NCT03525730

LRAs United as a Novel Anti-HIV Strategy.

LRAs United as a Novel Anti-HIV Strategy (LUNA): a Randomized Controlled Trial.

• Status: Completed
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 28 (actual)
• Sponsor: Erasmus Medical Center · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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.

Conditions

• HIV-1-infection

Interventions

Type	Name	Description
DRUG	Valproic Acid	Valproic acid (enteric) 30mg/kg, divided over 2 doses per day, orally on day 1-14.
DRUG	Pyrimethamine	Pyrimethamine 200mg once daily (QD) orally on day 1 and 100mg on day 2-14.

Timeline

• Start date: 2018-04-18
• Primary completion: 2019-07-25
• Completion: 2020-10-01
• First posted: 2018-05-16
• Last updated: 2021-04-29

Locations

1 site across 1 country: Netherlands