Combining Latency Reversing Agents to Address the HIV Reservoir

Rationale Though combined antiretroviral therapy (ART) has made HIV a clinically manageable chronic illness by preventing viral replication, HIV poses great burdens on PLWH and society to this day. Due to the presence of a stable, latent viral reservoir, the virus rebounds when ART is stopped. Additionally this reservoir fuels inflammation with related comorbidities. Finding therapies to reduce the reservoir are therefore an important research objective. One strategy to shrink or eliminate the latent reservoir aims to reverse the reservoir from latency, leading to increased antigen presentation and trigger immune recognition (the "shock and kill" strategy). Several latency reversal agents (LRA) have been identified. Though single LRA treatment are effective to a limited extent, they have not resulted in significant HIV reservoir reduction. PLUTO, aims to study novel combinations of promising LRAs with different targets to reactivate and reduce the latent viral reservoir by identifying the combination with strongest latency reversal of phase I of our study and assessing latency reversal and reservoir decay after prolonged treatment in phase II of our study. Objectives Primary objectives phase I: \- To assess the efficacy of LRA combinations during a one day treatment on HIV reservoir reactivation in people living with HIV. Primary objectives phase II: \- Efficacy of dual LRA combination treatments on HIV reservoir reduction. Main trial endpoints Phase I Primary endpoint: • Fold change in cell-associated HIV-RNA at time points 6, and 24 hours compared to baseline Phase II Primary endpoint: • Log transformed HIV-DNA at T=4w compared to T=0 Trial design Proof of concept two-phase sequential randomized controlled trial. Phase I consists of three arms receiving a single dose combination treatment, with a 7-day follow-up. Phase II consists of a single arm receiving a four-week treatment with the selected treatment from phase I, and a with a total follow-up duration of five weeks. Trial population Phase I 30 people with HIV-1 with inclusion criteria: ≥18years of age, plasma HIV-RNA \>1000c/mL before ART, current plasma HIV-RNA \<50c/ml for at least two measurements on uninterrupted ART and current CD4+T-cells \> 200/mm3. Phase II A minimum of 16 people with HIV-1 with the same inclusion criteria. All participants from phase I are eligible, and may move on to, phase II with additional consent. In case the required number of participants are not reached from phase I, new participants can be recruited following the same selection procedure as in phase I. Interventions Phase I The investigational drugs are Pyrimethamine, Lenalidomide, and Topiramate. Patients will be randomized 1:1:1 in one of three arms to receive a single dose of LRA combination of two investigational drugs Phase II Compound combination with highest latency reversing potential, within safety limits and taking patient participant preference into account is the phase II intervention. Dosing is adjusted to achieve steady state concentrations similar to phase I.