF. Stability of the latent reservoir for HIV-1 in patients receiving valproic acid. J Infect Dis. 2007 Mar 15;195(6):833-6. doi: 10.1086/511823. Epub 2007 Jan 30.

  PMID: 17299713 BACKGROUND

• Smith SM. Valproic acid and HIV-1 latency: beyond the sound bite. Retrovirology. 2005 Sep 19;2:56. doi: 10.1186/1742-4690-2-56.

  PMID: 16168066 BACKGROUND

MeSH Terms

Conditions

HIV Infections

Interventions

Enfuvirtide; Valproic Acid

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Peptide Fragments; Peptides; Amino Acids, Peptides, and Proteins; HIV Envelope Protein gp41; Viral Fusion Proteins; Membrane Fusion Proteins; Membrane Proteins; Proteins; HIV Antigens; Antigens, Viral; Viral Proteins; env Gene Products, Human Immunodeficiency Virus; Gene Products, env; Retroviridae Proteins; Human Immunodeficiency Virus Proteins; Viral Envelope Proteins; Viral Structural Proteins; Antigens; Biological Factors; Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids

Study Officials

• David M. Margolis, MD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 6, 2006
• First Posted: April 10, 2006
• Study Start: June 1, 2006
• Primary Completion: April 1, 2009
• Study Completion: October 1, 2009
• Last Updated: May 14, 2012

Record last verified: 2012-05

Locations

US (1)