treatment in mean log10 HCV RNA titer (23.5 6 1.71 and 23.7 6 1.62 IU/mL in the ..... aStandard care versus pioglitazone plus standard care (intention-to treat ...
Chronic Hepatitis C Genotype 1 Patients With Insulin Resistance Treated with Pioglitazone and Peginterferon Alpha-2a Plus Ribavirin Stephen A. Harrison,1 Fayez M. Hamzeh,2 Jian Han,2 Prashant K. Pandya,3 Muhammed Y. Sheikh,4 and John M. Vierling5 Patients with chronic hepatitis C and insulin resistance are less likely to respond to antihepatitis C virus (HCV) therapy and are at risk for more rapid fibrosis progression. Coadministration of pioglitazone with peginterferon/ribavirin improves insulin sensitivity and increases virologic response rates in insulin-resistant HCV genotype 4 patients, but it is unclear whether this finding applies to genotype 1 patients. For this reason we randomized treatment-naive HCV genotype 1 patients with insulin resistance to receive either standard care (peginterferon alpha-2a plus ribavirin for 48 weeks, n 5 73) or pioglitazone 30-45 mg/day plus standard care (n 5 77) in an open-label multicenter trial. Patients randomized to pioglitazone received the drug during a 16-week run-in phase, the 48-week standardcare phase, and the 24-week untreated follow-up phase. Pioglitazone treatment improved hemoglobin A1c (HbA1c), plasma glucose, insulin levels, and homeostasis model assessment of insulin resistance score and increased serum adiponectin levels during the 16-week run-in phase and maintained these improvements during the standard-care phase. However, we observed no statistically significant difference between the two groups in the primary efficacy endpoint, the decrease from baseline to Week 12 of peginterferon alpha-2a/ribavirin treatment in mean log10 HCV RNA titer (23.5 6 1.71 and 23.7 6 1.62 IU/mL in the pioglitazone and standard-care groups, respectively, D 5 0.21 IU/mL, P 5 0.4394). Conclusion: Treatment with pioglitazone before and during treatment with peginterferon alpha-2a plus ribavirin improved several indices of glycemic control in patients with chronic hepatitis C and insulin resistance, but did not improve virologic response rates compared with peginterferon alpha-2a plus ribavirin alone. (HEPATOLOGY 2012;56:464-473)
I
nfection with hepatitis C virus (HCV) is often associated with changes in lipid and carbohydrate metabolism.1 These changes result in insulin resistance and have been associated with a higher prevalence of type 2 diabetes mellitus, accelerated progression of hepatic fibrosis, and increased carotid artery intima thickness.2-4 The association between HCV infection and impaired glucose metabolism is strong. Diabetes is more prevalent in patients with chronic HCV-related cirrhosis than in patients with cirrhosis attributed to a cause other than HCV infection.5 Conversely, the prevalence of HCV infection is higher among patients with diabetes than in the general population.6,7 The
exact prevalence of impaired glucose metabolism in patients with HCV infection is not known, but ranges from 30% to 70% and varies with HCV genotype.1,8 There is growing evidence that metabolic perturbations associated with HCV infection may result from interactions between viral and host proteins.9-14 HCV core protein reduces expression of insulin receptor substrates (IRS) 1 and 2 and interferes with the cellular response to insulin. Eradication of HCV with peginterferon plus ribavirin therapy restores the expression of IRS-1 and IRS-2 and improves insulin resistance.15 HCV NS5A induces oxidative stress and increases the levels of inflammatory cytokines, which contributes indirectly to insulin resistance by stimulating nuclear
Abbreviations: HbA1c, hemoglobin A1c; HCV, hepatitis C virus; HOMA-IR, homeostasis model assessment of insulin resistance; IRS, insulin receptor substrates; NF-jB, nuclear factor kappaB; PPAR, peroxisome proliferator-activated receptor; SVR, sustained virologic response. From the 1Division of Gastroenterology and Hepatology, Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, TX; 2Genentech, South San Francisco, CA; 3Kansas University School of Medicine, Kansas City VA Medical Center, Kansas City, MO; 4University of California San Francisco, Fresno, CA; and 5 Baylor College of Medicine, Houston, TX. Received December 7, 2011; Revised January 24, 2012; accepted February 7, 2012. 464
HEPATOLOGY, Vol. 56, No. 2, 2012
factor-jB (NF-jB).9 Insulin resistance and increasing homeostasis model assessment of insulin resistance (HOMA-IR) scores have been associated with high serum HCV RNA levels.16-18 Patients with chronic hepatitis C and insulin resistance are less likely to respond to anti-HCV therapy and are at risk for more rapid fibrosis progression.19-23 Indeed, it is estimated that sustained virologic response (SVR) rates may be reduced by as much as 50% in HCV genotype 1 patients with insulin resistance.19 This suggests that measures that restore or improve insulin sensitivity might lead to better virologic response rates. Pioglitazone reduces insulin resistance in the liver and peripheral tissues by stimulating the nuclear receptors peroxisome proliferator-activated receptor (PPAR)c and -a that control expression of insulin-sensitive genes. Based on these molecular mechanisms, we hypothesized that correcting insulin resistance prior to initiating anti-HCV therapy might improve the virologic response to peginterferon plus ribavirin therapy. Subsequent to initiating this study, it has been reported that the addition of pioglitazone to peginterferon plus ribavirin therapy improved both on-treatment virologic response rates and SVR rates in patients with HCV genotype 4 and insulin resistance.24 It remains to be determined whether treatment with pioglitazone can produce a similar effect in patients infected with HCV genotype 1. For this reason, the randomized, multicenter SENSITIZE study was designed to evaluate the impact of pioglitazone on virologic and metabolic outcomes in insulin-resistant genotype 1 patients receiving peginterferon alpha-2a plus ribavirin.
Patients and Methods Patients. Patients eligible for the randomized, multicenter, open-label SENSITIZE study were at least 18 years old, had chronic HCV genotype 1 infection, insulin resistance, and a fasting plasma glucose 2, fasting blood glucose >100 mg/dL, or fasting blood insulin >10 lU/mL. Patients were required to have had either a liver biopsy within the previous 2 years that showed an absence of cirrhosis (fibrosis stage F0-3 by Metavir, F0-4 by Ishak, or
