LRAs United as a Novel Anti-HIV Strategy.

• Status: Completed
• Trial end date: 2020-10-01
• Target enrollment: 0
• Participant gender: All

Summary

A translational proof of concept study in humans on the primary research question whether novel anti-human immunodeficiency virus (HIV) latency strategies, including a BAF inhibitor and a histone deacetylase inhibitor, result in HIV reservoir reduction in HIV patients on antiretroviral therapy.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Erasmus Medical Center
• Treatments: Pyrimethamine; Valproic Acid

Criteria

Inclusion Criteria:

1. HIV-1 infected patients ≥18 years.

2. World Health Organization (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. Transmitted mutations and acquired mutations due to virological failure associated with resistance of at highest low-level resistance are allowed.

5. On cART.

6. Current plasma HIV-RNA <50 copies/mL for at least 365 days and measured on at least 2 occasions of which at least 1 must be obtained within 365 and 90 days prior to study entry.

7. Current CD4 T-cell count at study entry of ≥200 cells/mm3.

8. Pre-cART HIV-RNA ≥10.000 copies/mL.

Exclusion Criteria:

1. Previous virological failure, defined as either acquired resistance mutations (>low level resistance) on cART or HIV-RNA >1000 copies/mL on two consecutive measurements during cART.

2. Uncontrolled hepatitis B or C co-infection. For hepatitis B: patients should be vaccinated, or on pre-exposure prophylaxis through the use of lamivudine/emtricitabine or tenofovir in their combination ART. Otherwise, standard serological testing should be available within the last 365 days for homosexual HIV positive men. For non-homosexual HIV positive persons, there should be at least one negative hepatitis B test (either by serology or PCR). For homosexual HIV positive men, a negative hepatitis C immunoglobulin G, hepatitis C (HCV) antigen, blot or HCV-RNA PCR should be available within the previous 365 days. For non-homosexual HIV positive persons, there should be at least one negative hepatitis C test (either IgG, blot or PCR) available.

3. Prior exposure to any HDACi, BAFi or other known LRA.

4. Prior exposure to cytotoxic myeloablative chemotherapy for hematological malignancies 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, antipsychotics, carbapenems, mefloquine, colestyramine, Any documented opportunistic infection related to HIV in the last 90 days.

7. Inadequate blood counts, renal and hepatic function tests

1. Haemoglobin <6.5 mmol/L (males) or <6.0 mmol/L (females), leucocytes <2.5 x109/L, absolute neutrophil count <1000 cells/mm3, thrombocytes <100 x109/L, international standardized ratio >1.6, activated partial thromboplastin time >40 seconds.

2. Estimated glomerular filtration rate <50 mL/min (CKD-EPI),

3. Alanine aminotransferase or total bilirubin >2.5x upper limit of normal.

4. 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, except if their sexual partner(s) use pre-exposure prophylaxis.

12. Patients with active substance abuse or registered allergies to the investigational medical products.

13. 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.