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

Eligibility 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.
• * 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.