Publications by authors named "Laurent Alric"

168 Publications

Cytolethal Distending Toxin Promotes Replicative Stress Leading to Genetic Instability Transmitted to Daughter Cells.

Front Cell Dev Biol 2021 7;9:656795. Epub 2021 May 7.

Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France.

The cytolethal distending toxin (CDT) is produced by several Gram-negative pathogenic bacteria. In addition to inflammation, experimental evidences are in favor of a protumoral role of CDT-harboring bacteria such as , , or . CDT may contribute to cell transformation and carcinogenesis in mice models, through the genotoxic action of CdtB catalytic subunit. Here, we investigate the mechanism of action by which CDT leads to genetic instability in human cell lines and colorectal organoids from healthy patients' biopsies. We demonstrate that CDT holotoxin induces a replicative stress dependent on CdtB. The slowing down of DNA replication occurs mainly in late S phase, resulting in the expression of fragile sites and important chromosomic aberrations. These DNA abnormalities induced after CDT treatment are responsible for anaphase bridge formation in mitosis and interphase DNA bridge between daughter cells in G1 phase. Moreover, CDT-genotoxic potential preferentially affects human cycling cells compared to quiescent cells. Finally, the toxin induces nuclear distension associated to DNA damage in proliferating cells of human colorectal organoids, resulting in decreased growth. Our findings thus identify CDT as a bacterial virulence factor targeting proliferating cells, such as human colorectal progenitors or stem cells, inducing replicative stress and genetic instability transmitted to daughter cells that may therefore contribute to carcinogenesis. As some CDT-carrying bacterial strains were detected in patients with colorectal cancer, targeting these bacteria could be a promising therapeutic strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2021.656795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138442PMC
May 2021

Predictive Factors for Hepatocellular Carcinoma in Chronic Hepatitis B Using Structural Equation Modeling: A Prospective Cohort Study.

Clin Res Hepatol Gastroenterol 2021 Apr 27:101713. Epub 2021 Apr 27.

Digestive Center, Centre Hospitalier Universitaire de Nice, INSERM U1065-8, Nice, France.

Background & Aims: The factors predicting hepatocellular carcinoma (HCC) occurrence in chronic hepatitis B need to be precisely known to improve its detection. We identified pathways and individual predictive factors associated with HCC in the ANRS CO22 HEPATHER cohort.

Methods: The study analyzed HBV-infected patients recruited at 32 French expert hepatology centers from August 6, 2012, to December 31, 2015. We excluded patients with chronic HCV, HDV and a history of HCC, decompensated cirrhosis or liver transplantation. Structural equation models were developed to characterize the causal pathways leading to HCC occurrence. The association between clinical characteristics (age, gender, body-mass index, liver fibrosis, alcohol consumption, smoking status, diabetes, hypertension, dyslipidemia, alpha-fetoprotein, HBV DNA levels, antiviral therapy) and incident HCC was quantified.

Results: Among the 4,489 patients included, 33 patients reported incident HCC. The median follow-up was 45.2 months. Age (β = 0.18 by decade, 95% CI 0.14-0.23), male gender (β = 0.23, 95% CI 0.18-0.29), metabolic syndrome (β = 0.28, 95% CI 0.22-0.33), alcohol consumption (β = 0.09, 95% CI 0.05-0.14) and HBV DNA (β = 0.25, 95% CI 0.17-0.34) had a significant and direct effect on the occurrence of advanced liver fibrosis. Liver fibrosis (β = 0.71, 95% CI 0.55-0.87) predicted, in turn, the occurrence of HCC.

Conclusions: Liver fibrosis mediates the effects of age, gender, alcohol, metabolic syndrome and HBV DNA on the occurrence of HCC. Elderly men with chronic hepatitis B, risky alcohol use, advanced liver fibrosis, metabolic syndrome and high HBV DNA levels should be monitored closely to detect the development of HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinre.2021.101713DOI Listing
April 2021

Pure red cell aplasia in systemic lupus erythematosus, a nationwide retrospective cohort and review of the literature.

Rheumatology (Oxford) 2021 Apr 19. Epub 2021 Apr 19.

Service de Médecine Interne, Centre National de Référence des Cytopénies Auto-Immunes de l'Adulte, Centre Hospitalier Universitaire Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.

Objectives: To characterize the clinical and biological course, management and response to treatment in Systemic Lupus Erythematosus (SLE)-associated Pure Red Cell Aplasia (PRCA).

Methods: Nationwide multicentre retrospective cohort study. From 2006 to 2018, we included adults with a diagnosis of PRCA supported by bone-marrow examination and SLE or biologic manifestations of SLE after ruling out parvovirus B19 infection.

Results: We enrolled 24 patients (20 women). SLE was diagnosed before PRCA for 14 patients (median delay 81 months). At PRCA diagnosis, mean age, haemoglobin level and reticulocyte and differential erythroblast count were 39.2 ± 13.2 years, 62 ± 20 g/L, 9.1 ± 7.6 x 109/L and 2.8 ± 2.5%, respectively. Eleven (45%) patients experienced multiple PRCA flares (median 6, range: 2-11). Corticosteroid therapy resulted in only three complete sustained responses, and 19 (79%) patients required immunosuppressive agents with highly variable regimens. After a median follow-up of 76 months (range 13-173), 17 (71%) patients showed complete response for PRCA, five (21%) partial response and two (8%) treatment failure. In total, 21 (87%) patients required red-blood-cell transfusion; five had a diagnosis of transfusion-related iron overload. Eighteen (75%) patients experienced severe infectious events requiring hospitalization.

Conclusion: SLE-associated PRCA is a severe condition. Repeated red-blood-cell transfusions and several lines of immunosuppressant therapy are mostly required with high risk of severe infectious events and iron overload. Despite sustained response for PRCA and SLE obtained in most patients, the best therapeutic strategy remains to be determined.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/keab363DOI Listing
April 2021

Combination of fibrates with obeticholic acid is able to normalise biochemical liver tests in patients with difficult-to-treat primary biliary cholangitis.

Aliment Pharmacol Ther 2021 05 25;53(10):1138-1146. Epub 2021 Mar 25.

Paris, France.

Background: Obeticholic acid (OCA) and fibrates are second-line therapies for patients with primary biliary cholangitis (PBC) with an inadequate response to ursodeoxycholic acid (UDCA).

Aim: To know whether OCA and fibrates, administered together in combination with UDCA, have additive beneficial effects in patients with difficult-to-treat PBC.

Methods: PBC patients treated for ≥3 months with UDCA, OCA and fibrates (bezafibrate or fenofibrate) due to failure of either second-line therapy were included in a multicentre, uncontrolled retrospective cohort study. Changes in biochemical liver tests and pruritus were analysed using a generalised linear mixed-effect model.

Results: Among 58 patients included, half received OCA as second-line and fibrates as third-line therapy (Group OCA-Fibrate), while the other half had the inverse therapeutic sequence (Group Fibrate-OCA). The mean duration of triple therapy was 11 months (range 3-26). Compared to dual therapy, triple therapy was associated with a significant gain in alkaline phosphatase (ALP) reduction: 22% per first year (95% CI 12%-31%), an effect that was stronger in OCA-Fibrate than in Fibrate-OCA group. Triple therapy was associated with a 3.4 (95% CI 1.4-8.2) odds ratio (OR) of reaching normal ALP and with a significant decrease in gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin. The ORs of achieving the Paris-2 and Toronto criteria of adequate biochemical response were 6.8 (95% CI 2.8-16.7) and 9.2 (95% CI 3.4-25.1) respectively. Finally, triple therapy significantly improved pruritus in OCA-Fibrate but not in Fibrate-OCA group.

Conclusions: Triple therapy with UDCA, OCA and fibrates is able to normalise biochemical liver tests and improve pruritus in patients with difficult-to-treat PBC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/apt.16336DOI Listing
May 2021

Epithelial production of elastase is increased in inflammatory bowel disease and causes mucosal inflammation.

Mucosal Immunol 2021 05 5;14(3):667-678. Epub 2021 Mar 5.

IRSD, Université de Toulouse, INSERM, INRAe, ENVT, UPS, Toulouse, France.

Imbalance between proteases and their inhibitors plays a crucial role in the development of Inflammatory Bowel Diseases (IBD). Increased elastolytic activity is observed in the colon of patients suffering from IBD. Here, we aimed at identifying the players involved in elastolytic hyperactivity associated with IBD and their contribution to the disease. We revealed that epithelial cells are a major source of elastolytic activity in healthy human colonic tissues and this activity is greatly increased in IBD patients, both in diseased and distant sites of inflammation. This study identified a previously unrevealed production of elastase 2A (ELA2A) by colonic epithelial cells, which was enhanced in IBD patients. We demonstrated that ELA2A hyperactivity is sufficient to lead to a leaky epithelial barrier. Epithelial ELA2A hyperactivity also modified the cytokine gene expression profile with an increase of pro-inflammatory cytokine transcripts, while reducing the expression of pro-resolving and repair factor genes. ELA2A thus appears as a novel actor produced by intestinal epithelial cells, which can drive inflammation and loss of barrier function, two essentials pathophysiological hallmarks of IBD. Targeting ELA2A hyperactivity should thus be considered as a potential target for IBD treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41385-021-00375-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075934PMC
May 2021

Colitis-linked to endoplasmic reticulum stress induces trypsin activity affecting epithelial functions.

J Crohns Colitis 2021 Feb 20. Epub 2021 Feb 20.

IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France.

Background: Intestinal epithelial cells (IECs) from inflammatory bowel disease (IBD) patients exhibit excessive induction of Endoplasmic Reticulum stress (ER stress) linked to altered intestinal barrier function and inflammation. Colonic tissues and luminal content of IBD patients are also characterized by increased serine protease activity. The possible link between ER stress and serine protease activity in colitis-associated epithelial dysfunctions is unknown.

Aims: We aimed at studying the association between ER stress and serine protease activity in enterocytes and its impact on intestinal functions.

Methods: the impact of ER stress induced by Thapsigargin on serine protease secretion was studied using either human intestinal cells lines or organoids. Moreover, treating human intestinal cells with Protease-Activated Receptors antagonists allows the investigation of the ER stress-resulting molecular mechanisms that induce proteolytic activity and alter intestinal epithelial cell biology.

Results: In our study, colonic biopsies from IBD patients exhibited increased epithelial trypsin-like activity associated with elevated ER stress. Induction of ER stress in human intestinal epithelial cells displayed enhanced apically trypsin-like activity. ER stress-induced increased trypsin activity destabilized intestinal barrier function by increasing permeability and by controlling inflammatory mediators such as C-X-C chemokine ligand 8 (CXCL8). The deleterious impact of ER stress-associated trypsin activity was specifically dependent on the activation of Protease-Activated Receptors 2 and 4.

Conclusions: In conclusion, excessive ER stress in IECs caused an increased release of trypsin activity that, in turn, altered intestinal barrier function, then promoting the development of inflammatory process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ecco-jcc/jjab035DOI Listing
February 2021

Mobilization of γδ T Cells and IL-10 Production at the Acute Phase of Hepatitis E Virus Infection in Cytomegalovirus Carriers.

J Immunol 2021 Mar 22;206(5):1027-1038. Epub 2021 Jan 22.

Université Toulouse III Paul-Sabatier, F-31024 Toulouse, France;

Alterations in the γδ T cell compartment have been reported in immunocompromised individuals infected with hepatitis E virus (HEV)-g3. We now report the analysis of blood γδ T cells from acutely HEV-infected individuals in the absence of immunosuppression. In these patients, non-Vδ2 (ND2) γδ T cells outnumbered otherwise predominant Vδ2 cells selectively in human CMV (HCMV)-seropositive patients and were higher than in HCMV controls, mimicking HCMV reactivation, whereas their serum was PCR-negative for HCMV. Stimulation of their lymphocytes with HEV-infected hepatocarcinoma cells led to an HEV-specific response in γδ subsets of HCMV individuals. HEV infection was associated with a lowered expression of TIGIT, LAG-3, and CD160 immune checkpoint markers on ND2 effector memory cells in HCMV but not in HCMV HEV patients. γδ cell lines, predominantly ND2, were generated from patients after coculture with hepatocarcinoma cells permissive to HEV and IL-2/12/18. Upon restimulation with HEV-infected or uninfected cells and selected cytokines, these cell lines produced IFN-γ and IL-10, the latter being induced by IL-12 in IFN-γ-producing cells and upregulated by HEV and IL-18. They were also capable of suppressing the proliferation of CD3/CD28-activated CD4 cells in transwell experiments. Importantly, IL-10 was detected in the plasma of 10 of 10 HCMV HEV patients but rarely in controls or HCMV HEV patients, implying that γδ cells are probably involved in IL-10 production at the acute phase of infection. Our data indicate that HEV mobilizes a pool of ND2 memory cells in HCMV carriers, promoting the development of an immunoregulatory environment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.2000187DOI Listing
March 2021

Increased Mucosal Thrombin is Associated with Crohn's Disease and Causes Inflammatory Damage through Protease-activated Receptors Activation.

J Crohns Colitis 2021 May;15(5):787-799

IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France.

Background And Aims: Thrombin levels in the colon of Crohn's disease patients have recently been found to be elevated 100-fold compared with healthy controls. Our aim was to determine whether and how dysregulated thrombin activity could contribute to local tissue malfunctions associated with Crohn's disease.

Methods: Thrombin activity was studied in tissues from Crohn's disease patients and healthy controls. Intracolonic administration of thrombin to wild-type or protease-activated receptor-deficient mice was used to assess the effects and mechanisms of local thrombin upregulation. Colitis was induced in rats and mice by the intracolonic administration of trinitrobenzene sulphonic acid.

Results: Active forms of thrombin were increased in Crohn's disease patient tissues. Elevated thrombin expression and activity were associated with intestinal epithelial cells. Increased thrombin activity and expression were also a feature of experimental colitis in rats. Colonic exposure to doses of active thrombin comparable to what is found in inflammatory bowel disease tissues caused mucosal damage and tissue dysfunctions in mice, through a mechanism involving both protease-activated receptors -1 and -4. Intracolonic administration of the thrombin inhibitor dabigatran, as well as inhibition of protease-activated receptor-1, prevented trinitrobenzene sulphonic acid-induced colitis in rodent models.

Conclusions: Our data demonstrated that increased local thrombin activity, as it occurs in the colon of patients with inflammatory bowel disease, causes mucosal damage and inflammation. Colonic thrombin and protease-activated receptor-1 appear as possible mechanisms involved in mucosal damage and loss of function and therefore represent potential therapeutic targets for treating inflammatory bowel disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ecco-jcc/jjaa229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095389PMC
May 2021

A standardised model for stool banking for faecal microbiota transplantation: a consensus report from a multidisciplinary UEG working group.

United European Gastroenterol J 2021 Mar 9;9(2):229-247. Epub 2021 Mar 9.

Department of Internal Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands.

Background: Faecal microbiota transplantation is an emerging therapeutic option, particularly for the treatment of recurrent Clostridioides difficile infection. Stool banks that organise recruitment and screening of faeces donors are being embedded within the regulatory frameworks described in the European Union Tissue and Cells Directive and the technical guide to the quality and safety of tissue and cells for human application, published by the European Council.

Objective: Several European and international consensus statements concerning faecal microbiota transplantation have been issued. While these documents provide overall guidance, we aim to provide a detailed description of all processes that relate to the collection, handling and clinical application of human donor stool in this document.

Methods: Collaborative subgroups of experts on stool banking drafted concepts for all domains pertaining to stool banking. During a working group meeting in the United European Gastroenterology Week 2019 in Barcelona, these concepts were discussed and finalised to be included in our overall guidance document about faecal microbiota transplantation.

Results: A guidance document for all domains pertaining to stool banking was created. This document includes standard operating manuals for several processes involved with stool banking, such as handling of donor material, storage and donor screening.

Conclusion: The implementation of faecal microbiota transplantation by stool banks in concordance with our guidance document will enable quality assurance and guarantee the availability of donor faeces preparations for patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2050640620967898DOI Listing
March 2021

A multi-ancestry sex stratified genome-wide association study of spontaneous clearance of hepatitis C virus.

J Infect Dis 2020 Oct 29. Epub 2020 Oct 29.

Johns Hopkins University, School of Medicine, Baltimore, MD. USA.

Background: Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors.

Methods: To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 males, 1520 females) of European, African and Hispanic ancestry. We performed autosomal, and X-chromosome sex-stratified and combined association analyses in each ancestry group.

Results: A male-specific region near ADP-ribosylation factor-like-5B gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have a chronic HCV infection compared to individuals with the T allele (ORMales=0.69,P-valueMales=1.98x10-07) and this was not seen in females. The ARL5B gene encodes an interferon stimulated gene that inhibits immune response to dsRNA viruses. We also identified suggestive associations near Septin6 and Ribosomal Protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared to the A allele (OR= 1.4, P-valueAll individuals=2.46 x 10-06). Septin6 facilitates HCV replication via interaction with the HCV NS5b protein and RPL39 acts as an HCV core interactor.

Conclusion: These novel gene associations support differential mechanisms of HCV clearance between sexes and provide biologic targets for treatment or vaccine development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiaa677DOI Listing
October 2020

Multi-ancestry fine mapping of interferon lambda and the outcome of acute hepatitis C virus infection.

Genes Immun 2020 11 28;21(5):348-359. Epub 2020 Oct 28.

Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, USA.

Clearance of acute infection with hepatitis C virus (HCV) is associated with the chr19q13.13 region containing the rs368234815 (TT/ΔG) polymorphism. We fine-mapped this region to detect possible causal variants that may contribute to HCV clearance. First, we performed sequencing of IFNL1-IFNL4 region in 64 individuals sampled according to rs368234815 genotype: TT/clearance (N = 16) and ΔG/persistent (N = 15) (genotype-outcome concordant) or TT/persistent (N = 19) and ΔG/clearance (N = 14) (discordant). 25 SNPs had a difference in counts of alternative allele >5 between clearance and persistence individuals. Then, we evaluated those markers in an association analysis of HCV clearance conditioning on rs368234815 in two groups of European (692 clearance/1 025 persistence) and African ancestry (320 clearance/1 515 persistence) individuals. 10/25 variants were associated (P < 0.05) in the conditioned analysis leaded by rs4803221 (P value = 4.9 × 10) and rs8099917 (P value = 5.5 × 10). In the European ancestry group, individuals with the haplotype rs368234815ΔG/rs4803221C were 1.7× more likely to clear than those with the rs368234815ΔG/rs4803221G haplotype (P value = 3.6 × 10). For another nearby SNP, the haplotype of rs368234815ΔG/rs8099917T was associated with HCV clearance compared to rs368234815ΔG/rs8099917G (OR: 1.6, P value = 1.8 × 10). We identified four possible causal variants: rs368234815, rs12982533, rs10612351 and rs4803221. Our results suggest a main signal of association represented by rs368234815, with contributions from rs4803221, and/or nearby SNPs including rs8099917.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41435-020-00115-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657970PMC
November 2020

[Crohn's disease and autologous hemapoietic cell transplantation: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

Bull Cancer 2020 Dec 14;107(12S):S140-S150. Epub 2020 Oct 14.

Centre de référence des maladies auto-immunes systémiques rares d'Île-de-France, hôpital St-Louis (AP-HP), unité de médecine interne : maladies auto-immunes et pathologie vasculaire (UF 04), 1, avenue Claude-Vellefaux, 75010 Paris, France; Université Paris-Denis-Diderot, institut de recherche Saint-Louis, EA 3518, Sorbonne Paris Cité, France; McGill University, department of internal medicine, Montreal, Canada. Electronic address:

Crohn's Disease (CD) is an auto-inflammatory disease, which may involve the entire gastro-intestinal tract. CD is diagnosed on several clinical, biological, endoscopic and histological criteria. First line therapy is based on oral or iv steroids. In case of steroids dependence or resistance, several types of immunosuppressive or immunomodulating therapies are available: classical antimetabolites (thiopurines or methotrexate) or monoclonal antibodies against TNFα, against interleukin 12/23 or against integrin. Nonetheless, Crohn's disease may remain active despite the use of several lines of therapy. In such cases, autologous hematopoietic cell transplantation (AHCT) is an effective therapeutic option in highly selected CD patients with specific criteria. The MATHEC-SFGM-TC Good Clinical Practice Guidelines (GCPG) were developed by a multidisciplinary group of experts including gastroenterologists, hematologists and members of the reference center for stem cell therapy in auto-immune diseases (MATHEC), including members of the French groupe d'étude thérapeutique des affections inflammatoires du tube digestif(GETAID) under the auspices of the French speaking Society of bone marrow transplantation and cellular therapy (SFGM-TC). The aim of the present guidelines is to define the eligibility criteria for CD patients when candidates to AHCT, the procedures for mobilization of hematopoietic stem cell (HSC), conditioning regimen and standardized follow-up after AHCT including monitoring of gastroenterological treatments during AHCT and thereafter throughout all follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bulcan.2020.08.009DOI Listing
December 2020

Atherosclerotic Cardiovascular Events in Patients Infected With Human Immunodeficiency Virus and Hepatitis C Virus.

Clin Infect Dis 2021 05;72(9):e215-e223

Centre Hospitalier Universitaire de Strasbourg, Le Trait d'Union, HIV Infection Care Center, Strasbourg, France.

Background: An increased risk of cardiovascular disease (CVD) was reported in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), without identifying factors associated with atherosclerotic CVD (ASCVD) events.

Methods: HIV-HCV coinfected patients were enrolled in the Agence Nationale de Recherches sur le Sida et les hépatites virales (ANRS) CO13 HEPAVIH nationwide cohort. Primary outcome was total ASCVD events. Secondary outcomes were coronary and/or cerebral ASCVD events, and peripheral artery disease (PAD) ASCVD events. Incidences were estimated using the Aalen-Johansen method. Factors associated with ASCVD were identified using cause-specific Cox proportional hazards models.

Results: At baseline, median age of the study population (N = 1213) was 45.4 (interquartile range [IQR] 42.1-49.0) years and 70.3% were men. After a median follow-up of 5.1 (IQR 3.9-7.0) years, the incidence was 6.98 (95% confidence interval [CI], 5.19-9.38) per 1000 person-years for total ASCVD events, 4.01 (2.78-6.00) for coronary and/or cerebral events, and 3.17 (2.05-4.92) for PAD ASCVD events. Aging (hazard ratio [HR] 1.06; 95% CI, 1.01-1.12), prior CVD (HR 8.48; 95% CI, 3.14-22.91), high total cholesterol (HR 1.43; 95% CI, 1.11-1.83), high-density lipoprotein cholesterol (HR 0.22; 95% CI, 0.08-0.63), statin use (HR 3.31; 95% CI, 1.31-8.38), and high alcohol intake (HR 3.18; 95% CI, 1.35-7.52) were independently associated with total ASCVD events, whereas undetectable baseline viral load (HR 0.41, 95% CI, 0.18-0.96) was associated with coronary and/or cerebral events.

Conclusions: HIV-HCV coinfected patients experienced a high incidence of ASCVD events. Some traditional cardiovascular risk factors were the main determinants of ASCVD. Controlling cholesterol abnormalities and maintaining undetectable HIV RNA are essential to control cardiovascular risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa1014DOI Listing
May 2021

Personalized surveillance for hepatocellular carcinoma in cirrhosis - using machine learning adapted to HCV status.

J Hepatol 2020 12 29;73(6):1434-1445. Epub 2020 Jun 29.

AP-HP, Groupe Hospitalier de La Pitié-Salpêtrière, Service d'Hépatologie, Paris.

Background & Aims: Refining hepatocellular carcinoma (HCC) surveillance programs requires improved individual risk prediction. Thus, we aimed to develop algorithms based on machine learning approaches to predict the risk of HCC more accurately in patients with HCV-related cirrhosis, according to their virological status.

Methods: Patients with compensated biopsy-proven HCV-related cirrhosis from the French ANRS CO12 CirVir cohort were included in a semi-annual HCC surveillance program. Three prognostic models for HCC occurrence were built, using (i) Fine-Gray regression as a benchmark, (ii) single decision tree (DT), and (iii) random survival forest for competing risks survival (RSF). Model performance was evaluated from C-indexes validated externally in the ANRS CO22 Hepather cohort (n = 668 enrolled between 08/2012-01/2014).

Results: Out of 836 patients analyzed, 156 (19%) developed HCC and 434 (52%) achieved sustained virological response (SVR) (median follow-up 63 months). Fine-Gray regression models identified 6 independent predictors of HCC occurrence in patients before SVR (past excessive alcohol intake, genotype 1, elevated AFP and GGT, low platelet count and albuminemia) and 3 in patients after SVR (elevated AST, low platelet count and shorter prothrombin time). DT analysis confirmed these associations but revealed more complex interactions, yielding 8 patient groups with varying cancer risks and predictors depending on SVR achievement. On RSF analysis, the most important predictors of HCC varied by SVR status (non-SVR: platelet count, GGT, AFP and albuminemia; SVR: prothrombin time, ALT, age and platelet count). Externally validated C-indexes before/after SVR were 0.64/0.64 [Fine-Gray], 0.60/62 [DT] and 0.71/0.70 [RSF].

Conclusions: Risk factors for hepatocarcinogenesis differ according to SVR status. Machine learning algorithms can refine HCC risk assessment by revealing complex interactions between cancer predictors. Such approaches could be used to develop more cost-effective tailored surveillance programs.

Lay Summary: Patients with HCV-related cirrhosis must be included in liver cancer surveillance programs, which rely on ultrasound examination every 6 months. Hepatocellular carcinoma (HCC) screening is hampered by sensitivity issues, leading to late cancer diagnoses in a substantial number of patients. Refining surveillance periodicity and modality using more sophisticated imaging techniques such as MRI may only be cost-effective in patients with the highest HCC incidence. Herein, we demonstrate how machine learning algorithms (i.e. data-driven mathematical models to make predictions or decisions), can refine individualized risk prediction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2020.05.052DOI Listing
December 2020

Characterization of Human Colon Organoids From Inflammatory Bowel Disease Patients.

Front Cell Dev Biol 2020 4;8:363. Epub 2020 Jun 4.

IRSD, INSERM, INRA, ENVT, UPS, Université de Toulouse, Toulouse, France.

Inflammatory Bowel Diseases (IBD) are chronic inflammatory disorders, where epithelial defects drive, at least in part, some of the pathology. We reconstituted human intestinal epithelial organ, by using three-dimension culture of human colon organoids. Our aim was to characterize morphological and functional phenotypes of control (non-IBD) organoids, compared to inflamed organoids from IBD patients. The results generated describe the epithelial defects associated with IBD in primary organoid cultures, and evaluate the use of this model for pharmacological testing of anti-inflammatory approaches. Human colonic tissues were obtained from either surgical resections or biopsies, all harvested in non-inflammatory zones. Crypts were isolated from controls (non-IBD) and IBD patients and were cultured up to 12-days. Morphological (size, budding formation, polarization, luminal content), cell composition (proliferation, differentiation, immaturity markers expression), and functional (chemokine and tight junction protein expression) parameters were measured by immunohistochemistry, RT-qPCR or western-blot. The effects of inflammatory cocktail or anti-inflammatory treatments were studied in controls and IBD organoid cultures respectively. Organoid cultures from controls or IBD patients had the same cell composition after 10 to 12-days of culture, but IBD organoid cultures showed an inflammatory phenotype with decreased size and budding capacity, increased cell death, luminal debris, and inverted polarization. Tight junction proteins were also significantly decreased in IBD organoid cultures. Inflammatory cytokine cocktail reproduced this inflammatory phenotype in non-IBD organoids. Clinically used treatments (5-ASA, glucocorticoids, anti-TNF) reduced some, but not all parameters. Inflammatory phenotype is associated with IBD epithelium, and can be studied in organoid cultures. This model constitutes a reliable human pre-clinical model to investigate new strategies targeting epithelial repair.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2020.00363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287042PMC
June 2020

Th22 cells are efficiently recruited in the gut by CCL28 as an alternative to CCL20 but do not compensate for the loss of Th17 cells in treated HIV-1-infected individuals.

Mucosal Immunol 2021 01 28;14(1):219-228. Epub 2020 Apr 28.

INSERM, UMR1043, Toulouse, F-31300, France.

Gut CD4 T cells are incompletely restored in most HIV-1-infected individuals on antiretroviral therapy, notably Th17 cells, a key subset in mucosal homeostasis. By contrast, gut Th22 cells are usually restored at normal frequencies. Th22 cells display a CCR6CCR10 phenotype and could thus respond to CCL20- and CCL28-mediated chemotaxis, while Th17 cells, which express CCR6 but not CCR10, depend on CCL20. Herein, we found that CCL28 is normally expressed by duodenal enterocytes of treated HIV-1-infected individuals, while CCL20 expression is blunted. Ex vivo, we showed that Th22 cells contribute to the reduction of CCL20 production by enterocytes through an IL-22- and IL-18-dependent mechanism. Th22 cells preferentially migrate via CCL20- rather than CCL28-mediated chemotaxis when both chemokines are available in the microenvironment. However, when the CCL20/CCL28 ratio drops, as in treated HIV-1-infected individuals, Th22 cells can migrate via the CCR10-CCL28 axis, as an alternative to CCR6-CCL20. This could explain the better reconstitution of gut Th22 compared with Th17 cells on antiretroviral therapy. Lastly, we assessed the relationships between the frequencies of gut Th17 and Th22 cells and inflammatory markers related to microbial translocation, and showed that Th22 cells do not compensate for the loss of Th17 cells in treated HIV-1-infected individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41385-020-0286-6DOI Listing
January 2021

Divergent Roles for Macrophage C-type Lectin Receptors, Dectin-1 and Mannose Receptors, in the Intestinal Inflammatory Response.

Cell Rep 2020 03;30(13):4386-4398.e5

UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France.

Colonic macrophages are considered to be major effectors of inflammatory bowel diseases (IBDs) and the control of gut inflammation through C-type lectin receptors is an emerging concept. We show that during colitis, the loss of dectin-1 on myeloid cells prevents intestinal inflammation, while the lack of mannose receptor (MR) exacerbates it. A marked increase in dectin-1 expression in dextran sulfate sodium (DSS)-exposed MR-deficient mice supports the critical contribution of dectin-1 to colitis outcome. Dectin-1 is crucial for Ly6CCCR2 monocyte population enrichment in the blood and their recruitment to inflamed colon as precursors of inflammatory macrophages. Dectin-1 also promotes inflammasome-dependent interleukin-1β (IL-1β) secretion through leukotriene B4 production. Interestingly, colonic inflammation is associated with a concomitant overexpression of dectin-1/CCL2/LTA4H and downregulation of MR on macrophages from IBD patients. Thus, MR and dectin-1 on macrophages are important mucosal inflammatory regulators that contribute to the intestinal inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2020.03.018DOI Listing
March 2020

Insertions and Duplications in the Polyproline Region of the Hepatitis E Virus.

Front Microbiol 2020 31;11. Epub 2020 Jan 31.

Laboratoire de Virologie, Centre National de Référence du virus de l'hépatite E, Hôpital Purpan, CHU de Toulouse, Toulouse, France.

Recombinant strains of hepatitis E virus (HEV) with insertions of human genomic fragments or HEV sequence duplications in the sequence encoding the polyproline region (PPR) were previously described in chronically infected patients. Such genomic rearrangements confer a replicative advantage but little is known about their frequency, location, or origin. As the sequences of only a few virus genomes are available, we analyzed the complete genomes of 114 HEV genotype 3 strains from immunocompromised ( = 85) and immunocompetent ( = 29) patients using the single molecular real-time sequencing method to determine the frequency, location, and origin of inserted genomic fragments, plus the proportions of variants with genomic rearrangements in each virus quasispecies. We also examined the amino acid compositions and post-translational modifications conferred by these rearrangements by comparing them to sequences without human gene insertions or HEV gene duplications. We found genomic rearrangements in 7/114 (6.1%) complete genome sequences (4 HEV-3f, 1 HEV-3e, 1 HEV-3 h, and 1 HEV-3chi-new), all from immunocompromised patients, and 3/7 were found at the acute phase of infection. Six of the seven patients harbored virus-host recombinant variants, including one patient with two different recombinant variants. We also detected three recombinant variants with genome duplications of the PPR or PPR + X domains in a single patient. All the genomic rearrangements (seven human fragment insertions of varying origins and three HEV genome duplications) occurred in the PPR. The sequences with genomic rearrangements had specific characteristics: increased net load ( < 0.001) and more ubiquitination ( < 0.001), phosphorylation ( < 0.001), and acetylation ( < 0.001) sites. The human fragment insertions and HEV genome duplications had slightly different characteristics. We believe this is the first description of HEV strains with genomic rearrangements in patients at the acute phase of infection; perhaps these strains are directly transmitted. Clearly, genomic rearrangements produce a greater net load with duplications and insertions having different features. Further studies are needed to clarify the mechanisms by which such modifications influence HEV replication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmicb.2020.00001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004952PMC
January 2020

Outcomes of 4 years of molecular genetic diagnosis on a panel of genes involved in premature aging syndromes, including laminopathies and related disorders.

Orphanet J Rare Dis 2019 12 11;14(1):288. Epub 2019 Dec 11.

Department of Medical Genetics, Assistance Publique Hopitaux de Marseille, Marseille, France.

Background: Segmental progeroid syndromes are a heterogeneous group of rare and often severe genetic disorders that have been studied since the twentieth century. These progeroid syndromes are defined as segmental because only some of the features observed during natural aging are accelerated.

Methods: Since 2015, the Molecular Genetics Laboratory in Marseille La Timone Hospital proposes molecular diagnosis of premature aging syndromes including laminopathies and related disorders upon NGS sequencing of a panel of 82 genes involved in these syndromes. We analyzed the results obtained in 4 years on 66 patients issued from France and abroad.

Results: Globally, pathogenic or likely pathogenic variants (ACMG class 5 or 4) were identified in about 1/4 of the cases; among these, 9 pathogenic variants were novel. On the other hand, the diagnostic yield of our panel was over 60% when the patients were addressed upon a nosologically specific clinical suspicion, excepted for connective tissue disorders, for which clinical diagnosis may be more challenging. Prenatal testing was proposed to 3 families. We additionally detected 16 variants of uncertain significance and reclassified 3 of them as benign upon segregation analysis in first degree relatives.

Conclusions: High throughput sequencing using the Laminopathies/ Premature Aging disorders panel allowed molecular diagnosis of rare disorders associated with premature aging features and genetic counseling for families, representing an interesting first-level analysis before whole genome sequencing may be proposed, as a future second step, by the National high throughput sequencing platforms ("Medicine France Genomics 2025" Plan), in families without molecular diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-019-1189-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907233PMC
December 2019

Performance of the Xpert HBV Viral Load assay versus the Aptima Quant assay for quantifying hepatitis B virus DNA.

Diagn Microbiol Infect Dis 2020 Feb 16;96(2):114946. Epub 2019 Nov 16.

INSERM, U1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, F-31300, France; CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, F-31300, France.

Quantification of HBV DNA is used for initiating and monitoring antiviral treatment. We have evaluated the Xpert HBV Viral Load (VL) assay on the GeneXpert instrument. We estimated its limit of detection to be 7.5 IU/mL. Reproducibility was 1.1-12.7% as assessed by the coefficients of variation for 3 different samples. The assay was linear from 2 to 8 log IU/mL for HBV genotypes A to F. Its clinical performance was evaluated by testing prospectively 100 HBV DNA-positive samples with the Xpert HBV VL and Aptima Quant HBV assays. The results from the 2 assays were correlated, with a modest bias (-0.10 log IU/mL) between them by Bland-Altman analysis. Patient monitoring with 80 samples performed with both assays gave similar patient profiles with trends in the same direction. The Xpert HBV Viral load assay is reliable enough for quantifying HBV DNA in clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.diagmicrobio.2019.114946DOI Listing
February 2020

Efficacy and safety of elbasvir/grazoprevir for 8 or 12 weeks for hepatitis C virus genotype 4 infection: A randomized study.

Liver Int 2020 05 22;40(5):1042-1051. Epub 2020 Mar 22.

Department of Hepatology, Hôpital de Hautepierre, Universitaires de Strasbourg, Strasbourg, France.

Background & Aims: Hepatitis C virus (HCV) genotype (GT) 4 infection is prevalent in sub-Saharan Africa and the Middle East, particularly in Egypt. This study evaluated the safety and efficacy of elbasvir/grazoprevir administered for 8 and 12 weeks in participants with HCV GT4 infection.

Methods: In this partially randomized, open-label multicentre study conducted in France (NCT03111108; Protocol MK5172-096), treatment-naive participants with GT4 infection and F0-F2 fibrosis were randomized 2:1 to elbasvir (50 mg)/grazoprevir (100 mg) for 8 or 12 weeks. Treatment-naive participants with F3-F4 fibrosis and all treatment-experienced participants (F0-F4) were assigned to elbasvir/grazoprevir for 12 weeks. The primary endpoint was sustained virologic response (SVR) 12 weeks after the end of therapy.

Results: One hundred and seventeen participants were enrolled. Among treatment-naive participants with F0-F2 fibrosis, SVR was achieved by 94% (50/53) and 96% (26/27) of those receiving elbasvir/grazoprevir for 8 or 12 weeks, respectively, and four participants relapsed. In the 12-week arm, 95% (35/37) achieved SVR and two participants relapsed. NS5A resistance-associated substitutions were present at baseline and virologic failure in five of the participants with relapse. Drug-related adverse events occurred in 42% (n = 22) and 50% (n = 32) of participants receiving 8 and 12 weeks of treatment, respectively. No participant discontinued treatment owing to an adverse event.

Conclusion: These data confirm the efficacy of elbasvir/grazoprevir administered for 12 weeks in treatment-experienced individuals with HCV GT4 infection and those with advanced fibrosis. Treatment-naive individuals with mild fibrosis can be treated effectively with an 8-week regimen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/liv.14313DOI Listing
May 2020

Whipple's disease: diagnosis and predictive factors of relapse.

Eur J Gastroenterol Hepatol 2020 03;32(3):325-328

Centre hospitalier Universitaire de Toulouse, service de rhumatologie, Toulouse, France.

Background: Whipple's disease is a very rare disease needing a long-term treatment. The most frequent symptoms are recurrent arthralgia or arthritis, chronic diarrhea, abdominal pain, and weight loss.

Objectives: In this article, we have highlighted the main clinical features and diagnostic procedures that lead to the diagnosis and comment on the clinical response, treatment, and the factors of relapse.

Methods: Subjects were recruited from the Internal Medicine and Rheumatologic Departments of an University Hospital from November 1997 to January 2016. Overall, 12 subjects were finally diagnosed.

Results: Mean age was 54.3 years (age range: 30-81), with more male patients (58.3%). Almost all patients had articular symptoms and impaired general condition (91.7%); and a majority had digestive symptoms (75%). Regardless of the symptoms, the most efficient diagnostic tools were the PCR screening on the gastrointestinal biopsies and saliva (83.3 and 72.7% positive results, respectively). More than half of the patients relapsed (55.6%). The relapsing patients were older [63.2 (44-81)] and mostly male with a majority (60%) of digestive symptoms and a delayed diagnosis.

Conclusions: In current practice, it is highly difficult to diagnose Whipple's disease. In order to decrease the delay between the first symptoms and the diagnosis, effective tools such as saliva and stools PCR should be used because higher delays of diagnosis lead to a higher number of relapses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MEG.0000000000001611DOI Listing
March 2020

Ribavirin for Chronic Hepatitis E Virus Infection in Ibrutinib-Exposed Patients.

Open Forum Infect Dis 2019 Sep 28;6(9):ofz345. Epub 2019 Jul 28.

Hematology Department, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France.

Ibrutinib is an oral first-in-class Bruton's tyrosine kinase inhibitor approved for the therapy of various B-cell lymphoid malignancies. Among ibrutinib-related infections, viral hepatitis are poorly described. We report our single-center experience with 4 cases of chronic hepatitis E virus infection and their management with ribavirin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ofid/ofz345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798245PMC
September 2019

Active thrombin produced by the intestinal epithelium controls mucosal biofilms.

Nat Commun 2019 07 19;10(1):3224. Epub 2019 Jul 19.

IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, U1220, CHU Purpan, CS60039, 31024, Toulouse, France.

Proteolytic homeostasis is important at mucosal surfaces, but its actors and their precise role in physiology are poorly understood. Here we report that healthy human and mouse colon epithelia are a major source of active thrombin. We show that mucosal thrombin is directly regulated by the presence of commensal microbiota. Specific inhibition of luminal thrombin activity causes macroscopic and microscopic damage as well as transcriptomic alterations of genes involved in host-microbiota interactions. Further, luminal thrombin inhibition impairs the spatial segregation of microbiota biofilms, allowing bacteria to invade the mucus layer and to translocate across the epithelium. Thrombin cleaves the biofilm matrix of reconstituted mucosa-associated human microbiota. Our results indicate that thrombin constrains biofilms at the intestinal mucosa. Further work is needed to test whether thrombin plays similar roles in other mucosal surfaces, given that lung, bladder and skin epithelia also express thrombin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-11140-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642099PMC
July 2019

Apple core pattern in skeletal sarcoidosis.

Joint Bone Spine 2020 Jan 4;87(1):85. Epub 2019 Jul 4.

Médecine interne, hôpital Purpan, Place du Dr Joseph Baylac, 31300 Toulouse, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jbspin.2019.06.011DOI Listing
January 2020

The burden of hepatitis E among patients with haematological malignancies: A retrospective European cohort study.

J Hepatol 2019 09 18;71(3):465-472. Epub 2019 May 18.

Hepatology Service, Assistance Publique - Hôpitaux de Paris, Hôpital Cochin, Université Paris Descartes, Paris, France; Institut National de la Santé et de la Recherche Médicale unité 1223, Institut Pasteur, Paris, France. Electronic address:

Background & Aims: The burden of hepatitis E virus (HEV) infection among patients with haematological malignancy has only been scarcely reported. Therefore, we aimed to describe this burden in patients with haematological malignancies, including those receiving allogeneic haematopoietic stem cell transplantation.

Methods: We conducted a retrospective, multicentre cohort study across 11 European centres and collected clinical characteristics of 50 patients with haematological malignancy and RNA-positive, clinically overt hepatitis E between April 2014 and March 2017. The primary endpoint was HEV-associated mortality; the secondary endpoint was HEV-associated liver-related morbidity.

Results: The most frequent underlying haematological malignancies were aggressive non-Hodgkin lymphoma (NHL) (34%), indolent NHL (iNHL) (24%), and acute leukaemia (36%). Twenty-one (42%) patients had received allogeneic haematopoietic stem cell transplantation (alloHSCT). Death with ongoing hepatitis E occurred in 8 (16%) patients, including 1 patient with iNHL and 1 patient >100 days after alloHSCT in complete remission, and was associated with male sex (p = 0.040), cirrhosis (p = 0.006) and alloHSCT (p = 0.056). Blood-borne transmission of hepatitis E was demonstrated in 5 (10%) patients, and associated with liver-related mortality in 2 patients. Hepatitis E progressed to chronic hepatitis in 17 (34%) patients overall, and in 10 (47.6%) and 6 (50%) alloHSCT and iNHL patients, respectively. Hepatitis E was associated with acute or acute-on-chronic liver failure in 4 (8%) patients with 75% mortality. Ribavirin was administered to 24 (48%) patients, with an HEV clearance rate of 79.2%. Ribavirin treatment was associated with lower mortality (p = 0.037) and by trend with lower rates of chronicity (p = 0.407) when initiated <24 and <12 weeks after diagnosis of hepatitis E, respectively. Immunosuppressive treatment reductions were associated with mortality in 2 patients (28.6%).

Conclusion: Hepatitis E is associated with mortality and liver-related morbidity in patients with haematological malignancy. Blood-borne transmission contributes to the burden. Ribavirin should be initiated early, whereas reduction of immunosuppressive treatment requires caution.

Lay Summary: Little is known about the burden of hepatitis E among patients with haematological malignancy. We conducted a retrospective European cohort study among 50 patients with haematological malignancy, including haematopoietic stem cell transplant recipients, with clinically significant HEV infection and found that hepatitis E is associated with hepatic and extrahepatic mortality, including among patients with indolent disease or among stem cell transplant recipients in complete remission. Hepatitis E virus infection evolved to chronic hepatitis in 5 (45.5%) patients exposed to a rituximab-containing regimen and 10 (47.6%) stem cell transplant recipients. Reducing immunosuppressive therapy because of hepatitis E was associated with mortality, while early ribavirin treatment was safe and effective.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2019.04.022DOI Listing
September 2019

Liver stiffness and fibrosis-4 alone better predict liver events compared with aspartate aminotransferase to platelet ratio index in a cohort of human immunodeficiency virus and hepatitis C virus co-infected patients from ANRS CO13 HEPAVIH cohort.

Eur J Gastroenterol Hepatol 2019 Nov;31(11):1387-1396

Bordeaux Population Health Research Center, ISPED, Inserm, Team MORPH3EUS, UMR 1219, Bordeaux University.

Objectives: HIV/hepatitis C virus (HCV) co-infection leads to major complications, and noninvasive markers developed to stage liver fibrosis could be used as prognostic markers. We aimed to compare the performances of liver stiffness (LS), fibrosis-4 (FIB-4), and aspartate aminotransferase to platelet ratio index (APRI) to predict liver-related events in HIV/HCV co-infected patients.

Patients And Methods: HIV/HCV co-infected patients from the ANRS CO13 HEPAVIH cohort were included if they had LS, FIB-4, and APRI measurements done in a window of 3 months. Primary outcome was the time between inclusion and occurrence of a liver-related event. Univariable and multivariable Fine and Gray models were performed. Predictive performances were compared by the area under the receiver operating characteristic (AUROC) differences after correction of optimistic by bootstrap samples. Best cutoffs to predict liver-related events were estimated by sensitivity and specificity maximization.

Results: A total of 998 patients were included. Overall, 70.7% were men. Their median age was 46.8 years. According to LS value, 204 (20.4%) patients had cirrhosis. Overall, 39 patients experienced at least one liver-related event. In univariable analysis, LS AUROC curve was significantly superior to FIB-4 and APRI AUROC curves, being 87.9, 78.2, and 75.0%, respectively. After adjustment on age, CD4 levels, and insulin resistance, no differences were observed. The best cutoffs to identify patients at low or high risk of liver-related events were below 8.5, 1.00, and 0.35 and above 16.5, 4.00, and 1.75 for LS, FIB-4, and APRI, respectively.

Conclusion: To predict HCV-related events, APRI had lower performance than LS and FIB-4. FIB-4 is as good as LS to predict HCV-related events, suggesting that it can be used for the management of HIV/HCV co-infected patients and replace LS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MEG.0000000000001408DOI Listing
November 2019

No evidence of occult hepatitis C or E virus infections in liver-transplant patients with sustained virological response after therapy with direct acting agents.

Transpl Infect Dis 2019 Aug 30;21(4):e13093. Epub 2019 Apr 30.

Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.

Background And Aims: It has been recently suggested that occult hepatitis C virus (HCV) infection and hepatitis E virus (HEV) reactivation might occur after direct acting antiviral agent-induced (DAA-induced) sustained virological response (SVR). The aim of our study was to identify occult HCV and HEV infection in a cohort of organ transplant patients who had achieved SVR and had persistent elevation in liver-enzyme levels.

Patients And Method: Sixty-six liver and/or kidney transplant patients were treated with DAAs. All but one achieved SVR12. Twenty-nine (8-39) months post-SVR12, 8 of the 65 patients (12.3%) who achieved SVR12 had persistently elevated liver enzyme levels. In 1 patient, this was related to hepatitis B virus reactivation. In the 7 remaining patients, blood samples (n = 7), liver biopsies (n = 4), and peripheral blood mononuclear cells (PBMCs) (n = 7) were collected simultaneously in order to identify occult HCV or HEV infection.

Results: Hepatitis C virus RNA and HEV RNA were not detected in serum, liver tissues, or PBMCs. No HEV reactivation was observed after HCV clearance in patients who had anti-HEV IgG.

Conclusion: Our study suggests that there is no occult HCV or HEV infection in transplant patients after successful treatment of HCV infection with DAAs, even in patients with a persistent elevation of liver enzyme levels. However, due to the small number of patients included in our study, this finding should be confirmed in a larger cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tid.13093DOI Listing
August 2019

Identification of 19 Novel Hepatitis C Virus Subtypes-Further Expanding HCV Classification.

Open Forum Infect Dis 2019 Mar 22;6(3):ofz076. Epub 2019 Feb 22.

Gilead Sciences Inc, Foster City, California.

Background: Hepatitis C virus (HCV) is currently classified into 8 genotypes and 86 subtypes. The objective of this study was to characterize novel HCV subtypes and to investigate the impact of subtypes on treatment outcome.

Methods: Full-genome sequencing was performed on HCV plasma samples with <85% sequence homology of NS3, NS5A, and/or NS5B to HCV genotype (GT) 1-8 reference strains.

Results: A total of 14 653 patients with GT1-6 HCV infection were enrolled in clinical studies of sofosbuvir-based regimens. For the majority of the patients, a specific subtype could be assigned based on a close genetic relationship to previously described subtypes. However, for 19 patients, novel subtypes were identified with <85% homology compared with previously described subtypes. These novel subtypes had the following genotypes: 9 in GT2, 5 in GT4, 2 in GT6, and 1 each in GT1, GT3, and GT5. Despite the presence of polymorphisms at resistance-associated substitution positions, 18 of the 19 patients treated with sofosbuvir-containing therapy achieved SVR12.

Conclusions: Nineteen novel HCV subtypes were identified, suggesting an even greater genetic diversity of HCV subtypes than previously recognized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ofid/ofz076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440686PMC
March 2019