Valproic Acid and Its Effects on HIV Latent Reservoirs

Sponsor

McGill University Health Centre/Research Institute of the McGill University Health Centre (Other)

Overall Status

Unknown status

CT.gov ID

NCT00289952

Collaborator

Canadian Foundation for AIDS Research (CANFAR) (Other), CIHR Canadian HIV Trials Network (Other)

Enrollment

Locations

Arms

Duration (Months)

8.3

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to examine whether the co-administration of valproic acid (Epival®), with highly active antiretroviral therapy (HAART) can reduce the size of HIV latent reservoirs in infected CD4 cells.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections	Drug: Valproic Acid Drug: HAART	Phase 2

Detailed Description

Participants must be on HAART with a suppressed viral load (< 50 copies/ml) for at least the previous 12 months. They will be randomly assigned to one of two groups, one group will start the valproic acid right away at week 1 for 16 weeks, and the other group will wait until week 17 to add valproic acid to their treatment for 32 weeks. Subjects will be followed every four weeks for one year and evaluated by a variety of assays, all carried out using well-established methods, to assess the main outcome defined by changes in HIV reservoir size measured by the mean frequency of resting CD4 memory cells carrying HIV proviral DNA.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Use of Valproic Acid to Purge HIV From Resting CD4+ Memory Cells/ A Proof-of-Concept Study

Study Start Date :

Jun 1, 2006

Anticipated Primary Completion Date :

Dec 1, 2008

Anticipated Study Completion Date :

Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1 HAART + valproic acid for 16 weeks followed by HAART alone for 32 weeks.	Drug: Valproic Acid Oral valproic acid twice daily for 16 or 32 weeks. Dosage varies based on plasma levels. Drug: HAART As per standard of care.
Experimental: Group 2 HAART alone for 16 weeks followed by HAART + valproic acid for 32 weeks.	Drug: Valproic Acid Oral valproic acid twice daily for 16 or 32 weeks. Dosage varies based on plasma levels. Drug: HAART As per standard of care.

Arm

Intervention/Treatment

Experimental: Group 1

HAART + valproic acid for 16 weeks followed by HAART alone for 32 weeks.

Drug: Valproic Acid

Oral valproic acid twice daily for 16 or 32 weeks. Dosage varies based on plasma levels.

Drug: HAART

As per standard of care.

Experimental: Group 2

HAART alone for 16 weeks followed by HAART + valproic acid for 32 weeks.

Drug: Valproic Acid

Oral valproic acid twice daily for 16 or 32 weeks. Dosage varies based on plasma levels.

Drug: HAART

As per standard of care.

Outcome Measures

Primary Outcome Measures

To assess the effect of VPA on HIV reservoirs measured by the frequency of resting CD4+ memory cells carrying HIV proviral DNA in peripheral blood of chronically HIV-infected subjects. [16 or 32 weeks]

Secondary Outcome Measures

To assess the clinical and biological tolerance of VPA in chronically HIV-infected patients with undetectable viral load. [16 or 32 weeks]
To explore the changes in CD4/CD8 ratio, as the size of reservoir is thought to be inversely correlated with the frequency of resting CD4+ memory cells carrying HIV proviral DNA. [48 weeks]
To explore the frequency of CD4+ memory cell subsets (Tcm, Tpm and Tem) carrying HIV proviral DNA. [48 weeks]
To explore level of T-cell activation after VPA intervention. [48 weeks]
To assess levels of certain cytokines and chemokines, which are involved in T-cell proliferation and differentiation. [48 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Documented HIV seropositive infection by Western Blot, EIA assays or viral load.

Aged 18 years old or older.
Viral load <50 copies/ml for at least the previous 12 months.
Circulating CD4+ cell count ³ 200 cells/ml.
Taking HAART.
Vital signs, physical examination and laboratory results do not exhibit evidence of diseases such as advanced cirrhosis and advanced liver disease (ALT or AST > 5 x upper limit of normal value).
Karnofsky performance status 80%.
Subject does not require and agrees not to take, for the duration of the study, any medication that is contraindicated with VPA.
Willing and able to give informed consent.
All participants will agree to abstinence or to used effective methods of contraception while on the study.

Exclusion Criteria:

Pregnant or breast-feeding women.
Psychiatric or cognitive disturbance or illness that could preclude compliance with the study.
Current use or use within four weeks prior to the baseline visit, of cytotoxic agents, systemic corticosteroids or any immunomodulatory agents such as intravenous immunoglobulin, or hydroxyurea.
HIV vaccine within six months of screening visit
Allergic reaction to VPA.
Active intravenous drug users.
History of bleeding disorders.
Unstable or treated hypertension.
Past-history of pancreatitis or chronic liver disease (ALT or AST > 5 x upper limit of normal value). However subject co-infected with hepatitis B or C can participate if ALT or AST is < 5 x upper limit of normal value.
Renal failure (creatinine > 2 x upper limit of normal value).
Ammonemia (> 2x upper limit of normal value).
Taking Zidovudine (AZT), or combination of drugs containing AZT like Combivir or Trizivir. However this subject will be asked to switch to another NRTI,at least two weeks prior to Valproic Acid initiation, to become eligible.
Taking on daily basis: phenytoin, carbamazepine, phenobarbital, warfarin or aspirin.
Subject has any of the following abnormal laboratory results Hemoglobin < 100 g/L. Absolute neutrophil count < 0.75 x 10 9 cells/L. Platelet count < 50 x 10 9 cells/L.
Subject suffering from urea cycle disorders.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	BC St-Paul's Hospital/Immunodeficiency Clinic	Vancouver	British Columbia	Canada	V6Z 1Y6
2	Ottawa Health Research Institute/Immunodeficiency Clinic	Ottawa	Ontario	Canada	K1H 8L6
3	Actuel Medical Clinic	Montreal	Quebec	Canada	H2L 4P9
4	Quartier Latin Medical Clinic	Montreal	Quebec	Canada	H2L 5B1
5	Montreal Chest Institute/Immunodeficiency Clinic	Montreal	Quebec	Canada	H2X 2P4
6	CHUL Ste-Foy	Ste-Foy	Quebec	Canada	G1V 4G2

Sponsors and Collaborators

McGill University Health Centre/Research Institute of the McGill University Health Centre
Canadian Foundation for AIDS Research (CANFAR)
CIHR Canadian HIV Trials Network