Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin. In this randomized, phase 3 trial, we evaluated the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response. A total of 663 patients were assigned to one of three groups: the T12PR48 group, which received telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks; the lead-in T12PR48 group, which received 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks; and the control group (PR48), which received peginterferon plus ribavirin for 48 weeks. The primary end point was the rate of sustained virologic response, which was defined as undetectable HCV RNA 24 weeks after the last planned dose of a study drug. Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (P<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%). Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase. (Funded by Tibotec and Vertex Pharmaceuticals; REALIZE ClinicalTrials.gov number, NCT00703118.)

Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5–10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5–10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P<0.001 for both comparisons). Patients in the 5–10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, −113 and −130 U per liter, respectively, vs. −14 U per liter; P<0.001 for both comparisons) and total bilirubin level (−0.02 and −0.05 mg per deciliter [−0.3 and −0.9 μmol per liter], respectively, vs. 0.12 mg per deciliter [2.0 μmol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5–10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group). The rate of serious adverse events was 16% in the 5–10-mg group, 11% in the 10-mg group, and 4% in the placebo group. Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524; Current Controlled Trials number, ISRCTN89514817.)

PURPOSE: To review the available evidence of chemoembolization for unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Computerized bibliographic searches with MEDLINE and CANCERLIT databases from 1980 through 2000 were supplemented with manual searches, with the keywords “hepatocellular carcinoma,” “liver cell carcinoma,” “randomized controlled trial [RCT],” and “chemoembolization.” Studies were included if patients with unresectable HCC were enrolled and if they were RCTs in which chemoembolization was compared with nonactive treatment (five RCTs) or if different transarterial modalities of therapy (13 RCTs) were compared. Data were extracted from each RCT according to the intention-to-treat method. Five of the RCTs with a nonactive treatment arm were combined by using the random-effects model, whereas all 18 RCTs were pooled from meta–regression analysis. RESULTS: Chemoembolization significantly reduced the overall 2-year mortality rate (odds ratio, 0.54; 95% CI: 0.33, 0.89; P = .015) c...

The effect of achieving a sustained virological response (SVR) following interferon-α (IFNα) treatment on the clinical outcomes of patients with HCV-related cirrhosis is unknown. In an attempt to assess the risk of liver-related complications, HCC and liver-related mortality in patients with cirrhosis according to the response to IFNα treatment, a retrospective database was developed including all consecutive patients with HCV-related, histologically proven cirrhosis treated with IFNα monotherapy between January 1992 and December 1997. SVR was an undetectable serum HCV-RNA by PCR 24 weeks after IFNα discontinuation. HCC was assessed by ultrasound every 6 months. Independent predictors of all outcomes were assessed by Cox regression analysis. Of 920 patients, 124 (13.5%) were classified as achieving a SVR. During a mean follow-up of 96.1 months (range: 6-167) the incidence rates per 100 person-years of liver-related complications, HCC and liver-related death were 0, 0.66, and 0.19 among SVR and 1.88, 2.10, and 1.44 among non-SVR ( P < 0.001 by log-rank test). Multivariate analyses found that non-SVR was associated with a higher risk of liver-related complications (hazard ratio, HR, not applicable), HCC (HR 2.59; 95% CI 1.13-5.97) and liver-related mortality (HR 6.97; 95% CI 1.71-28.42) as compared to SVR. Conclusion: Thus, in patients with HCV-related, histologically proven cirrhosis, achievement of a SVR after IFNα therapy was associated with a reduction of liver-related mortality lowering both the risk of complications and HCC development. Irrespective of SVR achievement, all patients should continue surveillance because the risk of occurrence of HCC was not entirely avoided. (Hepatology 2007;45:579–587.)

Hepatitis B virus (HBV) causes self-limited infections in the majority of adult patients; however, in less than 5% of infected adults and in a larger proportion of children, HBV infection evolves into a chronic liver disease, which may lead to severe sequelae. Available data indicate a vigorous and broad T-cell response in patients with acute self-limited hepatitis B, which is in contrast with the much weaker and often barely detectable T-cell response observed during chronic HBV infections, in which HBV-specific T-lymphocytes have been described to be deeply dysfunctional.¹ x 1 Bertoletti, A. and Ferrari, C. Kinetics of the immune response during HBV and HCV infection. Hepatology. 2003; 38: 4–13 Google Scholar See all References ^{, 2} x 2 Rehermann, B. and Nascimbeni, M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol. 2005; 5: 215–229 Google Scholar See all References ^{, 3} x 3 Das, A., Hoare, M., Davies, N. et al. Functional skewing of the global CD8 T-cell population in chronic hepatitis B virus infection. J Exp Med. 2008; 205: 2111–2124 Google Scholar See all References Among the different mechanisms proposed to explain such a functional T-cell impairment, exhaustion by persistent exposure to high antigen concentrations represents a possible cause,⁴ x 4 Chang, J.J., Thompson, A.J.V., Visvanathan, K. et al. The phenotype of hepatitis B virus-specific T cells differs in the liver and blood in chronic hepatitis B virus infection. Hepatology. 2007; 46: 1332–1340 Google Scholar See all References ^{, 5} x 5 Zhang, Z., Zhang, J.-Y., Wherry, E.J. et al. Dynamic programmed death 1 expression by virus-specific CD8 T cells correlates with the outcome of acute hepatitis B. Gastroenterology. 2008; 134: 1938–1949 Abstract | Full Text | Full Text PDF | Scopus (94) | Google Scholar See all References ^{, 6} x 6 Boni, C., Fisicaro, P., Valdatta, C. et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol. 2007; 81: 4215–4225 Google Scholar See all References and T-cell attrition through Bcl2 signalling⁷ x 7 Lopes, A.R., Kellam, P., Das, A. et al. Bim-mediated deletion of antigen-specific CD8+ T cells in patients unable to control HBV infection. J Clin Invest. 2008; 118: 1835–1845 Google Scholar See all References as well as impaired T-cell receptor signaling through the ζ-chain³ x 3 Das, A., Hoare, M., Davies, N. et al. Functional skewing of the global CD8 T-cell population in chronic hepatitis B virus infection. J Exp Med. 2008; 205: 2111–2124 Google Scholar See all References have been shown to be involved.