[Show description][Hide description] DESCRIPTION: Objective and subjective parameters are helpful in the accurate assessment of long-term outcome in liver transplantation (LT) recipients. Seventy-two recipients with a functional first graft at 10 years post-LT underwent liver biopsy and completed a quality of life (QOL) questionnaire. Logistic regression analysis was used to explore associations between histological, clinical and QOL criteria. Ten years after LT, fibrosis was detected in 53% of patients, and affected the general health perception, while ductopenia, present in 36%, affected the well-being (p=0.05). Hepatic steatosis (HS) was present in 33% of patients and was associated with the worst QOL score on multiple domains. When compared to patients without HS, patients with HS had significantly higher incidence of fibrosis (p=0.03), HCV virus infection (p=0.007), and more patients had retired from their job (p=0.03). Recurrent or de novo HCV-associated fibrosis and patient retirement as objective variables, and abdominal pain or discomfort and joint aches or pains as subjective variables, emerged as independent determinants of HS. In conclusion, long-term liver graft lesions, mainly HS presumably as a surrogate marker of HCV infection, may have a substantial impact on QOL 10 years after LT.
[Show abstract][Hide abstract] ABSTRACT: An increasing number of noncoding RNAs (ncRNAs) have been implicated in various human diseases including cancer; however, the ncRNA transcriptome of hepatocellular carcinoma (HCC) is largely unexplored. We used CAGE to map transcription start sites across various types of human and mouse HCCs with emphasis on ncRNAs distant from protein-coding genes. Here, we report that retroviral LTR promoters, expressed in healthy tissues such as testis and placenta but not liver, are widely activated in liver tumors. Despite HCC heterogeneity, a subset of LTR-derived ncRNAs were more than 10-fold up-regulated in the vast majority of samples. HCCs with a high LTR activity mostly had a viral etiology, were less differentiated, and showed higher risk of recurrence. ChIP-seq data show that MYC and MAX are associated with ncRNA de-regulation. Globally, CAGE enabled us to build a mammalian promoter map for HCC, which uncovers a new layer of complexity in HCC genomics.
Genome Research 10/2015; DOI:10.1101/gr.191031.115 · 14.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatitis C virus (HCV) infection is one of the leading causes of end-stage liver disease and the main indication for liver transplantation (LT) in most countries. All patients who undergo LT with detectable serum HCV RNA experience graft reinfection progressing to cirrhosis within five years in 20% to 30% of them. Obtaining a sustained virological response (SVR) greatly improves overall and graft survival. Until 2011, standard antiviral therapy using PEGylated interferon (PEG-IFN) and ribavirin (RBV) was the only effective therapy, with an SVR rate around 30% in this setting. For patients infected with genotype 1, first generation NS3/4A protease inhibitors (PIs), boceprevir (BOC) or telaprevir (TVR), associated with PEG-IFN and RBV for 48 weeks have increased the SVR rates to 60% in non-transplant patients. However, tolerability and drug-drug interactions with calcineurin inhibitors (CNI) are both limiting factors of their use in the liver transplant setting. Over recent years, the efficacy of antiviral C therapy has improved dramatically using new direct-acting antiviral (DAA) agents without PEG-IFN and/or RBV, leading to SVR rates over 90% in non-transplant patients. Results available for transplant patients showed a better efficacy and tolerability and less drug-drug interactions than with first wave PIs. However, some infrequent cases of viral resistance have been reported using PIs or NS5A inhibitors pre- or post-LT that can lead to difficulties in the management of these patients.
[Show abstract][Hide abstract] ABSTRACT: Background and aims:
First generation protease inhibitors (PI) with peg-interferon (PEG-IFN) and ribavirin (RBV) have been the only therapy available for hepatitis C virus (HCV) genotype 1 infection in most countries for 3 years. We have investigated the efficacy and tolerance of this triple therapy in transplanted patients experiencing a recurrence of HCV infection on the liver graft.
This cohort study enrolled 81 liver transplant patients (Male: 76%, mean age: 55.8±9.7 years) with severe HCV recurrence (F3 or F4: n = 34 (42%), treatment experienced: n = 44 (54%)), treated with boceprevir (n = 36; 44%) or telaprevir (n = 45; 56%). We assessed the percentages of patients with sustained virological responses 24 weeks after therapy (SVR24), and safety.
The SVR24 rate was 47% (telaprevir: 42%; boceprevir: 53%, P = ns). At baseline, a normal bilirubin level (p = 0.0145) and albumin level >35g/L (p = 0.0372) and an initial RBV dosage of ≥800 mg/day (p = 0.0033) predicted SVR24. During treatment, achieving an early virological response after 12 weeks was the strongest independent factor to predict SVR24 (p<0.0001). A premature discontinuation of anti-HCV therapy due to a serious adverse event (SAE) was observed in 22 patients (27%). Hematological toxicity, infections and deaths were observed in 95%, 28% and 7% of patients, respectively. A history of post-LT antiviral therapy and thrombocytopenia (<50G/L) during treatment were both independent predictors of the occurrence of infections or SAE (p = 0.0169 and p = 0.011).
The use of first generation PI after liver transplantation enabled an SVR24 rate of 47% in genotype 1 patients, but induced a high rate of SAE. The identification of predictive factors for a response to treatment, and the occurrence of SAE, have enabled us to establish limits for the use of this anti-HCV therapy in the transplant setting.
PLoS ONE 09/2015; 10(9):e0138091. DOI:10.1371/journal.pone.0138091 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Should organs from hepatitis C antibody positive donors (HCVD+) be used for transplantation? Organ shortage forces transplant teams to use donor with extended criteria. The decision to transplant a HCVD+ graft is a balance between the risk of transmission of a virus that could lead to end stage liver diseases and the benefit of access to transplantation, specifically in patient with life-threatening disease. The other issue is the impact of HCV-related liver fibrosis in the donor graft on the long term outcome in the recipient. Thus, the use of HCVD+ demonstrated a shorter meantime on waiting list in kidney transplantation. When a HCVD+ graft is transplanted, the risk of HCV transmission depends on 1) the quality of screening of the donor, 2) the presence of viral replication in the donor at the time of transplantation and the ability to detect it, 3) the HCV status of the recipient but also the type of transplanted organ. In liver transplantation, use of HCVD+ graft is usually restricted to recipients with a chronic HCV infection. Several reports showed some competition between HCV donor and recipient strain without deleterious impact on graft and patient survival. Controversies are still on pending regarding quality of the graft and progression of fibrosis. The recent approval of direct antiviral acting agents (DAA) dramatically changes the landscape of HCV infection treatment. After transplantation, combinations of DAA show high efficacy and good safety profile. In the next future, extensive use of DAA should reduce the number of HCVD+ with a positive HCV RNA, limiting the risk of transmission but also the number of patients on waiting list for a disease related to HCV.
Journal of Hepatology 09/2015; DOI:10.1016/j.jhep.2015.09.002 · 11.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. Until recently, liver transplantation (Ltx) was the only available treatment for hereditary transthyretin (TTR) amyloidosis; today, however, several pharmacotherapies are tested. Herein, we present survival data from the largest available database on transplanted hereditary TTR patients to serve as a base for comparison. Methods. Liver transplantation was evaluated in a 20-year retrospective analysis of the Familial Amyloidosis Polyneuropathy World Transplant Registry. Results. From April 1990 until December 2010, data were accumulated from 77 liver transplant centers. The Registry contains 1940 patients, and 1379 are alive. Eighty-eight Ltx were performed in combination with a heart and/or kidney transplantation. Overall, 20-year survival after Ltx was 55.3%. Multivariate analysis revealed modified body mass index, early onset of disease (<50 years of age), disease duration before Ltx, and TTR) Val30Met versus non-TTR Val30Met mutations as independent significant survival factors. Early-onset patients had an expected mortality rate of 38% that of the late-onset group (P < 0.001). Furthermore, Val30Met patients had an expected mortality rate of 61% that of non-TTR Val30Met patients (P < 0.001). With each year of duration of disease before Ltx, expected mortality increased by 11% (P < 0.001). With each 100-unit increase in modified body mass index at Ltx, the expected mortality decreased to 89%of the expectedmortality (P < 0.001). Cardiovascular death wasmarkedlymore common than that observed in patients undergoing Ltx for end-stage liver disease. Conclusions. Long-term survival after Ltx, especially for early-onset TTR Val30Met patients, is excellent. The risk of delaying Ltx by testing alternative treatments, especially in earlyonset
TTR Val30Met patients, requires consideration.
[Show abstract][Hide abstract] ABSTRACT: Objective:
To compare the natural history of Familial transthyretin amyloid polyneuropathies (FAP) due to the Val30Met, Ser77Tyr and Ile107Val mutations in France with the classical Portuguese Val30Met FAP.
We compared 84 French patients with a control group of 110 Portuguese patients carrying the Val30Met mutation also living in France, all referred to and followed at the French National FAP Reference Center from 1988 to 2010. Clinical examination, functional and walking disability scores, nerve conduction studies and muscle biopsies are reported. We also conducted a comprehensive literature review in order to further determine the range of phenotypic expression.
By comparison with Portuguese Val30Met FAP, French Ile107Val, Ser77Tyr and LateVal30Met FAP showed more rapid and severe disease progression: onset of gait disorders was three times more rapid (p<0.0001), the rate of modified Norris test decline was up to 40 times faster in Ile107Val patients (p<0.0001). Median survival was much shorter in Ile107Val and LateVal30Met FAP (p=0.0005). Other distinctive features relative to the Portuguese patients included atypical clinical presentations, demyelination on nerve conduction studies (p=0.0005), difficult identification of amyloid deposits in nerve and muscle biopsies.
Ile107Val and LateMet30 mutations are associated with the most debilitating and severe FAP ever described, with rapid onset of tetraparesis and shorter median survival. It could be explained by the frequent large-fibers involvement, associated demyelination and more severe axonal loss. These findings have major implications for genetic counseling and patient management as new therapeutic options are being assessed in clinical trials (TTR gene silencing). This article is protected by copyright. All rights reserved.
Annals of Neurology 09/2015; DOI:10.1002/ana.24519 · 9.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Treatment options for HCV genotype 4 (GT4) are limited. This phase 3 study (COMMAND-4; AI444-042) evaluated the efficacy and safety of daclatasvir (DCV), a pan-genotypic HCV NS5A inhibitor, with peginterferon-alfa-2a/ribavirin (pegIFN/RBV) in treatment-naive patients with HCV GT4 infection.
Patients were randomly assigned (2:1; blinded) to treatment with DCV 60 mg (n = 82) or placebo (n = 42) once daily plus pegIFN 180 µg weekly and RBV 1000-1200 mg/day (weight-based) twice daily. DCV-treated patients with undetectable HCV RNA at weeks 4 and 12 (eRVR) received 24 weeks of DCV plus pegIFN/RBV; those without eRVR received an additional 24 weeks of pegIFN/RBV. All placebo-treated patients received 48 weeks of pegIFN/RBV. The primary endpoint was SVR at post-treatment week 12 (SVR12).
Patients were 75% IL28B non-CC and 11% had cirrhosis. SVR rates (HCV RNA <LLOQ) at post-treatment week 12 or later (imputed to include patients missing SVR12 assessments but had SVR after post-treatment week 12) were 82% (67/82) with DCV plus pegIFN/RBV vs 43% (18/42) with pegIFN/RBV (p <0.0001).In DCV recipients, SVR12 rates were comparable across subgroups. The safety and tolerability profile of DCV plus pegIFN/RBV was comparable to that of pegIFN/RBV. Discontinuations due to AEs occurred in 4.9% of patients receiving DCV plus pegIFN/RBV and 7.1% of patients receiving pegIFN/RBV.
In treatment-naive patients with HCV GT4 infection, DCV plus pegIFN/RBV achieved higher SVR12 rates than pegIFN/RBV alone. These data support DCV-based regimens for treatment of HCV GT4 infection, including all-oral combinations with other direct-acting antivirals. (AI444-042; ClinicalTrials.gov NCT01448044).
[Show abstract][Hide abstract] ABSTRACT: Antiviral treatment of hepatitis B virus (HBV) cirrhosis using entecavir or tenofovir suppresses replication of HBV and can reverse liver insufficiency in some cases, which might imply delisting. After liver transplantation, combination HBV prophylaxis with lowdose hepatitis B immune globulin and antivirals effectively prevents HBV recurrence in >90 % of transplant recipients. Some forms of prevention of HBV recurrence should be continued indefinitely post-transplant, but in patients with a low risk of recurrence (i.e., HBV DNA levels undetectable pre-transplant), discontinuation of hepatitis B immune globulin (HBIG) is possible if patients are treated with long-term nucleos(t)ide(s) analogue( s) therapy. A more cautious approach is necessary for patients with high pre-transplant HBV replication, patients with HIV or hepatitis D virus coinfection or preexisting HBV drug resistance, those with a high risk of hepatocellular carcinoma recurrence, and those at risk of noncompliance with antiviral therapy. In this group, HBIG-free prophylaxis cannot be recommended.
[Show abstract][Hide abstract] ABSTRACT: Few studies have investigated infections in human immunodeficiency virus (HIV)-infected liver transplant patients. The aim of this study was to describe the prevalence, time of onset, mortality of infectious complications, other than hepatitis C virus (HCV), and to identify risk factors for their development in a large single- center cohort of HIV-infected liver transplant patients.
We studied 109 consecutive HIV-infected patients who underwent liver transplantation (LT) between 1999 and 2010 and followed until December 2012.
The median age was 44 years (interquartile range [IQR] 41-49), 82.6% were male, and the median follow-up was 45.7 months (IQR 14-65). The major indications for LT were HCV cirrhosis (61%) and hepatocellular carcinoma (19%). Forty patients (37%) developed at least 1 infection during the first year after LT. Twenty-eight (26%) patients had an episode of bacteremia. Five (4.6%) patients developed a cytomegalovirus infection. Fungal infections occurred in 5 (4.5%) patients. Four (3.6%) patients developed an HIV-related opportunistic infection. A total of 43 (39.4%) patients died during follow-up. Mortality related to infection occurred in 9 (7%) cases, and 20 (42.5%) patients died because of the HCV recurrence. No patients died from opportunistic infections. Model for end-stage liver disease (MELD) score >17 was associated with a 2-fold higher risk (hazard ratio 1.96; 95% confidence interval 1.01-3.80) of developing infectious complications.
Infections are not a major cause of mortality after LT in HIV patients and opportunistic infections of acquired immunodeficiency syndrome are infrequent. A MELD score >17 increased the risk of developing post-LT infectious complications. Recurrence of HCV infection remains a major cause of mortality. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: The prognosis of hepatocellular carcinoma (HCC) is hampered by frequent tumour recurrence and metastases. Epithelial-Mesenchymal Transition (EMT) is now recognized as a key process in tumour invasion, metastasis and the generation of cancer initiating cells. The morphological identification of EMT in tumour samples from the expression of novel mesenchymal markers could provide relevant prognostic information and aid in understanding the metastatic process.
The expression of Smooth Muscle Actins was studied using immunofluorescence and immunohistochemistry assays in cultured liver cells during an induced EMT process and in liver specimens from adult and paediatric HCC series.
We report here that in HCC cell lines treated with TGF-β and in HCC specimens, the expression of αSMA, a known mesenchymal marker of EMT, could never be detected. In addition, our in vitro studies identified the enteric form of SMA, γSMA, as being a marker of EMT. Moreover, this SMA isoform was expressed in 46% of 58 tumours from 42 adult HCC patients and in 90% of 16 tumours from 12 paediatric HCC patients. Interestingly, this expression was significantly correlated with poor tumour differentiation and progenitor cell features characterized by the expression of EpCAM and K19.
Taken together, our results support the conclusion that γSMA expression in HCC is strongly correlated with the EMT process, HCC aggressiveness and the identification of cancer stem cells. This correlation suggests that γSMA represents a novel and powerful marker to predict HCC progression.
PLoS ONE 06/2015; 10(6):e0130559. DOI:10.1371/journal.pone.0130559 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antiviral therapy using newer nucleos(t)ide analogues with lower resistance rates, such as entecavir or tenofovir, suppress hepatitis B virus (HBV) replication, improve liver function in patients with compensated or decompensated cirrhosis, and delay or obviate the need for liver transplantation in some patients. After liver transplantation, the combination of long-term antiviral and low-dose hepatitis B Immune globulin (HBIG) can effectively prevent HBV recurrence in greater than 90% of transplant recipients. Some forms of HBV prophylaxis need to be continued indefinitely after transplantation but, in patients with a low-risk of HBV recurrence (i.e., HBV DNA levels undetectable before transplantation), it is possible to discontinue HBIG and maintain only long-term nucleos(t)ide analogue(s) therapy. A more cautious approach is necessary for those patients with high pretransplant HBV DNA levels, those with limited antiviral options if HBV recurrence occurs (i.e., HIV or hepatitis D virus coinfection, preexisting drug resistance), those with a high risk of hepatocellular carcinoma recurrence, and those at risk of noncompliance with antiviral therapy. In this group, HBIG-free prophylaxis cannot be recommended.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0.
[Show abstract][Hide abstract] ABSTRACT: Chronic hepatitis C virus (HCV) infection causes severe liver disease in HIV-infected patients and liver transplant recipients. The impact of serum and immunoglobulin on viral entry was analysed in these patients.
Sera from 60 anti-HCV positive patients, including 30 who were also anti-HIV positive, were tested with HCVpp from different genotypes (1a, 1b, 3 and 4) and with HCVcc (H77/JFH1). Seventeen HIV-seropositive and 13 HIV-seronegative patients with decompensated liver disease were studied before and after liver transplant.
Serum neutralization was markedly lower after liver transplant and in HIV patients than in mono-infected immune-competent individuals. This effect was due to low antibody-mediated neutralization. In HIV patients, low neutralization was correlated with low lymphocyte T CD4 cell counts and the severity of liver disease. To characterize neutralization, we tested HCVpp lacking hypervariable region (HVR1) and SR-BI receptor cholesterol transfer inhibition by BLT-4. These experiments showed that neutralization was strongly dependent on the HVR1 and the SR-BI receptor. HVR1 sequences showed that selective pressures were low in immune-compromised patients and highly correlated to HCV neutralization after liver transplant. Neutralization experiments were reproduced with HCV strain JFH1.
Serum neutralization in HIV-coinfected patients and HCV-infected liver transplant recipients is poor enhancing HCV entry through HVR1/SR-BI interplay. This may contribute to the severity of hepatitis C in these settings.
AIDS 06/2015; 29(9):1025-1033. DOI:10.1097/QAD.0000000000000651 · 5.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Management of portal inflow to the graft in patients with spontaneous splenorenal shunts (SRS) is a matter of concern especially in case of large varices (more than 1 cm). In case of portal vein (PV) thrombosis (PVT), renoportal anastomosis (RPA) directly diverts the splanchnic and renal venous blood assuring a good portal inflow to the graft. Disconnection of the portacaval shunt by left renal vein ligation (LRVL) is another option but requires a patent PV. The indication of primary RPA rather than LRVL in patients with small native PV, especially in case of large graft, should be questioned in these complex cases of liver transplantation.
From 1998 to 2012, 17 patients with RPA and 15 patients with LRVL were transplanted in our center. We compared these 2 techniques for short- and long-term results.
The rate of preliver transplantation PVT (76% vs 27%) and graft weight (1538 ± 383 g vs 1293 ± 216 g) was significantly higher in the RPA group. Renoportal anastomosis was performed in 4 cases of small but patent PV. Three-month mortality, morbidity, and massive ascitis were similar. No patient was retransplanted. One year after transplantation, PV diameter was still larger in RPA group. Three-year survival was similar (RPA: 79% vs LRVL: 53%, P = 0.1).
In cirrhotic patients transplanted with large splenorenal shunts, RPA and LRVL reach similar survivals. In case of complete PVT and failure of thrombectomy, the RPA offers satisfactory long-term results.