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Background & Aims: Management of patients with cirrhosis includes endoscopic screening and surveillance to detect esophageal varices (EV) and prevent bleeding. However, the Baveno VI guidelines recommend avoiding endoscopies for patients with liver stiffness measurements below 20 kPa and platelet counts above 150,000 (favorable Baveno VI status) and endoscopic assessment of patients with higher levels of liver stiffness and platelet counts (unfavorable Baveno VI status). We aimed to validate the Baveno VI guidelines, evaluating outcomes of patients in the ANRS-CO12 CirVir cohort with compensated cirrhosis associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, with or without a sustained response to antiviral therapy., Methods: We performed an ancillary study using data from 891 patients in the ANRS CO12 CirVir cohort, treated at 35 centers in France, with HCV or HBV infection and biopsy-proven cirrhosis, Child-Pugh A scores, no previous complications, and no hepatocellular carcinoma who underwent an endoscopic procedure and had interpretable liver stiffness measurements and platelet counts. Progression of portal hypertension (PHT) was defined as the onset of varices needing treatment (VNT) or PHT-related bleeding. An sustained response to antiviral therapy was defined as undetectable level of HCV RNA by polymerase chain reaction assay (<50 IU/mL) 12 weeks after the end of treatment (SVR) or an undetectable level of HBV DNA. The primary aims were to validate the Baveno VI guidelines for screening and surveillance of EV in patients with compensated cirrhosis and to study the effects of an SVR on the progression of PHT., Results: A total of 200 patients achieved an SVR (22.4%) (94 patients with HCV infection, 98 patients with HBV infection, and 8 patients with both); 80 of these patients had favorable Baveno VI status and none had VNT. Progression of PHT was studied in 548 patients; during a follow-up period of 61.2 months (interquartile range, 39.5-80.6 months), 105 of these patients (19.1%) had progression of PHT. Lack of an SVR and grade 1 EV were independently associated with progression of PHT. At the time of PHT progression, all patients had unfavorable Baveno VI status. Achieving favorable Baveno VI status after an SVR was associated with the absence of PHT progression. Favorable Baveno VI status and SVR were independently associated with survival., Conclusions: In an analysis of data from a large cohort of patients with HBV- or HCV-associated cirrhosis in France, we validated the Baveno VI guidelines on screening and surveillance of PHT, even for patients who achieved a sustained response to antiviral therapy., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: There is debate over the effects of long-term oral fluoroquinolone therapy in patients with advanced cirrhosis. We performed a randomized controlled trial to evaluate the effects of long-term treatment with the fluoroquinolone norfloxacin on survival of patients with cirrhosis., Methods: We performed a double-blind trial of 291 patients with Child-Pugh class C cirrhosis who had not received recent fluoroquinolone therapy. The study was performed at 18 clinical sites in France from April 2010 through November 2014. Patients were randomly assigned to groups given 400 mg norfloxacin (n = 144) or placebo (n = 147) once daily for 6 months. Patients were evaluated monthly for the first 6 months and at 9 months and 12 months thereafter. The primary outcome was 6-month mortality, estimated by the Kaplan-Meier method, censoring spontaneous bacterial peritonitis, liver transplantation, or loss during follow-up., Results: The Kaplan-Meier estimate for 6-month mortality was 14.8% for patients receiving norfloxacin and 19.7% for patients receiving placebo (P = .21). In competing risk analysis that took liver transplantation into account, the cumulative incidence of death at 6 months was significantly lower in the norfloxacin group than in the placebo group (subdistribution hazard ratio, 0.59; 95% confidence interval, 0.35-0.99). The subdistribution hazard ratio for death at 6 months with norfloxacin vs placebo was 0.35 (95% confidence interval, 0.13-0.93) in patients with ascites fluid protein concentrations <15 g/L and 1.39 (95% confidence interval, 0.42-4.57) in patients with ascites fluid protein concentrations ≥15 g/L. Norfloxacin significantly decreased the incidence of any and Gram-negative bacterial infections without increasing infections caused by Clostridium difficile or multiresistant bacteria., Conclusions: In a randomized controlled trial of patients with advanced cirrhosis without recent fluoroquinolone therapy, norfloxacin did not reduce 6-month mortality, estimated by the Kaplan-Meier method. Norfloxacin, however, appears to increase survival of patients with low ascites fluid protein concentrations. ClinicalTrials.gov ID: NCT01037959., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Retrospective studies have found an unexpectedly high incidence of hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV)-associated cirrhosis who received direct-acting antiviral (DAA) agents. We analyzed data from the ANRS CO12 CirVir cohort to compare the incidence of HCC in patients with cirrhosis who received DAA therapy vs patients treated with interferon (IFN)., Methods: Data were collected from 1270 patients with compensated biopsy-proven HCV-associated cirrhosis recruited from 2006 through 2012 at 35 centers in France. For descriptive purpose, patients were classified as follows: patients who received DAA treatment (DAA group, n = 336), patients who achieved a sustained virologic response (SVR) following an IFN-based regimen (SVR-IFN group, n = 495), or patients who never received DAA treatment and never had an SVR following IFN therapy (non-SVR group, n = 439). The patients were included in HCC surveillance programs based on ultrasound examination every 6 months, and clinical and biological data were recorded. To account for confounding by indication due to differences in patient characteristics at treatment initiation, we constructed a time-dependent Cox regression model weighted by the inverse probability of treatment and censoring (IPTCW) to assess the treatment effects of DAA on time until HCC., Results: Compared with patients in the SVR-IFN group, patients in the DAA group were older, higher proportions had diabetes or portal hypertension, and liver function was more severely impaired. The crude 3-year cumulative incidences of HCC were 5.9% in the DAA group, 3.1% in the SVR-IFN group, and 12.7% in the non-SVR group (overall P < .001; unadjusted hazard ratio [HR] for HCC 2.03; 95% confidence interval [CI] 1.07-3.84; P = .030 for the DAA group vs the SVR-IFN group). HCC characteristics were similar among groups. Among patients with HCC, the DAA group received less-frequent HCC screening than the other 2 groups (P = .002). After Cox analyses weighted by the IPTCW, we found no statistically significant increase in risk of HCC associated with DAA use (HR 0.89; 95% CI 0.46-1.73; P = .73)., Conclusions: Analysis of data from the ANRS CO12 CirVir cohort reveals that the apparent increase in HCC incidence observed in patients with cirrhosis treated with DAAs compared with patients who achieved SVR following an IFN therapy can be explained by patient characteristics (age, diabetes, reduced liver function) and lower screening intensity., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Semi-annual surveillance for hepatocellular carcinoma (HCC) is recommended for patients with cirrhosis. We aimed to determine how compliance with HCC surveillance guidelines affects survival times of patients with hepatitis C virus- or hepatitis B virus-associated compensated cirrhosis who developed HCC., Methods: We collected data from the prospective ANRS CO12 CirVir study, from March 2006 through June 2012, on 1671 patients with biopsy-proven viral cirrhosis and no previous liver complications who were undergoing surveillance for HCC at 35 centers in France. Only 216 patients who developed HCC during the follow-up period were included in the analysis. Patients were considered to be compliant with surveillance guidelines if the time between their last surveillance image evaluation and diagnosis of HCC were fewer than 7 months and noncompliant if this time was 7 months or longer., Results: HCC was detected in 216 patients, at a median follow-up time of 59.7 months. Of these patients, 140 (80.5%) were Barcelona Clinic Liver Cancer stage 0/A, 135 (69.9%) received first-line curative treatment (15 underwent transplantation, 29 underwent resection, 89 received percutaneous ablation, and 2 received resection and percutaneous ablation), and 129 (60.0%) were compliant with surveillance guidelines. Seventy-nine of the patients with HCC died; 49 deaths were associated with tumor progression. After lead-time adjustment, overall survival (OS) time was longer in patients compliant with surveillance guidelines (median OS time, 53.2 months) than noncompliant patients (median OS time, 25.4 months) (P = .0107); this difference remained significant even when we changed lead time assumptions. In multivariate analysis adjusted for a propensity score, compliance with HCC surveillance guidelines was associated with low tumor burden, allocation of curative treatment, and increased OS time compared with noncompliance (hazard ratio for OS, 2.19; 95% confidence interval, 1.16-4.14; P = .0150)., Conclusions: In an analysis of data from the ANRS CO12 CirVir cohort, we associated compliance with HCC surveillance guidelines (fewer than 7 months between image evaluations) with early diagnosis, allocation of curative treatment, and longer adjusted OS of patients with hepatitis C virus- or hepatitis B virus-associated compensated cirrhosis and a diagnosis of HCC., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: We performed a prospective study to investigate the effects of a sustained viral response (SVR) on outcomes of patients with hepatitis C virus (HCV) infection and compensated cirrhosis., Methods: We collected data from 1323 patients included in the prospective Agence Nationale pour la Recherche sur le SIDA et les hépatites virales (ANRS) viral cirrhosis (CirVir) cohort, recruited from 35 clinical centers in France from 2006 through 2012. All patients had HCV infection and biopsy-proven cirrhosis, were Child-Pugh class A, and had no prior liver complications. All patients received anti-HCV treatment before or after inclusion (with interferon then with direct antiviral agents) and underwent an ultrasound examination every 6 months, as well as endoscopic evaluations. SVR was considered as a time-dependent covariate; its effect on outcome was assessed by the Cox proportional hazard regression method. We used a propensity score to minimize confounding by indication of treatment and capacity to achieve SVR., Results: After a median follow-up period of 58.2 months, 668 patients (50.5%) achieved SVR. SVR was associated with a decreased incidence of hepatocellular carcinoma (hazard ratio [HR] compared with patients without an SVR, 0.29; 95% confidence interval [CI], 0.19-0.43; P < .001) and hepatic decompensation (HR, 0.26; 95% CI, 0.17-0.39; P < .001). Patients with SVRs also had a lower risk of cardiovascular events (HR, 0.42; 95% CI, 0.25-0.69; P = .001) and bacterial infections (HR, 0.44; 95% CI, 0.29-0.68; P < .001). Metabolic features were associated with a higher risk of hepatocellular carcinoma in patients with SVRs, but not in patients with viremia. SVR affected overall mortality (HR, 0.27 compared with patients without SVR; 95% CI, 0.18-0.42; P < .001) and death from liver-related and non-liver-related causes. Similar results were obtained in a propensity score-matched population., Conclusions: We confirmed a reduction in critical events, liver-related or not, in a prospective study of patients with HCV infection and compensated cirrhosis included in the CirVir cohort who achieved an SVR. We found an SVR to reduce overall mortality and risk of death from liver-related and non-liver-related causes. A longer follow-up evaluation is required to accurately describe and assess specific risk factors for complications in this population., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: We investigated the effectiveness of the protease inhibitors peginterferon and ribavirin in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis., Methods: In the Compassionate Use of Protease Inhibitors in Viral C Cirrhosis study, 511 patients with HCV genotype 1 infection and compensated cirrhosis who did not respond to a prior course of peginterferon and ribavirin (44.3% relapsers or patients with viral breakthrough, 44.8% partial responders, and 8.0% null responders) were given either telaprevir (n = 299) or boceprevir (n = 212) for 48 weeks. We assessed percentages of patients with sustained viral responses 12 weeks after therapy and safety. This observational study did not allow for direct comparison of the 2 regimens., Results: Among patients given telaprevir, 74.2% of relapsers, 40.0% of partial responders, and 19.4% of null responders achieved SVR12. Among those given boceprevir, 53.9% of relapsers, 38.3% of partial responders, and none of the null responders achieved SVR12. In multivariate analysis, factors associated with SVR12 included prior response to treatment response, no lead-in phase, HCV subtype 1b (vs 1a), and baseline platelet count greater than 100,000/mm(3). Severe adverse events occurred in 49.9% of cases, including liver decompensation, severe infections in 10.4%, and death in 2.2%. In multivariate analysis, baseline serum albumin level less than 35 g/L and baseline platelet counts of 100,000/mm(3) or less predicted severe side effects or death., Conclusions: Relatively high percentages of real-life, treatment-experienced patients with HCV genotype 1 infection and cirrhosis respond to the combination of peginterferon and ribavirin with telaprevir or boceprevir. However, side effects are frequent and often severe. Baseline levels of albumin and platelet counts can be used to guide treatment decisions. ClinicalTrials.gov number: NCT01514890., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: We performed a meta-analysis to evaluate the effects of ursodeoxycholic acid (UDCA) on pruritus, liver test results, and outcomes of babies born to women with intrahepatic cholestasis of pregnancy (ICP)., Methods: We performed a systematic review of 9 published, randomized controlled trials (3 double blinded) that compared the effects of UDCA to other drugs, placebo, or no specific treatment (controls) in patients with ICP. We analyzed data from 454 patients: 207 received only UDCA, 70 received only placebo, 42 received cholestyramine, 36 received dexamethasone for 1 week and then placebo for 2 weeks, 65 received S-adenosyl-methionine, and 34 received no specific treatment. To achieve consistency among end points, a standard questionnaire was sent to all corresponding authors. For each end point, we performed pooled analysis that compared the effects of UDCA with those of all controls and UDCA with those of placebos., Results: In pooled analyses that compared UDCA with all controls, UDCA was associated with total resolution of pruritus (odds ratio [OR], 0.23; 95% confidence interval [CI], 0.07-0.74; P < .01), reduced pruritis (OR, 0.27; 95% CI, 0.13-0.55; P < .0001), normalization of serum levels of alanine aminotransferase (ALT) (OR, 0.23; 95% CI, 0.10-0.50; P < .001), decreased serum level of ALT (OR, 0.24; 95% CI, 0.11-0.52; P < .0001), reduced serum levels of bile acids (OR, 0.37; 95% CI, 0.19-0.75; P < .001), fewer premature births (OR, 0.44; 95% CI, 0.24-0.79; P < .01), reduced fetal distress (OR, 0.46; 95% CI, 0.25-0.86; P < .01), less frequent respiratory distress syndrome (OR, 0.30; 95% CI, 0.12-0.74; P < .01), and fewer neonates in the intensive care unit (OR, 0.49; 95% CI, 0.25-0.98; P = .046). In pooled analyses that compared the effects of UDCA with placebo, UDCA reduced pruritus (OR, 0.21; 95% CI, 0.07-0.62; P < .01), normalized (OR, 0.18; 95% CI, 0.06-0.52; P < .001) or decreased serum levels of ALT (OR, 0.12; 95% CI, 0.05-0.31; P < .0001), and reduced serum levels of bile acids (OR, 0.30; 95% CI, 0.12-0.73; P < .01)., Conclusions: Based on a meta-analysis, UDCA is effective in reducing pruritus and improving liver test results in patients with ICP; UDCA therapy might also benefit fetal outcomes., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: The outcome of chronic hepatitis B and the efficacy of interferon alfa (IFN-alpha) remain controversial in human immunodeficiency virus (HIV)-positive patients. We analyzed the influence of HIV coinfection on the response to IFN-alpha therapy, long-term virologic status, progression to cirrhosis, and mortality., Methods: This was a retrospective follow-up cohort study of 141 consecutive hepatitis B e antigen-positive patients (69 HIV positive) followed up for 45 months., Results: The short-term response to IFN-alpha therapy was not significantly different in HIV-positive and HIV-negative patients (28% vs. 51%; P = 0.06) but was poorer in cases of low CD4 cell count (P = 0.038). The hepatitis B virus (HBV) reactivation rate was higher in HIV-positive patients (P = 0.033) and was associated with low CD4 cell count. The risk of cirrhosis was higher in HIV-positive patients with a CD4 cell count <200/mm(3) (relative risk [RR], 4.57; P = 0.007), in IFN-alpha-untreated patients (RR, 2.63; P = 0.041), in patients older than 33 years (RR, 4.59; P = 0.008), and in cases of high necroinflammatory score at baseline (RR, 1.27; P = 0.010). Cirrhosis-related death was more frequent in HIV-positive patients with low CD4 cell count at baseline (P = 0.041), in alcohol consumers (P = 0.001), in IFN-alpha-untreated patients (P = 0.052), and in patients with high histology activity index at baseline (P = 0.005)., Conclusions: HIV coinfection was associated with poorer response to IFN-alpha therapy, more frequent HBV reactivations, and increased incidence of cirrhosis and cirrhosis-related death in cases of low CD4 count. IFN-alpha therapy decreased the incidence of HBV cirrhosis regardless of HIV status or serologic response.

Background & Aims: During hepatitis C virus (HCV) infection, liver fibrosis progression after renal transplantation remains controversial. The aim of this cohort study with controls was to compare liver histopathologic features during HCV infection between renal transplant recipients and matched groups of hemodialyzed patients or controls without renal disease and untreated for HCV., Methods: Each renal transplant recipient (group 1, n = 30) was matched at first liver biopsy (LB) using the main factors known to influence progression of fibrosis with one HCV hemodialyzed patient (group 2, n = 30) and one HCV-infected patient (nonhemodialyzed, nontransplanted; group 3, n = 30). Patients from group 1 were also matched with those of group 3 on the time between 2 consecutive LBs performed 37 months apart. LBs were evaluated according to the Knodell index, METAVIR score, and rate of fibrosis progression per year (fibrosis unit)., Results: The rate of fibrosis progression per year between the first and second LBs was significantly lower (P = 0.03) in group 1 (0.067; 95% confidence interval: -0.05, 0.18) than group 3 (0.20; 95% confidence interval: 0.13, 0.26). At the second LB, the Knodell index and activity or fibrosis in METAVIR were lower in group 1 than group 3 (4.2 +/- 0.4 vs. 7.5 +/- 0.6, 0.5 +/- 0.1 vs. 1.3 +/- 0.2, and 1.4 +/- 0.2 vs. 2.3 +/- 0.2 respectively, P < 0.01)., Conclusions: Our study suggests that liver fibrosis progression is low in most HCV-infected renal transplant recipients with moderate liver disease at baseline.

Background & Aims: We have observed a high prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in heart transplant recipients (HTRs). The aim of this study was to assess the epidemiology, natural history, and clinical and biological characteristics of viral hepatitis in HTRs., Methods: From 1983 to 1992, 874 patients underwent heart transplantation at the Pitié-Salpêtrière Hospital, Paris, France, 459 of whom qualified for analysis. A total of 140 patients had posttransplantation hepatitis B, C, or non-A-E. Sixty-nine patients developed HBV infection, 49 HCV infection, 11 HBV-HCV coinfection, and 11 non-A-E hepatitis., Results: HBV was transmitted nosocomially from patient to patient, most likely during endomyocardial biopsies. HCV was mainly transmitted through blood transfusions or the transplanted organ. Clinical and biological findings after 2 years of follow-up showed that 3 patients with an HBV genotype A precore mutant had severe or subfulminant hepatitis and that patients with HBV and HCV infection always progressed to chronicity. In general, patients had mild alanine aminotransferase level increases, a high level of viral replication, and few severe histologic lesions, except for patients infected by precore HBV mutants. Patients coinfected by HBV and HCV tended to have more severe liver lesions. The survival rate 5 years after transplantation in patients with viral hepatitis (HBV, 81%; HCV, 89%; HBV and HCV coinfection, 100%; non-A-E hepatitis, 73%) was similar to that in patients without liver test abnormalities (76%). The actuarial survival curve was also similar in patients with or without liver test abnormalities., Conclusions: In our experience, histologic liver lesions do not progress rapidly in patients with post-heart transplant infection caused by HBV or HCV. HBV or HCV infection seems to have little impact on the 5-year survival rate of HTRs.