Improving Fibrosis Outcomes With Metformin
Improving Fibrosis Outcomes With Metformin
This study will evaluate the role of Metformin on liver fibrosis in HCV-HIV co-infected and
 HCV mono-infected patients with insulin resistance receiving DAA HCV treatment.
HCV antiviral therapy has evolved rapidly in recent years and access to these medications has
 improved. While SVR is associated with improved liver outcomes, the rate of liver fibrosis
 regression with SVR is variable and predictors of regression are not well established. In
 addition, achieving SVR in patients with cirrhosis does not necessarily prevent
 decompensation or eliminate the risk of HCC. A better understanding of the role insulin
 resistance and impaired glucose metabolism have on these outcomes in HCV patients who achieve
 SVR are needed.

 Identifying and targeting potentially modifiable risk factors such as IR may be of
 significant importance in preventing progression of and promoting regression of liver
 fibrosis, reducing mortality and improving outcomes for HCV-HIV co-infected and
 HCV-mono-infected patients.

 This proposed 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 Metformin is effective in reducing liver fibrosis in this patient population, this will
 represent a well-tolerated, easy to administer, inexpensive therapy that will protect against
 negative HCV outcomes. This study will also be an opportunity to evaluate the impact of
 insulin resistance and hyperglycemia have on viral clearance HCV-infected patients treated
 with interferon-free regimens. In addition, the study will further explore the relationship
 between HCV, insulin resistance and AFP levels.
Inclusion Criteria:

 1. Male or female, 18 to 79 years old inclusive

 2. Provision of informed consent

 3. Documented history of chronic HCV RNA infection

 4. Intending to start on any 8-12 week IFN-free HCV antiviral therapy

 5. If HIV-infected and not on HIV antiretroviral therapy, a CD4 count at least > 200

 6. Insulin resistance as determined by a HOMA-IR of > 2.0 at screening

 7. Evidence of fibrosis on FibroScan® > 8.0 kPa, OR liver biopsy score > 2 (Batts-Ludwig
 System) [55] (within 2 years)

 Exclusion Criteria:

 1. Pregnant, suspected to be pregnant, planning to become pregnant or breastfeeding

 2. Chronic HBV infection

 3. HbA1c > 8.0

 4. Use of immune suppressing medications

 5. Active malignancy

 6. Current or any previous treatment with Metformin, other oral diabetes
 medications,insulin

 7. Pre-existing diabetes (type 1, type 2 or gestational diabetes)

 8. Clinical evidence of decompensated cirrhosis (ascites, esophageal varices, hepatic
 encephalopathy, hepatocellular carcinoma)

 9. Presence of renal impairment or when renal function is not known, and also in patients
 with serum creatinine levels above upper limit of normal range. Renal disease or renal
 dysfunction (e.g., as suggested by serum creatinine levels >= 136 umol/L (males), >=
 124 umol/L (females) or abnormal creatinine clearance (60 mL/min))

 10. History of congestive heart failure requiring pharmacologic therapy

 11. Wilson's disease

 12. Alpha-1 antitrypsin

 13. Hemochromatosis

 14. Biliary Cirrhosis

 15. Alcohol consumption > 50 g / day on average (see Appendix B for conversion to volume)

 16. Participation in other clinical investigations during the study

 17. History of lactic acidosis, irrespective of precipitating factors

 Active illicit drug use and stable health illness will not be exclusionary assuming it is
 unlikely to compromise study adherence to protocol and study drug. In HIV-infected
 participants, HIV antiretroviral use and suppressed HIV viral load will not be required for
 participation.

 HCV antiviral therapy will not be withheld for any participant that is eligible and desires
 to start treatment. If HCV treatment is anticipated to be started during the 48-week period
 of assessment, then participants will not be enrolled.