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

The study aims to assess the impact of metformin on immune dysregulation among 100 adults (ages 18-64) with a history of injection drug use. Participants will be randomized 1:1 to metformin (500mg increasing to 1000mg) or placebo for 16 weeks, during which they will receive Jynneos (MPOX) and Capvaxvie (PCV21, pneumococcal) vaccines. Immunologic responses will be monitored over 6 months post-enrollment.

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.