Publications by authors named "Rodolphe Sobesky"

28 Publications

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Corrigendum to "ATP7B variant spectrum in a French pediatric Wilson disease cohort" [Eur. J. Med. Genet. 64(10) (2021) 104305].

Eur J Med Genet 2021 Sep 17:104341. Epub 2021 Sep 17.

Hospices Civils de Lyon, National Center for Wilson's Disease, Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Department of Biochemistry and Molecular Biology, LBMMS, Hospices Civils de Lyon, France.

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http://dx.doi.org/10.1016/j.ejmg.2021.104341DOI Listing
September 2021

ATP7B variant spectrum in a French pediatric Wilson disease cohort.

Eur J Med Genet 2021 Oct 13;64(10):104305. Epub 2021 Aug 13.

Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Department of Biochemistry and Molecular Biology, LBMMS, Hospices Civils de Lyon, France.

Background/aim: The spectrum of ATP7B variants varies significantly according to geographic distribution, and there is insufficient data on the variants observed in the French population.

Methods: Clinical data of 113 children included in the French WD national registry were gathered from March 01, 1995 to July 01, 2020. Data included epidemiological, clinical, laboratory, genetics.

Results: Diagnosis was made at a mean age of 11.0 ± 4.1 years (range 1-18 years). At diagnosis, 91 patients (79.8 %) had hepatic manifestations, 18 (15.8 %) presented neurological manifestations, and 4 patients (3.5 %) were asymptomatic. Only 29 patients (25 %) were homozygous for a variant. We have found a total of 102 different variants including 14 novel variants. Recurrent variant p.His1069Gln was the most prevalent, n = 31 alleles (14,2%), with only seven homozygous; in contrast 55% of variants are identified in only one family. 45% were truncating variants. In respect of mutated exon, the three most prevalent were exon 14 (16.5%), exon 8 (13.8%), and exon 3 (11.5%). When considering patients with two Nonsense / Frameshift variants as a group and those with two Missense variants, we found significantly lower ceruloplasmin for the former: 2.8 ± 0.7 mg/dl vs 8.4 ± 5mg/dl (p<0.05).

Conclusion: p.His1069Gln is the most frequent variant (14,2%) and exons 14, 8, and 2 of the ATP7B gene account for 41.7% of total variants. However, there is significant heterogeneity in the French population concerning the other ATP7B variants. Nonsense / Frameshift variants were associated with lower ceruloplasmin levels.
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http://dx.doi.org/10.1016/j.ejmg.2021.104305DOI Listing
October 2021

Peripheral Arrangement of Steatosis Microvacuoles in Wilson's Disease.

Clin Gastroenterol Hepatol 2021 Aug 5. Epub 2021 Aug 5.

Service d'Anatomo-Pathologie, Villejuif, France; INSERM, Unité 1193, Villejuif, France; FHU Hepatinov, Villejuif, France.

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http://dx.doi.org/10.1016/j.cgh.2021.08.005DOI Listing
August 2021

NON-INVASIVE DIAGNOSIS AND FOLLOW-UP OF RARE GENETIC LIVER DISEASES.

Clin Res Hepatol Gastroenterol 2021 Jul 28:101768. Epub 2021 Jul 28.

Service d'hépatologie, Hôpital Rangueil, CHU Toulouse, Toulouse.

Rare genetic liver diseases can result in multi-systemic damage, which may compromise the patient's prognosis. Wilson's disease, must be investigated in any patient with unexplained liver disease and/or unexplained neurological or neuropsychiatric disorders. The diagnosis is based on a combination of clinical, biological features, including copper balance. The exchangeable copper/total copper ratio is a new sensible and specific biological marker, useful for the diagnosis of the disease. Timely diagnosis and treatment will prevent serious complications from the disease. Neurological evaluation and familial screening are essential in patients with Wilson's disease.
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http://dx.doi.org/10.1016/j.clinre.2021.101768DOI Listing
July 2021

Pediatric Wilson's Disease: Phenotypic, Genetic Characterization and Outcome of 182 Children in France.

J Pediatr Gastroenterol Nutr 2021 Oct;73(4):e80-e86

Hospices Civils de Lyon, National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon.

Objectives: To describe a cohort of Wilson disease (WD) pediatric cases, and to point out the diagnostic particularities of this age group and the long-term outcome.

Methods: Clinical data of 182 pediatric patients included in the French WD national registry from 01/03/1995 to 01/06/2019 were gathered.

Results: Diagnosis of WD was made at a mean age of 10.7 ± 4.2 years (range 1-18 years). At diagnosis, 154 patients (84.6%) had hepatic manifestations, 19 (10.4%) had neurological manifestations, and 9 patients (4.9%) were asymptomatic. The p.His1069Gln mutation was the most frequently encountered (14% of patients).Neurological patients were diagnosed at least 1 year after they presented their first symptoms. At diagnosis, the median urinary copper excretion (UCE) was 4.2 μmol/24 hours (0.2-253). The first-line treatment was d-penicillamine (DP) for 131 (72%) patients, zinc salts for 24 (13%) patients, and Trientine for 17 (9%) patients. Liver transplantation was performed in 39 (21.4%) patients, for hepatic indications in 33 of 39 patients or for neurological deterioration in 6 of 39 patients, mean Unified Wilson's Disease Rating Scale of the latter went from 90 ± 23.1 before liver transplantation (LT) to 26.8 ± 14.1 (P < 0.01) after a mean follow-up of 4.3 ± 2.5 years. Overall survival rate at 20 years of follow-up was 98%, patient and transplant-free combined survival was 84% at 20 years.

Conclusion: Diagnosis of WD can be challenging in children, particularly at the early stages of liver disease and in case of neurological presentation; hence the support of clinical scores and genetic testing is essential. Diagnosis at early stages and proper treatment ensure excellent outcomes, subject to good long-term treatment compliance. LT is a valid option for end-stage liver disease not responding to treatment and can be discussed for selected cases of neurological deterioration.
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http://dx.doi.org/10.1097/MPG.0000000000003196DOI Listing
October 2021

High trough levels of everolimus combined to sorafenib improve patients survival after hepatocellular carcinoma recurrence in liver transplant recipients.

Transpl Int 2021 07 7;34(7):1293-1305. Epub 2021 Jun 7.

AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris- Saclay, Villejuif, France.

Recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) occurs in 10%-20% of patients transplanted for HCC. The treatment of HCC recurrence after LT remains a challenge. Consecutive patients who underwent LT for HCC between 2005 and 2015 at our center were recruited. Characteristics of patients with recurrence, modalities of treatment and outcome were collected retrospectively. Patient survival was analyzed according to HCC recurrence therapeutic strategy. Among 306 transplanted patients, 43 patients (14.1%) developed recurrence with a median survival time after recurrence of 10.9 months (95%CI: 6.6-18.6). Survival of patients treated with Sorafenib (SOR) and everolimus (EVL) (n = 19) was significantly better than that of the group treated with other strategies (n = 24) (P = 0.001). Multivariable analysis demonstrated that SOR plus EVL therapy and absence of dissemination at diagnosis of recurrence were independent predictive factors of prolonged survival after recurrence. Among the patients who treated with EVL, survival of patients with controlled EVL blood trough levels ≥5 ng/ml was significantly better compared to those with EVL trough levels <5 ng/ml (P = 0.021). Combination therapy of sorafenib and everolimus was an independent predictor for better survival after HCC recurrence. Patients with controlled everolimus trough level ≥5 ng/ml might get the best survival benefit.
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http://dx.doi.org/10.1111/tri.13897DOI Listing
July 2021

Early Versus Late Hepatocellular Carcinoma Recurrence After Transplantation: Predictive Factors, Patterns, and Long-term Outcome.

Transplantation 2021 08;105(8):1778-1790

AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris-Saclay, Villejuif, France.

Background: Hepatocellular carcinoma (HCC) is currently the first indication of liver transplantation (LT) in Europe and Asia-Pacific region and the third in the United States. HCC recurrence is the main complication affecting short- and medium-term outcomes after LT.

Methods: A total of 433 consecutive adult recipients transplanted for HCC between 2000 and 2017 (mean age: 57.8 ± 8.5 y; 83.8% were males) with a mean follow-up of 74.6 ± 58.6 months were included. Patients had to meet Milan criteria and, since 2014, alpha-fetoprotein score to be listed. Patients with HCC recurrence were classified into early (≤2 y) and late recurrence (>2 y) and were retrospectively reviewed.

Results: Patients who developed recurrence (75 patients, 17%) had more tumors outside Milan and University of California San Francisco criteria, high alpha-fetoprotein score, and microvascular invasion at pathology. Early recurrence developed in 46 patients (61.3%); the overall 5- and 10-year survival rates of these patients from time of LT were 6.7% and 0%, which were significantly lower than those with late recurrence 64.0% and 27.1%, respectively (P < 0.001). The median survival times from the diagnosis of HCC recurrence were 15 and 17 months, respectively, in the 2 groups (P < 0.001). Multivariable Cox regression analysis identified alcoholic cirrhosis as etiology of the underlying liver disease (hazard ratio [HR] = 3.074; P = 0.007), bilobar tumor at time of LT (HR = 2.001; P = 0.037), and a tumor size (>50 mm) in the explant (HR = 1.277; P = 0.045) as independent predictors of early recurrence.

Conclusions: Improving the prediction of early HCC recurrence could optimize patient selection for LT, potential adjuvant therapy with new targeted drugs and hence, improve long-term survival.
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http://dx.doi.org/10.1097/TP.0000000000003434DOI Listing
August 2021

Time to Conversion to an Everolimus-Based Regimen: Renal Outcomes in Liver Transplant Recipients From the EVEROLIVER Registry.

Liver Transpl 2020 11 12;26(11):1465-1476. Epub 2020 Oct 12.

Unité de Transplantation Hépatique, Hôpital Edouard Herriot, Lyon, France.

Longterm use of a calcineurin inhibitor (CNI)-based regimen is one of the major reasons for chronic renal failure in liver transplantation recipients (LTRs). The Everolimus Liver registry (EVEROLIVER) evaluated renal function in LTRs who were converted to everolimus (EVR). This observational registry included all LTRs receiving EVR across 9 centers from France. Data are being collected in an electronic database over 10 years (12 visits/patient) to evaluate efficacy, renal function (estimated glomerular filtration rate [eGFR]), and safety of EVR use in clinical practice, and the current analysis is reporting up to 60 months of findings. Until September 2017, 1045 patients received EVR after a mean time of 3.6 ± 5.1 years. CNI withdrawal was feasible in 57.7% of patients as of month 60. Mean eGFR improved in patients with baseline eGFR <60 mL/minute/1.73 m and was maintained in those with baseline eGFR ≥60 mL/minute/1.73 m . Among patients with chronic kidney disease (CKD; baseline eGFR <60 mL/minute/1.73 m ), 55% converted to EVR within 3 months (early conversion) and 39.4% converted between 4 and 12 months after transplantation (mid-conversion) experienced improvement in eGFR (≥60 mL/minute/1.73 m ) at month 36. Only 20.9% and 17.4% among those converted beyond 12 months (late conversion) experienced improvement respectively at month 36 and 60. A logistic regression analysis in patients with CKD stage ≥3 demonstrated that late conversion, age, and female sex were associated with nonimprovement of eGFR (≥60 mL/minute/1.73 m ). Data from this real-life use of EVR indicate that renal function was maintained from the preconversion period until month 36 even in patients with advanced CKD. However, early rather than late conversion appears to be a safe approach to preserve longterm renal function in LTRs.
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http://dx.doi.org/10.1002/lt.25879DOI Listing
November 2020

Liver transplantation as a rescue therapy for severe neurologic forms of Wilson disease.

Neurology 2020 05 12;94(21):e2189-e2202. Epub 2020 May 12.

From the Neurology Department (A.P., P.C., J.-M.T., F.W.), AP-HP, Lariboisière University Hospital; National Reference Centre for Wilson's Disease (A.P., P.C., J.-M.T., F.W.), AP-HP, Lariboisière University Hospital, Paris; Hepatobiliary Centre (R.S., D.C., D.S., J.-C.D.-V.), DHU Hepatinov, UMR-1193, AP-HP, Paul Brousse Hospital, Villejuif; Service de Neurologie (W.G.M.), CHU Bordeaux; Université de Bordeaux (W.G.M.), Institut des Maladies Neurodégénératives, CNRS UMR 5393, France; Department of Medicine (W.G.M.), University of Otago and New Zealand Brain Research Institute (W.G.M.), Christchurch; Hepatology, Gastroenterology and Nutrition Department (A.-S.B., A.L.), Hôpital Femme Mère Enfant, Hospices Civils de Lyon; National Reference Centre for Wilson's Disease (A.-S.B., E.B., C.L., L.L.-F., O.G., A.L.), Hospices Civils de Lyon; Neurology Department (E.B., C.L.), Hôpital Neurologique Pierre-Wertheimer, Hospices Civils de Lyon; CNRS (E.B., C.L.), UMR 5229, Institut des Sciences Cognitives Marc-Jeannerod, Bron; Faculté de Médecine Lyon Sud Charles-Mérieux (E.B., C.L., A.L.), Université Claude-Bernard Lyon 1; Neurology and Paediatrics Department (L.L.-F.), Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron; Hepatogastroenterology Department (O.G.), Edouard Herriot Hospital, Hospices Civils de Lyon; Internal Medicine Department (F.M.), National Reference Centre for Inborn Errors of Metabolism, Université François Rabelais; Neurology Department (J.B.), CHRU Bretonneau, Tours; Surgery, Oncology and Liver Transplantation Department (E.S.), CHRU Tours; Hepatology and Gastroenterology Department (C.V.) and Surgery and Liver Transplantation Department (B.H.), CHU Besançon; Neurology and Paediatrics Department (C. Bellesme), AP-HP, Bicêtre University Hospital, Kremlin-Bicetre; Pediatric Hepatology and Pediatric Liver Transplantation Unit (U.H) and National Reference Centre for Rare Pediatric Liver Diseases (U.H), Bicêtre University Hospital, Faculty of Medicine Paris-Sud, University of Paris-Sud 11, DHU Hepatinov, AP-HP, Le Kremlin Bicêtre; INSERM (D.H.), UMR-S1174, Hepatinov, University of Paris Sud 11, Orsay; Hepatology and Gastroenterology Department (C. Bureau) and Neurology Department (F.O.-M.), CHU Toulouse; Centre D'investigation de la Fibrose Hépatique (V.L.), Hôpital Haut-Lévêque, CHU Bordeaux; and INSERM U1053 (V.d.L.), Université de Bordeaux, France. A. Poujois is currently at Neurology Department, Rothschild Foundation Hospital, and National Reference Centre for Wilson's Disease, Rothschild Foundation Hospital, Paris.

Objective: To evaluate the effect of liver transplantation (LT) in patients with Wilson disease (WD) with severe neurologic worsening resistant to active chelation.

Methods: French patients with WD who underwent LT for pure neurologic indication were retrospectively studied. Before LT and at the last follow-up, neurologic impairment was evaluated with the Unified Wilson's Disease Rating Scale (UWDRS) score, disability with the modified Rankin Scale (mRS) score, and hepatic function with the Model for End-stage Liver Disease score, together with the presence of a Kayser-Fleischer ring (KFR), brain MRI scores, and copper balance. The survival rate and disability at the last follow-up were the coprimary outcomes; evolution of KFR and brain MRI were the secondary outcomes. Prognosis factors were further assessed.

Results: Eighteen patients had LT. All were highly dependent before LT (median mRS score 5). Neurologic symptoms were severe (median UWDRS score 105), dominated by dystonia and parkinsonism. The cumulated survival rate was 88.8% at 1 year and 72.2% at 3 and 5 years. At the last follow-up, 14 patients were alive. Their mRS and UWDRS scores improved ( < 0.0001 and = 0.0003). Eight patients had a major improvement (78% decrease of the UWDRS score), 4 a moderate one (41% decrease), and 2 a stable status. KFR and brain MRI scores improved ( = 0.0007). Severe sepsis ( = 0.011) and intensive care unit admission ( = 0.001) before LT were significantly associated with death.

Conclusions: LT is a rescue therapeutic option that should be carefully discussed in selected patients with neurologic WD resistant to anticopper therapies (chelators or zinc salts) as it might allow patients to gain physical independency with a reasonable risk.

Classification Of Evidence: This study provides Class IV evidence that for patients with WD with severe neurologic worsening resistant to active pharmacologic therapy, LT might decrease neurologic impairment.
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http://dx.doi.org/10.1212/WNL.0000000000009474DOI Listing
May 2020

Prognostic factors of survival in HIV/HCV co-infected patients with hepatocellular carcinoma: The CARCINOVIC Cohort.

Liver Int 2019 01 30;39(1):136-146. Epub 2018 Jul 30.

Centre Hépato-Biliaire, AP-HP Hôpital Paul-Brousse, Villejuif, France.

Background & Aims: HIV/HCV co-infected patients with hepatocellular carcinoma (HCC) have poorer survival than HCV mono-infected patients. We aimed to evaluate the prognostic factors for survival.

Methods: From 2006 to 2013, 55 incident HCCs among HIV+/HCV+ patients, from three ANRS cohorts, were compared with 181 HCCs in HIV-/HCV+ patients from the ANRS Cirvir cohort.

Results: HIV+/HCV+ patients were younger (50 years [IQR: 47-53] vs 62 [54-70], P < 0.001), male (89% vs 63%, P < 0.001) than HIV-/HCV+ patients. At HCC diagnosis, both groups had a majority of non-responders to anti-HCV-therapy, and HIV+/HCV+ patients had more frequently known a previous cirrhosis decompensation (31% vs 14%, P = 0.005). At diagnostic imaging, there were more infiltrative forms of HCC in HIV+/HCV+ group (24% vs 14%, P < 0.001), associated with tumour portal thrombosis in 29%. During a median follow-up period of 11.96 [5.51-27] months since HCC diagnosis, a majority of palliative treatments were decided in HIV+/HCV+ patients (51% vs 19%, P < 0.001). The 1 and 2-year crude survival rates were 61% versus 78% and 47% versus 63%, P = 0.003 respectively. In a Cox model multivariate analysis adjusted for the cohort, age and sex, the most important prognostic factor for survival was the infiltrative form of the tumour (aRR: 8.10 [4.17-15.75], P < 0.001).

Conclusions: The radiological aggressiveness of the tumour is the best prognostic factor associated with poorer survival of HCC in HIV+/HCV+ patients. High α-foetoprotein level and decompensated cirrhosis are other ones. This justifies a particular attention to the detection and the management of small nodules in this high-risk population.
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http://dx.doi.org/10.1111/liv.13921DOI Listing
January 2019

Rapid and reliable diagnosis of Wilson disease using X-ray fluorescence.

J Pathol Clin Res 2016 Jul 6;2(3):175-86. Epub 2016 Jun 6.

INSERMUnité 1193, Villejuif, F-94800France; Univ Paris-SudUMR-S 1193, Villejuif, F-94800France; DHU HepatinovVillejuif, F-94800France.

Wilson's disease (WD) is a rare autosomal recessive disease due to mutations of the gene encoding the copper-transporter ATP7B. The diagnosis is hampered by the variability of symptoms induced by copper accumulation, the inconstancy of the pathognomonic signs and the absence of a reliable diagnostic test. We investigated the diagnostic potential of X-ray fluorescence (XRF) that allows quantitative analysis of multiple elements. Studies were performed on animal models using Wistar rats (n = 10) and Long Evans Cinnamon (LEC) rats (n = 11), and on human samples including normal livers (n = 10), alcohol cirrhosis (n = 8), haemochromatosis (n = 10), cholestasis (n = 6) and WD (n = 22). XRF experiments were first performed using synchrotron radiation to address the elemental composition at the cellular level. High-resolution mapping of tissue sections allowed measurement of the intensity and the distribution of copper, iron and zinc while preserving the morphology. Investigations were further conducted using a laboratory X-ray source for irradiating whole pieces of tissue. The sensitivity of XRF was highlighted by the discrimination of LEC rats from wild type even under a regimen using copper deficient food. XRF on whole formalin-fixed paraffin embedded needle biopsies allowed profiling of the elements in a few minutes. The intensity of copper related to iron and zinc significantly discriminated WD from other genetic or chronic liver diseases with 97.6% specificity and 100% sensitivity. This study established a definite diagnosis of Wilson's disease based on XRF. This rapid and versatile method can be easily implemented in a clinical setting.
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http://dx.doi.org/10.1002/cjp2.48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958738PMC
July 2016

Predictive factors for survival and score application in liver retransplantation for hepatitis C recurrence.

World J Gastroenterol 2016 May;22(18):4547-58

Alice Tung Wan Song, Rodolphe Sobesky, Bruno Roche, Denis Castaing, Jean-Charles Duclos-Vallée, Didier Samuel, INSERM Unit 785, Villejuif 94800, France.

Aim: To identify risk factors associated with survival in patients retransplanted for hepatitis C virus (HCV) recurrence and to apply a survival score to this population.

Methods: We retrospectively identified 108 patients retransplanted for HCV recurrence in eight European liver transplantation centers (seven in France, one in Spain). Data collection comprised clinical and laboratory variables, including virological and antiviral treatment data. We then analyzed the factors associated with survival in this population. A recently published score that predicts survival in retransplantation in patients with hepatitis C was applied. Because there are currently no uniform recommendations regarding selection of the best candidates for retransplantation in this setting, we also described the clinical characteristics of 164 patients not retransplanted, with F3, F4, or fibrosing cholestatic hepatitis (FCH) post-first graft presenting with hepatic decompensation.

Results: Overall retransplantation patient survival rates were 55%, 47%, and 43% at 3, 5, and 10 years, respectively. Patients who were retransplanted for advanced cirrhosis had survival rates of 59%, 52%, and 49% at 3, 5, and 10 years, while those retransplanted for FCH had survival rates of 34%, 29%, and 11%, respectively. Under multivariate analysis, and adjusting for the center effect and the occurrence of FCH, factors associated with better survival after retransplantation were: negative HCV viremia before retransplantation, antiviral therapy after retransplantation, non-genotype 1, a Model for End-stage Liver Disease (MELD) score < 25 when replaced on the waiting list, and a retransplantation donor age < 60 years. Although the numbers were small, in the context of the new antivirals era, we showed that outcomes in patients who underwent retransplantation with undetectable HCV viremia did not depend on donor age and MELD score. The Andrés score was applied to 102 patients for whom all score variables were available, producing a mean score of 43.4 (SD = 6.6). Survival rates after the date of the first decompensation post-first liver transplantation (LT1) in the liver retransplantation (reLT) group (94 patients decompensated) at 3, 5, and 10 years were 62%, 59%, and 51%, respectively, among 78 retransplanted individuals with advanced cirrhosis, and 42%, 32%, and 16% among 16 retransplanted individuals with FCH. In the non-reLT group with hepatic decompensation, survival rates were 27%, 18%, and 9% at 3, 5, and 10 years, respectively (P < 0.0001). Compared with non-retransplanted patients, retransplanted patients were younger at LT1 (mean age 48 ± 8 years compared to 53 ± 9 years in the no reLT group, P < 0.0001), less likely to have human immunodeficiency virus (HIV) co-infection (4% vs 14% among no reLT patients, P = 0.005), more likely to have received corticosteroid bolus therapy after LT1 (25% in reLT vs 12% in the no reLT group, P = 0.01), and more likely to have presented with sustained virological response (SVR) after the first transplantation (20% in the reLT group vs 7% in the no reLT group, P = 0.028).

Conclusion: Antiviral therapy before and after retransplantation had a substantial impact on survival in the context of retransplantation for HCV recurrence, and with the new direct-acting antivirals now available, outcomes should be even better in the future.
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http://dx.doi.org/10.3748/wjg.v22.i18.4547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858636PMC
May 2016

[Hepatic encephalopathy].

Presse Med 2016 Jan 17;45(1):46-59. Epub 2015 Nov 17.

CHU de Limoges, service d'hépato-gastroentérologie, 2, avenue Luther-King, 87042 Limoges, France; Université de Limoges, faculté de médecine, Inserm UMR 1092, 2, rue du Docteur-Marcland, 87025 Limoges cedex, France.

Hepatic encephalopathy is a severe complication of liver cirrhosis and is an important therapeutic challenge, with a social and economic issue. If, now, the pathophysiology is not totally understood (main role of ammonia, but a better understanding of cerebral mechanisms), the clinical presentation is well-known. Some treatments are useful (disaccharides, treatment of the trigger) but their efficiency is limited. Nevertheless, the emergence of new treatments, such as non-absorbable antibiotics (rifaximin essentially), is an interesting therapeutic tool.
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http://dx.doi.org/10.1016/j.lpm.2015.02.021DOI Listing
January 2016

Imaging Features and Prognosis of Hepatocellular Carcinoma in Patients with Cirrhosis Who Are Coinfected with Human Immunodeficiency Virus and Hepatitis C Virus.

Radiology 2015 Nov 6;277(2):443-53. Epub 2015 May 6.

From the Department of Radiology, AP-HP Hôpital Paul Brousse, 12-14 avenue Paul Vaillant Couturier, 94800 Villejuif, France (M.L.); Université Paris-Sud, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France (M.L., D.S., J.C.D.V.); Hepatobiliary Center, AP-HP Hôpital Paul Brousse, Villejuif, France (M.G.S., M.O., R.S., D.S., J.C.D.V.); DHU Hepatinov, Villejuif, France (M.G.S., M.O., R.S., E.T., D.S., J.C.D.V.); Department of Hepatogastroenterology, CHU de Pointe-à-Pitre, Pointe-à-Pitre, Guadeloupe, France (M.G.S.); Department of Epidemiology and Public Health, AP-HP Hôpital Bicêtre, Le Kremlin-Bicêtre, France (F.B., L.M.); INSERM U785, Villejuif, France (R.S., E.T., D.S., J.C.D.V.); Department of Infectious Diseases, AP-HP Hôpital Bicêtre and Université Paris-Sud INSERM U1018, Le Kremlin-Bicêtre, France (E.T.); Hepatology Unit, AP-HP Hôpital Cochin and Université Paris Descartes INSERM U1016, Paris, France (H.F.); Department of Infectious and Tropical Diseases, AP-HP Hôpital Cochin and Université Paris Descartes, Paris, France (D.S.C.); Department of Radiology, AP-HP Hôpital Jean Verdier, Université Paris 13, INSERM UMR 1162, Bondy, France (O.S.); and Department of Hepatogastroenterology, AP-HP Hôpital Jean Verdier, Université Paris 13, INSERM UMR 1162, Bondy, France (J.C.T.).

Purpose: To evaluate the effect of human immunodeficiency virus (HIV) coinfection on hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infected patients with cirrhosis in terms of HCC morphologic subtypes and survival prognosis at the time of radiologic diagnosis.

Materials And Methods: The study was approved by the institutional review board and patients gave their written informed consent. Two databases, one for HIV-HCV patients and the other for HCV-infected patients without HIV infection, were obtained from prospective multicenter cohorts. Inclusion criteria were a confirmed diagnosis of cirrhosis and the discovery of HCC at imaging between January 2008 and December 2012. This study included 35 HIV-HCV patients with cirrhosis (32 men and three women; median age, 50 years [age range, 40-65 years]; Child-Pugh classification A, 21 patients; classification B, 10 patients; classification C, four patients) and 35 infected HCV patients with cirrhosis (29 men and six women; median age, 56 years [age range, 41-83 years]; Child-Pugh classification A, 26 patients; classification B, six patients; classification C, three patients) who were the control group. Computed tomographic or magnetic resonance images were analyzed for HCC subtypes, the number and size of nodules, and evidence of portal obstructing tumors. Fisher exact and Wilcoxon tests were used for comparisons and Kaplan-Meier plots were used for survival analysis.

Results: Infiltrative HCC was found in eight HIV-HCV patients with cirrhosis (23%) and in no HCV patients with cirrhosis (P = .002). All other HCCs were of a nodular type, with similar nodule sizes in the two groups. Portal-obstructing tumors were found in 10 HIV-HCV patients (eight of eight tumors were infiltrative and two of 27 tumors were nodular) but none were found in HCV patients (P = .001). Survival was dramatically shorter for HIV-HCV patients than for those with HCV, with a median of 17.2 months versus 54.7 months (P = .004). Survival time was dependent on the type of HCC, with probabilities of death at 12 months of 87% in infiltrative-type HCC, 32% in multiple-nodule type, and 5% in single-nodule type, which was found in both groups (log-rank test, P < .001).

Conclusion: Unlike HCV-infected patients with cirrhosis, patients with cirrhosis coinfected with HIV and HCV frequently present at radiologic diagnosis with infiltrative-type HCC and portal-obstructing tumors, which results in dramatically shorter survival.
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http://dx.doi.org/10.1148/radiol.2015141500DOI Listing
November 2015

Do the epidemiology, physiological mechanisms and characteristics of hepatocellular carcinoma in HIV-infected patients justify specific screening policies?

AIDS 2014 Jun;28(10):1379-91

aAP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire bDHU Hepatinov cInserm U785, Villejuif dUniversité Paris-Sud, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre eAP-HP Hôpital Paul Brousse, Département Virologie, Villejuif fAP-HP Hôpital Bicêtre, Service de Médecine Interne, Immunologie Clinique et Maladies Infectieuses, Le Kremlin-Bicêtre gAP-HP Hôpital Cochin, Unité d'Hépatologie et Université Paris Descartes, Inserm U1016 hAP-HP Hôpital Cochin, Service des Maladies Infectieuses et Tropicales et Université Paris Descartes, Paris iAP-HP Hôpital Bicêtre, Service d'Epidémiologie et de Santé Publique et Université Paris-Sud, Inserm U1018, Le Kremlin-Bicêtre jAP-HP Hôpital Jean Verdier, Service d'Hépato-Gastro-Entérologie et Université Paris 13, Inserm UMR 1162, Bondy kAP-HP Hôpital Paul Brousse, Service de Radiologie, Villejuif lCHU de Pointe-à-Pitre, Service d'Hépato-Gastro-Entérologie, Pointe-à-Pitre, Guadeloupe, France.

Reducing the incidence of hepatocellular carcinoma (HCC) in HIV-infected patients has become a serious problem when managing these patients. There are many explanations for this disease evolution, which notably include their longer survival under effective antiviral therapy and also the more rapid evolution of chronic liver disease. Despite recent advances in the management of hepatitis B (HBV) and hepatitis C (HCV) viral diseases, which will probably increase the number of patients achieving a virological response, HIV-infected patients with cirrhosis are still at risk of the onset of HCC. This evolution to HCC is also correlated to other comorbidities such as excessive alcohol consumption and nonalcoholic steatohepatitis (NASH). HCC thus remains a public health issue in this population. The poor prognosis and aggressiveness of HCC have been fully demonstrated, but the mechanisms underlying this aggressiveness are not yet well defined. As well as underlying mechanisms that contribute to accelerating hepatocarcinogenesis in HIV-infected patients, there are other reasons why HIV-infected patients should be considered a higher risk population. This review discusses the principal epidemiological determinants; the mechanisms of pathogenesis; and the treatment of HCC in HIV/HBV and HIV/HCV coinfected patients. It also discusses the probable need to develop a specific screening policy for HCC in this population in order to prevent the rapid development and to make them more amenable to a curative treatment.
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http://dx.doi.org/10.1097/QAD.0000000000000300DOI Listing
June 2014

Long term results of liver transplantation for Wilson's disease: experience in France.

J Hepatol 2014 Mar 6;60(3):579-89. Epub 2013 Nov 6.

Centre National de Référence de la Maladie de Wilson/Centre Hépato-Biliaire, Hôpital Paul Brousse, AP-HP, Villejuif, France; UMR 785, INSERM, France; UMR-S 785, Univ Paris-Sud, Villejuif, France; DHU Hepatinov, Villejuif, France.

Background & Aims: Liver transplantation (LT) is the therapeutic option for severe complications of Wilson's disease (WD). We aimed to report on the long-term outcome of WD patients following LT.

Methods: The medical records of 121 French patients transplanted for WD between 1985 and 2009 were reviewed retrospectively. Seventy-five patients were adults (median age: 29 years, (18-66)) and 46 were children (median age: 14 years, (7-17)). The indication for LT was (1) fulminant/subfulminant hepatitis (n = 64, 53%), median age = 16 years (7-53), (2) decompensated cirrhosis (n = 50, 41%), median age = 31.5 years (12-66) or (3) severe neurological disease (n = 7, 6%), median age = 21.5 years (14.5-42). Median post-transplant follow-up was 72 months (0-23.5).

Results: Actuarial patient survival rates were 87% at 5, 10, and 15 years. Male gender, pre-transplant renal insufficiency, non elective procedure, and neurological indication were significantly associated with poorer survival rate. None of these factors remained statistically significant under multivariate analysis. In patients transplanted for hepatic indications, the prognosis was poorer in case of fulminant or subfulminant course, non elective procedure, pretransplant renal insufficiency and in patients transplanted before 2000. Multivariate analysis disclosed that only recent period of LT was associated with better prognosis. At last visit, the median calculated glomerular filtration rate was 93 ml/min (33-180); 11/93 patients (12%) had stage II renal insufficiency and none had stage III.

Conclusions: Liver failure associated with WD is a rare indication for LT (<1%), which achieves an excellent long-term outcome, including renal function.
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http://dx.doi.org/10.1016/j.jhep.2013.10.025DOI Listing
March 2014

Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial.

JAMA 2013 Sep;310(10):1033-41

Service des Maladies de l'Appareil digestif, Hôpital Huriez, Lille, France.

Importance: Prednisolone or pentoxifylline is recommended for severe alcoholic hepatitis, a life-threatening disease. The benefit of their combination is unknown.

Objective: To determine whether the addition of pentoxifylline to prednisolone is more effective than prednisolone alone.

Design, Setting, And Participants: Multicenter, randomized, double-blind clinical trial conducted between December 2007 and March 2010 in 1 Belgian and 23 French hospitals of 270 patients aged 18 to 70 years who were heavy drinkers with severe biopsy-proven alcoholic hepatitis, as indicated by recent onset of jaundice in the prior 3 months and a Maddrey score of at least 32. Duration of follow-up was 6 months. The last included patient completed the study in October 2010. None of the patients were lost to follow-up for the main outcome.

Intervention: Patients were randomly assigned to receive either a combination of 40 mg of prednisolone once a day and 400 mg of pentoxifylline 3 times a day (n=133) for 28 days, or 40 mg of prednisolone and matching placebo (n=137) for 28 days.

Main Outcomes And Measures: Six-month survival, with secondary end points of development of hepatorenal syndrome and response to therapy based on the Lille model, which defines treatment nonresponders after 7 days of initiation of treatment.

Results: In intention-to-treat analysis, 6-month survival was not different in the pentoxifylline-prednisolone and placebo-prednisolone groups (69.9% [95% CI, 62.1%-77.7%] vs 69.2% [95% CI; 61.4%-76.9%], P = .91), corresponding to 40 vs 42 deaths, respectively. In multivariable analysis, only the Lille model and the Model for End-Stage Liver Disease score were independently associated with 6-month survival. At 7 days, response to therapy assessed by the Lille model was not significantly different between the 2 groups (Lille model score, 0.41 [95% CI, 0.36-0.46] vs 0.40 [95% CI, 0.35-0.45], P = .80). The probability of being a responder was not different in both groups (62.6% [95% CI, 53.9%-71.3%] vs 61.9% [95% CI, 53.7%-70.3%], P = .91). The cumulative incidence of hepatorenal syndrome at 6 months was not significantly different in the pentoxifylline-prednisolone and the placebo-prednisolone groups (8.4% [95% CI, 4.8%-14.8%] vs 15.3% [95% CI, 10.3%-22.7%], P = .07).

Conclusion And Relevance: In patients with alcoholic hepatitis, 4-week treatment with pentoxifylline and prednisolone, compared with prednisolone alone, did not result in improved 6-month survival. The study may have been underpowered to detect a significant difference in incidence of hepatorenal syndrome, which was less frequent in the group receiving pentoxifylline.

Trial Registration: clinicaltrials.gov Identifier: NCT01214226.
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http://dx.doi.org/10.1001/jama.2013.276300DOI Listing
September 2013

Immunoproteomic analysis of potentially severe non-graft-versus-host disease hepatitis after allogenic bone marrow transplantation.

Hepatology 2013 Feb 8;57(2):689-99. Epub 2013 Jan 8.

INSERM, Unité 785, Villejuif, France.

Unlabelled: The development of potentially severe non-graft-versus-host disease (GVHD) hepatitis resembling autoimmune hepatitis (AIH) has been reported after bone marrow transplantation (BMT). The aim of this study was to better characterize this form of hepatitis, particularly through the identification of autoantigens recognized by patient sera. Five patients who received an allogeneic BMT for the treatment of hematological diseases developed liver dysfunction with histological features suggestive of AIH. Before and during the onset of hepatic dysfunction, sera were tested on immunoblottings performed with cytosolic, microsomal, mitochondrial, and nuclear proteins from rat liver homogenate and resolved by two-dimensional electrophoresis. Antigenic targets were identified by mass spectrometry. During the year that followed BMT, all patients presented with GVHD. Acute hepatitis then occurred after the withdrawal, or during the tapering, of immunosuppressive therapy. At that time, no patients had a history of liver toxic drug absorption, patent viral infection, or any histopathological findings consistent with GVHD. Immunoreactive spots stained by sera collected at the time of hepatic dysfunction were more numerous and more intensely expressed than those stained by sera collected before. Considerable patient-dependent pattern heterogeneity was observed. Among the 259 spots stained exclusively by sera collected at the time of hepatitis, a total of 240 spots were identified, corresponding to 103 different proteins. Twelve of them were recognized by sera from 3 patients.

Conclusions: This is the first immunological description of potentially severe non-GVHD hepatitis occurring after BMT, determined using a proteomic approach and enabling a discussion of the mechanisms that transform an alloimmune reaction into an autoimmune response. Any decision to withdraw immunosuppression after allogeneic BMT should be made with caution.
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http://dx.doi.org/10.1002/hep.26024DOI Listing
February 2013

Toward optimizing the indications for orthotopic liver transplantation in hepatocellular carcinoma.

Liver Transpl 2011 Oct;17 Suppl 2:S6-13

Centre Hepato-Biliaire, AP-HP Hopital Paul Brousse, Villejuif, France.

Key Points: 1. Liver transplantation is currently an effective therapy for patients with HCC who meet the Milan criteria. 2. The proportion of patients on waiting lists for liver transplantation who have HCC has increased substantially in recent years. HCC is currently one of the major indications for liver transplantation; it is the indication for approximately one-third of liver transplants. 3. If the Milan criteria are not met, the survival rates after liver transplantation for HCC tend to decrease, mainly because of the catastrophic consequences of HCC recurrence. 4. A few studies have supported liver transplantation when the Milan criteria are exceeded, but extensions beyond the Milan criteria remain controversial. Even if an individual patient with HCC who does not meet the Milan criteria might benefit from liver transplantation, the limited number of currently available donor organs limits the indications for liver transplantation to those patients with HCC who have the greatest likelihood of survival after the procedure. 5. To patients with early-stage HCC, surgical resection can be offered if the hepatocellular function is well maintained and severe portal hypertension is not present. 6. To enable patients with HCC to have access to liver transplantation that is similar to the access for other patients without HCC in the MELD allocation system, additional points based on the number and size of HCC lesions are assigned to patients on the waiting list. However, this system requires further refinement to ensure that it is as fair as possible. 7. Liver transplantation for HCC should be restricted to those patients who are expected to have the same posttransplant survival as that of patients with nonneoplastic end-stage chronic liver disease. 8. On the basis of these considerations, a 5-year survival rate of 50% after liver transplantation for HCC seems too low.
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http://dx.doi.org/10.1002/lt.22423DOI Listing
October 2011

Pathological evolution of hepatitis C virus-"Healthy carriers".

World J Gastroenterol 2008 Jun;14(24):3861-5

INSERM U785, Centre Hepato-Biliaire, Hopital Paul Brousse, Villejuif, France.

Aim: To determine factors associated with fibrosis progression in hepatitis C virus (HCV)-infected patients without significant initial pathological lesions.

Methods: Seventy six untreated HCV-infected patients with initially normal liver as defined by a Knodell score < or = 3, with 2 liver biopsies and detectable HCV-RNA were included. Markers of fibrosis progression were assessed.

Results: Median duration of infection and time between paired biopsies was 13 (95% CI: 1-28) and 4 (95% CI: 2-16) years respectively. Alanine-transaminase (ALT) activity was normal in 43.4% of cases. 50% demonstrated progression of the necro-inflammation and 34% of fibrosis after a median time evolution of 4 years (95% CI: 2-16). The median difference in the necro-inflammation and fibrosis score between biopsies was low, 1.5 and 0.0 respectively. Univariate analysis showed there was no difference between fibrosis activity or evolution according to genotype or viral load. A higher fibrosis progression (P = 0.03) was observed in patients with body mass index (BMI) > 25. Fibrosis progression correlated with the time interval between biopsies (P = 0.01). A significant progression of activity (1.7 vs 0.4, P < 0.05) or fibrosis (0.9 vs 0.0, P < 0.01) was observed in patients with elevated ALT. There was a significant correlation between activity progression and fibrosis progression (P = 0.003). Multivariate analysis demonstrated that fibrosis progression was associated with elevated ALT, BMI > 25 and the time interval between 2 biopsies.

Conclusion: There is no fibrosis progression in 66% of patients without significant initial histopathological lesion. Fibrosis progression is associated with elevated ALT and BMI > 25.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721443PMC
http://dx.doi.org/10.3748/wjg.14.3861DOI Listing
June 2008

Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis.

Gastroenterology 2008 Feb 12;134(2):416-23. Epub 2007 Nov 12.

AP-HP, Hôpital Beaujon, Service d'Hépatologie, Clichy F-92110, France.

Background & Aims: Our study was designed to test the association between insulin resistance (IR) and hepatitis C virus (HCV) genotypes, serum HCV RNA level and liver fibrosis stage in a large prospective cohort of chronic hepatitis C (CHC) patients.

Methods: Six hundred consecutive patients (CHC, n = 500; chronic hepatitis B (CHB), n = 100) were evaluated on the day of liver biopsy. IR (Homeostasis Model for Assessment of Insulin Resistance) and all components of the metabolic syndrome were assessed. By logistic regression, independent factors associated with IR and those associated with significant fibrosis were assessed in nondiabetic and noncirrhotic CHC, respectively. Parameters of IR were compared between hepatitis B and 240 CHC matched by epidemiologic, metabolic, and histologic features.

Results: IR was present in 32.4% of the 462 nondiabetic CHC and associated with the metabolic syndrome, genotypes 1 and 4, significant fibrosis, and severe steatosis. IR was diagnosed in 15% of 145 CHC without metabolic syndrome or significant fibrosis, and associated with genotypes 1 and 4, high serum HCV RNA level, and moderate-severe necroinflammation. Significant fibrosis was present in 51.1% of the 454 noncirrhotic CHC patients and associated with male sex, age >40 years, IR, moderate-severe necroinflammation, and severe steatosis. IR was less frequent in CHB than in matched CHC (5% vs 35%, respectively, P < .001).

Conclusions: IR is a specific feature of CHC, associated with genotypes 1 and 4 and high serum HCV RNA level. Significant fibrosis is associated with IR independent from steatosis.
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http://dx.doi.org/10.1053/j.gastro.2007.11.010DOI Listing
February 2008

Distinct hepatitis C virus core and F protein quasispecies in tumoral and nontumoral hepatocytes isolated via microdissection.

Hepatology 2007 Dec;46(6):1704-12

Institut National de la Santé et de la Recherche Médicale (INSERM), U785, Villejuif, France.

Unlabelled: Hepatitis C virus (HCV) genetic variability may be involved in liver carcinogenesis. We investigated HCV core and corresponding putative F protein genetic variability in hepatocellular carcinoma (HCC) and cirrhotic nodules. Hepatocyte clusters from 7 patients with HCC and HCV1b-related cirrhosis were isolated via microdissection of HCC tissues and 2 nontumoral cirrhotic nodules. The HCV core complementary DNA was cloned and sequenced from each liver compartment and from the serum of 2 patients. Nucleotide diversity and synonymous and nonsynonymous substitutions were analyzed within and between compartments via phylogenetic analysis and Mantel's test. Liver HCV RNA accumulation was lower in HCC. Increased quasispecies diversity and complexity was observed with HCC in 6 of 7 patients. Mantel's test demonstrated marked compartmentalization of quasispecies between HCC and cirrhotic nodules in all 7 patients and also between the 2 nontumoral nodules in 5 of them. Synonymous-nonsynonymous substitution analysis indicated low selection against tumoral core quasispecies in all patients and a more selective pressure against F protein quasispecies in all compartments. In the 2 subjects analyzed, HCC and nontumoral hepatocyte quasispecies were only minor or undetected in serum.

Conclusion: In tumoral hepatocytes, low-replicating hepatitis C quasispecies are compartmentalized and more diversified and are subjected to low selective pressure. Our study supports the importance of core genetic variability in hepatocellular carcinogenesis.
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http://dx.doi.org/10.1002/hep.21898DOI Listing
December 2007

[Hepatitis C and liver transplantation: fibrosis progression and treatment. Or how to improve management].

Gastroenterol Clin Biol 2006 Nov;30(11):1281-95

Service d'Hépatologie et Unité INSERM CRB3, Université Paris VII.

Hepatitis C virus-related end-stage liver disease, alone or in combination with alcohol, has become the leading indication for liver transplantation in most transplant programs accounting for approximately half of transplants performed in European centers. Hepatitis C virus infection recurs virtually in every post-transplant patient. The natural history of hepatitis C after liver transplantation is variable. Progression of chronic hepatitis C virus is more aggressive after liver transplantation with a cumulative probability of developing graft cirrhosis estimated to reach 30% at 5 years. Approximately 10% of the patients with recurrent disease will die or require re-transplantation within 5 years post-transplantation. Several factors, including those related to the virus, the host, the environment and the donor, are probably implicated in the outcome. The immune status represents the main significant variable in influencing disease severity in hepatitis C virus-infected patients; with higher HCV viral load and the significant association described between the degree of immunosuppression and disease severity. Interventions to prevent, improve, or halt the recurrence of hepatitis C virus infection have been evaluated by multiple small studies worldwide with similar overall rates of virological clearance of approximately 9-30%. Current consensus recommends combination therapy with pegylated interferon and ribavirin for those patients with histological recurrence of hepatitis C virus infection and fibrosis. Therapy is adjusted to tolerance and rescued with granulocyte colony-stimulating factor and erythropoietin for bone marrow suppression. In this article we present a comprehensive review of post-transplant hepatitis C virus infection; in particular fibrosis progression and the major challenges according to treatment.
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http://dx.doi.org/10.1016/s0399-8320(06)73536-9DOI Listing
November 2006

The impact of haematopoietic growth factors on the management and efficacy of antiviral treatment in patients with hepatitis C virus.

Antivir Ther 2005 ;10(6):769-76

Unité d'Hépatologie, Hôpital Necker, Paris, France.

Aim: To evaluate the benefits of haematopoietic growth factors (HGFs) during the treatment of chronic hepatitis C virus (HCV) infection with severe haematotoxicity.

Methods: This was a 1-year retrospective study of HCV-positive patients receiving pegylated interferon and ribavirin. Patients received different HGFs, depending on certain criteria: they received erythropoietin (EPO) when their haemoglobin (Hb) levels were less than 10 g/dl and granulocyte colony-stimulating factor (G-CSF) when their neutrophil count was less than 750 cells/mm3. Haematological data, adherence and virological response were analysed and compared according to HGF use.

Results: In total, 132 patients were studied and 31 (23.5%) required HGF. Under multivariate analysis, baseline Hb levels of less than 13g/dl or a drop in Hb levels of over 2% per week predicted severe anaemia, and a baseline neutrophil count under 2900/mm3 predicted severe neutropaenia. HGF administration restored Hb values and the neutrophil count to above 10 g/dl and 1500 cells/mm3, respectively, in all 31 patients. Adherence to antiviral treatment was achieved in 25% of patients versus 58% of controls without severe haematotoxicity. The primary and sustained virological response did not differ statistically between HGF support and the control group (61% versus 57% and 32% versus 39%, respectively).

Conclusion: HGF administration counteracts the severe haematological adverse effects which occur during antiviral therapy and maintains the rate of sustained response.
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November 2005

Hepatitis C virus core variants isolated from liver tumor but not from adjacent non-tumor tissue interact with Smad3 and inhibit the TGF-beta pathway.

Oncogene 2005 Sep;24(40):6119-32

Inserm U370, Paris V University, Pasteur Institute, 156 rue de Vaugirard 75730 Paris cedex 15, France.

Hepatitis C virus (HCV) is a major risk factor for human hepatocellular carcinoma (HCC) but the mechanisms underlying HCV-induced carcinogenesis are still poorly understood. We have hypothesized that viral variants, selected during long-term infection, might contribute to cellular transformation. To address this issue, we have investigated the effect of natural HCV core variants isolated from liver tumors (T), or their non-tumor (NT) counterparts, on the tumor growth factor-beta (TGF-beta) pathway, a major regulator of cellular proliferation, differentiation and apoptosis. We have found a significant reduction in TGF-beta reporter gene activity with the expression of core sequences isolated from liver tumors. In contrast, moderate or no effects were observed with non-tumor mutants or a core reference sequence. The molecular mechanisms have been characterized and involved the inhibition, by tumor-derived cores, of the DNA-binding activity of the Smad3/4 transcription factors complex. This inhibition occurs through a direct interaction between the central domain (amino acids 59-126) of tumor-derived core and the MH1 DNA-binding domain of Smad3, thus preventing its binding to DNA. We have therefore identified a new cell-signaling pathway targeted by HCV core and inhibited by tumor-derived core sequences. These results suggest that during chronic infection, there is selection of viral variants that may promote cell transformation by providing, to clonally expanding cells, resistance to TGF-beta antiproliferative effects.
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http://dx.doi.org/10.1038/sj.onc.1208749DOI Listing
September 2005

Immunomodulatory drugs and therapeutic vaccine in chronic hepatitis B infection.

J Hepatol 2003 ;39 Suppl 1:S151-9

Service d'Hépatologie, Hôpital Necker Enfants Malades, 75730 Paris Cédex 15, France.

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http://dx.doi.org/10.1016/s0168-8278(03)00336-2DOI Listing
February 2004

Septicaemia and liver abscesses secondary to non-O1/non-O139 Vibrio cholerae colitis.

Eur J Gastroenterol Hepatol 2003 Jun;15(6):699-700

Department of Gastroenterology, Hôpital Louis Mourier, Colombes, France.

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http://dx.doi.org/10.1097/00042737-200306000-00018DOI Listing
June 2003
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