Transjugular Intrahepatic Portosystemic Shunts With Covered Stents Increase Transplant-Free Survival of Patients With Cirrhosis and Recurrent Ascites.

BACKGROUND & AIMS: There is controversy over the ability of transjugular intrahepatic portosystemic shunts (TIPS) to increase survival times of patients with cirrhosis and refractory ascites. The high rate of shunt dysfunction with the use of uncovered stents counteracts the benefits of TIPS. We performed a randomized controlled trial to determine the effects of TIPS with stents covered with polytetrafluoroethylene in these patients. METHODS: We performed a prospective study of 62 patients with cirrhosis and at least 2 large-volume paracenteses within a period of at least 3 weeks; the study was performed at 4 tertiary care centers in France from August 2005 through December 2012. Patients were randomly assigned to groups that received covered TIPS (n = 29) or large-volume paracenteses and albumin as necessary (LVP+A, n = 33). All patients maintained a low-salt diet and were examined at 1 month after the procedure then every 3 months until 1 year. At each visit, liver disease-related complications, treatment modifications, and clinical and biochemical variables needed to calculate Child-Pugh and Model for End-Stage Liver Disease scores were recorded. Doppler ultrasonography was performed at the start of the study and then at 6 and 12 months after the procedure. The primary study end point was survival without a liver transplant for 1 year after the procedure. RESULTS: A higher proportion of patients in the TIPS group (93%) met the primary end point than in the LVP+A group (52%) (P = .003). The total number of paracenteses was 32 in the TIPS group vs 320 in the LVP+A group. Higher proportions of patients in the LVP+A group had portal hypertension-related bleeding (18% vs 0%; P = .01) or hernia-related complications (18% vs 0%; P = .01) than in the TIPS group. Patients in LVP+A group had twice as many days of hospitalization (35 days) as the TIPS group (17 days) (P = .04). The 1-year probability of remaining free of encephalopathy was 65% for each group. CONCLUSIONS: In a randomized trial, we found covered stents for TIPS to increase the proportion of patients with cirrhosis and recurrent ascites who survive transplantation-free for 1 year, compared with patients given repeated LVP+A. These findings support TIPS as the first-line intervention in such patients. ClinicalTrials.gov ID: NCT00222014.

Longterm Risk of Solid Organ De Novo Malignancies After Liver Transplantation: A French National Study on 11,226 Patients.

De novo malignancies are one of the major late complications and causes of death after liver transplantation (LT). Using extensive data from the French national Agence de la Biomédecine database, the present study aimed to quantify the risk of solid organ de novo malignancies (excluding nonmelanoma skin cancers) after LT. The incidence of de novo malignancies among all LT patients between 1993 and 2012 was compared with that of the French population, standardized on age, sex, and calendar period (standardized incidence ratio; SIR). Among the 11,226 LT patients included in the study, 1200 de novo malignancies were diagnosed (10.7%). The risk of death was approximately 2 times higher in patients with de novo malignancy (48.8% versus 24.3%). The SIR for all de novo solid organ malignancies was 2.20 (95% confidence interval [CI], 2.08-2.33). The risk was higher in men (SIR = 2.23; 95% CI, 2.09-2.38) and in patients transplanted for alcoholic liver disease (ALD; SIR = 2.89; 95% CI, 2.68-3.11). The cancers with the highest excess risk were laryngeal (SIR = 7.57; 95% CI, 5.97-9.48), esophageal (SIR = 4.76; 95% CI, 3.56-6.24), lung (SIR = 2.56; 95% CI, 2.21-2.95), and lip-mouth-pharynx (SIR = 2.20; 95% CI, 1.72-2.77). In conclusion, LT recipients have an increased risk of de novo solid organ malignancies, and this is strongly related to ALD as a primary indication for LT.

Treatment of recurrent HCV infection following liver transplantation: results of a multicenter, randomized, versus placebo, trial of ribavirin alone as maintenance therapy after one year of PegIFNα-2a plus ribavirin.

BACKGROUND & AIMS: We aimed at determining the effect of maintenance therapy with ribavirin alone, after a year of combined peginterferon-alfa 2a (PegIFNα-2a) and ribavirin therapy, on viral response and liver histology after liver transplantation (LT). METHODS: Hundred and one patients with recurrent HCV and a minimum of stage 1 fibrosis (METAVIR scoring), 1-5years after LT, were enrolled. PegIFNα-2a and ribavirin were initiated at 90 µg/wk and 600 mg/d, respectively, then increased or adjusted as a function of tolerance. At 12 months, combination therapy was discontinued and patients were randomized to ribavirin or placebo for a further 12 months. Growth factor use was permitted. RESULTS: At 18 months, a sustained virological response (SVR) was obtained in 47.9% of patients in Per Protocol (PP) analysis, and was higher in patients with genotype 2 or 3 than in patients with genotype 1 or 4, in patients with genotypes 1+4 receiving ciclosporine than in those receiving tacrolimus, in patients with worse renal function, in those having received EPO, in patients with lower weight, and in those with lower viral load at 3 months. Using logistic regression, only the early viral response, recipient weight and renal function were independently associated with better SVR. SVR, viral load, activity, and fibrosis scores were similar, at M18 and M30, in patients randomized to ribavirin, or to placebo. CONCLUSIONS: A PP SVR was achieved in 47.9% of patients with established recurrent hepatitis C after LT. Maintenance therapy with ribavirin alone does not improve the virological response or the histological parameters.

Usefulness of viral kinetics for early prediction of a sustained virological response in HCV-1 non-responders re-treated with pegylated interferon and ribavirin.

BACKGROUND & AIMS: Undetectable HCV RNA at 12 weeks is the stopping rule recommended in HCV patients in whom previous treatment has failed. Whether earlier virological criteria may be useful for deciding treatment discontinuation remains subject of debate. The aim of this study was to identify, in HCV-1 non-responders and relapsers to IFN or Peg-IFN and ribavirin, the earliest and most accurate predictor of failure to respond to a new treatment combining Peg-IFN and ribavirin. METHODS: Prediction of SVR was assessed using the area under the ROC (AUROC) curve of reduction in viral load at different time points. RESULTS: This study included 151 patients (32% with extensive fibrosis or cirrhosis). A SVR was reached in 34% (21% in non-responders and 59% in relapsers). In non-responders, 1 month was the most accurate time point for predicting SVR (AUROC: 0.787 ± 0.075, p = 0.0001). Thirty-seven percent of non-responders did not have a 1-log drop in viral load at 1 month. All these patients had detectable HCV RNA at 3 months (p < 0.0001) and only 4% attained a SVR (p = 0.004). The same high negative predictive value for SVR was found in sensitivity analysis restricted to non-responders to Peg-IFN and ribavirin. In contrast, in relapsers, undetectable HCV RNA at 3 months was the earliest criterion with high negative predictive value (92%, p < 0.0001). CONCLUSIONS: All HCV-1 non-responders who did not have a 1-log drop in viral load at 1 month remained HCV-RNA-detectable at 3 months, and only 4% attained a SVR. This new criterion can be used early on as a first stopping rule.

Impact of pegylated interferon and ribavirin on morbidity and mortality in patients with chronic hepatitis C and normal aminotransferases in France.

UNLABELLED: Clinicians continue to raise questions concerning the necessity of treating chronic hepatitis C virus (HCV)-infected patients with normal alanine aminotransferase (N-ALT), in light of their slower progression to cirrhosis than patients with elevated alanine aminotraferase (E-ALT). This study was undertaken to predict the impact of pegylated interferon (IFN) and ribavirin on HCV-related morbidity and mortality in patients with N-ALT. A previous Markov model was adapted to separately simulate patients with N-ALT (30%) and those with E-ALT (70%). The model estimates fibrosis progression rates according to age, sex, and whether ALT levels are normal or elevated, assuming that patients with E-ALT have a 2.6 times higher progression than those with N-ALT. It takes into account improvement in HCV screening and treatment and competitive mortality. We assumed that N-ALT patients were treated 80% less frequently between 2002 and 2004 and 70% less frequently from 2005 on, as obtained in real life from three multicentric cohorts (Hepatys, Adequation, Persee). Antiviral treatment of HCV-infected populations might reduce 2008-2025 HCV-related morbidity and mortality by 34,200 cases of cirrhosis (36%, 33,000-35,000), 22,400 complications (28%, 21,000-23,000) and 17,500 deaths (25%, 17,000-18,000), including 3000 cases of cirrhosis (22%, 2000-5000), 1200 complications (15%, 1000-1700), and 1000 deaths (14%, 900-1300) in the N-ALT population, despite a probability of receiving treatment that is three to five times less in this population. If N-ALT patients are treated at the same proportions as those with E-ALT, morbidity and mortality could be further reduced by 1400 cases of cirrhosis (13%, 1200-2200), 600 complications (9%, 600-1000), and 500 deaths (9%, 500-800). CONCLUSION: Treatment of N-ALT patients would decrease HCV morbidity and mortality. These patients should be considered candidates for treatment just as others are.