A double blinded, phase II, placebo controlled, single center randomized clinical trial to evaluate metformin compared with placebo for reversal of accelerated biological aging in persons living with HIV 50 years or older and with suppressed virologic replication.

INTERVENTION: Trade Name: Metformina Product Name: Metformina Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: METFORMIN CAS Number: 657‐24‐9 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 850‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use CONDITION: Patients with HIV and accelerated biological aging Therapeutic area: Diseases [C] ‐ Virus Diseases [C02] PRIMARY OUTCOME: Main Objective: To evaluate the anti‐aging affect of metformin compared to placebo as assessed by difference in epigenetic age acceleration (EAA) by Phenoage at week 96 Primary end point(s): EAA difference by Phenoage epigenetic clock Secondary Objective: • To evaluate the anti‐ageing effect of metformin compared to placebo as assessed by difference in EAA by four epigenetic clocks at week 48, 96 and 144 ; • To evaluate the effect of metformin compared to placebo as assessed by the immune profile recovery at week 48, 96 and 144 ; • To evaluate the effect of metformin compared to placebo as assessed by the inflammatory biomarkers’ changes at week 48, 96 and 144 ; • To evaluate the effect of metformin compared to placebo as assessed by the leucocyte telomere length changes at week 48, 96 and 144; • To evaluate the effect of metformin compared to placebo as assessed by the different aging biomarkers changes at week 48, 96 and 144 ; • To evaluate the effect of metformin compared to placebo as assessed by the frailty phenotype improvement at week 48, 96 and 144; • To evaluate the security of metformin compared to placebo as assessed by lab parameters at week 24, 48, 72, 96, 120 and 144 Timepoint(s) of evaluation of this end point: 96 weeks SECONDARY OUTCOME: Secondary end point(s): • EAA difference by Horvath´s clock, Hannum´s clock, GrimAge and PhenoAge; • Immune profile: % and absolute number of CD4+ T cells, CD8+ T cells, CD4+/CD8+ ratio, haematopoietic progenitors, CD4+ and CD8+ T‐cell subsets (recent thymic emigrants, naïve, central and effector memory, TEMRA, activated, exhausted and senescent), T‐reg, B‐cell subsets (naïve, class‐switched memory, non‐class switched memory), NK subsets (CD56dim CD16hi, CD56hi CD16‐/low) and monocytes (classic, non‐classic and intermediate); • Changes in the inflammatory markers: IL‐6, CRP, D‐Dimer; • Changes in Telomere length in PBMC; Changes in the following aging biomarkers:; • TAME biomarkers: IL‐6, TNFR II, hsCRP, GDF15, IGF‐1, fasting insulin, cystatin C; NT‐proBNP, haemoglobin A1c. ; • Oxidative stress and DNA damage: reactive oxygen species (ROS), catalase expression, superoxide dismutase 1 ‐ 2 levels, ?H2AX histone levels.; • Other inflammatory and pro‐coagulant biomarkers: IL‐1 beta, TNF‐alfa, D‐dimer; • Changes in the following Frailty battery: Fried frailty index, grip strength, walking speed and short physical performance battery; • Changes in creatinine Timepoint(s) of evaluation of this end point: ‐ Weeks 48, 96 and 144; ‐ Weeks 48, 96 and 144; ‐ Weeks 48, 96 and 144; ‐ Weeks 48, 96 and 144; ‐ Weeks 48, 96 and 144; ‐ Weeks 48, 96 and 144; ‐ Weeks 24, 48, 72, 96, 120 and 144 INCLUSION CRITERIA: Age 1. Participant must be 50 years old or older, at the time of signing the informed consent. Type of Participant and Disease Characteristics 2. Participants with HIV‐1 infection and an uninterrupted ART regimen in the 3 months prior to study entry a. Only switch for tolerability/convenience/access reasons to generic drugs or switch from ritonavir to cobicistat would be allowed in the 3‐month window and as long as the components of the regimen are unchanged. 3. HIV viral load (VL) <50 copies/mL at screening and in the year prior to study entry. a. A blip (50‐200 copies/ml) would be allowed within 12 months prior to inclusion in the study, if preceded and followed by an undetectable VL determination. 4. CD4 count > 500 cel/µL at screening. 5. Participants with normal vitamin B12 levels at screening 6. Participants with normal HOMA‐IR (= 2.6) Weight 7. Body mass index (BMI) less than 30 Kg/m2. Sex and Contraceptive/Barr