Study of Valproic Acid to Treat HIV Infected Adults

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier:
NCT00312546
First received: April 6, 2006
Last updated: May 11, 2012
Last verified: May 2012
  Purpose

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.


Condition Intervention Phase
HIV Infections
Drug: Enfuvirtide
Drug: Valproic acid
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Inhibiting Histone Deacetylase: Toward Eradication of HIV

Resource links provided by NLM:


Further study details as provided by University of North Carolina, Chapel Hill:

Primary Outcome Measures:
  • Frequencies of replication-competent HIV detected in resting CD4 cells [ Time Frame: At pre-entry and Week 0 to Weeks 12 and 16 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change in integrated proviral genomes [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Genital tract proviral DNA and viral load [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
  • Detectable viral load during VPA therapy and if it remains undetectable after VPA is discontinued [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
  • HIV-specific antibody changes and CTL responses [ Time Frame: From Week 0 to 16 ] [ Designated as safety issue: No ]
  • 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 [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Changes in viral load after intensification of HAART with or without VPA [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]

Enrollment: 14
Study Start Date: June 2006
Study Completion Date: October 2009
Primary Completion Date: April 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 2A
Discontinuation of VPA and enfuvirtide administered for 24 weeks. As of 05/20/08 this step was discontinued.
Drug: Enfuvirtide
90 mg subcutaneously twice daily
Other Name: T-20
Experimental: 2B
Continuation of VPA for up to 96 weeks. As of 05/20/08 this step was discontinued.
Drug: Valproic acid
500 to 750 mg, taken orally twice daily
Experimental: 3A
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
90 mg subcutaneously twice daily
Other Name: T-20
Drug: Valproic acid
500 to 750 mg, taken orally twice daily
Experimental: 3B
Enfuvirtide may be continued for up to 96 weeks. As of 05/20/08 this step was discontinued.
Drug: Enfuvirtide
90 mg subcutaneously twice daily
Other Name: T-20

  Hide Detailed Description

Detailed Description:

VPA is a type of medication normally used to treat seizures and other nervous system problems. It has been found that VPA works against HIV by releasing the virus from resting CD4 cells, allowing other anti-HIV medications to attack it. The purpose of this study is to assess the efficacy of VPA when used in HIV infected participants using highly active antiretroviral therapy (HAART). The expected duration of participation for individually enrolled participants will depend on which study group the participant is placed in but may range from approximately 24 to 144 weeks.

An initial screening visit will occur about 30 to 120 days prior to study entry. A physical exam, medical and medication history assessment, and blood and urine collection will occur at screening. Leukapheresis and genital secretion collection will occur once 30 to 120 days prior to study entry, separate from the initial screening.

In Step 1, all participants will receive VPA while continuing their current HAART. Doses of VPA will vary by participant. Study visits will occur on Days 0 and 3 and Weeks 1, 2, 4, 8, 12, 16, and 24. A physical exam and blood and urine collection will occur at most visits. Leukapheresis and genital secretion collection will occur at study entry and Weeks 12 and 16. After 24 weeks, participants will enter Step 2. Those participants not responding to VPA in Step 1 will enroll in Step 2A. Participants responding to VPA in Step 1 will enroll in Step 2B.

In Step 2A, participants will discontinue VPA and will receive intensified therapy (enfuvirtide) administered for 24 weeks twice daily. Study visits will occur at Weeks 25, 28, 32, 36, 40, and 48. A physical exam and blood and urine collection will occur at all visits. Leukapheresis will occur at Weeks 36 and 40. Participants who do not respond to intensified therapy in Step 2A will enroll in Step 3A. Participants who respond to intensified therapy in Step 2A will enroll in Step 3B.

In Step 2B, participants will continue to receive VPA for up to 96 weeks. Study visits will occur every 8 weeks until Week 120. A physical exam and blood and urine collection will occur at each visit. Leukapheresis will occur once between Week 72 and Week 120.

In Step 3A, VPA will be added to enfuvirtide for 16 weeks. The study will be discontinued for participants who do not respond. Study visits will occur at screening, entry, Day 0, and Weeks 1, 2, 4, 8, 12, 16, and 22. A physical exam and blood and urine collection will occur at all visits. Leukapheresis will occur after screening, at entry, Day 0 and Weeks 12 and 16.

In Step 3B, participants may continue receiving enfuvirtide for up to 96 weeks. Study visits will occur every 8 weeks until Week 144. A physical exam and blood and urine collection will occur at each visit. Leukapheresis will occur at Week 96 or 144.

Participants may choose to enter an observational period at any time before they start Step 2 or Step 3. During the observational period, participants continue to take HAART but not VPA or enfuvirtide. Upon entering an observational period, study staff will contact the participant every 8 weeks for a review of their medical records. Each participant will have a study visit within 8 weeks of beginning a new step. These interim study screenings include a physical exam, medical history, and blood and urine collection. Participants may be asked to have additional leukapheresis performed if they have discontinued study medications for 12 weeks or more.

Each leukapheresis procedure will take place at the University of North Carolina Apheresis Clinic in Chapel Hill, North Carolina. This study will not provide participants' current HAART regimen medications.

NOTE: As of 05/20/08, the observational period and Steps 1, 2, 2A, 2B, and 3B were discontinued.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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)
  • Pregnancy or breastfeeding
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00312546

Locations
United States, North Carolina
University of North Carolina Memorial Hospital
Chapel Hill, North Carolina, United States, 27599
Sponsors and Collaborators
University of North Carolina, Chapel Hill
Investigators
Principal Investigator: David M. Margolis, MD University of North Carolina, Chapel Hill
  More Information

Additional Information:
Publications:
Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT00312546     History of Changes
Other Study ID Numbers: U01AI067854-02, CID 0703, 7R01AI64074-01A1, 7R01AI45297-08, U01A125868
Study First Received: April 6, 2006
Last Updated: May 11, 2012
Health Authority: United States: Federal Government

Keywords provided by University of North Carolina, Chapel Hill:
Virus Latency
Valproic Acid
Histone Deacetylase

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Valproic Acid
Enfuvirtide
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
HIV Fusion Inhibitors
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents

ClinicalTrials.gov processed this record on April 17, 2014