Assessment of Metformin for Restoration of Immune Homeostasis in HIV+ and HIV- Individuals With a History of Injection Drug Use

Inclusion Criteria: * Provision of signed and dated informed consent. * Stated willingness to comply with all study procedures and availability for the study duration. * Aged 18 to 64 years old. * Weight of at least 110 lbs. * Body Mass Index (BMI) of 18.5-40. Enrollment of individuals with BMI \>40, deemed in good health, may be considered with approval. * Willingness to receive Jynneos (MPOX) and Capvaxvie vaccines. * Ability to take oral medication and willingness to adhere to the metformin treatment regimen. * History of injection opioid, amphetamine, and/or cocaine use within the past 10 years (self-report). * Use of non-prescription opioid, amphetamine, and/or cocaine within the past 30 days (self-report). * Clinically confirmed urine drug screen for opioid, amphetamine, and/or cocaine within the past 30 days. * Serum CRP \> 3 mg/dL. * Glucose level between 70-180 mg/dL (non-fasting). * Hemoglobin A1c (HbA1c) of 5.0-6.4%. * CD4 count \> 200 cells/ml. * If HIV-positive, HIV viral load \< 200 copies/ml. * If HIV-positive, on anti-retroviral therapy (ART) for \>12 months. Exclusion Criteria: * Inability to give informed consent. * Refusal or inability to have blood drawn. * Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, platelet disorder requiring precautions). * Pregnant or nursing individuals. * Diabetes mellitus. * History of severe renal impairment or eGFR \<60 mL/min/1.73m². * Creatinine clearance \<60 mL/min. * History of liver disease. * ALT/AST \> 3× the upper limit of normal. * Total bilirubin \>1.4 mg/dL. * Albumin \<3.5 g/dL. * Prothrombin \>1.5× the upper limit of normal. * AUDIT-C score ≥8. * Hemoglobin \<9.0 g/L. * Absolute neutrophil count \<1,000/mL. * Platelet count \<100,000/mL. * History of acute or chronic metabolic acidosis. * Serum bicarbonate \<22 mEq/L. * Anion gap \>10 mEq/L. * Serum lactate \>2.2 mmol/L. * Serum vitamin B12 \<250 pg/mL. * History of chronic diarrhea. * Current use of metformin or other diabetes medications. * History of myocardial infarction, endocarditis, stroke, heart failure, chronic obstructive pulmonary disease, or sepsis. * Use of medications such as furosemide, nifedipine, ranolazine, vandetanib, or cimetidine (current or within the past 30 days). * Active hepatitis B infection. * Hepatitis C infection within 6 months of study entry; individuals with prior hepatitis C must be at least 6 months post-treatment with direct-acting antivirals. * Previous receipt of Jynneos or pneumococcal vaccine within the past two years (self-report). * Severe allergic reaction to metformin, Jynneos, or Capvaxvie (self-report). Blood donations exceeding 450 mL in the 8 weeks prior to enrollment, accounting for study-related blood draws. * Any medical, psychiatric, social condition, or responsibility that, in the investigator's judgment, could interfere with study procedures.