A. Minello

Ribavirin for Chronic Hepatitis E Virus Infection in Transplant Recipients

BACKGROUND There is no established therapy for hepatitis E virus (HEV) infection. The aim of this retrospective, multicenter case series was to assess the effects of ribavirin as monotherapy for solid-organ transplant recipients with prolonged HEV viremia. METHODS We examined the records of 59 patients who had received a solid-organ transplant (37 kidney-transplant recipients, 10 liver-transplant recipients, 5 heart-transplant recipients, 5 kidney and pancreas-transplant recipients, and 2 lung-transplant recipients). Ribavirin therapy was initiated a median of 9 months (range, 1 to 82) after the diagnosis of HEV infection at a median dose of 600 mg per day (range, 29 to 1200), which was equivalent to 8.1 mg per kilogram of body weight per day (range, 0.6 to 16.3). Patients received ribavirin for a median of 3 months (range, 1 to 18); 66% of the patients received ribavirin for 3 months or less. RESULTS All the patients had HEV viremia when ribavirin was initiated (all 54 in whom genotyping was performed had HEV genotype 3). At the end of therapy, HEV clearance was observed in 95% of the patients. A recurrence of HEV replication occurred in 10 patients after ribavirin was stopped. A sustained virologic response, defined as an undetectable serum HEV RNA level at least 6 months after cessation of ribavirin therapy, occurred in 46 of the 59 patients (78%). A sustained virologic response was also observed in 4 patients who had a recurrence and were re-treated for a longer period. A higher lymphocyte count when ribavirin therapy was initiated was associated with a greater likelihood of a sustained virologic response. Anemia was the main identified side effect and required a reduction in ribavirin dose in 29% of the patients, the use of erythropoietin in 54%, and blood transfusions in 12%. CONCLUSIONS This retrospective, multicenter study showed that ribavirin as monotherapy may be effective in the treatment of chronic HEV infection; a 3-month course seemed to be an appropriate duration of therapy for most patients.

Time trends and age-period-cohort effects on the incidence of primary liver cancer in a well-defined French population: 1976–1995

BACKGROUND/AIMS There is growing interest worldwide in primary liver cancer. The aim of this study was to describe the incidence of this cancer over a 20-year period in a well-defined French population. METHODS Time trends by 4-year period were studied by sex, age group, place of residence, histological type and associated cirrhosis. Trends were also analysed using the age-period-cohort model. RESULTS Primary liver cancer incidence in men increased from 7.5/100000 for the period 1976-79 to 10.2/100000 for the period 1992-95. The mean annual variation was +2.2%, (p<0.05). The increase in incidence was seen mainly in the 55-64 and 65-74 age groups and concerned hepatocellular carcinomas. In men, the increase in incidence rates with time was observed mainly in rural areas, whereas incidence rates in urban areas remained stable. The rise in incidence was due mostly to an increase in primary liver cancer with cirrhosis, in relation to a progressive increase in post-hepatitic cirrhosis and a recent increase in alcoholic cirrhosis. The estimated cumulative risk for the life span 30-74 years increased from 0.8% for the 1904-1908 cohort to 2.1% for the 1934-1938 cohort. There was no significant trend in female rates. CONCLUSIONS In France, incidence rates for primary liver cancer are increasing in men, whilst they are remaining stable in women. Our data confirm the primary importance of alcohol in the aetiology of this cancer. Further studies are necessary to unravel the respective roles of alcohol and hepatitis C virus in the increasing incidence of primary liver cancer.

Transjugular intrahepatic portosystemic shunt for the management of acute variceal hemorrhage

Acute variceal hemorrhage, a life-threatening condition that requires a multidisciplinary approach for effective therapy, is defined as visible bleeding from an esophageal or gastric varix at the time of endoscopy, the presence of large esophageal varices with recent stigmata of bleeding, or fresh blood visible in the stomach with no other source of bleeding identified. Transfusion of blood products, pharmacological treatments and early endoscopic therapy are often effective; however, if primary hemostasis cannot be obtained or if uncontrollable early rebleeding occurs, transjugular intrahepatic portosystemic shunt (TIPS) is recommended as rescue treatment. The TIPS represents a major advance in the treatment of complications of portal hypertension. Acute variceal hemorrhage that is poorly controlled with endoscopic therapy is generally well controlled with TIPS, which has a 90% to 100% success rate. However, TIPS is associated with a mortality of 30% to 50% in such a setting. Emergency TIPS should be considered early in patients with refractory variceal bleeding once medical treatment and endoscopic sclerotherapy failure, before the clinical condition worsens. Furthermore, admission to specialized centers is mandatory in such a setting and regional protocols are essential to be organized effectively. This review article discusses initial management and then focuses on the specific role of TIPS as a primary therapy to control acute variceal hemorrhage, particularly as a rescue therapy following failure of endoscopic approaches.

A 30-Year, Population-Based Study Shows Improved Management and Prognosis of Hepatocellular Carcinoma

BACKGROUND & AIMS Little is known about the impact of changes in the management of hepatocellular carcinoma (HCC) over time. We assessed trends in the pattern of care and in prognosis at a population level. METHODS Data on diagnostic conditions, treatment, and prognosis from 1976-2005 were collected by the population-based digestive cancer registry of Burgundy (France). A nonconditional logistic regression was used to identify factors associated with treatment for cure. A multivariate relative survival analysis was also performed. RESULTS The context of HCC diagnosis has changed; the proportion of asymptomatic patients increased from 5.6% (1976-1985) to 37.2% (1996-2005). The proportion of cases diagnosed on the basis of morphologic criteria increased from 14% during 1976-1985 to 35.6% during 1996-2005, whereas histologically verified cases decreased from 62.2% to 41.2% between the same time periods. The proportion of patients who were treated with intent to cure increased from 2.7% (1976-1985) to 19.6% (1996-2005). This increase was associated with improvements in relative survival from 4.7% (1976-1985) to 32.8% (1996-2005) at 1 year and from 1.4% to 10.0% at 5 years. The 5-year relative survival of patients treated with curative intent increased, reaching 46.6% for the 1996-2005 period. In the multivariate relative survival analysis, age, period of diagnosis, clinical presentation, alpha-fetoprotein level, and treatment were independent prognostic factors. CONCLUSIONS During a 30-year period, there was an increase in the number of HCCs diagnosed in asymptomatic subjects that was associated with the development of new effective therapies; this association might account for improvements in prognosis of patients with HCC.

Causes of death in people with chronic HBV infection: A population-based cohort study

BACKGROUND & AIMS Mortality related to hepatitis B virus (HBV) is not well known in developed countries. The aim of this study was to investigate in a population-based cohort the excess risk of death in HBV patients compared with mortality in the general population and to identify risk factors related to all-cause mortality and HBV-related mortality. METHODS A specialized population-based registry has recorded data from patients with chronic HBV infection in a population of one million inhabitants in France since 1994. Standardized mortality rates for all-cause death and HBV-related death were calculated. Cumulative mortality rates were calculated using the Kaplan-Meier method. Multivariate analysis was performed using a Cox model. RESULTS Between 1994 and 2009, 1117 people were diagnosed with chronic HBV infection. Of these 136 (12.2%) died. All-cause mortality was significantly higher in HBV-infected people (standardized mortality ratio (SMR) 1.7 [1.4-2.0]). There was substantial excess mortality due to hepatocellular carcinoma (SMR 15.9 [10-24.1]), non-Hodgkin lymphoma (SMR 8.6 [3.1-18.6]) and liver disease (SMR 10.2 [5.8-16.6]). The cumulative rates for all-cause mortality were 8.6% at 5 years, 12.6% at 10 years and 18.5% at 15 years. The corresponding values for HBV-related mortality were 3.5%, 4.2%, and 5.8%. The multivariate analysis for all-cause mortality and for HBV-related mortality showed that male sex, age over 45 at diagnosis, current alcoholism and nosocomial risk factors were predictors of increased mortality. CONCLUSION This study shows increased all-cause mortality in HBsAg-positive patients, with considerable excess mortality due to chronic liver disease, hepatocellular carcinoma and non-Hodgkin lymphoma.

Long-term outcome of chronic hepatitis C in a population-based cohort and impact of antiviral therapy: a propensity-adjusted analysis

Summary.  This population‐based study aimed to assess the determinants of the outcome of chronic hepatitis C with analysis of the impact of antiviral therapy with or without sustained virological response (SVR) on cirrhosis decompensation, hepatocellular carcinoma, liver‐related and non‐liver‐related mortality. A total of 1159 HCV‐positive patients newly detected between 1994 and 2001 were included. For each outcome, the prognostic effect of patients’ baseline characteristics was estimated by time‐dependent Cox models using age as the time‐scale and adjusting for treatment received during follow‐up. The impact of antiviral therapy was assessed by using a propensity score in a sample including 184 patients treated in the first 24 months following diagnosis who were matched to 184 untreated patients. At the end of a 59‐month median follow‐up, 100 cases of compensated disease, 58 liver cancer and 163 deaths (55 liver related) were recorded. The 5‐year rates of decompensated cirrhosis, hepatocellular carcinoma, liver‐related and non‐liver‐related death were 4.4%, 2.7%, 5.0% and 8.9%, respectively. Multivariate analyses identified two variables with pejorative influence: alcohol consumption (RR = 4.29 for CD; RR = 5.76 for HCC; RR = 6.69 for liver‐related death; P < 0.0001); HCV diagnosis unrelated to systematic screening (RR = 2.25 for CD; RR = 3.05 for HCC; RR = 4.31 for liver‐related death, P < 0.03). In the matched subset, no significant benefit of antiviral therapy was observed. Nevertheless, among the 144 patients who achieved SVR, no death was observed. This population‐based study showed substantial rates of decompensated cirrhosis, hepatocellular carcinoma and non‐liver‐related mortality. Alcohol consumption and absence of systematic screening were significant determinants of poor outcome, whereas treatment did not have significant influence.

Pilot Study of Transarterial Chemoembolization With Pirarubicin and Amiodarone for Unresectable Hepatocellular Carcinoma

Objective:Further to a previous study whereby we reported that an in vitro emulsion of pirarubicin, amiodarone, and lipiodol was more stable and cytotoxic than a classic doxorubicin-lipiodol mixture, we designed a pilot study to evaluate efficacy and toxicity of a transarterial chemoembolization (TACE) procedure using a combination of pirarubicin, amiodarone, lipiodol, and gelatin sponge. Methods:The 43 patients included in this study underwent TACE for unresectable hepatocellular carcinoma. Computed tomography scans were performed to assess tumor response (RECIST) and lipiodol uptake after the first session. Median follow-up lasted 30 months. Endpoints were overall and progression-free survival. Survival was estimated using Kaplan Meier estimations and compared using log-rank tests. Univariate and multivariate Cox analyses were used to calculate hazard ratios with their 95% confidence interval (CI). Results:Twenty-seven (67.5%) patients had alcoholic cirrhosis. Mean tumor size was 9.5 cm (1–20 cm) and 37/43 were multifocal or diffuse. Cancer of the liver Italian program score was 0 in 7/40 and 1 in 16/40. Mean number of TACE sessions was 3.5 (1–11). There were 3 treatment-related deaths (2 severe sepsis, 1 bowel perforation). A partial response and a stable disease were observed in 12 (28%) and 29 (67%) patients, respectively. Median overall and progression-free survivals were 29 months (95% CI: 13.8–45) and 15 months (95% CI: 11.5–20.8), respectively. Cancer of the liver Italian program score ≤1 (P = 0.042) and lipiodol uptake >25% (P = 0.003) were independent prognostic factors for better overall survival. Conclusion:This new TACE procedure is safe with a high overall survival rate and certainly deserves phase III investigation to compare it with classic treatments such as doxorubicin-lipiodol TACE.

Compound heterozygous PKHD1 variants cause a wide spectrum of ductal plate malformations

Ductal plate malformations (DPM) present with a wide phenotypic spectrum comprising Von Meyenburg complexes (VMC), Caroli disease (CD), Caroli syndrome (CS), and autosomal recessive polycystic kidney disease (ARPKD). Variants in PKHD1 are responsible for ARPKD and CS with a high inter‐ and intra‐familial phenotypic variability. Rare familial cases of CD had been reported and exceptional cases of CD are associated with PKHD1 variants. In a family of three siblings presenting with a wide spectrum of severity of DPM, we performed whole exome sequencing and identified two PKHD1 compound heterozygous variants (c.10444G>A; p.Arg3482Cys and c.5521C>T; p.Glu1841Lys), segregating with the symptoms. Two compound heterozygous PKHD1 variants, including one hypomorphic variant, were identified in two other familial cases of DPM with at least one patient presenting with CD. This report widens the phenotypic variability of PKHD1 variants to VMC, and others hepatic bile ducts malformations with inconstant renal phenotype in adults and highlights the important intra‐familial phenotypic variability. It also showed that PKHD1 might be a major gene for CD. This work adds an example of the contribution of exome sequencing, not only in the discovery of new genes but also in expanding the phenotypic spectrum of well‐known disease‐associated genes, using reverse phenotyping.

P1288 : Budd chiari syndrome (BCS) in France from a large national cohort

increased in recent years. This increase may be due to factors such as high HCV viral load in blood and semen, sex with risk of mucosal damage, a higher number of sexual partners, presence of concomitant ulcerative sexually transmitted diseases and the use of recreational drugs. The aim of our study was to investigate the dynamics of HCV transmission in an outbreak of acute hepatitis C in HIV-infected MSM in Barcelona. Methods: Between 2008 and 2013, 113 cases of acute hepatitis C in HIV-infected MSM were diagnosed in the Infectious Diseases Unit, Hospital Clinic, Barcelona. Phylogenetic analysis of the HCV NS5B gene was performed in a total of 70 patients. Viral RNA was extracted from serum samples collected from each patient at the time of diagnosis. Massive sequencing was performed using the Roche 454 GS Junior platform. To define possible transmission networks, phylogenetic trees and multidimensional scaling maps were constructed from genetic distance matrices (Da). Results: At the time of diagnosis of acute hepatitis C, 53 of the 70 (76%) patients included in the study were receiving antiretroviral therapy. HIV viral load was undetectable in 48 patients (69%) and the mean CD4 cell count was 923 cells /ul. HCV viral load was 6.37 log IU/mL (range 3.73–6.99). Thirty-five of 53 (66%) patients treated with pegIFN and ribavirin achieved a sustained virological response. The prevalence of HCV genotypes was: 4d 51% (n =36), 1a 40% (n =28), 1b 7% (n =5) and 3a 1% (n =1). Phylogenetic analysis showed the existence of at least 13 monophyletic groups: 5 of genotype 1a, 2 of genotype 1b and 6 genotype 4d. Molecular analysis showed that the genetic distances between genotype 4d viruses (Da 5.42) were significantly lower than those of the subtypes 1a (Da 18.50, p < 2.2×10−16) and 1b (Da 15.25, p < 1.1×10−6). This result may suggest the existence of a single source of infection for genotype 4d and different sources for subtypes 1a and 1b. Conclusions: HCV infection spreads rapidly among HIV-infected MSM through a local network in Barcelona. The implementation of public health campaigns and preventive measures, as well as treatment interventions with the new direct-acting antivirals will allow the development of strategies to reduce the HCV transmission of HCV within these high-risk groups.