Viral clade is associated with severity of symptomatic genotype 3 hepatitis E virus infections in Belgium, 2010-2018.

BACKGROUND & AIMS: HEV genotype (gt) 3 infections are prevalent in high-income countries and display a wide spectrum of clinical presentations. Host - but not viral - factors are reported to be associated with worse clinical outcomes. METHODS: Demographic, clinical, and biochemical data laboratory-confirmed HEV infections (by PCR and/or a combination of IgM and IgG serology) at the Belgian National Reference Centre between January 2010 and June 2018 were collected using standardised case report forms. Genotyping was based on HEV open reading frame 2 sequences. Serum CXCL10 levels were measured by a magnetic bead-based assay. H&E staining was performed on liver biopsies. RESULTS: A total of 274 HEV-infected individuals were included. Subtype assignment was possible for 179/218 viraemic cases, confirming gt3 as dominant with an almost equal representation of clades abchijklm and efg. An increased hospitalisation rate and higher peak serum levels of alanine aminotransferase, bilirubin, and alkaline phosphatase were found in clade efg-infected individuals in univariate analyses. In multivariable analyses, clade efg infections remained more strongly associated with severe disease presentation than any of the previously identified host risk factors, being associated with a 2.1-fold higher risk of hospitalisation (95% CI 1.1-4.4, p = 0.034) and a 68.2% higher peak of bilirubin levels (95% CI 13.3-149.9, p = 0.010), independently of other factors included in the model. In addition, acute clade efg infections were characterised by higher serum CXCL10 levels (p = 0.0005) and a more pronounced liver necro-inflammatory activity (p = 0.022). CONCLUSIONS: In symptomatic HEV gt3 infections, clade efg is associated with a more severe disease presentation, higher serum CXCL10 levels, and liver necro-inflammatory activity, irrespective of known host risk factors. CLINICAL TRIAL REGISTRATION: The protocol was submitted to clinicaltrials.gov (NCT04670419). IMPACT AND IMPLICATIONS: HEV genotype (gt) 3 infections display a wide spectrum of clinical presentations currently ascribed to host factors. Here we examined the role of viral factors on liver disease outcomes by combining viral phylogeny with clinical, biochemical, cytokine, and histological data from 274 Belgian adults infected with HEV presenting between 2010 and 2018. HEV gt 3 clade efg infections were associated with a more severe disease presentation, higher serum CXCL10 levels and liver necro-inflammatory activity, irrespective of known host risk factors. HEV gt3 clade-dependent clinical outcomes call for broad HEV gt3 subtyping in clinical practice and research to help identify those at higher risk for worse outcomes and to further unravel underlying virus-host interactions.

A phase II study of human allogeneic liver-derived progenitor cell therapy for acute-on-chronic liver failure and acute decompensation.

BACKGROUND & AIMS: Human allogeneic liver-derived progenitor cells (HALPC, HepaStem®; Promethera Biosciences, Mont-Saint-Guibert, Belgium) are an advanced therapy medicinal product that could potentially alleviate systemic inflammation and ameliorate liver function in patients with acute-on-chronic liver failure (ACLF) or acute decompensation of cirrhosis (AD). METHODS: This open-label phase II study was conducted in 9 centres in Belgium, Spain, and Bulgaria between 2016 and 2019. The primary objective was to assess the safety of HALPC therapy up to Day 28 and the secondary objectives were to assess its safety and preliminary efficacy up to Month 3. RESULTS: The 24 treated patients (mean age: 51 years) were mostly male with an alcoholic cirrhosis. On pre-infusion Day 1, 15 patients had ACLF and 9 patients had AD. Two of the 3 initial patients treated with high HALPC doses (∼5×106 cells/kg body weight [BW]) had severe adverse bleeding events attributed to treatment. In 21 patients subsequently treated with lower HALPC doses (0.6 or 1.2×106 cells/kg BW, 1 or 2 times 7 days apart), no serious adverse events were related to treatment, and the other adverse events were in line with those expected in patients with ACLF and AD. Overall, markers of systemic inflammation and altered liver function decreased gradually for the surviving patients. The Day-28 and Month-3 survival rates were 83% (20/24) and 71% (17/24), and at Month 3, no patient had ACLF. CONCLUSIONS: The treatment of patients with ACLF or AD with up to 2 doses of 1.2×106 HALPC/kg BW appeared safe. The results of this study support the initiation of a proof-of-concept study in a larger cohort of patients with ACLF to further confirm the safety and evaluate the efficacy of HALPC therapy. CLINICAL TRIALS REGISTRATION: EudraCT 2016-001177-32. LAY SUMMARY: Patients with liver cirrhosis may suffer from the rapid onset of organ failure or multiple organ failure associated with a high risk of death in the short term. This clinical study of 24 patients suggests that an advanced therapy based on the intravenous infusion of low doses of human allogeneic liver-derived progenitor cells is safe and supports the next phase of clinical development of this type of therapy.

Sofosbuvir in Combination with Simeprevir +/- Ribavirin in Genotype 4 Hepatitis C Patients with Advanced Fibrosis or Cirrhosis: A Real-World Experience from Belgium.

INTRODUCTION: Hepatitis C virus (HCV) is a major global health issue and successful treatment has been associated with a reduction of risk of all-cause mortality. Advancements have been made in HCV treatment through the use of interferon-free regimens. Most trials have been conducted in HCV genotype (GT) 1 and data for interferon-free regimens in GT4 patients are limited. The aim of this study was to evaluate the safety and efficacy of sofosbuvir plus simeprevir in a real-world cohort of HCV GT4 patients with advanced fibrosis. PATIENTS AND METHODS: Eighty-seven GT4 treatment-naïve or -Interferon (IFN) ribavirin (RBV) experienced patients treated with sofosbuvir and simeprevir +/- ribavirin (RBV) were enrolled in this cohort study (41% severe fibrosis, 59% cirrhosis). RESULTS: Patients were 51.7% male, 78.2% IFN/RBV treatment-experienced, and 37.9% received RBV treatment. The overall sustained virologic response at least 12 weeks after treatment (SVR12) rate was 87.4% while patients treated with and without RBV had rates of 87.9% and 87% (p = 0.593), respectively, and patients with advanced fibrosis (F3) and patients with cirrhosis had SVR12 rates of 94.4% and 82.4% (p = 0.087), respectively. SVR12 rates in treatment-naïve patients and in IFN/RBV -experienced patients were 78.9% and 89.7% (p = 0.191), respectively. Treatment failure occurred most commonly in patients with cirrhosis and severe disease. The treatment was well tolerated and no patient died or discontinued treatment due to adverse events. CONCLUSIONS: Sofosbuvir in combination with simeprevir +/- ribavirin in GT 4 HCV patients with advanced fibrosis achieved high SVR12 rates and was well tolerated. RBV did not appear to increase the rate of SVR12.

Alcohol intake increases the risk of HCC in hepatitis C virus-related compensated cirrhosis: A prospective study.

BACKGROUND & AIMS: Whether alcohol intake increases the risk of complications in patients with HCV-related cirrhosis remains unclear. The aim of this study was to determine the impact of alcohol intake and viral eradication on the risk of hepatocellular carcinoma (HCC), decompensation of cirrhosis and death. METHODS: Data on alcohol intake and viral eradication were prospectively collected in 192 patients with compensated HCV-related cirrhosis. RESULTS: 74 patients consumed alcohol (median alcohol intake: 15g/day); 68 reached viral eradication. During a median follow-up of 58months, 33 patients developed HCC, 53 experienced at least one decompensation event, and 39 died. The 5-year cumulative incidence rate of HCC was 10.6% (95% CI: 4.6-16.6) in abstainers vs. 23.8% (95% CI: 13.5-34.1) in consumers (p=0.087), and 2.0% (95% CI: 0-5.8) vs. 21.7% (95% CI: 14.2-29.2) in patients with and without viral eradication (p=0.002), respectively. The lowest risk of HCC was observed for patients without alcohol intake and with viral eradication (0%) followed by patients with alcohol intake and viral eradication (6.2% [95% CI: 0-18.4]), patients without alcohol intake and no viral eradication (15.9% [95% CI: 7.1-24.7]), and patients with alcohol intake and no viral eradication (29.2% [95% CI: 16.5-41.9]) (p=0.009). In multivariate analysis, lack of viral eradication and alcohol consumption were associated with the risk of HCC (hazard ratio for alcohol consumption: 3.43, 95% CI: 1.49-7.92, p=0.004). Alcohol intake did not influence the risk of decompensation or death. CONCLUSIONS: Light-to-moderate alcohol intake increases the risk of HCC in patients with HCV-related cirrhosis. Patient care should include measures to ensure abstinence. LAY SUMMARY: Whether alcohol intake increases the risk of complications in patients with HCV-related cirrhosis remains unclear. In this prospective study, light-to-moderate alcohol intake was associated with the risk of hepatocellular carcinoma in multivariate analysis. No patients who did not use alcohol and who reached viral eradication developed hepatocellular carcinoma during follow-up. The risk of hepatocellular carcinoma increased with alcohol intake or in patients without viral eradication and was highest when alcohol intake was present in the absence of viral eradication. Patients with HCV-related cirrhosis should be strongly advised against any alcohol intake. Patient care should include measures to ensure abstinence.

Intensive Enteral Nutrition Is Ineffective for Patients With Severe Alcoholic Hepatitis Treated With Corticosteroids.

BACKGROUND & AIMS: Severe alcoholic hepatitis (AH) is a life-threatening disease for which adequate oral nutritional support is recommended. We performed a randomized controlled trial to determine whether the combination of corticosteroid and intensive enteral nutrition therapy is more effective than corticosteroid therapy alone in patients with severe AH. METHODS: We enrolled 136 heavy consumers of alcohol (age, 18-75 y) with recent onset of jaundice and biopsy-proven severe AH in our study, performed at 18 hospitals in Belgium and 2 in France, from February 2010 through February 2013. Subjects were assigned randomly (1:1) to groups that received either intensive enteral nutrition plus methylprednisolone or conventional nutrition plus methylprednisolone (controls). In the intensive enteral nutrition group, enteral nutrition was given via feeding tube for 14 days. The primary end point was patient survival for 6 months. RESULTS: In an intention-to-treat analysis, we found no significant difference between groups in 6-month cumulative mortality: 44.4% of patients died in the intensive enteral nutrition group (95% confidence interval [CI], 32.2%-55.9%) and 52.1% of controls died (95% CI, 39.4%-63.4%) (P = .406). The enteral feeding tube was withdrawn prematurely from 48.5% of patients, and serious adverse events considered to be related to enteral nutrition occurred in 5 patients. Regardless of group, a greater proportion of patients with a daily calorie intake less than 21.5 kcal/kg/day died (65.8%; 95% CI, 48.8-78.4) than patients with a higher intake of calories (33.1%; 95% CI, 23.1%-43.4%) (P < .001). CONCLUSIONS: In a randomized trial of patients with severe AH treated with corticosteroids, we found that intensive enteral nutrition was difficult to implement and did not increase survival. However, low daily energy intake was associated with greater mortality, so adequate nutritional intake should be a main goal for treatment. ClinicalTrials.gov number: NCT01801332.

Ethnic epidemiological profiles and antiviral therapy among patients infected with hepatitis C virus genotype 4: a multicenter study from Belgium.

BACKGROUND: Hepatitis C virus genotype 4 (HCV-4) is the most prevalent genotype in Central Africa. AIM: To compare epidemiology, clinical characteristics and any differences in access to HCV therapy in two populations of HCV-4 patients residing in Belgium. METHODS: This multicenter study selected 473 HCV-4 patients from seven hospital databases and compared them according to ethnic origin, i.e., Black African (n=331) or not (n=142), for epidemiological, clinical, biological and histological characteristics. Interleukin 28B polymorphism (CC-genotype) was evaluated in a second cohort of 69 Black African and 30 non-Black African patients. RESULTS: Compared to other patients, the Black African patients were more likely to be female and were older, commonly overweight, frequently had abnormal glucose metabolism and arterial hypertension ; they were less likely to have dyslipidemia, a history of alcohol consumption or ALT elevation. The route of infection was more frequently unknown in Black African than in other patients. Black African patients had more HCV-4 subtypes, were less frequently of IL28B CC-genotype and had less severe liver fibrosis. The proportion of patients who received antiviral treatment was similar in the two groups. CONCLUSION: In this Belgian cohort, patients with HCV-4 infection were more frequently of Black African origin than of other origin. Infected Black African patients were more commonly -female, older at diagnosis, and had more co-morbidities than other patients; they also had less advanced liver fibrosis than infected non-Black African patients and fewer had a CC genotype.

Good long-term outcome of Budd-Chiari syndrome with a step-wise management.

UNLABELLED: Budd-Chiari syndrome (BCS) is a rare, life-threatening disease caused by obstruction of hepatic venous outflow. The aim of the study was to assess long-term outcome and identify prognostic factors in BCS patients managed by a step-wise approach using anticoagulation, angioplasty/thrombolysis, transjugular intrahepatic portosystemic shunting (TIPS), and orthotopic liver transplantation (OLT). We reviewed long-term data on 157 patients previously included by the European Network for Vascular Disorders of the Liver, a multicenter prospective study of newly diagnosed BCS patients in nine European countries. Patients were followed for a median of 50 months (range, 0.1-74.0). During the study, 88 patients (56%) received at least one invasive intervention (22 patients angioplasty/thrombolysis, 62 TIPS, and 20 OLT) and 36 (22.9%) died. Most interventions and/or deaths occurred in the first 2 years after diagnosis. The Rotterdam score was excellent in predicting intervention-free survival, and no other variable could significantly improve its prognostic ability. Moreover, BCS-TIPS prognostic index (PI) score (based on international normalized ratio, bilirubin, and age) was strongly associated with survival and had a discriminative capacity, which was superior to the Rotterdam score. CONCLUSIONS: The current study confirms, in a large cohort of patients with BCS recruited over a short period, that a step-wise treatment approach provides good long-term survival. In addition, the study validates the Rotterdam score for predicting intervention-free survival and the BCS-TIPS PI score for predicting survival.

Enteral nutrition with or without N-acetylcysteine in the treatment of severe acute alcoholic hepatitis: a randomized multicenter controlled trial.

BACKGROUND & AIMS: Severe acute alcoholic hepatitis is associated with a high mortality rate. Oxidative stress is involved in the pathogenesis of acute alcoholic hepatitis. Previous findings had also suggested that enteral nutritional support might increase survival in patients with severe acute alcoholic hepatitis. Therefore, the aim of the present study was to evaluate the efficacy of N-acetylcysteine in combination with adequate nutritional support in patients with severe acute alcoholic hepatitis. METHODS: Patients with biopsy-proven acute alcoholic hepatitis and mDF ≥32 were randomized to receive N-acetylcysteine intravenously or a placebo perfusion along with adequate nutritional support for 14 days. The primary endpoint was 6-month survival; secondary endpoints were biological parameter evolution and infection rate. RESULTS: Fifty-two patients were randomized in the study (28 into the N-acetylcysteine arm, 24 into the control arm), and among them, five were excluded from the analysis for protocol violation. The two groups did not differ in baseline characteristics. Survival rates at 1 and 6 months in N-acetylcysteine and control groups were 70.2 vs. 83.8% (p=0.26) and 62.4 vs. 67.1% (p=0.60), respectively. Early biological changes, documented infection rate at 1 month, and incidence of hepatorenal syndrome did not differ between the two groups. CONCLUSIONS: In this study, high doses of intravenous N-acetylcysteine therapy for 14 days conferred neither survival benefits nor early biological improvement in severe acute alcoholic hepatitis patients with adequate nutritional support. However, these results must be viewed with caution, since the study suffered from a lack of power.

Upper gastrointestinal bleeding related to emphysematous cholecystitis due to Clostridium perfringens.

We describe the case of a 46-year-old man admitted for upper gastrointestinal bleeding in the context of cirrhosis. A deep bleeding duodenal ulcer was treated by sclerotherapy. Abdominal pain and fever lead us to perform an abdominal computed tomography, which demonstrated emphysematous cholecystitis. An emergency cholecystectomy was performed and antimicrobial therapy initiated. The patient recovered uneventfully. Links between ulcers and emphysematous cholecystitis are discussed.

Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.

UNLABELLED: Current recommendations for early anticoagulation in acute portal vein thrombosis unrelated to cirrhosis or malignancy are based on limited evidence. The aim of this study was to prospectively assess the risk factors, outcome, and prognosis in patients managed according to these recommendations. We enrolled 102 patients with acute thrombosis of the portal vein, or its left or right branch. Laboratory investigations for prothrombotic factors were centralized. Thrombus extension and recanalization were assessed by expert radiologists. A local risk factor was identified in 21% of patients, and one or several general prothrombotic conditions in 52%. Anticoagulation was given to 95 patients. After a median of 234 days, the portal vein and its left or right branch were patent in 39% of anticoagulated patients (versus 13% initially), the splenic vein in 80% (versus 57% initially), and the superior mesenteric vein in 73% (versus 42% initially). Failure to recanalize the portal vein was independently related to the presence of ascites (hazard ratio 3.8, 95% confidence interval 1.3-11.1) and an occluded splenic vein (hazard ratio 3.5, 95% confidence interval 1.4-8.9). Gastrointestinal bleeding and intestinal infarction occurred in nine and two patients, respectively. Two patients died from causes unrelated to thrombosis or anticoagulation therapy. CONCLUSION: Recanalization occurs in one-third of patients receiving early anticoagulation for acute portal vein thrombosis, whereas thrombus extension, intestinal infarction, severe bleeding, and death are rare. Alternative therapy should be considered when ascites and splenic vein obstruction are present.

Etiology, management, and outcome of the Budd-Chiari syndrome.

BACKGROUND: The Budd-Chiari syndrome (BCS) is hepatic venous outflow obstruction. What is known about the syndrome is based on small studies of prevalent cases. OBJECTIVE: To characterize the causes and treatment of incident BCS. DESIGN: Consecutive case series of patients with incident BCS, enrolled from October 2003 to October 2005 and followed until May 2006. SETTING: Academic and nonacademic hospitals in France, Spain, Italy, Great Britain, Germany, Belgium, the Netherlands, Portugal, and Switzerland. PATIENTS: Persons older than 16 years with definite hepatic outflow obstruction diagnosed by imaging. Persons with hepatic outflow obstruction due to heart failure, sinusoidal obstruction syndrome, cancer, or liver transplantation were excluded. MEASUREMENTS: Signs and symptoms; laboratory and imaging findings; diagnosis; treatment; and overall, transplantation-free, and intervention-free survival. RESULTS: 163 incident cases of BCS were identified. Median follow-up was 17 months (range, 0.1 to 31 months). Most patients (84%) had at least 1 thrombotic risk factor, and many (46%) had more than 1; the most common was myeloproliferative disorders (49% of 103 tested patients). Patients were mainly treated with anticoagulation (140 patients [86%]), transjugular intrahepatic portosystemic shunting (56 patients [34%]), or liver transplantation (20 patients [12%]), and 80 patients (49%) were managed noninvasively. Only 3 patients underwent surgical shunting. The survival rate was 87% (95% CI, 82% to 93%) at 1 year and 82% (CI, 75% to 88%) at 2 years. LIMITATION: Treatment was not standardized across all centers, and data on important clinical variables were missing for some patients. CONCLUSION: Most patients with BCS have at least 1 thrombotic risk factor, and many have more than 1; myeloproliferative disorders are most common. One- and 2-year survival rates are good with contemporary management, which includes noninvasive therapies (anticoagulation and diuretics) and invasive techniques. Transjugular intrahepatic portosystemic shunting seems to have replaced surgical shunting as the most common invasive therapeutic procedure. PRIMARY FUNDING SOURCE: Fifth Framework Programme of the European Commission.

What is the optimal duration of therapy in patients with hepatitis C genotype 2 or 3 infection?: a review.

Pegylated interferon plus ribavirin is the standard treatment for chronic hepatitis C (HCV). Even if genotype 2 and 3 patients only request a treatment of 24 weeks, this treatment remains very costly and difficult to tolerate due to numerous side effects. Recently several studies focused on the possibility of further reducing treatment duration in chronic HCV genotype 2 and 3 patients without compromising sustained virological response (SVR). Based on the available data, patients presenting a negative PCR at week 4 named a rapid virological response (RVR) probably are the best candidates to benefit from shorter treatment duration. In contrast patients without RVR should at least be treated for 24 weeks and retrospective data suggest that a more intensive or prolonged therapy for 48 weeks could be necessary. However, at this moment it remains impossible to propose general recommendations for all patients with genotype 2 and 3. Therefore more randomized prospective trials are needed to clarify several issues that are discussed in this review article.