Clinical trial NCT03525730: LRAs United as a Novel Anti-HIV Strategy.
Official title: LRAs United as a Novel Anti-HIV Strategy (LUNA): a Randomized Controlled Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV-1-infection
Keywords: HIV
Latency reversing agents
HDAC inhibitor
BAF inhibitor
HIV reservoir
HIV cure
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
First posted: 2018-05-16
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 6 week study, including 2 week intervention and 4 week post-treatment period.
Primary purpose: TREATMENT

Brief 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.

Detailed description: The retrovirus HIV integrates as proviral DNA in the genome of cluster of differentiation (CD)4+ T cells. A subset form a reservoir of latently infected long-lived memory T-cells with nearly absent HIV-DNA transcription. This persistent latent HIV reservoir is the major obstacle for a cure. HIV latency is sustained by multiple host factors that restrict the viral promotor and expression of the viral genome. Latency reversing agents (LRA) can remove these restrictive components and mediate HIV latency reversal. LRA monotherapy with histone deacetylase inhibitors (HDACi) alone, including valproic acid, vorinostat, romidepsin, or panobinostat, reactivate HIV but seems insufficient to eliminate the reservoir in vivo. Our research group has identified the BAF complex as another repressive factor that maintains HIV latency. Pyrimethamine acts as an inhibitor of this BAF complex, is capable of reactivating HIV from latency at clinical tolerable concentrations, and acts synergistic with other LRA classes. This offers new opportunities for cure research. This is the first translational clinical study with BAF inhibitors and it assesses the potential synergism of 2 LRA with different modes of action on the reservoir in HIV patients.

Primary objective:

The longitudinal assessment of the effects of the BAF inhibitor pyrimethamine and of the HDACi valproic acid on the HIV reservoir in HIV patients on antiretroviral therapy.

Study design:

Open label 6 week randomized controlled intervention trial.

Study population:

Participants must be HIV infected, ≥18 years and on antiretroviral therapy with plasma HIV-RNA \<50 copies/mL and CD4+ T cell count ≥200 cells/mm3 at enrollment. The HIV-RNA was ≥10.000 copies/mL before antiretroviral therapy initiation.

Intervention:

Participants are randomized to either of 4 arms and receive valproic acid, pyrimethamine, both for 2 weeks, or no intervention. Total study duration is 6 weeks and includes a 2 week treatment period and a 4 week post-treatment period.

Primary endpoint:

The change in HIV reactivation in the reservoir in vivo at treatment initiation and at the end of treatment, measured as the change in cell associated HIV-RNA. The change in reactivation is compared between the treatment arms.

Secondary endpoints:

See below.

Eligibility 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.

Primary outcomes:
measure: Cell associated HIV-RNA
timeFrame: 6 week
Secondary outcomes:
measure: Tat/rev induced limiting dilution assay (TILDA)
timeFrame: 6 week
measure: Synergy
timeFrame: 6 week
measure: Cell associated HIV-RNA
timeFrame: 6 week
measure: Cell associated HIV-DNA
timeFrame: 6 week
measure: Plasma HIV-RNA
timeFrame: 6 week
measure: Histone deacetylation
timeFrame: 6 week
measure: Expression of BAF subunits
timeFrame: 6 week
measure: Immunological functionality
timeFrame: 6 week
measure: Immunological cytotoxicity
timeFrame: 6 week
measure: Immunological phenotype
timeFrame: 6 week
measure: Reservoir biomarkers
timeFrame: 6 week
measure: In vivo/ex vivo reservoir reactivation correlation
timeFrame: 6 week
measure: Incidence of Treatment-Emergent Adverse Events
timeFrame: 6 week
measure: Plasma HIV-RNA
timeFrame: 6 week
measure: Pharmacokinetics of dolutegravir
timeFrame: 6 week
measure: Pharmacokinetics of dolutegravir
timeFrame: 6 week
measure: Pharmacokinetics of valproic acid
timeFrame: 6 week
measure: Pharmacokinetics of valproic acid
timeFrame: 6 week
measure: Pharmacokinetics of pyrimethamine
timeFrame: 6 week
measure: Pharmacokinetics of pyrimethamine
timeFrame: 6 week
Other outcomes:
Locations:
city: Rotterdam
country: Netherlands
facility: Erasmus MC
Study officials:
affiliation: Erasmus Medical Center
name: Casper Rokx, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Erasmus Medical Center
name: Tokameh Mahmoudi, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bollen PDJ, Prins HAB, Colbers A, Velthoven-Graafland K, Rijnders BJA, de Vries-Sluijs TEMS, van Nood E, Nouwen J, Bax H, de Mendonca Melo M, Verbon A, Burger DM, Rokx C. The dolutegravir/valproic acid drug-drug interaction is primarily based on protein displacement. J Antimicrob Chemother. 2021 Apr 13;76(5):1273-1276. doi: 10.1093/jac/dkab021.