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.

Hepatitis C reinfection in former and active injecting drug users in Belgium.

BACKGROUND: There is currently no systematic screening for hepatitis C (HCV) reinfection in people who inject drugs (PWID) after treatment in Belgium. However, in a recent meta-analysis, the overall HCV reinfection rate was 5.9/100 person-years (PY) among PWID. Accordingly, this study was undertaken to investigate the reinfection rate in former and active PWID who achieved the end of treatment response after direct-acting antiviral (DAA) treatment in Belgium. METHODS: This observational cross-sectional study recruited individuals with a history of injecting drug use who had achieved the end of treatment response to any DAA treatment between 2015 and 2020. Participants were offered a post-treatment HCV RNA test. RESULTS: Eighty-five potential participants were eligible to participate and contacted, of whom 60 participants were enrolled in the study with a median age of 51.0 (IQR 44.3-56.0) years; it was reported that 23.3% continued to inject drugs intravenously after DAA treatment. Liver cirrhosis was present in 12.9%. The majority had genotype 1a (51.7%) or genotype 3 (15.0%) infection. We detected no reinfections in this study population. The total time patients were followed up for reinfection in the study was 78.5 PY (median 1.0 years IQR 0.4-2.0). CONCLUSION: Reinfection after successful treatment with DAA initially appears to be very low in Belgian PWID. Therefore, efforts should be made to screen individuals with persistent risk behaviors for reinfection systematically. In addition, a national HCV registry should be established to accurately define the burden of HCV infection and reinfection in Belgium and support the elimination of viral hepatitis C in Europe. Trial registration clinicaltrials.gov NCT04251572, Registered 5 Feb 2020-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04251572 .

Characteristics of patients with hepatitis B virus and hepatitis C virus dual infection in a Western European country: Comparison with monoinfected patients.

The epidemiology of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is continuously evolving. Updated data on dual HBV and HCV infection are still needed. AIMS: To assess the main characteristics of patients with HBV and HCV dual infection, to compare these with those of patients infected with either HBV or HCV and, among patients with dual infection, to assess fibrosis according to HCV replication. METHODS: Data of 23 patients with dual infection were compared to data from 92 age and sex-matched HBV or HCV monoinfected patients. RESULTS: Patients with dual infection were more often immigrants from Africa or Asia than HCV or HBV patients (52% vs. 20% and 22%, respectively, P=0.01). Intravenous drug use was the route of transmission in 22% of patients with dual infection, which was less frequent than in HCV patients (41%) but more frequent than in HBV patients (0%). Extensive fibrosis or cirrhosis was as frequent among dual-infected patients as among those with HCV or chronic hepatitis B infection (19% vs. 29% vs. 14%, respectively, P=0.4), even when fibrosis stage was reported considering the duration of infection. In dual-infected patients, the prevalence of extensive fibrosis or cirrhosis was similar in patients with and without detectable HCV RNA (18% vs. 20%). CONCLUSIONS: Patients with HBV and HCV dual infection were more often immigrants from Africa or Asia and had similar fibrosis stages than HCV or HBV monoinfected patients. In patients with dual infection, extensive fibrosis or cirrhosis was not associated with HCV replication.

Belgian experience with direct acting antivirals in people who inject drugs.

BACKGROUND AND AIM: Hepatitis C viral infection (HCV) has become a curable disease due to the development of direct acting antivirals (DAA). The WHO has set a target to eliminate HCV completely. Therefore, people who inject drugs (PWID) also need to be treated. In this study, we compared the real-life uptake and outcome of DAA treatment for HCV in PWID and non-PWID. METHODS: We performed a nation-wide, retrospective cohort study in 15 hospitals. All patients who were treated with simeprevir-sofosbuvir, daclatasvir-sofosbuvir, or ombitasvir/paritaprevir ritonavir-dasabuvir between December 2013 and November 2015 were included. RESULTS: The study population consisted of 579 patients: 115 PWID (19.9%) and 464 non-PWID (80.1%). Of the PWID 18 were active PWID (15.6%), 35 still received opiate substitution therapy (OST) (30.4%) and 62 were former PWID without OST (53.9%). PWID were more infected with genotype 1a and 3 (p=0.001). There were equal rates of side-effects (44.7% vs. 46.6%; p=0.847), similar rates of treatment completion (95.7% vs 98.1%; p=0.244) and SVR (93.0% vs 94.8%; p=0.430) between PWID and non-PWID, respectively. CONCLUSION: PWID, especially active users, are underserved for DAA treatment in real life in Belgium. Reimbursement criteria based on fibrosis stage make it difficult to treat PWID. Treatment adherence is similar in PWID and the general population, even in patients with active abuse. DAA were safe and effective in PWID despite the higher prevalence of difficult-to-treat genotypes. Based on these data more efforts to treat PWID are needed and policy changes are necessary to reach the WHO targets.

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.

Control of AA amyloidosis complicating Crohn's disease: a clinico-pathological study.

BACKGROUND: Immunosuppressive drugs may prevent or partially reverse progression of renal AA-amyloidosis, a rare complication of Crohn's disease, often fatal due to renal failure. MATERIALS AND METHODS: The clinical, biological and pathological data of 16 patients treated since 1976 were reviewed. Serum amyloid A was determined in surviving patients. RESULTS: The median age of the 16 patients (13 men) was 23·5 years (range 16-69). At Crohn's disease onset, Montreal phenotypes were similar to reported data. Out of 15 patients with renal insufficiency, 8 developed a nephrotic syndrome and 7 a low grade proteinuria. The single patient without renal insufficiency had nephrotic syndrome. A significant correlation (P < 0·05) between the extension of renal amyloid A and sclerosis was found in 12 patients. One patient had a 10 year remission of nephrotic syndrome with immunosuppressive drugs. In 6 patients treated with anti-TNF-α (Tumor-Necrosis-Factor-α) agents, anaphylactic reaction (1/6), death from septic shock (1/6), 5-year remission (1/6) or reduction of nephrotic syndrome (1/6) and stabilization of renal insufficiency (2/6) were observed. Surgery was performed in 10 patients. Kidney transplantation was performed in 5 of the 8 patients dialysed for end-stage renal failure. Among 6/16 patients (37%) still alive, 3 belong to the 5 transplanted patients (survival: 3-20 years) and 3 to the anti-TNF-α drugs treated patients; all but one exhibited a low serum amyloid A level. CONCLUSIONS: Suppression of Crohn's disease inflammation potentially leads to the control of amyloid A production, assessed by a decrease of serum amyloid A. Kidney transplantation provides a long survival.

Hepatitis B virus and hepatitis C virus infections in Belgium: similarities and differences in epidemics and initial management.

INTRODUCTION: Nationwide studies comparing patients with hepatitis B and C virus (HBV and HCV) infections are mandatory for assessing changes in epidemiology. AIM: The aim of this study was to compare epidemiological data and initial management of newly diagnosed patients with persistent HBV (HBsAg positive) or HCV (detectable HCV RNA) infection in Belgium. PATIENTS AND METHODS: Data were extracted from two Belgian observational databases. RESULTS: A total of 655 patients (387 HBV and 268 HCV) were included. Compared with HCV patients, HBV patients were younger, more frequently men, more often of Asian or African origin (43 vs. 10%, P<0.0001), and less frequently contaminated by transfusion or intravenous drug use (9 and 6% vs. 34 and 44%, P<0.0001). Viral replication was assessed in 89% of HBV patients. Compared with HCV patients, HBV patients more frequently had normal alanine aminotransferase (ALT) levels (65 vs. 29%, P<0.0001), less frequently underwent liver biopsy (29 vs. 67%, P<0.0001), and were less often considered for antiviral therapy (25 vs. 54%, P<0.0001). When taking only HBV patients with detectable viral replication into consideration, results remained unchanged. During the multivariate analysis, ALT was a major factor for performing liver biopsy or considering antiviral therapy in both groups. CONCLUSION: HBV and HCV screening policies should be targeted toward immigrants and intravenous drug users, respectively. Guidelines recommending systematic search for viral replication should be reinforced in HBV patients. HBV patients less frequently underwent liver biopsy and were less often considered for antiviral therapy compared with HCV patients. Despite the lack of sensitivity and specificity, ALT remains a pivotal decision-making tool for liver biopsy and antiviral therapy in both infections.

HBV infection in Belgium: results of the BASL observatory of 1,456 HBsAg carriers.

INTRODUCTION: Nationwide studies are mandatory to assess changes in the epidemiology of HBV infection in Europe. AIM: To describe epidemiological characteristics of HBsAg-positive patients, especially inactive carriers, and to evaluate how practitioners manage HBV patients in real life. METHODS: Belgian physicians were asked to report all chronically infected HBV patients during a one-year period. RESULTS: Among 1,456 patients included, 1,035 (71%) were classified into one of four phases of chronic infection: immune tolerance (n = 10), HBeAg-positive hepatitis (n = 248), HBeAg-negative hepatitis (n = 420) and inactive carrier state (n = 357 HBeAg-negative patients with ALT