An upcoming pilot study will test the hypothesis of whether the use of metformin will prevent progression or promote regression of liver fibrosis in hepatitis C virus and HIV (HCV-HIV) co-infected patients, and in HCV mono-infected patients with insulin resistance (IR) planning to initiate antiviral HCV treatment.

The secondary objective of the study will evaluate the effect metformin has on virological response rates based on SVR on the progression and regression of liver fibrosis, using aspartate aminotransferase (AST)-to-platelet ratio index (APRI).

Researchers will also consider the effect metformin and lifestyle modification has on metabolic parameters (fasting insulin, fasting glucose, and fasting lipid levels), inflammatory markers (IL-6, IL-8, TNF-α, TGF-β, and C-reactive protein), anthropometric measurements (BMI, weight, and waste circumference), AFP levels, HCV viral status, HIV viral status, and liver enzymes.

The study is a prospective 48 week randomized, open-label, single-center, controlled trial of HIV-HCV co-infected and HCV mono-infected patients with IR (HOMA-IR ≥ 2.0) who are planning to initiate HCV antiviral therapy. There will be 60 patients between 18- and 79-years-old enrolled in the study. Recruitment began in July 2016 from The Ottawa Hospital Viral Hepatitis Clinic.

Participants will be randomized to receive metformin 2 g [1 g twice a day (BID)] plus lifestyle, or lifestyle alone (control arm). The metformin group will receive metformin and lifestyle treatment during a 12-week period before starting HCV therapy, during the 12-week treatment phase, and 24 weeks post HCV treatment. Those in the lifestyle alone arm will receive lifestyle treatment during the same 3 periods.

Individuals in the Metformin arm will be given the following recommended dose adjustments and will be advised to increase the dose accordingly: week 1, 500 mg once daily (QD); week 2, 500 mg BID; week 3, 500 mg 3 times daily (TID); and week 4, 1 g BID or 500 mg QD.

The dosing will also be based on renal function and dosed as follows: if creatinine clearance (CrCl) 30-60 mL/min, metformin will be reduced to 50% of the dose or 500 mg BID; if CrCl < 30 mL/min, the metformin will be stopped. 

Both arms will be given counseling on lifestyle and dietary modifications that may help prevent liver fibrosis progression. Participants will be encouraged to aim for 150 minutes of moderate-to-vigorous aerobic exercise and 2 to 3 sessions of resistance training, and will be given tips on how to become more active. They will also receive recommendations for dietary modifications and tips for healthy eating. Recommended limits for alcohol consumption will also be reviewed, with educational sessions repeated during 6-month follow-ups.

The primary outcome of the study will evaluate the change in FibroScan score (kPa) from baseline to week 12, the end of HCV treatment (week 24), and 24 weeks post HCV treatment (week 48).

The secondary outcomes evaluated will be the following: virological response rates compared between the treatment groups; the change in APRI measurements from baseline to the start of HCV treatment, to the end of treatment, and 24 weeks post HCV treatment will be compared between treatment groups; changes in glucose metabolism from baseline to 4, 8, 12, 24, 36, and 48 weeks; changes in lipid levels from baseline to 0, 12, 36, and 48 weeks; changes in anthropometric measures from baseline to 0, 4, 8, 12, 24, 36, and 48 weeks; changes in liver-related inflammatory markers from baseline to 0, 4, 8, 12, 24, and 36 weeks; changes in AFP levels from baseline to 0, 12, 24, 36, and 48 weeks; participant acceptability to study medication dosing will be assessed in arm 1 only at weeks 8, 24, and 48 by questionnaire. Changes in scores from week 8 to the end of the study will be evaluated; and changes in diet and physical exercise parameters from baseline to 24 and 48 weeks using dietary and physical activity questionnaires.

The pilot study will be the first to evaluate the role of metformin on liver fibrosis in HCV-HIV co-infected and HCV mono-infected patients with IR receiving DAA HCV treatment. If the study is successful and metformin demonstrates efficacy in reducing liver fibrosis in the participants, it will represent a well-tolerated, inexpensive, easy-to-administer therapy that will protect patients against negative HCV outcomes.

The study will also provide researchers with an opportunity to examine the impact of IR and hyperglycemia on viral clearance in HCV-infected individuals treated with interferon-free regimens. Furthermore, they will be able to gain more knowledge on the relationship between AFP levels, IR, and HCV which could improve therapy outcomes for liver and metabolic disease, help guide further innovative research in this specific area, and inform patient care.