Safety of peginterferon alfa-2a plus ribavirin in a large multinational cohort of chronic hepatitis C patients.

BACKGROUND & AIMS: Peginterferon plus ribavirin has been the standard of care for chronic hepatitis C for a decade and an essential component of combination regimens for this disease. This large multinational open-label study aimed to better define the incidence of serious adverse events (SAEs) and non-serious adverse events of special interest in patients receiving peginterferon alfa-2a/ribavirin. METHODS: Patients were assigned at the investigator's discretion to 24- or 48-week treatment with peginterferon alfa-2a 180 µg/week and ribavirin 800 mg/day or 1000/1200 mg/day. All AEs, defined as SAEs and non-SAEs of special interest, were recorded during treatment and for 12 weeks thereafter. Non-SAEs of special interest included those leading to dose reduction/discontinuation, neutropenia, thrombocytopenia, anaemia, ALT elevations leading to dose modification and unknown/unexpected AEs. RESULTS: Of 1675 and 7178 patients assigned to 24 and 48 weeks of treatment, respectively, 87.6 and 68.3% completed therapy, whereas 6.4 and 10.3% prematurely stopped peginterferon alfa-2a treatment because of AEs. Among patients assigned to 24 and 48 weeks, 37.4 and 46.9%, respectively, reported any AE (SAE or non-SAE of special interest); 4.2 and 6.6% reported SAEs and 35.2 and 44.0% reported non-SAEs of special interest. Female gender, increasing age and cirrhosis were significantly associated with dose reductions of either drug. Increasing age (and female gender in the case of ribavirin) was significantly associated with treatment discontinuation. CONCLUSION: This study confirmed the safety and tolerability profile of peginterferon alfa-2a/ribavirin and identified patient subgroups at higher risk of dose reductions and discontinuations, thus allowing optimum management of AEs.

Intrahepatic insulin resistance in a murine model of steatohepatitis: effect of PPARgamma agonist pioglitazone.

Hepatic insulin resistance is associated with hepatic steatosis and is thought to play an important role in the pathogenesis of steatohepatitis. Using a murine model of steatohepatitis (mice fed a diet deficient in methionine and choline-MCD diet), we tested the effects of the insulin-sensitising, PPARgamma agonist drug pioglitazone (PGZ) on systemic and intrahepatic insulin sensitivity and on liver pathology. Compared to controls, mice fed the MCD diet develop a significant steatohepatitis, have enhanced glucose tolerance and enhanced systemic response to insulin. PGZ did not affect the systemic insulin sensitivity in control or MCD-fed mice as assessed in vivo by intraperitoneal glucose or insulin dynamic tests. However, PGZ prevented hepatic fat accumulation and steatohepatitis induced by the MCD diet. This effect was associated with an increased mass of adipose tissue and increased expression and release of adiponectin, while hepatic acyl co-enzyme A oxidase and acyl-co-enzyme A carboxylase, regulating hepatic beta-oxidation of fatty acid, remained unchanged. Steatohepatitis in MCD-diet-fed mice was associated with intrahepatic insulin resistance as shown by a reduced phosphorylation of hepatic insulin receptor, and Akt in response to an insulin stimulus. PGZ to MCD-fed mice restored the activation of the insulin receptor and of the Akt pathway in response to insulin. In conclusion, PGZ alleviates steatosis and steatohepatitis induced by the MCD diet, an effect associated with correction of intrahepatic insulin resistance.