Clinical trial NCT00289952: Valproic Acid and Its Effects on HIV Latent Reservoirs
Official title: Use of Valproic Acid to Purge HIV From Resting CD4+ Memory Cells/ A Proof-of-concept Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: HIV infections
Histone deacetylase Inhibitor
HIV Reservoirs
Peripheral Blood Mononuclear Cells
Valproic Acid
Treatment Experienced
Lead sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Sponsor class: OTHER
Collaborators: name: Canadian Foundation for AIDS Research (CANFAR)
name: CIHR Canadian HIV Trials Network
First posted: 2006-02-10
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: 16 or 32 weeks
Secondary outcomes:
measure: To assess the clinical and biological tolerance of VPA in chronically HIV-infected patients with undetectable viral load.
timeFrame: 16 or 32 weeks
measure: 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.
timeFrame: 48 weeks
measure: To explore the frequency of CD4+ memory cell subsets (Tcm, Tpm and Tem) carrying HIV proviral DNA.
timeFrame: 48 weeks
measure: To explore level of T-cell activation after VPA intervention.
timeFrame: 48 weeks
measure: To assess levels of certain cytokines and chemokines, which are involved in T-cell proliferation and differentiation.
timeFrame: 48 weeks
Other outcomes:
Locations:
city: Vancouver
country: Canada
facility: BC St-Paul's Hospital/Immunodeficiency Clinic
state: British Columbia
city: Ottawa
country: Canada
facility: Ottawa Health Research Institute/Immunodeficiency Clinic
state: Ontario
city: Montreal
country: Canada
facility: Actuel Medical Clinic
state: Quebec
city: Montreal
country: Canada
facility: Quartier Latin Medical Clinic
state: Quebec
city: Montreal
country: Canada
facility: Montreal Chest Institute/Immunodeficiency Clinic
state: Quebec
city: Ste-Foy
country: Canada
facility: CHUL Ste-Foy
state: Quebec
Study officials:
affiliation: Royal-Victoria Hospital/McGill University Health Centre
name: Jean-Pierre Routy, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Routy JP, Angel JB, Spaans JN, Trottier B, Rouleau D, Baril JG, Harris M, Trottier S, Singer J, Chomont N, Sekaly RP, Tremblay CL. 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. doi: 10.1310/hct1306-301.
citation: Routy JP, Tremblay CL, Angel JB, Trottier B, Rouleau D, Baril JG, Harris M, Trottier S, Singer J, Chomont N, Sekaly RP, Boulassel MR. 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. doi: 10.1111/j.1468-1293.2011.00975.x. Epub 2012 Jan 26.