Clinical outcomes after treatment with direct antiviral agents: beyond the virological response in patients with previous HCV-related decompensated cirrhosis.

BACKGROUND: In HCV-infected patients with advanced liver disease, the direct antiviral agents-associated clinical benefits remain debated. We compared the clinical outcome of patients with a previous history of decompensated cirrhosis following treatment or not with direct antiviral agents from the French ANRS CO22 HEPATHER cohort. METHODS: We identified HCV patients who had experienced an episode of decompensated cirrhosis. Study outcomes were all-cause mortality, liver-related or non-liver-related deaths, hepatocellular carcinoma, liver transplantation. Secondary study outcomes were sustained virological response and its clinical benefits. RESULTS: 559 patients met the identification criteria, of which 483 received direct antiviral agents and 76 remained untreated after inclusion in the cohort. The median follow-up time was 39.7 (IQR: 22.7-51) months. After adjustment for multivariate analysis, exposure to direct antiviral agents was associated with a decrease in all-cause mortality (HR 0.45, 95% CI 0.24-0.84, p = 0.01) and non-liver-related death (HR 0.26, 95% CI 0.08-0.82, p = 0.02), and was not associated with liver-related death, decrease in hepatocellular carcinoma and need for liver transplantation. The sustained virological response was 88%. According to adjusted multivariable analysis, sustained virological response achievement was associated with a decrease in all-cause mortality (HR 0.29, 95% CI 0.15-0.54, p < 0.0001), liver-related mortality (HR 0.40, 95% CI 0.17-0.96, p = 0.04), non-liver-related mortality (HR 0.17, 95% CI 0.06-0.49, p = 0.001), liver transplantation (HR 0.17, 95% CI 0.05-0.54, p = 0.003), and hepatocellular carcinoma (HR 0.52, 95% CI 0.29-0.93, p = 0.03). CONCLUSION: Treatment with direct antiviral agents is associated with reduced risk for mortality. The sustained virological response was 88%. Thus, direct antiviral agents treatment should be considered for any patient with HCV-related decompensated cirrhosis. TRIAL REGISTRATION:  ClinicalTrials.gov registry number: NCT01953458.

Predictive factors for hepatocellular carcinoma in chronic hepatitis B using structural equation modeling: a prospective cohort study.

BACKGROUND & AIMS: The factors predicting hepatocellular carcinoma (HCC) occurrence in chronic hepatitis B need to be precisely known to improve its detection. We identified pathways and individual predictive factors associated with HCC in the ANRS CO22 HEPATHER cohort. METHODS: The study analyzed HBV-infected patients recruited at 32 French expert hepatology centers from August 6, 2012, to December 31, 2015. We excluded patients with chronic HCV, HDV and a history of HCC, decompensated cirrhosis or liver transplantation. Structural equation models were developed to characterize the causal pathways leading to HCC occurrence. The association between clinical characteristics (age, gender, body-mass index, liver fibrosis, alcohol consumption, smoking status, diabetes, hypertension, dyslipidemia, alpha-fetoprotein, HBV DNA levels, antiviral therapy) and incident HCC was quantified. RESULTS: Among the 4489 patients included, 33 patients reported incident HCC. The median follow-up was 45.5 months. Age (ß = 0.18 by decade, 95% CI 0.14-0.23), male gender (ß = 0.23, 95% CI 0.18-0.29), metabolic syndrome (ß = 0.28, 95% CI 0.22-0.33), alcohol consumption (ß = 0.09, 95% CI 0.05-0.14) and HBV DNA (ß = 0.25, 95% CI 0.170.34) had a significant and direct effect on the occurrence of advanced liver fibrosis. Liver fibrosis (ß = 0.71, 95% CI 0.55-0.87) predicted, in turn, the occurrence of HCC. CONCLUSIONS: Liver fibrosis mediates the effects of age, gender, alcohol, metabolic syndrome and HBV DNA on the occurrence of HCC. Elderly men with chronic hepatitis B, risky alcohol use, advanced liver fibrosis, metabolic syndrome and high HBV DNA levels should be monitored closely to detect the development of HCC.

Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study.

BACKGROUND: Although direct-acting antivirals have been used extensively to treat patients with chronic hepatitis C virus (HCV) infection, their clinical effectiveness has not been well reported. We compared the incidence of death, hepatocellular carcinoma, and decompensated cirrhosis between patients treated with direct-acting antivirals and those untreated, in the French ANRS CO22 Hepather cohort. METHODS: We did a prospective study in adult patients with chronic HCV infection enrolled from 32 expert hepatology centres in France. We excluded patients with chronic hepatitis B, those with a history of decompensated cirrhosis, hepatocellular carcinoma, or liver transplantation, and patients who were treated with interferon-ribavirin with or without first-generation protease inhibitors. Co-primary study outcomes were incidence of all-cause mortality, hepatocellular carcinoma, and decompensated cirrhosis. The association between direct-acting antivirals and these outcomes was quantified using time-dependent Cox proportional hazards models. This study is registered with ClinicalTrials.gov, number NCT01953458. FINDINGS: Between Aug 6, 2012, and Dec 31, 2015, 10 166 patients were eligible for the study. 9895 (97%) patients had available follow-up information and were included in analyses. Median follow-up was 33·4 months (IQR 24·0-40·7). Treatment with direct-acting antivirals was initiated during follow-up in 7344 patients, and 2551 patients remained untreated at the final follow-up visit. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated). Exposure to direct-acting antivirals was associated with increased risk for hepatocellular carcinoma (unadjusted hazard ratio [HR] 2·77, 95% CI 2·07-3·71) and decompensated cirrhosis (3·83, 2·29-6·42). After adjustment for variables (age, sex, body-mass index, geographical origin, infection route, fibrosis score, HCV treatment-naive, HCV genotype, alcohol consumption, diabetes, arterial hypertension, biological variables, and model for end-stage liver disease score in patients with cirrhosis), exposure to direct-acting antivirals was associated with a decrease in all-cause mortality (adjusted HR 0·48, 95% CI 0·33-0·70) and hepatocellular carcinoma (0·66, 0·46-0·93), and was not associated with decompensated cirrhosis (1·14, 0·57-2·27). INTERPRETATION: Treatment with direct-acting antivirals is associated with reduced risk for mortality and hepatocellular carcinoma and should be considered in all patients with chronic HCV infection. FUNDING: INSERM-ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche.

Prognostic factors of survival in HIV/HCV co-infected patients with hepatocellular carcinoma: The CARCINOVIC Cohort.

BACKGROUND & AIMS: HIV/HCV co-infected patients with hepatocellular carcinoma (HCC) have poorer survival than HCV mono-infected patients. We aimed to evaluate the prognostic factors for survival. METHODS: From 2006 to 2013, 55 incident HCCs among HIV+/HCV+ patients, from three ANRS cohorts, were compared with 181 HCCs in HIV-/HCV+ patients from the ANRS Cirvir cohort. RESULTS: HIV+/HCV+ patients were younger (50 years [IQR: 47-53] vs 62 [54-70], P < 0.001), male (89% vs 63%, P < 0.001) than HIV-/HCV+ patients. At HCC diagnosis, both groups had a majority of non-responders to anti-HCV-therapy, and HIV+/HCV+ patients had more frequently known a previous cirrhosis decompensation (31% vs 14%, P = 0.005). At diagnostic imaging, there were more infiltrative forms of HCC in HIV+/HCV+ group (24% vs 14%, P < 0.001), associated with tumour portal thrombosis in 29%. During a median follow-up period of 11.96 [5.51-27] months since HCC diagnosis, a majority of palliative treatments were decided in HIV+/HCV+ patients (51% vs 19%, P < 0.001). The 1 and 2-year crude survival rates were 61% versus 78% and 47% versus 63%, P = 0.003 respectively. In a Cox model multivariate analysis adjusted for the cohort, age and sex, the most important prognostic factor for survival was the infiltrative form of the tumour (aRR: 8.10 [4.17-15.75], P < 0.001). CONCLUSIONS: The radiological aggressiveness of the tumour is the best prognostic factor associated with poorer survival of HCC in HIV+/HCV+ patients. High α-foetoprotein level and decompensated cirrhosis are other ones. This justifies a particular attention to the detection and the management of small nodules in this high-risk population.

Submucosal hematoma: a new distinctive sign during emergency upper digestive endoscopy for ammonia ingestion.

BACKGROUND: Submucosal hematoma has never been associated with caustic injuries. Long-term follow-up of patients who ingested ammonia is not well known and ammonia ingestion is rare. METHODS: In a Single-center observational study, prospective data were collected from 2009 to 2013, in patients over the age of 14 years old referred for ammonia ingestion. The emergency and follow-up endoscopic data and the outcome were reported. RESULTS: Ammonia ingestion occurred in 43 patients. Submucosal hematoma of the gastric wall was a distinctive endoscopic sign observed in 15 (34.8%) cases. Oropharyngeal lesions were present in 30 (69.8%) patients, which was associated with ingestion with suicidal intent in 18 cases. Mild and severe endoscopic lesions (grade IIB to IIIB) were found in 16 (37.2%) cases with 10 (23.3%) cases presenting submucosal hematoma at initial endoscopy. A complete spontaneous gastric healing was frequently observed in 36 (83.7%) cases. In 11 cases with submucosal hematoma, a favourable outcome was observed with a medical treatment, however 6 of these patients had severe endoscopic lesions initially. CONCLUSIONS: Submucosal hematoma of the gastric wall is an endoscopic sign occurring frequently in ammonia ingestion. Submucosal hematoma should be distinguished from necrosis in order to avoid false misclassification in favour of more severe lesions, which would lead to an abusive surgery.

Chlordecone potentiates hepatic fibrosis in chronic liver injury induced by carbon tetrachloride in mice.

Chronic liver damage due to viral or chemical agents leads to a repair process resulting in hepatic fibrosis. Fibrosis may lead to cirrhosis, which may progress to liver cancer or a loss of liver function, with an associated risk of liver failure and death. Chlordecone is a chlorinated pesticide used in the 1990s. It is not itself hepatotoxic, but its metabolism in the liver triggers hepatomegaly and potentiates hepatotoxic agents. Chlordecone is now banned, but it persists in soil and water, resulting in an ongoing public health problem in the Caribbean area. We assessed the probable impact of chlordecone on the progression of liver fibrosis in the population of contaminated areas, by developing a mouse model of chronic co-exposure to chlordecone and a hepatotoxic agent, carbon tetrachloride (CCl4). After repeated administrations of chlordecone and CCl4 by gavage over a 12-week period, we checked for liver damage in the exposed mice, by determining serum liver transaminase (AST, ALT) levels, histological examinations of the liver and measuring the expression of genes encoding extracellular matrix components. The co-exposure of mice to CCl4 and chlordecone resulted in significant increases in ALT and AST levels. Chlordecone also increased expression of the Col1A2, MMP-2, TIMP-1 and PAI-1 genes in CCl4-treated mice. Finally, we demonstrated, by quantifying areas of collagen deposition and alpha-SMA gene expression, that chlordecone potentiated the hepatic fibrosis induced by CCl4. In conclusion, our data suggest that chlordecone potentiates hepatic fibrosis in mice with CCl4-induced chronic liver injury.

Imaging Features and Prognosis of Hepatocellular Carcinoma in Patients with Cirrhosis Who Are Coinfected with Human Immunodeficiency Virus and Hepatitis C Virus.

PURPOSE: To evaluate the effect of human immunodeficiency virus (HIV) coinfection on hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infected patients with cirrhosis in terms of HCC morphologic subtypes and survival prognosis at the time of radiologic diagnosis. MATERIALS AND METHODS: The study was approved by the institutional review board and patients gave their written informed consent. Two databases, one for HIV-HCV patients and the other for HCV-infected patients without HIV infection, were obtained from prospective multicenter cohorts. Inclusion criteria were a confirmed diagnosis of cirrhosis and the discovery of HCC at imaging between January 2008 and December 2012. This study included 35 HIV-HCV patients with cirrhosis (32 men and three women; median age, 50 years [age range, 40-65 years]; Child-Pugh classification A, 21 patients; classification B, 10 patients; classification C, four patients) and 35 infected HCV patients with cirrhosis (29 men and six women; median age, 56 years [age range, 41-83 years]; Child-Pugh classification A, 26 patients; classification B, six patients; classification C, three patients) who were the control group. Computed tomographic or magnetic resonance images were analyzed for HCC subtypes, the number and size of nodules, and evidence of portal obstructing tumors. Fisher exact and Wilcoxon tests were used for comparisons and Kaplan-Meier plots were used for survival analysis. RESULTS: Infiltrative HCC was found in eight HIV-HCV patients with cirrhosis (23%) and in no HCV patients with cirrhosis (P = .002). All other HCCs were of a nodular type, with similar nodule sizes in the two groups. Portal-obstructing tumors were found in 10 HIV-HCV patients (eight of eight tumors were infiltrative and two of 27 tumors were nodular) but none were found in HCV patients (P = .001). Survival was dramatically shorter for HIV-HCV patients than for those with HCV, with a median of 17.2 months versus 54.7 months (P = .004). Survival time was dependent on the type of HCC, with probabilities of death at 12 months of 87% in infiltrative-type HCC, 32% in multiple-nodule type, and 5% in single-nodule type, which was found in both groups (log-rank test, P < .001). CONCLUSION: Unlike HCV-infected patients with cirrhosis, patients with cirrhosis coinfected with HIV and HCV frequently present at radiologic diagnosis with infiltrative-type HCC and portal-obstructing tumors, which results in dramatically shorter survival.

Do the epidemiology, physiological mechanisms and characteristics of hepatocellular carcinoma in HIV-infected patients justify specific screening policies?

Reducing the incidence of hepatocellular carcinoma (HCC) in HIV-infected patients has become a serious problem when managing these patients. There are many explanations for this disease evolution, which notably include their longer survival under effective antiviral therapy and also the more rapid evolution of chronic liver disease. Despite recent advances in the management of hepatitis B (HBV) and hepatitis C (HCV) viral diseases, which will probably increase the number of patients achieving a virological response, HIV-infected patients with cirrhosis are still at risk of the onset of HCC. This evolution to HCC is also correlated to other comorbidities such as excessive alcohol consumption and nonalcoholic steatohepatitis (NASH). HCC thus remains a public health issue in this population. The poor prognosis and aggressiveness of HCC have been fully demonstrated, but the mechanisms underlying this aggressiveness are not yet well defined. As well as underlying mechanisms that contribute to accelerating hepatocarcinogenesis in HIV-infected patients, there are other reasons why HIV-infected patients should be considered a higher risk population. This review discusses the principal epidemiological determinants; the mechanisms of pathogenesis; and the treatment of HCC in HIV/HBV and HIV/HCV coinfected patients. It also discusses the probable need to develop a specific screening policy for HCC in this population in order to prevent the rapid development and to make them more amenable to a curative treatment.

Seroepidemiology of chronic hepatitis B and C in the French Caribbean Island of Guadeloupe.

BACKGROUND: The prevalence of chronic hepatitis B and C was evaluated some twenty years ago among specific populations in Guadeloupe. The present study was designed to update these data and determine epidemiological features of chronic hepatitis B and C infections in the French Caribbean island of Guadeloupe. FINDINGS: The present study was carried out at the Sainte Genevieve Health and Prevention Center (Guadeloupe), between May 2006 and July 2007. This is a medical center where patients can attend a free medical check-up paid for by the Social Security system. Data on hepatitis B (HBV) and C (HCV) status and epidemiological factors were collected for this study.A total of 2,200 patients were included in the study. The prevalence of HBV surface antigen was 1.41% (95% CI: 1.0-2.0), and 0.55% (95% CI: 0.28-0.96) for HCV. The vaccination rate against HBV was 42.0%. HBV transmission was associated with piercing (12.9%, p = 0.014) and familial exposure (6.4%, p < 0.001) and HCV transmission with gynecological surgery (50.0%, p = 0.01). The HBV profile was generally hepatitis B e antigen-negative (94.5%). No hepatitis delta was found. For HCV, genotype 1 was predominant (80%). CONCLUSIONS: This is the first study on the prevalence of HBV and HCV among a general clinic based population in Guadeloupe and the Caribbean islands. This study reveals that Guadeloupe is an area of low endemicity for HBV and low HCV prevalence. The reasons for these low prevalence rates are mainly related to the vaccination campaigns carried out during the past twenty years for HBV and the decrease of nosocomial transmission for HCV.