Publications by authors named "Yves Horsmans"

134 Publications

Muscle fat content is strongly associated with NASH: a longitudinal study in patients with morbid obesity.

J Hepatol 2021 Apr 15. Epub 2021 Apr 15.

Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium. Electronic address:

Background And Aims: To evaluate the association between muscle mass and fatty infiltration and biopsy-assessed NAFLD in patients with obesity.

Materials And Methods: At inclusion (n=184) and 12 months after a dietary intervention (n=15) or a bariatric surgery (n=24), we evaluated NAFLD with liver biopsy, skeletal muscle mass index with computed tomography (CT-SMI) and bioelectrical impedance analysis (BIA-SMI). We developed an index to evaluate absolute fat content in muscle (skeletal muscle fat index; SMFI) from CT-based psoas muscle density (SMFI).

Results: Muscle mass was higher in patients with NAFLD than in those without (CT-SMI 56.8±9.9 vs 47.4±6.5 cm/m, p<0.0001). There was no association between sarcopenia and NASH. SMFI was higher in NASH ≥F2 and early NASH F0-1 than in NAFL (78.5±23.6 and 73.1±15.6 vs 61.2±12.6, p<0.001). One point in score for any of the individual cardinal NASH features (i.e. steatosis, inflammation or ballooning) associated with an increase in SMFI (all p<0.05). The association between SMFI and NASH was highly significant even after adjustment for multiple confounders (all p<0.025). After intervention (n=39), NASH improvement, defined by NAS <3 or 2-point NAS score reduction, was achieved in more than 75% of patients (n=25 or n=27, respectively) that had pre-established NASH at inclusion (n=32) and associated with a significant decrease in SMFI (p<0.001). Strikingly, all patients who had ≥11% reduction in SMFI achieved NASH improvement (14/14, p<0.05).

Conclusions: Muscle fat content, but not muscle mass, is strongly and independently associated with NASH. All individuals who achieved a ≥11% decrease in SMFI after intervention improved their NASH. These data call to explore muscle fatty infiltration as a potential marker for (and perhaps a pathophysiological contributor to) NASH.

Lay Summary: The fat content in skeletal muscles is highly reflective of the severity of non-alcoholic fatty liver disease (NAFLD) in patients with morbid obesity. In particular, muscle fat content is strongly associated with non-alcoholic steatohepatitis (NASH) and decreases upon NASH improvement. These data call to explore muscle fatty infiltration as a potential marker and perhaps a pathophysiological contributor to NASH.
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http://dx.doi.org/10.1016/j.jhep.2021.02.037DOI Listing
April 2021

Rationale of adding muscle volume to muscle fat infiltration in the definition of an adverse muscle composition is unclear.

JHEP Rep 2021 Apr 25;3(2):100235. Epub 2021 Jan 25.

Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.

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http://dx.doi.org/10.1016/j.jhepr.2021.100235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957149PMC
April 2021

Seroprevalence of Viral Hepatitis B and C and Knowledge of the Hepatitis B Virus among Pregnant Women Attending Prenatal Care in the Democratic Republic of Congo.

Am J Trop Med Hyg 2021 Jan 4. Epub 2021 Jan 4.

Hepato-GastroenterologyDepartment, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels Belgium.

Viral hepatitis B (HBV) and C (HCV) can significantly influence maternal and child health. Although HIV infection, malaria, and syphilis in pregnant women are likely to be systematically screened for and managed according to national guidelines in the Democratic Republic of Congo, there is no plan for HBV and HCV. Furthermore, there is no documentation regarding pregnant women's knowledge about HBV and HCV. This situation has motivated the researchers to undertake the current study, which was designed to estimate the seroprevalence of HBV and HCV. We have also assessed knowledge of the HBV infection among pregnant women who consulted for antenatal care for the first time at Vanga Evangelical Hospital in Vanga. A cross-sectional study was conducted with 457 pregnant women who attended antenatal care. Sociodemographic, obstetric, and previous medico-surgical data, as well as information related to women's HBV knowledge, were collected using a questionnaire. Rapid tests were used to detect HBV surface antigen and HCV antibodies. Most pregnant women were aged 20-24 years. Only 6.8% of respondents had knowledge of HBV, and the main source of this knowledge was health facilities (4.6%). Only 0.7% reported having been tested, whereas 98.5% said that they had not been offered a test. Overall, 18 (3.9%) participants were HBV positive and 22 (4.8%) were positive for HCV. There is limited knowledge about HBV and HCV among pregnant women in rural Vanga. All pregnant women should be screened during antenatal care, and a well-implemented program of management is needed.
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http://dx.doi.org/10.4269/ajtmh.20-0804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941832PMC
January 2021

Modulatory effect of rapamycin and tacrolimus on monocyte-derived dendritic cells phenotype and function.

Immunobiology 2021 Jan 23;226(1):152031. Epub 2020 Nov 23.

Sorbonne Université, INSERM, Institute of Cardiometabolism and Nutrition (ICAN), UMR_S 938, Centre de Recherche Saint-Antoine (CRSA), Paris, France; AP-HP, Hôpital de la Pitié-Salpêtrière, Liver Transplantation Unit, F-75012 Paris, France.

Background: Immunosuppressive-drugs are needed after solid organ transplantation to prevent allograft rejection but induce severe side effects. Understanding the alloimmune response is critical to modulate it and to achieve graft operational tolerance. The role of regulatory T cells and tolerogenic dendritic cells (Tol-DCs) is undoubtedly essential in tolerance induction. Tacrolimus is considered as the cornerstone of immunosuppression in solid organ transplantation. mTOR inhibitor such as rapamycin are thought to induce tolerance and are used as anticancer drugs in several cancers. The aim of this study was to better understand the effect of these immunosuppressive drugs on the differentiation, maturation and function of human monocyte derived dendritic cells (DCs).

Material And Methods: DCs were differentiated from monocytes of healthy donors with either rapamycin (Rapa-DCs) or tacrolimus (Tac-DCs). The phenotype was evaluated by flow cytometry analysis. The production of pro- and anti-inflammatory cytokines was assessed by ELISA. The mRNA expression level of IDO and PD-L1 was assessed by RTqPCR. Mixed leukocytes reactions were performed to analyse suppressive activity of DCs.

Results: Rapa-DC were characterised by a lower expression of the co-stimulatory molecules and CD83 than control-DCs (CTR-DC) (p < 0.05). In contrast, tacrolimus had no effect on the expression of surface markers compared to CTR-DCs. Rapamycin reduced both IL-12 and IL-10 secretions (p < 0.05). Rapa-DCs had a suppressive effect on CD4 allogenic T cells compared to CTR-DCs (p < 0.05). However, neither Rapa-DCs nor Tac-DCs favoured the emergence of a CD4CD25Foxp3 population compared to CTR-DCs. Surprisingly, Rapa-DCs had a reduced expression of IDO and PD-L1 compared to Tac-DCs and CTR-DCs.

Conclusion: Rapa-DCs exhibit an incomplete phenotypic tolerogenic profile. To our knowledge this is the first paper showing a reduction of expression of pro-tolerogenic enzyme IDO in DCs. Tacrolimus does not change the phenotypical or functional characteristics of moDCs.
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http://dx.doi.org/10.1016/j.imbio.2020.152031DOI Listing
January 2021

Myosteatosis rather than sarcopenia associates with non-alcoholic steatohepatitis in non-alcoholic fatty liver disease preclinical models.

J Cachexia Sarcopenia Muscle 2021 Feb 26;12(1):144-158. Epub 2020 Nov 26.

Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, UCLouvain, Brussels, Belgium.

Background: Non-alcoholic fatty liver (NAFL) disease (NAFLD) is the most common chronic liver disease in the world. While most subjects have 'inert' NAFL, a subset will progress to non-alcoholic steatohepatitis (NASH) and its life-threatening complications. A substantial body of literature supports that a low muscle mass, low strength, and/or muscle fatty infiltration (myosteatosis) are associated with NAFLD severity. Here, we evaluated the muscle compartment in NASH preclinical models to decipher the kinetics of muscle alterations in relation with liver disease progression.

Methods: We developed and validated a micro-computed tomography-based methodology to prospectively study skeletal muscle mass and density in muscle and liver (i.e. reflecting fatty infiltration) in a high-throughput and non-invasive manner in three preclinical NAFLD/NASH rodent models: fat aussie (FOZ) mice fed a high-fat diet (FOZ HF), wild-type (WT) mice fed a high-fat high-fructose diet (WT HFF), and WT mice fed a high-fat diet (WT HF). We compared them with WT mice fed a normal diet (WT ND) used as controls.

Results: -FOZ HF with fibrosing NASH had sarcopenia characterized by a reduced muscle strength when compared with WT HF and WT HFF with early NASH and WT ND controls (165.2 ± 5.2 g vs. 237.4 ± 11.7 g, 256 ± 5.7 g, and 242.9 ± 9.3 g, respectively, P 60; 0.001). Muscle mass or strength was not lower in FOZ HF, WT HF, and WT HFF with early NASH than in controls. Myosteatosis was present in FOZ HF with fibrosing NASH, but also in FOZ HF, WT HF, and WT HFF with early NASH (muscle density = 0.50 ± 0.02, 0.62 ± 0.02, 0.70 ± 0.05, and 0.75 ± 0.03, respectively, with P 60; 0.001 when compared with respective controls). Myosteatosis degree was strongly correlated with NAFLD activity score (r = -0.87, n = 67, P 60; 0.001). In multivariate analysis, the association between myosteatosis and NASH was independent from homeostatic model assessment of insulin resistance and visceral fat area (P 60; 0.05). Myosteatosis degree powerfully discriminated NASH from benign NAFL and normal liver (area under the receiver operating characteristic = 0.96, n = 67, P 60; 0.001).

Conclusions: Taken together, our data support that there is no sarcopenia in obese mice with early NASH. In contrast, the severity of myosteatosis reflects on hepatocellular damage and inflammation during early NASH development. This observation prompts us to exploit myosteatosis as a novel non-invasive marker of NASH.
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http://dx.doi.org/10.1002/jcsm.12646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890270PMC
February 2021

The Liver in COVID-19-Related Death: Protagonist or Innocent Bystander?

Pathobiology 2021 27;88(1):88-94. Epub 2020 Oct 27.

Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.

Introduction: The coronavirus disease 2019 (COVID-19) infection, caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), involves several organs through participation of angiotensin-conversion enzyme 2 (ACE2) receptors. The presence of ACE2 receptors in the liver renders this organ a potential target for the novel coronavirus.

Methods: We performed 14 complete autopsies of patients infected with SARS-CoV-2. In each case we stained liver tissue sections with haematoxylin/eosin, Masson blue trichrome stain, periodic acid-Schiff (PAS), Perls, and performed cytokeratin-7 (CK7) immunochemistry.

Results: Macroscopically, livers were pale and yellowish in 8 of 14 (57%) patients, and had a nutmeg appearance in the other 6 cases (42%). Histologically, centrolobular necrosis was observed in 12 cases (86%), and was associated with discreet to moderate lobular or portal inflammation. Steatosis was seen in 8 cases (57%), but fibrosis was rare. Cholestasis and discrete bile duct proliferation was observed in 5 cases (36%).

Discussion/conclusion: The main histological changes can be explained by the hypoxic status as a result of severe hypoxemic pneumonia leading to death. Drug toxicity may also play a role in certain cases. Other histological changes may be explained by previous hepatic conditions or underlying hepatic diseases. We concluded that COVID-19 infection was not associated with a specific histopathological pattern of the liver.
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http://dx.doi.org/10.1159/000512008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705929PMC
February 2021

Intestinal permeability, microbial translocation, changes in duodenal and fecal microbiota, and their associations with alcoholic liver disease progression in humans.

Gut Microbes 2020 11 26;12(1):1782157. Epub 2020 Jun 26.

Institute of Experimental and Clinical Research, Laboratory of Hepato-gastroenterology, UCLouvain, Université Catholique de Louvain , Brussels, Belgium.

Background: Animal data suggest a role of the gut-liver axis in progression of alcoholic liver disease (ALD), but human data are scarce especially for early disease stages.

Methods: We included patients with alcohol use disorder (AUD) who follow a rehabilitation program and matched healthy controls. We determined intestinal epithelial and vascular permeability (IP) (using urinary excretion of Cr-EDTA, fecal albumin content, and immunohistochemistry in distal duodenal biopsies), epithelial damage (histology, serum iFABP, and intestinal gene expression), and microbial translocation (Gram - and Gram + serum markers by ELISA). Duodenal mucosa-associated microbiota and fecal microbiota were analyzed by 16 S rRNA sequencing. ALD was staged by Fibroscan® (liver stiffness, controlled attenuation parameter) in combination with serum AST, ALT, and CK18-M65.

Results: Only a subset of AUD patients had increased Cr-EDTA and fecal albumin together with disrupted tight junctions and vasculature expression of plasmalemma Vesicle-Associated Protein-1. The so-defined increased intestinal permeability was not related to changes of the duodenal microbiota or alterations of the intestinal epithelium but associated with compositional changes of the fecal microbiota. Leaky gut alone did not explain increased microbial translocation in AUD patients. By contrast, duodenal dysbiosis with a dominance shift toward specific potential pathogenic bacteria genera (), increased IP and elevated markers of microbial translocation characterized AUD patients with progressive ALD (steato-hepatitis, steato-fibrosis).

Conclusion: Progressive ALD already at early disease stages is associated with duodenal mucosa-associated dysbiosis and elevated microbial translocation. Surprisingly, such modifications were not linked with increased IP. Rather, increased IP appears related to fecal microbiota dysbiosis.
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http://dx.doi.org/10.1080/19490976.2020.1782157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524402PMC
November 2020

Hepatitis B virus infection and the risk of liver disease progression in type 2 diabetic patients with potential nonalcoholic fatty liver disease: a retrospective, observational, cohort study in the United Kingdom Clinical Practice Research Datalink.

Eur J Gastroenterol Hepatol 2020 01;32(1):101-109

GSK, Wavre, Belgium Present address: Germano Ferreira: Pharmacoepidemiologist and data scientist consultant; Tom Cattaert: DICE, Data Investigation Company Europe, Brussels, Belgium; Yang Feng: Ningyang Group Co., Limited, C/O GSK, Wavre, Belgium.

Objective: Assess the risk of progression to cirrhosis and hepatocellular carcinoma (HCC) due to hepatitis B virus (HBV)-infection in patients with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM).

Methods: Retrospective cohort study in the UK Clinical Practice Research Datalink with three cohorts: subjects with T2DM and HBV infection (T2DM+HBV cohort; N = 297), with T2DM without HBV-infection (T2DM cohort; N = 261 865), and with HBV-infection without T2DM (HBV cohort; N = 3630). Primary analyses were performed on the three cohorts and secondary analyses on subcohorts including patients with NAFLD diagnosis code (N = 6599). Case/outcome definitions were formulated with International Classification of Diseases/Read codes/laboratory results and classified using validated algorithms. Adjusted incidence rate ratios (IRR) were estimated with a Poisson regression model.

Results: When comparing the T2DM+HBV and T2DM cohorts, adjusted IRRs were 14.06 (95% confidence interval: 4.47-44.19) for cirrhosis and 2.83 (1.06-7.55) for HCC. When comparing the T2DM+HBV and HBV cohorts, adjusted IRRs were 0.68 (0.21-2.27) for cirrhosis and 1.39 (0.46-4.20) for HCC. No cirrhosis cases were identified in T2DM+NAFLD+HBV patients; IRs were 16.92/10 000 person-years (12.97-21.69) and 85.24/10 000 person-years (10.32-307.91) in the T2DM+NAFLD and NAFLD+HBV cohorts.

Conclusion: HBV-infection increased significantly the risk for cirrhosis among T2DM patients, however, not beyond the expected incremental risk among infected non-T2DM subjects. Our approach to evaluate the role of T2DM/NAFLD and HBV-infection in liver disease progression could be applied to other settings with higher HBV prevalence.
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http://dx.doi.org/10.1097/MEG.0000000000001537DOI Listing
January 2020

Comparison of Sanger sequencing for hepatitis C virus genotyping with a commercial line probe assay in a tertiary hospital.

BMC Infect Dis 2019 Aug 22;19(1):738. Epub 2019 Aug 22.

Microbiology Department, Cliniques universitaires St Luc, Université catholique de Louvain, Brussels, Belgium.

Background: The technique most frequently used to genotype HCV is quantitative RT-PCR. This technique is unable to provide an accurate genotype/subtype for many samples; we decided to develop an in-house method with the goal of accurately identifying the genotype of all samples. As a Belgium National Centre of reference for hepatitis, we developed in-house sequencing not only for 5'UTR and core regions starting from VERSANT LiPA amplicons but also for NS5B regions. The sequencing of VERSANT LiPA amplicons might be useful for many laboratories worldwide using the VERSANT LiPA assay to overcome undetermined results.

Methods: 100 samples from Hepatitis C virus infected patients analysed by the VERSANT HCV Genotype 2.0 LiPA Assay covering frequent HCV types and subtypes were included in this study. NS5B, 5'UTR and Core home-made sequencing were then performed on these samples. The sequences obtained were compared with the HCV genomic BLAST bank.

Results: All the samples were characterised by the VERSANT LiPA assay (8 G1a, 17 G1b, 6 G2, 11 G3, 13 G4, and 10 G6). It was not possible to discriminate between G6 and G1 by the VERSANT LiPA assay for 8 samples and 27 had an undetermined genotype. Forty-one samples were sequenced for the three regions: NS5B, 5'UTR and Core. Twenty-three samples were sequenced for two regions: 5' UTR and Core and 36 samples were sequenced only for NS5B. Of the 100 samples included, 64 samples were analysed for 5'UTR and Core sequencing and 79 samples were analysed for NS5B sequencing. The global agreement between VERSANT LiPA assay and sequencing was greater than 95%.

Conclusions: In this study, we describe a new, original method to confirm HCV genotypes of samples not discriminated by a commercial assay, using amplicons already obtained by the screening method, here the VERSANT LiPA assay. This method thus saves one step if a confirmation assay is needed and might be of usefulness for many laboratories worldwide performing VERSANT LiPA assay in particular.
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http://dx.doi.org/10.1186/s12879-019-4386-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704641PMC
August 2019

Ombitasvir/paritaprevir/ritonavir plus ribavirin for 24 weeks in patients with HCV GT4 and compensated cirrhosis (AGATE-I Part II).

Health Sci Rep 2019 Mar 1;2(3):e92. Epub 2019 Mar 1.

AbbVie, Inc Chicago Illinois.

Background And Aims: AGATE-I Part I previously reported high sustained virologic response rates in hepatitis C genotype 4 patients with cirrhosis, with 12 and 16 weeks' treatment with a combination of two direct-acting antivirals, ombitasvir and paritaprevir (codosed with ritonavir), plus ribavirin. Part II, reported here, extended the trial to include a 24-week treatment arm to fully assess treatment duration in patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis.

Methods: Enrollment took place between June and November of 2015. Treatment-naive and interferon-experienced patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis were enrolled into Arm C; patients previously treated with a sofosbuvir-based regimen were enrolled into Arm D. All patients received a 24-week treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin. The primary outcome was the proportion of patients with a sustained virologic response (hepatitis C virus RNA < 25 IU/mL) at posttreatment week 12 in the intention-to-treat population. The safety population included all patients who received at least one dose of study drug.

Results: In total, 64 patients were enrolled into AGATE-I Part II. Sustained virologic response at posttreatment week 12 was achieved in 57 of 61 patients (93.4%; 97.5% confidence interval, 92.6-97.7) in Arm C and 3 of 3 patients (100%) in Arm D. Two patients were missing SVR12 data, and two prematurely discontinued treatment. The most common adverse events for Arm C were fatigue (16 [26%]) and asthenia (15 [25%]). Results were comparable with those reported in Part I.

Conclusions: AGATE-I Part II indicates that extending treatment beyond 12 weeks in genotype 4-infected patients with compensated cirrhosis does not offer additional benefit.
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http://dx.doi.org/10.1002/hsr2.92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427060PMC
March 2019

Reactive cholangiocytes differentiate into proliferative hepatocytes with efficient DNA repair in mice with chronic liver injury.

J Hepatol 2019 06 20;70(6):1180-1191. Epub 2019 Feb 20.

Laboratory of Hepato-gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium. Electronic address:

Background & Aim: Chronic liver diseases are characterized by expansion of the small immature cholangiocytes - a mechanism named ductular reaction (DR) - which have the capacity to differentiate into hepatocytes. We investigated the kinetics of this differentiation, as well as analyzing several important features of the newly formed hepatocytes, such as functional maturity, clonal expansion and resistance to stress in mice with long-term liver damage.

Methods: We tracked cholangiocytes using osteopontin-iCreER and hepatocytes with AAV8-TBG-Cre. Mice received carbon tetrachloride (CCl) for >24 weeks to induce chronic liver injury. Livers were collected for the analysis of reporter proteins, cell proliferation and death, DNA damage, and nuclear ploidy; hepatocytes were also isolated for RNA sequencing.

Results: During liver injury we observed a transient DR and the differentiation of DR cells into hepatocytes as clones that expanded to occupy 12% of the liver parenchyma by week 8. By lineage tracing, we confirmed that these new hepatocytes derived from cholangiocytes but not from native hepatocytes. They had all the features of mature functional hepatocytes. In contrast to the exhausted native hepatocytes, these newly formed hepatocytes had higher proliferative capability, less apoptosis, a lower proportion of highly polyploid nuclei and were better at eliminating DNA damage.

Conclusions: In chronic liver injury, DR cells differentiate into stress-resistant hepatocytes that repopulate the liver. The process might account for the observed parenchymal reconstitution in livers of patients with advanced-stage hepatitis and could be a target for regenerative purposes.

Lay Summary: During chronic liver disease, while native hepatocytes are exhausted and genetically unstable, a subset of cholangiocytes clonally expand to differentiate into young, functional and robust hepatocytes. This cholangiocyte cell population is a promising target for regenerative therapies in patients with chronic liver insufficiency.
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http://dx.doi.org/10.1016/j.jhep.2019.02.003DOI Listing
June 2019

Tamoxifen-induced hepatotoxicity caused by drug interaction with direct-acting antiviral agents for hepatitis C.

J Oncol Pharm Pract 2019 Dec 18;25(8):2038-2040. Epub 2018 Dec 18.

Department of Hepatogastroenterology, Cliniques universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.

A 68-year-old man develops acute hepatocellular injury during treatment with direct-acting antiviral agents (DAA) for hepatitis C. Medical history reveals the intake of tamoxifen as adjuvant treatment for breast cancer, currently in remission. After stopping tamoxifen, despite the continuation of the anti-HCV agents, a complete resolution of liver injury occurs. This interesting case illustrates tamoxifen hepatotoxicity induced by CYP3A4 interaction with direct anti-HCV agents. It stresses the importance of checking for interactions before starting treatment for hepatitis C.
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http://dx.doi.org/10.1177/1078155218819742DOI Listing
December 2019

Does haemophilia slow down the development of liver fibrosis?

Haemophilia 2019 01 14;25(1):e32-e35. Epub 2018 Nov 14.

Cliniques Universitaires Saint-Luc, Brussels, Belgium.

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http://dx.doi.org/10.1111/hae.13630DOI Listing
January 2019

Glecaprevir/Pibrentasvir in patients with chronic HCV genotype 3 infection: An integrated phase 2/3 analysis.

J Viral Hepat 2019 03 11;26(3):337-349. Epub 2018 Dec 11.

Denver Health Medical Center, Denver, Colorado.

Glecaprevir coformulated with pibrentasvir (G/P) is approved to treat hepatitis C virus (HCV) infection and was highly efficacious in phase 2 and 3 studies. Treating HCV genotype (GT) 3 infection remains a priority, as these patients are harder to cure and at a greater risk for liver steatosis, fibrosis progression and hepatocellular carcinoma. Data were pooled from five phase 2 or 3 trials that evaluated 8-, 12- and 16-week G/P in patients with chronic HCV GT3 infection. Patients without cirrhosis or with compensated cirrhosis were either treatment-naïve or experienced with interferon- or sofosbuvir-based regimens. Safety and sustained virologic response 12 weeks post-treatment (SVR12) were assessed. The analysis included 693 patients with GT3 infection. SVR12 was achieved by 95% of treatment-naïve patients without cirrhosis receiving 8-week (198/208) and 12-week (280/294) G/P. Treatment-naïve patients with cirrhosis had a 97% (67/69) SVR12 rate with 12-week G/P. Treatment-experienced, noncirrhotic patients had SVR12 rates of 90% (44/49) and 95% (21/22) with 12- and 16-week G/P, respectively; 94% (48/51) of treatment-experienced patients with cirrhosis treated for 16 weeks achieved SVR12. No serious adverse events (AEs) were attributed to G/P; AEs leading to study drug discontinuation were rare (<1%). G/P was well-tolerated and efficacious for patients with chronic HCV GT3 infection, regardless of cirrhosis status or prior treatment experience. Eight- and 12-week durations were efficacious for treatment-naïve patients without cirrhosis and with compensated cirrhosis, respectively; 16-week G/P was efficacious in patients with prior treatment experience irrespective of cirrhosis status.
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http://dx.doi.org/10.1111/jvh.13038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379735PMC
March 2019

Activation of brown adipose tissue enhances the efficacy of caloric restriction for treatment of nonalcoholic steatohepatitis.

Lab Invest 2019 01 26;99(1):4-16. Epub 2018 Sep 26.

Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.

Nonalcoholic steatohepatitis (NASH) is the form of nonalcoholic fatty liver disease that can evolve into cirrhosis. Lifestyle modifications achieving 10% weight loss reverse NASH, but there are no effective approved drug treatments. We previously identified defective adaptive thermogenesis as a factor contributing to metabolic syndrome and hepatic steatosis. We have now tested whether increasing nonshivering thermogenesis can improve preexisting NASH in mice. In high-fat diet-fed foz/foz mice with established NASH, treatment with β3AR agonist restored brown adipose tissue (BAT) function, decreased body weight, improved glucose tolerance, and reduced hepatic lipid content compared to untreated counterparts, but had no impact on liver inflammation or on nonalcoholic fatty liver disease activity score (NAS). Similarly, β3AR agonist did not alter liver pathology in other steatohepatitis models, including MCD diet-fed diabetic obese db/db mice. Caloric restriction alone alleviated the hepatic inflammatory signature in foz/foz mice. Addition of a β3AR agonist to mice subjected to caloric restriction enhanced weight loss and glucose tolerance, and improved liver steatosis, hepatocellular injury, and further reduced liver inflammation. These changes contributed to a significantly lower NAS score such as no (0/9) animals in this group fulfilled the criteria for NASH pathology compared to eight out of ten mice under caloric restriction alone. In conclusion, β3AR agonist counteracts features of the metabolic syndrome and alleviates steatosis, but does not reverse NASH. However, when coupled with weight loss therapy, BAT stimulation provides additional therapeutic advantages and reverses NASH.
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http://dx.doi.org/10.1038/s41374-018-0120-xDOI Listing
January 2019

Pharmacokinetic Interactions between Simeprevir and Ledipasvir in Treatment-Naive Hepatitis C Virus Genotype 1-Infected Patients without Cirrhosis Treated with a Simeprevir-Sofosbuvir-Ledipasvir Regimen.

Antimicrob Agents Chemother 2017 12 22;61(12). Epub 2017 Nov 22.

Janssen Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium.

Interactions between simeprevir (hepatitis C virus [HCV] NS3/4A protease inhibitor) and ledipasvir (HCV NS5A replication complex inhibitor) were investigated in treatment-naive HCV genotype 1-infected patients without cirrhosis, treated with simeprevir-sofosbuvir-ledipasvir in a two-panel, phase 2, open-label study. Patients had stable background treatment with sofosbuvir (400 mg once daily [QD]). In panel 1 ( = 20), the effect of ledipasvir (90 mg QD) on simeprevir (150 mg QD) was studied. Patients received simeprevir and sofosbuvir from days 1 to 14; steady-state pharmacokinetics (PK) of simeprevir was assessed (day 14). On day 15, ledipasvir was added and steady-state PK of simeprevir in the combination was evaluated (day 28). In panel 2 ( = 20), the effect of simeprevir on ledipasvir was investigated. From days 1 to 14, patients received ledipasvir and sofosbuvir and steady-state PK of ledipasvir was assessed (day 14). On day 15, simeprevir was added and a full PK profile was obtained (day 28). The least-squares mean maximum plasma concentration and area under the concentration-time curve (90% confidence interval) increased 2.3-fold (2.0- to 2.8-fold) and 3.1-fold (2.4- to 3.8-fold) for simeprevir, respectively (panel 1), and 1.6-fold (1.4- to 1.9-fold) and 1.7-fold (1.6- to 2.0-fold) for ledipasvir, respectively (panel 2), in the presence versus the absence of the other drug. All patients achieved sustained virologic responses 12 weeks after treatment end. Adverse events, mainly grade 1/2, occurred in 80% of patients; the most common was photosensitivity (45%). Due to the magnitude of interaction and the limited amount of safety data available, the use of this treatment combination is not recommended. (This study has been registered at ClinicalTrials.gov under registration no. NCT02421211.).
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http://dx.doi.org/10.1128/AAC.01217-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700296PMC
December 2017

Efficacy of Glecaprevir/Pibrentasvir for 8 or 12 Weeks in Patients With Hepatitis C Virus Genotype 2, 4, 5, or 6 Infection Without Cirrhosis.

Clin Gastroenterol Hepatol 2018 03 22;16(3):417-426. Epub 2017 Sep 22.

AbbVie Inc, North Chicago, Illinois.

Background & Aims: Hepatitis C virus (HCV) has high genotypic diversity and global distribution. Agents that are effective against all major HCV genotypes, with shorter treatment duration, are needed to reduce disease burden. Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) have a high barrier to resistance and synergistic antiviral activity. We evaluated the safety and efficacy of 8 and 12 weeks' treatment with glecaprevir/pibrentasvir in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis in 3 separate phase 3 trials.

Methods: We performed 2 open label, single-arm studies (SURVEYOR-II, Part 4 and ENDURANCE-4) and a randomized, double-blind, placebo-controlled study (ENDURANCE-2). In the ENDURANCE-2 study, adult patients with untreated or previously treated HCV genotype 2 infection without cirrhosis were randomly assigned (2:1) to groups given once-daily oral glecaprevir/pibrentasvir (n = 202; 300 mg/120 mg) or placebo (n = 100) for 12 weeks. In the SURVEYOR-II, Part 4 and ENDURANCE-4 studies, adult patients with untreated or previously treated patients with HCV genotype 2, genotype 4, genotype 5, or genotype 6 infection, without cirrhosis, were given once-daily oral glecaprevir/pibrentasvir (n = 121 in ENDURANCE-4 and n = 145 in SURVEYOR-II) for 12 or 8 weeks, respectively. In all studies the primary endpoint was sustained virologic response at 12 weeks after treatment (SVR12) in the intention-to-treat population.

Results: Among patients receiving glecaprevir/pibrentasvir for 8 weeks, rates of SVR12 were 98% (95% CI, 94.1-99.3) in those infected with HCV genotype 2 and 93% (95% CI, 83.6-97.3) in those infected with HCV genotypes 4, 5, or 6. Among patients receiving glecaprevir/pibrentasvir for 12 weeks, rates of SVR12 were 99.5% (95% CI, 98.5-100) in those infected with HCV genotype 2 and 99% (95% CI, 97.6-100) in those infected with HCV genotype 4, 5, or 6. No virologic failures occurred in patients with HCV genotype 4, 5, or 6 infections. The frequency and severity of adverse events in patients receiving glecaprevir/pibrentasvir were similar to those of patients who received placebo.

Conclusion: In 3 Phase 3 studies, 8 weeks' treatment with glecaprevir/pibrentasivr produced an SVR12 in at least 93% of patients with chronic HCV genotype 2, 4, 5, or 6 infection without cirrhosis, with virologic failure in less than 1%. The drug combination had a safety profile comparable to 12 week's treatment with glecaprevir/pibrentasvir. ClinicalTrials.gov numbers: NCT02640482 (ENDURANCE-2), NCT02636595 (ENDURANCE-4), and NCT02243293 (SURVEYOR-II).
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http://dx.doi.org/10.1016/j.cgh.2017.09.027DOI Listing
March 2018

Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial.

Lancet Infect Dis 2017 10 14;17(10):1062-1068. Epub 2017 Aug 14.

AbbVie, North Chicago, IL, USA.

Background: The once-daily, ribavirin-free, pangenotypic, direct-acting antiviral regimen, glecaprevir coformulated with pibrentasvir, has shown high rates of sustained virological response in phase 2 and 3 studies. We aimed to assess the efficacy and safety of 12 weeks of coformulated glecaprevir and pibrentasvir in patients with hepatitis C virus (HCV) infection and compensated cirrhosis.

Methods: We did this single-arm, open-label, multicentre phase 3 study at 40 sites in Belgium, Canada, Germany, South Africa, Spain, and the USA. We enrolled patients aged 18 years or older with HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. Patients were either HCV treatment-naive or had not responded to treatment with interferon or pegylated interferon with or without ribavirin, or sofosbuvir plus ribavirin with or without pegylated interferon. Oral glecaprevir (300 mg) coformulated with pibrentasvir (120 mg) was administered once daily for 12 weeks. The primary efficacy endpoint was sustained virological response at post-treatment week 12 (HCV RNA <15 IU/mL). We assessed efficacy and safety in all patients who received at least one dose of study drug (intention-to-treat population). This study is registered with ClinicalTrials.gov, number NCT02642432.

Findings: Between Dec 7, 2015, and May 4, 2016, we enrolled 146 patients with compensated cirrhosis, of whom 48 (33%) had genotype 1a HCV infection, 39 (27%) had genotype 1b infection, 34 (23%) had genotype 2 infection, 16 (11%) had genotype 4 infection, two (1%) had genotype 5 infection, and seven (5%) had genotype 6 infection. 12 weeks after treatment, 145 patients (99%, 95% CI 98-100) achieved sustained virological response, with one (1%) relapse at post-treatment week 8. We recorded 101 (69%) adverse events, of which 65 (64%) were mild. The most common adverse events were fatigue (n=28 [19%]) and headache (n=20 [14%]). 11 (8%) patients had serious adverse events, none of which were deemed related to study drugs. No patients had elevations in alanine aminotransferase and no patients prematurely discontinued treatment because of adverse events.

Interpretation: Our results show that 99% of patients treated with once-daily glecaprevir plus pibrentasvir achieved a sustained virological response at 12 weeks. Furthermore, this drug regimen had a favourable safety profile in previously treated or untreated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. These findings could help simplify treatment algorithms and reduce treatment burden.

Funding: AbbVie.
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http://dx.doi.org/10.1016/S1473-3099(17)30496-6DOI Listing
October 2017

Effects of Mild to Severe Hepatic Impairment on the Pharmacokinetics of Sonidegib: A Multicenter, Open-Label, Parallel-Group Study.

Clin Pharmacokinet 2018 03;57(3):345-354

Division of Clinical Pharmacology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA.

Background And Objective: Sonidegib is a potent, selective and orally bioavailable inhibitor of the Hedgehog signaling pathway, primarily metabolized by the liver. In order to make dose recommendations for patients with hepatic impairment, we have assessed here the pharmacokinetics (PKs) and safety of sonidegib in subjects with varying degrees of hepatic function.

Methods: The primary objective of this phase I, multicenter, open-label study was to evaluate the PKs of a single oral 800 mg dose of sonidegib in subjects with impaired hepatic function compared with healthy subjects. PK parameters (e.g. area under the concentration-time curve from time zero to infinity [AUC], area under the concentration-time curve from time zero to the last measurable concentration [AUC], maximum concentration [C ], apparent clearance [CL/F], and terminal half-life [t ]) for parent drug and the metabolite were compared with the normal group, as the reference. Metabolite ratio, unbound PK parameters, and the relationship between specific PK parameters and liver function parameters were assessed.

Results: In total, 33 subjects entered the study and received sonidegib. Plasma concentrations peaked at approximately 2-3 h in all groups after dosing. Compared with the normal group, AUC decreased by 35 and 23% and increased by 14% in the mild, severe, and moderate hepatic impairment groups, respectively. The C values were lower in all groups with respect to the normal group (decreases of 20, 21 and 60% in the mild, moderate and severe hepatic impairment groups, respectively). Protein binding was independent of hepatic function, and similar trends in the PK parameters were observed for unbound sonidegib and the metabolite. Protein binding was similar across all groups. Weak to no correlation between specific PK and hepatic function parameters was found.

Conclusions: Overall, sonidegib exposures were similar or decreased in the hepatic impairment groups compared with the normal group, and sonidegib was generally well-tolerated in all subjects. Dose adjustment is not considered necessary for subjects with mild, moderate, or severe hepatic impairment.
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http://dx.doi.org/10.1007/s40262-017-0560-2DOI Listing
March 2018

Genetic and phylogenic characterization of hepatitis B virus in the eastern part of the Democratic Republic of Congo.

J Med Virol 2018 02 11;90(2):250-254. Epub 2017 Nov 11.

Department of Clinical Biology, Virology Laboratory, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCL), Bruxelles, Belgium.

Hepatitis B virus (HBV) genotypes show a distinctive geographical distribution worldwide and genotypes A, D, and E are the most frequently found in Africa. There are only limited studies on HBV genotype distribution in Democratic Republic of Congo (DRC), all done in the western part showing a vast majority of genotype E. In our study, HBV strains from South Kivu, an eastern province of the DRC, were analyzed. Sequencing of 41 serum samples from HBV infected patients revealed strains of genotype A in 40/41 (97.6%) and genotype E in 1/41 (2.4%). The phylogenetic analysis showed that nearly all genotypes A (38/40) were closely related to A1 subgenotype strains found in Rwanda, Haiti, and Martinique while only two strains attached to the A2 subgenotype cluster were isolated. The remaining genotype E case was linked to the western African E crescent. Only the I169T nucleotide substitution was observed in two genotype A samples. In conclusion, the genotype A seems to be the most predominant genotype in eastern DRC with the majority belonging to the Afro-Asian subgenotype (A1). This contrasts with the western part of DRC where genotype E is predominant. These results support the hypothesis of an East-West genotypic demarcation.
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http://dx.doi.org/10.1002/jmv.24837DOI Listing
February 2018

Persistence of Virologic Response after Liver Transplant in Hepatitis C Patients Treated with Ledipasvir / Sofosbuvir Plus Ribavirin Pretransplant.

Ann Hepatol 2017 May - Jun;16(3):375-381

Department for Gastroenterology and Hepatology, University Hospital Zurich, Switzerland.

Introduction: Recurrence of HCV infection in patients with chronic hepatitis C virus (HCV) at the time of liver transplantation is nearly universal and reduces the likelihood of graft and patient survival.

Materials And Methods: We evaluated outcomes of 17 patients (16 with HCV genotype 1 and 1 with genotype 4) who received up to 12 or 24 weeks of ledipasvir/sofosbuvir plus ribavirin prior to or up to the time of liver transplant in the SOLAR-1 and SOLAR-2 trials. In all patients, HCV RNA was < 15 IU/mL prior to transplant. At screening, 6 patients were Child-Pugh-Turcotte (CPT) class B and 11 were CPT class C. Seven patients underwent transplant prior to completing assigned treatment, with 4 treated for < 12 weeks. The primary endpoint was posttransplant virologic response 12 weeks after transplant (pTVR12) in patients with HCV RNA < 15 IU/mL at their last measurement prior to transplant.

Results: Overall, 94% (16/17) achieved pTVR12. All who achieved pTVR12 received at least 11 weeks of treatment. The single patient who did not achieve pTVR12 discontinued study drug on day 21 and underwent liver transplant the following day. The patient had HCV RNA < 15 IU/mL at post-transplant week 2 but died 15 days post-transplant because of multi-organ failure and septic shock.

Conclusion: Among a small population of HCV patients with decompensated cirrhosis, virologic response to ledipasvir / sofosbuvir plus ribavirin prior to liver transplantation was maintained after transplantation, even if treatment was stopped early. Administration of ledipasvir / sofosbuvir plus ribavirin before liver transplant can prevent post-transplant HCV recurrence.
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http://dx.doi.org/10.5604/16652681.1235480DOI Listing
October 2017

Efficacy, safety and pharmacokinetics of simeprevir and TMC647055/ritonavir with or without ribavirin and JNJ-56914845 in HCV genotype 1 infection.

BMC Gastroenterol 2017 Feb 10;17(1):26. Epub 2017 Feb 10.

Janssen Research & Development BVBA, Beerse, Belgium.

Background: A Phase 2a, open-label study (NCT01724086) was conducted to assess the efficacy and safety of a once-daily, 2-direct-acting-antiviral-agent (2-DAA) combination of simeprevir + TMC647055/ritonavir ± ribavirin and of the 3-DAA combination of simeprevir + TMC647055/ritonavir + JNJ-56914845 in chronic hepatitis C virus genotype (GT)1-infected treatment-naïve and prior-relapse patients.

Methods: The study comprised four 12-week treatment panels: Panel 1 (n = 10; GT1a) and Panel 2-Arm 1 (n = 12; GT1b): simeprevir 75 mg once daily + TMC647055 450 mg once daily/ritonavir 30 mg once daily + ribavirin 1000-1200 mg/day; Panel 2-Arm 2 (n = 9; GT1b): simeprevir 75 mg + TMC647055 450 mg/ritonavir 30 mg without ribavirin; Panel 3: simeprevir 75 mg + TMC647055 600 mg/ritonavir 50 mg with (Arm 1: GT1a; n = 7) or without (Arm 2: GT1b; n = 8) ribavirin; Panel 4: simeprevir 75 mg + TMC647055 450 mg/ritonavir 30 mg + JNJ-56914845 30 mg once daily (Arm 1: n = 22; GT1a/GT1b) or 60 mg once daily (Arm 2: n = 22; GT1a/GT1b). Primary endpoint was sustained virologic response 12 weeks after end of treatment (12 weeks of combination treatment; SVR12).

Results: In Panel 1 and Panel 2-Arm 1, 5/10 and 6/12 (50%) GT1a/GT1b + ribavirin patients achieved SVR12, versus 3/9 (33%) GT1b without ribavirin patients in Panel 2-Arm 2. In Panel 3-Arm 1 and Panel 3-Arm 2, 6/7 (86%) GT1a + ribavirin and 4/8 (50%) GT1b without ribavirin patients, respectively, achieved SVR12. In Panel 4, 10/14 (71%) and 14/15 (93%) GT1a patients in Arms 1 and 2 achieved SVR12 compared with 8/8 and 7/7 (100%) GT1b patients in each arm, respectively. No deaths, serious adverse events (AEs), Grade 4 AEs or AEs leading to treatment discontinuation occurred.

Conclusions: The 2- and 3-DAA combinations were well tolerated. High SVR rates of 93% and 100% in GT1a- and GT1b-infected patients, respectively, were achieved in this study by combining simeprevir with JNJ-56914845 60 mg and TMC647055/ritonavir.

Trial Registration: NCT01724086 (date of registration: September 26, 2012).
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http://dx.doi.org/10.1186/s12876-017-0580-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5303260PMC
February 2017

Simeprevir and daclatasvir for 12 or 24 weeks in treatment-naïve patients with hepatitis C virus genotype 1b and advanced liver disease.

Liver Int 2017 09 13;37(9):1304-1313. Epub 2017 Mar 13.

Department of Gastroenterology and Hepatology, J.W. Goethe University, Frankfurt, Germany.

Background & Aims: We investigated the efficacy and safety of simeprevir plus daclatasvir in treatment-naïve patients with chronic, genotype 1b hepatitis C virus infection and advanced liver disease, excluding patients with pre-defined NS5A resistance-associated substitutions.

Methods: This phase II, open-label, single-arm, multicentre study included patients aged ≥18 years with advanced fibrosis or compensated cirrhosis (METAVIR F3/4). Patients with NS5A-Y93H or L31M/V resistance-associated substitutions at screening were excluded. Simeprevir (150 mg)+daclatasvir (60 mg) once daily was administered for 12 or 24 weeks; treatment could be extended to 24 weeks prior to or at the Week 12 visit. Primary efficacy endpoint was sustained virological response 12 weeks after the end of treatment.

Results: A total of 106 patients were treated; 27% patients were aged >65 years, 39% had cirrhosis, 53% had estimated glomerular filtration rate 30-89 mL/min, 14% had diabetes, and 38% had arterial hypertension. Overall, 42/106 received 12 weeks of treatment and 64/106 received 24 weeks of treatment. Ninety-seven (92%) patients achieved a sustained virological response 12 weeks after the end of treatment. The reasons for failure were viral breakthrough (n=7) at weeks 4-16, early treatment discontinuation (n=1) and viral relapse (n=1). Seventy-four (70%) patients had ≥1 adverse event during treatment, including six (6%) patients with ≥1 serious adverse event. Three (3%) patients discontinued treatment owing to adverse events.

Conclusions: Simeprevir+daclatasvir demonstrated strong antiviral activity and was well-tolerated in patients with hepatitis C virus genotype 1b infection, advanced liver disease and a high prevalence of comorbidities. However, viral breakthrough occurred in seven patients, making this regimen unsatisfactory.
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http://dx.doi.org/10.1111/liv.13376DOI Listing
September 2017

Aging enhances liver fibrotic response in mice through hampering extracellular matrix remodeling.

Aging (Albany NY) 2016 12;9(1):98-113

Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium.

Clinical data identify age as a factor for severe liver fibrosis. We evaluate whether and how aging modulates the fibrotic response in a mouse model. Liver fibrosis was induced by CCl injections (thrice weekly for 2 weeks) in 7 weeks- and 15 months-old mice (young and old, respectively). Livers were analyzed for fibrosis, inflammation and remodeling 48 and 96 hours after the last injection. Old mice developed more severe fibrosis compared to young ones as evaluated by sirius red morphometry. Expression of pro-fibrogenic genes was equally induced in the two age-groups but enhanced fibrolysis in young mice was demonstrated by a significantly higher induction and collagenase activity. While fibrosis resolution occurred in young mice within 96 hours, no significant fibrosis attenuation was observed in old mice. Although recruitment of monocytes-derived macrophages was similar in young and old livers, young macrophages had globally a remodeling phenotype while old ones, a pro-fibrogenic phenotype. Moreover, we observed a higher proportion of thick fibers and enhanced expression of enzymes involved in collagen maturation in old mice.

Conclusion: Impaired fibrolysis of a matrix less prone to remodeling associated with a pro-inflammatory phenotype of infiltrated macrophages contribute to a more severe fibrosis in old mice.
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http://dx.doi.org/10.18632/aging.101124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310658PMC
December 2016

Knowledge, Attitudes, and Practices of Health-Care Workers About Viral Hepatitis B and C in South Kivu.

Am J Trop Med Hyg 2017 Feb 5;96(2):400-404. Epub 2016 Dec 5.

Department of Hepatogastroenterology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCL), Brussels, Belgium.

Health-care workers (HCWs) are at risk of infections associated with accidental exposure to blood, including viral hepatitis B (HBV) and C (HCV). A survey using a questionnaire was conducted on 250 HCW in Bukavu, an eastern town of the Democratic Republic of Congo, to analyze their attitude and knowledge about these two viruses. A response rate of 86.8% (217/250) was obtained. The mean age of the respondents was 39.6 ± 9.8 years, in majority from paramedical staff (66.4%) and with more than 5 years of professional experience (60.8%). The mean proportion of adequate answers on HBV and HCV was 33.2% (±11%) and 30.6% (±7%), respectively. Ninety-three HCW (42.8%) reported recent experience of blood exposure accident, more frequently among the paramedical staff (50%) than physicians (28.8%; = 0.002). This was mainly related to inadequate protection resources (76.9%). Among all participants, only 24.4% had a history of at least one injection of HBV vaccine; this was more frequently found among physicians than among paramedical staff (49.3% versus 11.8%; < 0.001). Moreover, only 3.8% of vaccinated HCW received the complete vaccination schedule of three vaccine doses. The efficiency of this vaccine is not well recognized by HCW, and the majority of them seemed to be more worried about the risk of infection by human immunodeficiency virus than by viral hepatitis. Our study reveals that the level of knowledge about HBV and HCV is rather low among HCW in Bukavu.
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http://dx.doi.org/10.4269/ajtmh.16-0287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5303044PMC
February 2017

Defective adaptive thermogenesis contributes to metabolic syndrome and liver steatosis in obese mice.

Clin Sci (Lond) 2017 02 1;131(4):285-296. Epub 2016 Nov 1.

Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, 1200 Brussels, Belgium

Fatty liver diseases are complications of the metabolic syndrome associated with obesity, insulin resistance and low grade inflammation. Our aim was to uncover mechanisms contributing to hepatic complications in this setting. We used foz/foz mice prone to obesity, insulin resistance and progressive fibrosing non-alcoholic steatohepatitis (NASH). Foz/foz mice are hyperphagic but wild-type (WT)-matched calorie intake failed to protect against obesity, adipose inflammation and glucose intolerance. Obese foz/foz mice had similar physical activity level but reduced energy expenditure. Thermogenic adaptation to high-fat diet (HFD) or to cold exposure was severely impaired in foz/foz mice compared with HFD-fed WT littermates due to lower sympathetic tone in their brown adipose tissue (BAT). Intermittent cold exposure (ICE) restored BAT function and thereby improved glucose tolerance, decreased fat mass and liver steatosis. We conclude that failure of BAT adaptation drives the metabolic complications of obesity in foz/foz mice, including development of liver steatosis. Induction of endogenous BAT function had a significant therapeutic impact on obesity, glucose tolerance and liver complications and is a potential new avenue for therapy of non-alcoholic fatty liver disease (NAFLD).
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http://dx.doi.org/10.1042/CS20160469DOI Listing
February 2017

Impact of adjuvants on CD4(+) T cell and B cell responses to a protein antigen vaccine: Results from a phase II, randomized, multicenter trial.

Clin Immunol 2016 08 25;169:16-27. Epub 2016 May 25.

GSK Vaccines, Rixensart/Wavre, Belgium.

Immunogenicity and safety of different adjuvants combined with a model antigen (HBsAg) were compared. Healthy HBV-naïve adults were randomized to receive HBs adjuvanted with alum or Adjuvant Systems AS01B, AS01E, AS03A or AS04 at Days 0 and 30. Different frequencies of HBs-specific CD4+ T cells 14days post dose 2 but similar polyfunctionality profiles were induced by the different adjuvants with frequencies significantly higher in the AS01B and AS01E groups than in the other groups. Antibody concentrations 30days post-dose 2 were significantly higher in AS01B, AS01E and AS03A than in other groups. Limited correlations were observed between HBs-specific CD4+ T cell and antibody responses. Injection site pain was the most common solicited local symptom and was more frequent in AS groups than in alum group. Different adjuvants formulated with the same antigen induced different adaptive immune responses and reactogenicity patterns in healthy naïve adults. The results summary for this study (GSK study number 112115 - NCT# NCT00805389) is available on the GSK Clinical Study Register and can be accessed at www.gsk-clinicalstudyregister.com.
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http://dx.doi.org/10.1016/j.clim.2016.05.007DOI Listing
August 2016

Occult HBV reactivation induced by ibrutinib treatment: a case report.

Acta Gastroenterol Belg 2015 Dec;78(4):424-6

Ibrutinib is a small molecule that has been recently developped for the treatment of B cell malignancies. Common side effects are diarrhoea, nausea, fatigue, infections, neutropenia and thrombocytopenia. Here we report the first case of Hepatitis B virus reactivation in a 80 years old chronic lymphocytic leukaemia patient receiving ibrutinib, suggesting that such treatment must be associated with HBV screening.
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December 2015

Sustained virologic response of 100% in HCV genotype 1b patients with cirrhosis receiving ombitasvir/paritaprevir/r and dasabuvir for 12weeks.

J Hepatol 2016 Feb 22;64(2):301-307. Epub 2015 Oct 22.

The Texas Liver Institute/University of Texas Health Science Center, San Antonio, TX, USA.

Background & Aims: Patients with chronic hepatitis C virus (HCV) infection and cirrhosis have a higher risk for liver-related complications and have historically been more difficult to cure than patients without cirrhosis. We evaluated the safety and efficacy of ombitasvir/paritaprevir/ritonavir and dasabuvir, without ribavirin, for 12weeks in patients with HCV genotype 1b infection and compensated cirrhosis.

Methods: Treatment-naïve and peginterferon/ribavirin treatment-experienced patients received 12weeks of ombitasvir/paritaprevir/ritonavir (25/150/100mg once daily) and dasabuvir (250mgtwicedaily). Key inclusion criteria were hemoglobin ⩾10g/dl, albumin ⩾2.8g/dl, platelet count ⩾25×10(9)/L, creatinine clearance ⩾30ml/min, and Child-Pugh score ⩽6. Efficacy was assessed by the percentage of patients achieving SVR (HCV RNA <25IU/ml) 12weeks post-treatment (SVR12). Efficacy and safety were assessed in all patients receiving study drug.

Results: Sixty patients with HCV genotype 1b infection and cirrhosis received treatment. The study population comprised 62% male, 55% treatment-experienced, 83% with IL28B non-CC genotype, 22% with platelet count <90×10(9)/L, and 17% with albumin <3.5g/dl. All 60 patients completed treatment, and SVR12 was achieved in 100% (95% CI, 94.0-100%) of patients. The most common adverse events were fatigue (22%), diarrhea (20%), and headache (18%). Only one patient (1.7%) experienced a serious adverse event. Laboratory abnormalities were infrequently observed and not clinically significant.

Conclusions: The HCV regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir without ribavirin for 12weeks achieved 100% SVR12 and was well tolerated in HCV genotype 1b-infected patients with cirrhosis, suggesting that this 12-week ribavirin-free regimen is sufficient in this population.
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http://dx.doi.org/10.1016/j.jhep.2015.10.005DOI Listing
February 2016