Adults with human immunodeficiency virus type-1 infection on antiretroviral treatment with adequate viral suppression and good cellular immunity.
Conditions
Interventions
Trade Name: Valproic acid
Product Name: Valproic acid
Pharmaceutical Form: Tablet
Trade Name: Pyrimethamine
Product Name: pyrimethamine
Pharmaceutical Form: Tablet
Sponsors
Erasmus MC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. HIV-1 infected patients =18 years. 2. WHO performance status 0 or 1. 3. Confirmed HIV-1 infection by 4th generation ELISA, Western Blot or PCR. 4. Wild type HIV infection or polymorphisms associated with at highest low-level resistance to any class of ART according to Stanford HIV drug resistance database. 5. On cART. 6. Current plasma HIV-RNA =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Previous virological failure, defined as either acquired resistance mutations on cART or HIV-RNA >1000 copies/mL twice during cART. 2. Uncontrolled hepatitis B or C co-infection. 3. Prior exposure to any HDACi, BAFi or other known LRA. 4. Prior exposure to cytotoxic chemotherapy during cART. 5. Concurrent exposure to strong interacting medication on glucuronidation. 6. Exposure within 90 days prior to study entry to immunomodulators, cytokines, systemic antifungals, dexamethasone, vitamin K antagonists, anti-epileptics, antipsychotica, carbapenems, mefloquine, colestyramine, Any documented opportunistic infection related to HIV in the last 90 days. 7. Inadequate blood counts, renal and hepatic function tests a. Haemoglobin 1.6, activated partial thromboplastin time >40 seconds. b. Estimated glomerular filtration rate 2.5x upper limit of normal. d. All laboratory values must be obtained within 42 days prior to the baseline visit. 8. Megaloblastic anemia due to folate deficiency. 9. Pancreatitis in last 6 months, or chronic pancreatitis. 10. Active malignancy during the past year with the exception of basal carcinoma of the skin, stage 0 cervical carcinoma, Kaposi Sarcoma treated with cART alone, or other indolent malignancies. 11. Females in the reproductive age cannot participate. Males cannot participate if they refuse to abstain from sex or condom use in serodiscordant sexual contact during the study. 12. Patients with active substance abuse or registered allergies to the investigational medical products. Last, any other condition (familial, psychological, sociological, geographical) which in the investigator’s opinion poses an unacceptable risk or would hamper compliance with the study protocol and follow up schedule, will prohibit participation.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To longitudinally assess the effects by pyrimethamine and valproic acid on the HIV reservoir in HIV infected patients on antiretroviral therapy.;Secondary Objective: 1. The evaluation of the in vivo and ex vivo anti-HIV latency capacities of pyrimethamine and valproic acid. 2. The evaluation of the in vivo effects pyrimethamine and valproic acid on the functionality and phenotype of the immune system. 3. Explore biomarkers of, and correlations between, the reactivation capacities of pyrimethamine and valproic acid ex vivo and in vivo. 4. The clinical safety and tolerability of administered compounds.;Primary end point(s): The change in reservoir size in vivo at treatment initiation week 0 and at the end of treatment week 6 measured as the number of CD4 T-cells with multiply spliced HIV-RNA with nested PCR based tat/rev induced limiting dilution assay (TILDA, Procopio et al. EBiomedicine 2016). The change in reservoir size is compared between the treatment arms.;Timepoint(s) of evaluation of this end point: Week 0, week 2 and week 6. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary endpoints are exploratory. 2.1 The change in reservoir size in vivo at treatment initiation week 0, at the end of treatment week 2, and at the end of the study week 6, measured with TILDA. The change in reservoir size is compared within and between the treatment arms. 2.2 Potential synergism or additive effects of the administration of both drugs will be assessed. 2.3 The change in cell-free HIV-RNA as measured by routine PCR and single copy assay, cell associated HIV-RNA, and cell-associated HIV-DNA at week 0, week 2 and week 6 within and between the treatment arms. 2.4 The change in the level of histone acetylation and expression of BAF subunits at the RNA and at the protein level at week 0, week 2 and week 6 within and between the treatment arms. 2.5 The change of the functionality and phenotype of innate immune cells, HIV specific CD4+ and CD8+ T cells and HIV specific B-cells using proliferation assays, flow cytometry, cytokine and cytotoxicity analysis at week 0, week 2 and week 6 within and between the treatment arms. 2.6 Explore and correlate clinical and markers of the viral reservoir (HIV-DNA, HIV-RNA), immune function and phenotype, and the level of acetylation/BAF expression with the change in reservoir size (TILDA) within and between the treatment arms. 2.7 Correlate the latency reversal activity with pyrimethamine and valproic acid in vitro in cell line based HIV latency models, in primary CD4 T cells ex vivo, and in vivo with TILDA, HIV-RNA, HIV-DNA and the level of acetylation/BAF expression. 2.8 Number and percentage of clinical and biochemical AE according to the latest version of the Common Toxicity Criteria. 2.9 Number and percentage of patients with HIV-1 RNA level greater than or equal to 20, 50 and 200 c/mL at week 0, week 2 and week 6 within and between the treatment arms.;Timepoint(s) of evaluation of this end point: week 0, week 2 and week 6. | — |
Countries
Netherlands
Contacts
Public ContactCasper Rokx
Erasmus MC
Outcome results
None listed