Multicenter, Double-Blind, Randomized Trial of Emricasan in Hepatitis C-Treated Liver Transplant Recipients With Residual Fibrosis or Cirrhosis.

Despite achieving sustained virologic response (SVR) to hepatitis C virus (HCV) therapy, there remains a post liver transplantation population with advanced fibrosis/cirrhosis. Emricasan is an orally active, pan-caspase inhibitor that suppresses apoptosis and inflammation, potentially decreasing hepatic inflammation and fibrosis. We aimed to determine the safety and efficacy of emricasan (IDN-6556-07) in a double-blind, randomized, placebo-controlled, multicenter study in reducing or preventing the progression of hepatic fibrosis in HCV liver transplant recipients with residual fibrosis or cirrhosis after achieving SVR. A total of 64 participants were randomly assigned to receive 25 mg twice daily of emricasan or placebo in a 2:1 ratio for 24 months. 41 participants were randomly assigned to emricasan and 23 to placebo; 32 participants in the emricasan group (78.0%) and 19 who took a placebo (82.6%) completed the study. There was no difference in the primary endpoint (Ishak fibrosis stages F2-F5, improvement in fibrosis or stability; Ishak fibrosis stage F6, improvement) between the emricasan (77.1%) and placebo groups (74.1%); P = NS. There was no difference between the emricasan (54.5%) and placebo (60.7%) arms in the rate of fibrosis improvement alone. However, those in the prespecified F3 to F5 subgroup had higher rates of stability or improvement in fibrosis in the emricasan group (95.2%) compared with placebo (54.6%) (P = 0.01). The tolerability and safety profiles were similar in both groups. In conclusion, overall stability in the Ishak fibrosis stage was similar between emricasan and placebo groups at 24 months. However, there was improvement and/or stability in fibrosis stage in the prespecified F3 to F5 subgroup with emricasan versus placebo, suggesting that patients with moderate fibrosis may benefit with emricasan.

Interferons alpha, beta, gamma each inhibit hepatitis C virus replication at the level of internal ribosome entry site-mediated translation.

Interferon (IFN)-alpha is the standard therapy for the treatment of chronic hepatitis C, but the mechanisms underlying its antiviral action are not well understood. In this report, we demonstrated that IFN-alpha, -beta and -gamma inhibit replication of the hepatitis C virus (HCV) in a cell culture model at concentrations between 10 and 100 IU/ml. We demonstrated that the antiviral actions each of each these IFNs are targeted to the highly conserved 5' untranslated region of the HCV genome, and that they directly inhibit translation from a chimeric clone between full-length HCV genome and green fluorescent protein (GFP). This effect is not limited to HCV internal ribosome entry site (IRES), since these IFNs also inhibit translation of the encephalomyocardititis virus (EMCV) chimeric mRNA in which GFP is expressed by IRES-dependent mechanisms (pCITE-GFP). These IFNs had minimal effects on the expression of mRNAs from clones in which translation is not IRES dependent. We conclude that IFN-alpha, -beta and -gamma inhibit replication of sub-genomic HCV RNA in a cell culture model by directly inhibiting two internal translation initiation sites of HCV- and EMCV-IRES sequences present in the dicistronic HCV sub-genomic RNA. Results of this in vitro study suggest that selective inhibition of IRES-mediated translation of viral polyprotein is a general mechanism by which IFNs inhibits HCV replication.

Umbilical hernia repair in cirrhotic patients: utility of temporary peritoneal dialysis catheter.

Umbilical herniorrhaphy in cirrhotic patients with ascites is associated with a significant morbidity, recurrence rate, and mortality and therefore is often managed expectantly. Operative repair is indicated if an ascites leak or infection develops. Surgeons must consider the management of postoperative ascites to reduce recurrence rates and complications. We present a unique method using temporary peritoneal dialysis catheter placement (PD). Eight patients with moderate to massive ascites underwent umbilical herniorrhaphy with concomitant peritoneal dialysis placement. Patients have been followed for 8 to 30 months. All patients had successful repair of their hernia with 1 recurrence at 6 months and 1 late death (14 months). Patients were able to effectively control ascites using the PD catheter at home. There were no postoperative infections. The placement of a temporary PD catheter during umbilical herniorrhaphy provides a method for effective control of ascites in patients with cirrhosis. The technique has several advantages including outpatient management during the postoperative period and for easy removal of the catheter when no longer needed.

Variceal Hemorrhage.

Reducing morbidity and mortality from esophageal varices remains a challenge for physicians managing patients with chronic liver disease. For patients who have never bled from varices, prophylactic therapy with nonselective beta-blockers reduces the risk of initial variceal bleeding and bleeding-related death. Thus, patients with newly diagnosed cirrhosis should be considered for endoscopic variceal screening. All patients with Child's class B and C cirrhosis should be offered endoscopic screening, whereas those with Child's class A with evidence of portal hypertension (eg, platelet count less than 140,000 per milliliter, portal vein diameter larger than 13 mm, evidence of splenic varices on ultrasound) should be screened. The principal risk factors for variceal bleeding are variceal size, the presence of color changes on the variceal wall (indicative of decreased wall thickness), and degree of liver dysfunction. Patients with moderate or large sized varices and those with varices exhibiting color changes (eg, red wale marks, cherry red spots) should be treated with beta-blockers. Individuals without varices and those with small varices should undergo repeat endoscopy at approximately 2-year intervals. Patients unwilling or unable to take beta-blockers do not need to be screened. For patients with acute variceal bleeding, the combination of pharmacologic therapy plus endoscopic therapy is superior to either therapy alone. Octreotide is the drug most often used as initial therapy in the United States. Terlipressin is the preferred agent; however, it is not available in the United States. Endoscopy is performed as early as possible, and endoscopic injection sclerotherapy or endoscopic variceal band ligation is employed if variceal bleeding is confirmed or suspected. Endoscopic therapy should be repeated until the varices are obliterated completely. The addition of beta-blockers to endoscopic sclerotherapy or ligation may decrease the rate of rebleeding compared with receiving endoscopic treatment alone. Patients with bleeding refractory to combined medical plus endoscopic therapy should be considered for transjugular intrahepatic portosystemic shunts or shunt surgery.