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 thestudy 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 ingood 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 treatmentregimen.

• History of injection opioid, amphetamine, and/or cocaine use within the past 10years (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 cocainewithin 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, chronicobstructive pulmonary disease, or sepsis.

• Use of medications such as furosemide, nifedipine, ranolazine, vandetanib, orcimetidine (current or within the past 30 days).

• Active hepatitis B infection.

• Hepatitis C infection within 6 months of study entry; individuals with priorhepatitis 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). Blooddonations exceeding 450 mL in the 8 weeks prior to enrollment, accounting forstudy-related blood draws.

• Any medical, psychiatric, social condition, or responsibility that, in theinvestigator's judgment, could interfere with study procedures.