Non-diabetic, aviremic HIV-infected individuals on antiretroviral therapy (ART) will be randomized to metformin therapy or to observation for 72 weeks. Primary objective is to assess change over 72 weeks in CD4 T cell negative checkpoint receptors (PD-1 and TIGIT). As secondary objectives the study will look at 72 week change in other immuno-virologic parameters (CD8 T cell negative checkpoint receptors, plasma indoleamine 2,3-dioxygenase (IDO) levels and CD4 T cell and monocyte intracellular HIV DNA and HIV RNA. The study will also explore the 72 week impact of metformin on change in carotid intima-media thickness (cIMT) as a surrogate marker of atherosclerosis, on neuropsychological (NP) performance, strength, and change in body composition.

Inclusion Criteria:

• HIV+
• On suppressive ART stable for > 1 year
• Plasma HIV RNA < 50 copies/mL within 3 months of entry, with no HIV RNA > 200 copies/mL within the past 6 months prior to entry
• Age >40 years
• Ability and willingness to provide written informed consent

Exclusion Criteria:

• Uncontrolled chronic medical condition or cancer

• Acute illness within 2 weeks of entry

• Diagnosis of diabetes by history, fasting blood glucose >126, or by HgbA1c > 6.5

• Chronic, uncontrolled diarrhea

• Known hypersensitivity or contraindication to metformin use

• Current presence of hepatitis C including currently on or intent to start therapy for hepatitis C within the 48 week duration of study.

• Serum B12 level below the reference normal range as listed by the commercial lab utilized for this study (Diagnostic Laboratory Services)

• Pregnancy, or intent to become pregnant or nursing an infant

• Any immunomodulator, HIV vaccine, any other vaccine, or investigational therapy within 30 days of study entry.

• Current uncontrolled coronary artery disease or NYHA Class 3 or 4 congestive heart failure

• History of liver cirrhosis

• Current use of zidovudine, stavudine or didanosine

• The following lab values

  • Hemoglobin < 9.0 g/dL
  • Absolute neutrophil count < 1000/μL
  • Platelet count < 50,000/μL
  • AST (SGOT) and ALT (SGPT) > 5x upper limit of normal (ULN)
  • Calculated creatinine clearance (Cockcroft and Gault) < 50 ml/min

• Active or recent past history (within past 2 years) of illicit substance or alcohol use or abuse which, in the judgment of the Investigator, will interfere with the patient's ability to comply with the protocol requirements

• Patients, who, in the opinion of the Investigator, are unable to comply with the dosing schedule and protocol evaluation or for whom the study may not be advisable

Dataset will be available to other researchers upon request once the primary manuscript is written

After the study analyses are completed and primary manuscript is published, and for a duration of at least 5 years afterwards

De-identified dataset will be provided upon request to legitimate researchers