Depletion of Latent HIV in CD4 Cells - Full Text View

Sponsor:	National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators:	Adult AIDS Clinical Trials Group University of North Carolina Merck Abbott
Information provided by:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00576290

Purpose

Valproic acid (VPA) is an antiseizure drug, but data suggest that it may allow anti-HIV drugs access to resting HIV. A reduction in resting HIV would mean better control of the disease. The purpose of this study is to determine if the addition of VPA and raltegravir to a successful anti-HIV drug regimen will reduce the amount of resting HIV.

Condition	Intervention	Phase
HIV Infections	Drug: Valproic Acid Drug: raltegravir	Phase I

Study Type:	Interventional
Study Design:	Treatment, Open Label, Uncontrolled, Single Group Assignment, Efficacy Study
Official Title:	MK-0518 Intensification and HDAC Inhibition in Depletion of Resting CD4+ T Cell HIV Infection

Resource links provided by NLM:

MedlinePlus related topics: AIDS

Drug Information available for: Divalproex sodium Valproic acid Raltegravir Valproate Sodium

U.S. FDA Resources

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

Frequency of replication-competent HIV detected in resting CD4 cells compared before, during and after the addition of VPA [ Time Frame: At Week 8, 20, and 24 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Frequency of replication-competent HIV detected in resting CD4 cells compared before and after the addition of VPA [ Time Frame: At Week 8 and Week 48 ] [ Designated as safety issue: No ]
Viral load [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Changes in HIV-specific antibody, and CTL response [ Time Frame: At Weeks 8, 24, and 48 ] [ Designated as safety issue: No ]
Change in integrated HIV proviral genome [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Comparison of genital tract proviral DNA and HIV RNA [ Time Frame: At Weeks 4, 8, 20, 24, 36, and 40 ] [ Designated as safety issue: No ]
HIV genome sequencing [ Time Frame: Weeks 8, 16, 30, and 48 ] [ Designated as safety issue: No ]

Estimated Enrollment:	8
Study Start Date:	September 2009
Estimated Study Completion Date:	September 2010
Estimated Primary Completion Date:	September 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
2A Early study discontinuation for participants who have not responded to raltegravir and valproic acid in Step 1	Drug: Valproic Acid oral medication initially dosed at 1000 to 2000 mg daily and escalated weekly until a plasma level of 50 to 100 ug/ml has been reached Drug: raltegravir Oral HDAC inhibitor initially dosed at 1000 to 2000 mg daily, then escalated weekly to as much as 60 mg/kg/day until a plasma level of 50 to 100 mcg/ml has been reached
2B: Experimental Continuation of raltegravir and current HAART regimen after treatment with valproic acid for those who responded to raltegravir and valproic acid in Step 1	Drug: Valproic Acid oral medication initially dosed at 1000 to 2000 mg daily and escalated weekly until a plasma level of 50 to 100 ug/ml has been reached Drug: raltegravir Oral HDAC inhibitor initially dosed at 1000 to 2000 mg daily, then escalated weekly to as much as 60 mg/kg/day until a plasma level of 50 to 100 mcg/ml has been reached

Detailed Description:

When HIV has just been made, it enters a CD4 cell's nucleus. An enzyme in the nucleus called integrase helps HIV hide in the cell's own DNA, and another enzyme called histone deacetylase (HDAC) helps it stay hidden. While HIV is hiding in the DNA, it is not active and cannot be targeted by currently available highly active antiretroviral therapy (HAART). VPA, a drug used to treat seizures, is an HDAC inhibitor, and raltegravir is a newly FDA-approved integrase inhibitor. Taking VPA and raltegravir may prevent HIV from being able to hide in CD4 cells, allowing HAART to eliminate HIV that would normally be hidden. The purpose of this study is to determine whether adding raltegravir and VPAto the participant's current HAART regimen will reduce the number of resting HIV in CD4 cells.

This study will last at least 24 weeks. In Step 1, participants will continue on their current HAART regimen, as determined by their own doctor, and begin taking raltegravir daily. At Week 8, participants will begin taking valproic acid daily. Participants will start at a low dose of valproic acid, and the dose will escalate weekly until appropriate levels are reached, as determined by blood test. Study visits for Step 1 will occur at screening, study entry, and Weeks 1, 2, 4, 8, 9, 10, 12, 16, 20, and 24. At these visits, physical exams and urine and blood collection will occur. At some visits, genital secretion collection will occur. Leukapheresis to determine resting HIV levels will occur at Weeks 4, 8, 20, and 24. Participants will not receive HAART through this study.

Step 2 will begin at Week 24; all participants will stop taking valproic acid at the start of this step. If they have not responded to the raltegravir and valproic acid given in Step 1, they will enter Step 2A and discontinue the study. Participants who have responded to raltegravir and valproic acid will continue take raltegravir and their current HAART regimen until Week 40. Leukapheresis to determine resting HIV level will occur at Weeks 36 and 40. A final follow-up visit will occur by Week 48. Other study visits will occur at Weeks 30, 36, and 40. At these visits, physical exams and urine and blood collection will occur. At some visits, genital secretion collection will occur.

Eligibility

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

Criteria

Inclusion Criteria:

HIV infected
Adherent to current HAART
Willing and able to comply with all study requirements
On effective HAART, defined as at least two NRTIs plus at least one PI or NNRTI, without any treatment changes in the 24 weeks prior to study entry
Adequate vascular access for leukapheresis
Viral load never more than 50 copies/ml on two consecutive tests for any period of 6 months or more prior to study entry
CD4 count greater than 300 cells/mm3
Have no contraindication to VPA therapy such as pregnancy, bleeding disorders, history of pancreatitis, or history of hepatitis)
Able to speak English
Willing to use acceptable forms of contraception

Exclusion Criteria:

Currently receiving zidovudine
Require certain medications known to interact with valproic acid or raltegravir
Anemic
Certain abnormal laboratory values
Seropositive for hepatitis C RNA
Positive for hepatitis B surface antigen
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. More information on this criterion can be found in the protocol.
Current drug or alcohol abuse that, in the opinion of the investigator, would interfere with the study
Serious illness requiring systemic treatment or hospitalization within 90 days prior to screening
Treatment for a current AIDS-defining opportunistic infection within 90 days prior to screening
Involuntarily incarcerated for treatment of either a psychiatric illness or physical illness (e.g., infectious disease)
Pregnancy and breastfeeding

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00576290

Contacts

Contact: David M. Margolis, MD

919-966-6638

dmargo@med.unc.edu

Locations

United States, North Carolina
University of North Carolina Memorial Hospital
Chapel Hill, North Carolina, United States

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Adult AIDS Clinical Trials Group

University of North Carolina

Merck

Abbott

Investigators

Principal Investigator:	David M. Margolis, MD	The University of North Carolina, Chapel Hill
Principal Investigator:	Joseph Eron, MD	The University of North Carolina, Chapel Hill

More Information

Additional Information:

Click here for more information on raltegravir This link exits the ClinicalTrials.gov site

Click here for more information on valproic acid This link exits the ClinicalTrials.gov site

Haga clic aquí para ver información sobre este ensayo clínico en español This link exits the ClinicalTrials.gov site

Publications:

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. Epub 2007 Aug 1.

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. Epub 2007 Jan 30.

Schmitt CM, Brazer SR. Creatine kinase isoenzymes in diagnosis of intestinal infarction. Dig Dis Sci. 1992 Jul;37(7):1146-7. No abstract available.

Responsible Party:	DAIDS ( Rona Siskind )
Study ID Numbers:	U01AI125868, CID 0704, R01 A164074, R01 AI45297, U01 A125868
Study First Received:	December 17, 2007
Last Updated:	September 24, 2008
ClinicalTrials.gov Identifier:	NCT00576290 History of Changes
Health Authority:	United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

Treatment Experienced
Histone deacetylase
Histone remodeling

Additional relevant MeSH terms:

Communicable Diseases
Neurotransmitter Agents
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Psychotropic Drugs
Infection
Valproic Acid
Therapeutic Uses
Retroviridae Infections
RNA Virus Infections
Tranquilizing Agents
Immune System Diseases

Acquired Immunodeficiency Syndrome
Central Nervous System Depressants
Enzyme Inhibitors
Antimanic Agents
Immunologic Deficiency Syndromes
Pharmacologic Actions
Virus Diseases
HIV Infections
Sexually Transmitted Diseases
Lentivirus Infections
GABA Agents
Central Nervous System Agents
Anticonvulsants

ClinicalTrials.gov processed this record on February 08, 2010