PLUTO

INTERVENTION: Product Name: LENALIDOMIDE, Product Code:SUB25389, Pharmaceutical Form: CAPSULE, Other descriptive name: , Strength: , Product Name: PYRIMETHAMINE, Product Code:SUB10169MIG, Pharmaceutical Form: TABLET, Other descriptive name: , Strength: , Product Name: TOPIRAMATE, Product Code:SUB11190MIG, Pharmaceutical Form: FILM‐COATED TABLET, Other descriptive name: , Strength: CONDITION: HIV‐1 ; MedDRA version: 28.0Level: LLTClassification code: 10020160Term: HIV disease Class: 10021881 Therapeutic area: Diseases [C] ‐ Virus Diseases [C02] PRIMARY OUTCOME: Main Objective: Primary objectives phase I: To assess the efficacy of 1‐day dual LRA combinations treatment on HIV reservoir reactivation in PLWH. ; Primary objectives phase II: Efficacy of a 4‐week dual LRA combination treatment on HIV reservoir reduction. Primary end point(s): Phase I : Fold change in cell‐associated HIV‐RNA at time points 6 (T=6) and 24 hours (T=24) after LRA treatment compared to baseline (T=0) before treatment. Phase II: Log transformed HIV‐DNA at T=4 weeks compared to T=0. Secondary Objective: Key secondary objective phase I and II: To assess clinical safety and tolerability of the LRA drug combinations., Phase I: To evaluate participant preference on drug combinations, trial experience, quality of life (QoL) and perceived stigma, Phase I: To measure plasma HIV‐RNA kinetics during interventional treatment., Phase I: To assess immunological functionality and phenotype., Phase I: To analyze pharmacokinetics and pharmacodynamics of the combined investigational compounds., Phase I: To analyze pharmacokinetics and pharmacodynamics of the combined investigational compounds., Phase I: To evaluate correlation of in vivo and ex vivo reservoir reactivation., Phase II: To evaluate participant trial experience, QoL and perceived stigma, Phase II: To assess the LRA effects on reservoir reactivation by prior LRA regimen exposure., Phase II: To measure plasma HIV‐RNA kinetics during interventional treatment., Phase II: To assess Immunological functionality and phenotype., Phase II: To analyze pharmacokinetics and pharmacodynamics of the combined investigational compounds., Phase II: To assess drug‐drug interactions between investigational drugs and ART, Phase II: To evaluate correlation of in vivo and ex vivo reservoir reactivation. SECONDARY OUTCOME: Secondary end point(s):Key secondary endpoint Phase I and phase II: The number and severity of clinical and biochemical adverse events using CTCAEv6.0. Secondary end point(s):Phase I: Change in plasma HIV‐RNA between and within arms at T=6hr, T=24hr and T = 7 days compared to T=0. Secondary end point(s):Phase I: Drug plasma levels of ART at T=0hr, T=6hr, T=24hr and T=7 days. Secondary end point(s):Phase I: Drug plasma levels of LRA compounds at T=0h, T= 6hr, T=24hr and T=7 days. Secondary end point(s):Phase I: Quantitative and qualitative patient reported outcomes of treatment satisfaction, QoL and stigma by validated questionnaires at T=0, T=24hr and T=7 days and by a semi‐structured interview before the intervention and at T=24hr. Secondary end point(s):Phase I: The change of the frequency, functionality and phenotype of immune cell subpopulations; total T cells and HIV specific CD4+ and CD8+ T cells, B‐cell differentiation, HIV specific B‐cell clonotype and immunoglobulin sequence, and HIV specific antibody function, between and within the groups at T=7 days, compared to T=0. Secondary end point(s):Phase I: The correlation between e Xvivo and in vivo fold change in cell‐associated HIV‐RNA from T=0 to T=24hr. Secondary end point(s):Phase II: Change in plasma HIV‐RNA absolute copies/mL and proportion with viral target detectable, >30, >50, and >200 c/mL within group at T=24hr, T=1, 2, 3, and 4 weeks compared to T=0. Secondary end point(s):Phase II: Drug plasma levels of LRA compounds at T=1, 2, 3, and 4 weeks. Secondary end point(s):Phase II: Drug plasma of ART levels T=1, 2, 3, and 4 weeks. Secondary end point(s):Phase II: Fold change cell associated HIV RNA from T=0 to T=24hr in participants in phase 2 com‐pared to T=0 to T=24hr in participants in phase 1 overall and by prior LRA exposure. Secondary end point(s):Phase II: Quantitative and qualitative patient reported outcomes of treatment satisfaction, QoL and stigma by questionnaires and by a semi‐structured interview at T=0 to T=4 weeks. Secondary end point(s):Phase II: The change of the frequency, functionality and phenotype of immune cell subpopulations; total T cells and HIV specific CD4+ and CD8+ T cells, B‐cell differentiation, HIV specific B‐cell clonotype and immunoglobulin sequence, and HIV specific antibody function, at T=1 and T=4 weeks compared to T=0. Secondary end point(s):Phase II: The correlation between e Xvivo and in vivo fold change in cell‐associated HIV‐RNA from T=0 to T=24hr overall and by prior LRA exposure. INCLUSION CRITERIA: In order to be eligible to participate in this study, a subject must meet all of the following criteria: 1. Documented HIV‐1 infection, confirmed by Western Blot or PCR. 2. Age = 18 years old. 2. Confirmed HIV1 subtype A, B, C or D. In case no HIV sequencing is available, proviral sequencing can be performed (preferably on left‐over blood samples) to assess subtype. People with other HIV1 subtypes can only be included after discussion with Sponsor and is contingent on possible primary endpoint assay adaptation. 3. Uninterrupted ART therapy for a minimum 6 months. 4. Plasma HIV RNA =50 copies/ml prior to inclusion at two consecutive measurements at least three months apart. 5. No disclosed missed ART on more than 2 days per month. 6. Current blood CD4+T‐cell count of =200 cells/mm3 7. No clinical signs of cellular immunodeficiency or AIDS. 8. Pre‐ART plasma HIV RNA =1000 copies/mL. 9. Able to understand provided information and to give informed consent.