ABO blood group does not influence Child-Pugh A cirrhosis outcome: An observational study from CIRRAL and ANRS CO12 CIRVIR cohorts.

BACKGROUND AND AIMS: Non-O blood group promotes deep vein thrombosis and liver fibrosis in both general population and hepatitis C. We aimed to evaluate the influence of Non-O group on the outcome of Child-Pugh A cirrhotic patients. METHODS: We used two prospective cohorts of Child-Pugh A cirrhosis due to either alcohol or viral hepatitis. Primary end point was the cumulated incidence of 'Decompensation' at 3 years, defined as the occurrence of ascites , hydrothorax, encephalopathy, gastrointestinal bleeding related to portal hypertension, or bilirubin >45 µmol/L. Secondary end points were the cumulated incidences of (1) 'Disease Progression' including a « decompensation¼ or « the occurrence of one or more parameters ¼ among: prothrombin time (PT) <45%, albumin <28 g/L, Child-Pugh worsening (B or C vs A or B, C vs B), hepatorenal syndrome, and hepato-pulmonary syndrome, (2) other events such as non-malignant portal vein thrombosis (nmPVT), and (3) overall survival. RESULTS: Patients (n = 1789; 59.9% Non-O group; 40.1% group O) were followed during a median of 65.4 months. At 3 years cumulated incidence of Decompensation was 8.3% in Non-O group and 7.2% in group O (P = .27). Cumulated incidence of Disease Progression was 20.7% in Non-O group and 18.9% in group O (P = .26). Cumulated incidence of nmPVT was 2.7% in Non-O group and 2.8% in group O (P = .05). At 3 years overall survival was 92.4% in Non-O group and 93.4% in group O (P = 1). CONCLUSION: Non-O group does not influence disease outcome in Child-Pugh A cirrhotic patients. Clinicals trial number NCT03342170.

Mass Spectrometry-Based Proteomics Reveal Alcohol Dehydrogenase 1B as a Blood Biomarker Candidate to Monitor Acetaminophen-Induced Liver Injury.

Acute liver injury (ALI) is a severe disorder resulting from excessive hepatocyte cell death, and frequently caused by acetaminophen intoxication. Clinical management of ALI progression is hampered by the dearth of blood biomarkers available. In this study, a bioinformatics workflow was developed to screen omics databases and identify potential biomarkers for hepatocyte cell death. Then, discovery proteomics was harnessed to select from among these candidates those that were specifically detected in the blood of acetaminophen-induced ALI patients. Among these candidates, the isoenzyme alcohol dehydrogenase 1B (ADH1B) was massively leaked into the blood. To evaluate ADH1B, we developed a targeted proteomics assay and quantified ADH1B in serum samples collected at different times from 17 patients admitted for acetaminophen-induced ALI. Serum ADH1B concentrations increased markedly during the acute phase of the disease, and dropped to undetectable levels during recovery. In contrast to alanine aminotransferase activity, the rapid drop in circulating ADH1B concentrations was followed by an improvement in the international normalized ratio (INR) within 10-48 h, and was associated with favorable outcomes. In conclusion, the combination of omics data exploration and proteomics revealed ADH1B as a new blood biomarker candidate that could be useful for the monitoring of acetaminophen-induced ALI.

Increased Intrahepatic Expression of Immune Checkpoint Molecules in Autoimmune Liver Disease.

Immune checkpoint molecules (ICM) are critical in maintaining immunologic homeostasis and participate in preventing or promoting autoimmune disease development. Exploring a large panel of intrahepatic inhibitory and stimulatory ICM is necessary for drawing a general picture of the immune alterations in autoimmune hepatitis (AIH). Here, we performed a multiparametric analysis of ICM, including PD-1, TIM3, LAG3, CTLA-4, OX40 and 4-1BB, and we determined their expression on intrahepatic lymphocyte subsets in untreated and in treated patients with AIH in comparison to normal liver tissue. AIH patient-derived liver tissue revealed the overexpression of ICM, mainly PD-1 and 4-1BB, as well as the strong correlation between PD-1+ CD8+ T-cell abundance and severity of AIH (alanine transaminase and aspartate transaminase levels). Our results show that the ICM play an important role in the loss of immune homeostasis in the liver, providing an attractive approach to investigate their role as targets for effective therapeutic interventions.

EASL-ALEH 2015 algorithm for the use of transient elastography in treatment-naive patients with hepatitis B: An independent validation.

Various non-invasive methods have been evaluated in chronic hepatitis B, but none of them have been fully validated for the assessment of liver fibrosis. The issued EASL-ALEH 2015 guidelines provide detailed algorithms based on LSM and ALT serum levels. The aim of our study was to validate the diagnostic accuracy of this algorithm and to better understand discrepancies. Four hundred and thirteen patients from 3 centres were retrospectively included. All included patients were classified for fibrosis stage according to results of a liver biopsy. The overall diagnostic value was expressed with AUROCs given with 95% confidence intervals for the diagnostic targets. For each diagnostic target, optimal cut-offs were determined according to the Youden method. For the population of patients with ALT9 kPa, respectively. For patients with ALT>N but ≤5N (n = 306), AUROCs of transient elastography were 0.79 (0.73-0.84) and 0.84 (0.75-0.92) for F ≥ 2 and F ≥ 3 diagnostic targets. The prevalence of significant fibrosis was, respectively, 15%, 52% and 85% when LSM was <6kPa, between 6 and 12 kPa or >12 kPa. Our study independently validates the EASL-ALEH algorithm based on ALT levels and LSM assessed by transient elastography.

Personalized surveillance for hepatocellular carcinoma in cirrhosis - using machine learning adapted to HCV status.

BACKGROUND & AIMS: Refining hepatocellular carcinoma (HCC) surveillance programs requires improved individual risk prediction. Thus, we aimed to develop algorithms based on machine learning approaches to predict the risk of HCC more accurately in patients with HCV-related cirrhosis, according to their virological status. METHODS: Patients with compensated biopsy-proven HCV-related cirrhosis from the French ANRS CO12 CirVir cohort were included in a semi-annual HCC surveillance program. Three prognostic models for HCC occurrence were built, using (i) Fine-Gray regression as a benchmark, (ii) single decision tree (DT), and (iii) random survival forest for competing risks survival (RSF). Model performance was evaluated from C-indexes validated externally in the ANRS CO22 Hepather cohort (n = 668 enrolled between 08/2012-01/2014). RESULTS: Out of 836 patients analyzed, 156 (19%) developed HCC and 434 (52%) achieved sustained virological response (SVR) (median follow-up 63 months). Fine-Gray regression models identified 6 independent predictors of HCC occurrence in patients before SVR (past excessive alcohol intake, genotype 1, elevated AFP and GGT, low platelet count and albuminemia) and 3 in patients after SVR (elevated AST, low platelet count and shorter prothrombin time). DT analysis confirmed these associations but revealed more complex interactions, yielding 8 patient groups with varying cancer risks and predictors depending on SVR achievement. On RSF analysis, the most important predictors of HCC varied by SVR status (non-SVR: platelet count, GGT, AFP and albuminemia; SVR: prothrombin time, ALT, age and platelet count). Externally validated C-indexes before/after SVR were 0.64/0.64 [Fine-Gray], 0.60/62 [DT] and 0.71/0.70 [RSF]. CONCLUSIONS: Risk factors for hepatocarcinogenesis differ according to SVR status. Machine learning algorithms can refine HCC risk assessment by revealing complex interactions between cancer predictors. Such approaches could be used to develop more cost-effective tailored surveillance programs. LAY SUMMARY: Patients with HCV-related cirrhosis must be included in liver cancer surveillance programs, which rely on ultrasound examination every 6 months. Hepatocellular carcinoma (HCC) screening is hampered by sensitivity issues, leading to late cancer diagnoses in a substantial number of patients. Refining surveillance periodicity and modality using more sophisticated imaging techniques such as MRI may only be cost-effective in patients with the highest HCC incidence. Herein, we demonstrate how machine learning algorithms (i.e. data-driven mathematical models to make predictions or decisions), can refine individualized risk prediction.

Non-invasive fibrosis tests to predict complications in compensated post-hepatitis C cirrhosis.

BACKGROUND AND AIMS: Markers predicting complications of post-hepatitis C cirrhosis are needed. We asked whether changes in noninvasive markers of fibrosis can predict liver-related complications. METHODS: This was a case-controlled study using a prospective national cohort (ANRS-CO12-CIRVIR) of 1323 HCV-infected patients with compensated cirrhosis: 97 patients who developed liver-related complications such as hepatocellular carcinoma or hepatic decompensation (cases) matched in age, sex and follow-up duration were compared with 257 patients without complications (controls). Actitest/Fibrotest™, Inflameter/Fibrometer™, ELF™ and Fibroscan™ were performed at baseline and yearly. Samples based on Propensity score matching were built and mixed linear models performed. Outcomes in a sustained virological response (SVR) negative population and a SVR-positive population were also described. RESULTS: At baseline, all characteristics of patients were similar between the groups. All fibrosis tests were statistically higher for cases compared to controls, Fibroscan™ excepted: Fibrotest™: 0.83±0.13 vs. 0.77±0.16; Fibrometer™: 0.93±0.07 vs. 0.90±0.11; ELF™: 11.4±1.0 vs. 11.0±1.2 (P<0.02). The mean follow-up was 5.7±1.9 years. Over a 3-year period, the significant difference in fibrosis marker values between cases and controls remained constant; with a trend toward a decrease in inflammation markers in controls, independent of SVR status. CONCLUSIONS: Baseline noninvasive serum fibrosis and inflammation markers were significantly higher in patients developing a complication than in controls. During the follow-up only inflammatory markers decreased in controls, but not in cases, and thus could potentially be used to predict the occurrence of complications in cirrhotic patients.

Safety and efficacy of the combination simeprevir-sofosbuvir in HCV genotype 1- and 4-mono-infected patients from the French ANRS CO22 hepather cohort.

BACKGROUND: Although real-life results of sofosbuvir/simeprevir have been extensively reported from the United States, data from other geographical areas are limited. In the French observational cohort, ANRS CO22 HEPATHER, 9432 patients were given the new oral antivirals from December 2013 to June 30, 2018. We report the results of sofosbuvir/simeprevir in genotypes 1- and 4-infected patients. METHODS: Demographics and history of liver disease were collected at entry in the cohort. Clinical, adverse events, and virological data were collected throughout treatment and post-treatment follow-up. The choice of treatment duration or addition of ribavirin was left up to the physician. RESULTS: Five hundred ninety-nine HCV (467 genotype 1 and 132 genotype 4) mono-infected, naïve for all oral-DAAs regimen patients were given sofosbuvir/simeprevir with (n = 63) or without ribavirin (n = 536) for 12 or 24 weeks; 56% had cirrhosis (4% decompensated) and 71% had prior treatment failure to interferon-based regimen. 7 patients (1.16%) were lost to follow-up. The overall SVR12 rate was 92.6%. The SVR12 was 90% in GT1a, 94.2% in GT1b and 91.6% in GT4 with no significant difference for genotype, treatment duration or ribavirin addition. Severity of liver disease was not associated with a lower SVR12 rate on multivariate analysis but was associated with a higher rate of severe side effects. Early treatment discontinuations were rare; no new safety signals were reported. CONCLUSION: In this real life, observational, prospective cohort study, the 12-week sofosbuvir/simeprevir+/-ribavirin combination appears to be efficient and safe. TRIAL REGISTRATION: Trial registration with ClinicalTrials.gov NCT01953458 .

Validation of Baveno VI Criteria for Screening and Surveillance of Esophageal Varices in Patients With Compensated Cirrhosis and a Sustained Response to Antiviral Therapy.

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.

Non-virological factors are drivers of hepatocellular carcinoma in virosuppressed hepatitis B cirrhosis: Results of ANRS CO12 CirVir cohort.

Worldwide, hepatocellular carcinoma (HCC) occurs mainly in Asian patients with hepatitis B virus (HBV) infection. This study aimed to decipher the environmental and virological factors associated with HCC occurrence and validate risk scoring systems in a French multicentre prospective cohort of HBV cirrhotic patients. Patients with biopsy-proven Child-Pugh A viral cirrhosis included in the ANRS CO12 CirVir cohort who were HBsAg(+) without hepatitis C coinfection were selected for: (a) interview through a standardized questionnaire reporting coffee consumption and HCC familial history; (b) HBsAg quantification using baseline and sequential 2-year frozen sera; (c) baseline HBV genotype determination; and (d) assessment of risk factors and applicability of HCC risk scores (Kaplan-Meier analysis, Cox models). Among 317 patients studied (261 men, median age 53 years, past or ongoing antiviral treatment 93.3% and baseline detectable HBV DNA in 88 patients), the baseline and 2-year median HBsAg levels were 810 and 463 IU/mL, respectively. After a median follow-up of 65.2 months, 27 HCC cases were diagnosed (annual incidence: 1.6%). Three factors were independently associated with HCC occurrence: age > 50 years, platelets ≤ 150 × 103 /mm3 and body mass index ≥ 30 kg/m2 . Two out of five risk scores were validated, and the most accurate was PAGE-B at 1 year. Moreover, HCC in patients without maintained virological suppression seems more aggressive and less accessible to curative treatment. In conclusion, in French patients with HBV cirrhosis mostly virally suppressed, independent HCC risk factors were host-related (age, obesity) or linked to the severity of cirrhosis (thrombopenia), and the European PAGE-B score was the most accurate risk score.

Impact of Non-alcoholic Fatty Liver Disease on long-term cardiovascular events and death in Chronic Obstructive Pulmonary Disease.

Chronic Obstructive Pulmonary Disease (COPD) and Non-Alcoholic Fatty Liver Disease (NAFLD) both independently increase cardiovascular risk. We hypothesized that NAFLD might increase the incidence of cardiovascular disease and death in COPD patients. The relationship between NAFLD, incident cardiovascular events, and death was assessed in a prospective cohort of COPD patients with 5-year follow-up. Noninvasive algorithms combining biological parameters (FibroMax®) were used to evaluate steatosis, non-alcoholic steatohepatitis (NASH) and liver fibrosis. Univariate and multivariate Cox regression models were used to assess the hazard for composite outcome at the endpoint (death or cardiovascular event) for each liver pathology. In 111 COPD patients, 75% exhibited liver damage with a prevalence of steatosis, NASH and fibrosis of 41%, 37% and 61%, respectively. During 5-year follow-up, 31 experienced at least one cardiovascular event and 7 died. In univariate analysis, patients with liver fibrosis had more cardiovascular events and higher mortality (Hazard ratio [95% CI]: 2.75 [1.26; 6.03]) than those with no fibrosis; this remained significant in multivariate analysis (Hazard ratio [95% CI]: 2.94 [1.18; 7.33]). We also found that steatosis and NASH were not associated with increased cardiovascular events or mortality. To conclude, early assessment of liver damage might participate to improve cardiovascular outcomes in COPD patients.

Estimate of hepatocellular carcinoma incidence in patients with alcoholic cirrhosis.

BACKGROUND & AIMS: More than 90% of cases of hepatocellular carcinoma (HCC) occur in patients with cirrhosis, of which alcohol is a major cause. The CIRRAL cohort aimed to assess the burden of complications in patients with alcoholic cirrhosis, particularly the occurrence of HCC. METHODS: Patients with biopsy-proven compensated alcoholic cirrhosis were included then prospectively followed. The main endpoint was the incidence of HCC. Secondary outcomes were incidence of hepatic focal lesions, overall survival (OS), liver-related mortality and event-free survival (EFS). RESULTS: From October 2010 to April 2016, 652 patients were included in 22 French and Belgian centers. During follow-up (median 29 months), HCC was diagnosed in 43 patients. With the limitation derived from the uncertainty of consecutive patients' inclusion and from a sizable proportion of dropouts (153/652), the incidence of HCC was 2.9 per 100 patient-years, and one- and two-year cumulative incidences of 1.8% and 5.2%, respectively. Although HCC fulfilled the Milan criteria in 33 cases (77%), only 24 patients (56%) underwent curative treatment. An explorative prognostic analysis showed that age, male gender, baseline alpha-fetoprotein, bilirubin and prothrombin were significantly associated with the risk of HCC occurrence. Among 73 deaths, 61 had a recorded cause and 27 were directly attributable to liver disease. At two years, OS, EFS and cumulative incidences of liver-related deaths were 93% (95% CI 90.5-95.4), 80.3% (95% CI 76.9-83.9), and 3.2% (95% CI 1.6-4.8) respectively. CONCLUSION: This large prospective cohort incompletely representative of the whole population with alcoholic cirrhosis showed: a) an annual incidence of HCC of up to 2.9 per 100 patient-years, suggesting that surveillance might be cost effective in these patients; b) a high proportion of HCC detected within the Milan criteria, but only one-half of detected HCC cases were referred for curative treatments; c) a two-year mortality rate of up to 7%. LAY SUMMARY: Cirrhosis is a risk factor for primary liver cancer, leading to recommendations for periodic screening. However, for alcohol-related liver disease the rational of periodic screening for hepatocellular carcinoma (HCC) is controversial, as registry and databased studies have suggested a low incidence of HCC in these patients and highly competitive mortality rates. In this study, a large cohort of patients with biopsy-proven alcoholic cirrhosis prospectively screened for HCC demonstrated a high annual incidence of HCC (2.9%) and a high percentage of small cancers theoretically eligible for curative treatment. This suggests that patients with liver disease related to alcohol should not be ruled out of screening.

Incidence of Hepatocellular Carcinoma After Direct Antiviral Therapy for HCV in Patients With Cirrhosis Included in Surveillance Programs.

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.

A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis.

BACKGROUND: Patients with primary biliary cholangitis who have an inadequate response to therapy with ursodeoxycholic acid are at high risk for disease progression. Fibrates, which are agonists of peroxisome proliferator-activated receptors, in combination with ursodeoxycholic acid, have shown potential benefit in patients with this condition. METHODS: In this 24-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 100 patients who had had an inadequate response to ursodeoxycholic acid according to the Paris 2 criteria to receive bezafibrate at a daily dose of 400 mg (50 patients), or placebo (50 patients), in addition to continued treatment with ursodeoxycholic acid. The primary outcome was a complete biochemical response, which was defined as normal levels of total bilirubin, alkaline phosphatase, aminotransferases, and albumin, as well as a normal prothrombin index (a derived measure of prothrombin time), at 24 months. RESULTS: The primary outcome occurred in 31% of the patients assigned to bezafibrate and in 0% assigned to placebo (difference, 31 percentage points; 95% confidence interval, 10 to 50; P<0.001). Normal levels of alkaline phosphatase were observed in 67% of the patients in the bezafibrate group and in 2% in the placebo group. Results regarding changes in pruritus, fatigue, and noninvasive measures of liver fibrosis, including liver stiffness and Enhanced Liver Fibrosis score, were consistent with the results of the primary outcome. Two patients in each group had complications from end-stage liver disease. The creatinine level increased 5% from baseline in the bezafibrate group and decreased 3% in the placebo group. Myalgia occurred in 20% of the patients in the bezafibrate group and in 10% in the placebo group. CONCLUSIONS: Among patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy. (Funded by Programme Hospitalier de Recherche Clinique and Arrow Génériques; BEZURSO ClinicalTrials.gov number, NCT01654731 .).

Compliance With Hepatocellular Carcinoma Surveillance Guidelines Associated With Increased Lead-Time Adjusted Survival of Patients With Compensated Viral Cirrhosis: A Multi-Center Cohort Study.

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.

Extrahepatic cancers are the leading cause of death in patients achieving hepatitis B virus control or hepatitis C virus eradication.

Data on extrahepatic cancers (EHCs) in compensated viral cirrhosis are limited. The objective of the prospective multicenter Agence Nationale de Recherche sur le SIDA et les Hépatites virales CO12 CirVir cohort was to assess the occurrence of all clinical events in patients with compensated viral cirrhosis, including all types of cancer. Patients with the following inclusion criteria were enrolled in 35 French centers: (1) biopsy-proven hepatitis B virus (HBV) or hepatitis C virus (HCV) cirrhosis, (2) Child-Pugh A, or (3) absence of previous liver complications including primary liver cancer (PLC). Patients were followed up prospectively every 6 months. The standardized mortality ratio (SMR) was calculated according to age and gender using 5-year periods. The impact of sustained viral response (SVR) in HCV patients and maintained viral suppression in HBV patients were assessed using time-dependent analysis. A total of 1,671 patients were enrolled between 2006 and 2012 (median age, 54.9 years; men, 67.3%; HCV, 1,323; HBV, 317; HCV-HBV, 31). Metabolic features and excessive alcohol and tobacco consumption were recorded in 15.2%, 36.4%, and 56.4% of cases, respectively. After a median follow-up of 59.7 months, 227 PLCs were diagnosed (5-year cumulative incidence [CumI] 13.4%) and 93 patients developed EHC (14 patients with lymphoid or related tissue cancer and 79 with solid tissue cancer; 5-year EHC CumI, 5.9%). Compared to the general French population, patients were younger at cancer diagnosis, with significantly higher risk of EHC in HCV patients (SMR, 1.31; 95 confidence interval [CI], 1.04-1.64; P = 0.017) and after SVR (SMR = 1.57; 95% CI, 1.08-2.22; P = 0.013). EHC was the fourth leading cause of death in the whole cohort and the first in patients with viral control/eradication. CONCLUSION: Compared to the general French population, HCV cirrhosis is associated with a higher risk of EHC and the first cause of death in patients with viral cirrhosis who achieve virological control/eradication. (Hepatology 2018).

Prognostic value of viral eradication for major adverse cardiovascular events in hepatitis C cirrhotic patients.

BACKGROUND: The objective was to examine the role of a sustained virological response (SVR) on major adverse cardiovascular events (MACEs) in patients with compensated hepatitis C virus (HCV) cirrhosis. METHODS: Patients with the following criteria were enrolled in 35 French centers: (1) biopsy-proven HCV cirrhosis; (2) Child-Pugh A; (3) positive viremia; and (4) no prior liver complication, and then prospectively followed. All patients received HCV treatment after inclusion. MACEs included stroke, myocardial infarction, ischemic heart disease, heart failure, peripheral arterial disease, cardiac arrest, and cardiovascular death. SVR, defined as negative viremia 12 weeks posttreatment, was considered as a time-dependent covariate, and its effect on MACE occurrence was assessed. The median follow up was 57.5 months, ending in December 2015. RESULTS: Sixty-two of 878 (7.1%) patients presented a total of 79 MACEs. The main predictive baseline factors of MACEs were Asian ethnic origin, history of MACEs, arterial hypertension, diabetes mellitus, current smoking, low serum albumin level, high total bilirubin level, and low platelet count. In multivariate analysis, SVR was associated with a decreased risk of MACEs (hazard ratio=0.35, 95% CI 0.09-0.97, P=.044), whereas Asian ethnic origin, arterial hypertension, smoking, and low serum albumin level remained predictive of MACE occurrence. The 5-year survival rate was 60.1% versus 87.5% in patients who did versus those who did not present a MACE (P<.001). CONCLUSIONS: In patients with compensated HCV-related cirrhosis, Asian ethnic origin, arterial hypertension, smoking, and low serum albumin are independent predictive factors of cardiovascular events, whereas an SVR is associated with a decreased rate of cardiovascular events.

Safety and efficacy of intra-arterial hepatic chemotherapy with doxorubicin-loaded nanoparticles in hepatocellular carcinoma.

BACKGROUND: Doxorubicin Transdrug (DT), a nanoformulation of doxorubicin, was demonstrated to overcome the chemoresistance of hepatocellular carcinoma (HCC) in preclinical models. Its efficacy and safety were thus investigated in phase I and randomised phase II trials in unresectable HCC. PATIENTS AND METHODS: Phase I was a single dose of DT through the hepatic intra-arterial (HIA) route, dose-escalating 3+3 trial, evaluating five-dose levels from 10 to 40 mg/m2 with maximal tolerated dose (MTD) as primary endpoint. The multicentre phase II trial randomly assigned (2:1 ratio) patients to receive either 30 mg/m2 of DT through HIA route every 4 weeks for up to three courses or best standard of care (BSC). Progression-free survival (PFS) rate at 3 months was the primary endpoint. Overall survival (OS) and disease control rate (DCR) were secondary endpoints. RESULTS: In phase I, haematological and respiratory limited toxicities were reported at 35 and 40 mg/m2, giving MTD at 30 mg/m2. Partial response rate was 10%, and stable disease 70%. Phase II was discontinued due to three severe acute respiratory distress events in the DT group while 17 patients had received 30 mg/m2 DT and 11 BSC. At 3 months, PFS was 64% (95% CI 31 to 89) vs 75% (95% CI 35 to 97), and DCR 35% vs 27% in DT and BSC, respectively (p=NS). Median OS was 32.6 months (95% CI 8.2 to 34.1) in DT group and 15 months (95% CI 8.0 to 18.8) in BSC group (p<0.05). CONCLUSION: DT increased OS in unresectable HCC but induced severe respiratory distress. Efficacy data deserve further investigation using a safer dosing and schedule regimen. TRIAL REGISTRATION NUMBER: EUDRACT 2006-004088-77; Results.

A Single Test Combining Blood Markers and Elastography is More Accurate Than Other Fibrosis Tests in the Main Causes of Chronic Liver Diseases.

BACKGROUND AND GOAL: International guidelines suggest combining a blood test and liver stiffness measurement (LSM) to stage liver fibrosis in chronic hepatitis C (CHC) and non-alcoholic fatty liver disease (NAFLD). Therefore, we compared the accuracies of these tests between the main etiologies of chronic liver diseases. STUDY: Overall, 1968 patients were included in 5 etiologies: CHC: 698, chronic hepatitis B: 152, human immunodeficiency virus/CHC: 628, NAFLD: 225, and alcoholic liver disease (ALD): 265. Sixteen tests [13 blood tests, LSM (Fibroscan), 2 combined: FibroMeters] were evaluated. References were Metavir staging and CHC etiology. Accuracy was evaluated mainly with the Obuchowski index (OI) and accessorily with area under the receiver operating characteristics (F≥2, F≥3, cirrhosis). RESULTS: OIs in CHC were: FibroMeters: 0.812, FibroMeters: 0.785 to 0.797, Fibrotest: 0.762, CirrhoMeters: 0.756 to 0.771, LSM: 0.754, Hepascore: 0.752, FibroMeter: 0.750, aspartate aminotransferase platelet ratio index: 0.742, Fib-4: 0.741. In other etiologies, most tests had nonsignificant changes in OIs. In NAFLD, CHC-specific tests were more accurate than NAFLD-specific tests. The combined FibroMeters had significantly higher accuracy than their 2 constitutive tests (FibroMeters and LSM) in at least 1 diagnostic target in all etiologies, except in ALD where LSM had the highest OI, and in 3 diagnostic targets (OIs and 2 area under the receiver operating characteristics) in CHC and NAFLD. CONCLUSIONS: Some tests developed in CHC outperformed other tests in their specific etiologies. Tests combining blood markers and LSM outperformed single tests, validating recent guidelines and extending them to main etiologies. Noninvasive fibrosis evaluation can thus be simplified in the main etiologies by using a unique test: either LSM alone, especially in ALD, or preferably combined to blood markers.

Nonalcoholic fatty liver disease in chronic obstructive pulmonary disease.

Nonalcoholic fatty liver disease (NAFLD) is independently linked to cardiometabolic morbidity and mortality. Low-grade inflammation, oxidative stress and ectopic fat, common features of chronic obstructive pulmonary disease (COPD), might contribute to the development of NAFLD.We aimed to investigate the prevalence of NAFLD and to evaluate the relationship between various types of liver damage and COPD severity, comorbidities and circulating inflammatory cytokines. Validated noninvasive tests (FibroMax: SteatoTest, NashTest and FibroTest) were used to assess steatosis, nonalcoholic steatohepatitis (NASH) and liver fibrosis. Patients underwent an objective assessment of COPD comorbidities, including sleep studies. Biological parameters included a complete lipid profile and inflammatory markers.In COPD patients the prevalence of steatosis, NASH and fibrosis were 41.4%, 36.9% and 61.3%, respectively. In multivariate analysis, SteatoTest and FibroTest were significantly associated with sex, body mass index (BMI), untreated sleep apnoea and insulin resistance, and, in addition, COPD Global Initiative for Chronic Obstructive Lung Disease stage for SteatoTest. Patients with steatosis had higher tumour necrosis factor-α levels and those with NASH or a combination of liver damage types had raised leptin levels after adjustment for age, sex and BMI.We concluded that NAFLD is highly prevalent in COPD and might contribute to cardiometabolic comorbidities.

Bacterial infection in compensated viral cirrhosis impairs 5-year survival (ANRS CO12 CirVir prospective cohort).

OBJECTIVE: To assess incidence and prognostic significance of bacterial infections (BIs) occurring in compensated viral cirrhosis. DESIGN: This prospective study involved 35 French centres. Inclusion criteria were biopsy-proven HCV or HBV cirrhosis, Child-Pugh A and no previous hepatic complications. Cumulative incidence (CumI) of events was estimated in a competing risks framework. RESULTS: 1672 patients were enrolled (HCV 1323, HBV 318, HCV-HBV 31). During a median follow-up of 43 months, 234 BIs occurred in 171 patients (5 year CumI: 12.9%), among whom 14.6% had septic shock. Main localisations included the urinary tract (27.4%), lung (25.2%) and peritoneum (10.7%) (other, 86 (36.7%)). Most BIs occurred as a first event prior to liver decompensation (n=140, 81.8%) and were community-acquired (CA, 84.2%). The risk of BI was higher in patients with HCV than in patients with HBV (5 year CumI: 15.2% vs 5.5%, p=0.0008). Digestive localisation, concomitant interferon-based treatment, isolation of resistant bacteria and non-CA BIs were associated with lowest probability of resolution. The occurrence of a first BI impaired survival in patients infected with HCV (5 year survival: 60.2% vs 90.4%, p<0.001) and patients infected with HBV (5 year survival: 69.2% vs 97.6%, p<0.001). BIs represented the third cause of death (14.1%) after liver failure and liver cancer. BI risk factors comprised older age, lower albumin, proton pump inhibitor intake and absence of virological eradication/control. CONCLUSION: BI mostly occurs as a first complication and represents a turning point in the course of compensated viral cirrhosis. Its occurrence impacts long-term prognosis and may define a subgroup of patients in whom adaptation of management is warranted.