Patients Treated for HCV Infection and Listed for Liver Transplantation in a French Multicenter Study: What Happens at Five Years?

BACKGROUND: Direct-acting antiviral (DAA) agents for the treatment of hepatitis C virus (HCV) infection have been proven safe and effective in cirrhotic patients awaiting liver transplantation (LT). However, in the long term, data remain minimal regarding the clinical impact of viral eradication on patients listed for decompensated cirrhosis or hepatocellular carcinoma (HCC). We aimed to elucidate the clinical outcomes of patients regarding delisting and the evolution of HCC during the long-term follow-up. METHODS: An observational, multicenter, retrospective analysis was carried out on prospectively collected data from HCV-positive patients treated with an interferon-free regimen while awaiting LT in 18 French hospitals. RESULTS: A total of 179 patients were included in the study. The indication for LT was HCC in 104 (58.1%) patients and cirrhosis in 75 (41.9%) patients. The sustained virological response was 84.4% and the treatment was well tolerated. At five years, among 75 patients with cirrhosis treated for HCV, 19 (25.3%) were delisted following improvement after treatment. Predictive factors for delisting highlighted an absence of ascites, MELD score ≤ 15, and Child-Pugh score ≤ 7. No patients with refractory ascites were delisted. Among patients with HCC, 82 (78.9%) were transplanted. The drop-out rate was low (6.7%) and few recurrences of HCC after LT were observed. CONCLUSIONS: DAAs are safe and effective in patients awaiting LT for cirrhosis or HCC. A quarter of patients with cirrhosis can be delisted because of clinical improvement. Predictive factors for delisting, as a result of improvement, may assist prescribers, before initiating HCV infection therapy in the long-term perspective.

Efficacy and safety of boceprevir-based triple therapy in HCV cirrhotic patients awaiting liver transplantation (ANRS HC29 BOCEPRETRANSPLANT).

BACKGROUND AND AIMS: In this French multicentre, open-label study, we analyzed the efficacy, safety and patient-reported outcomes of a boceprevir-based triple therapy in HCV genotype 1 cirrhotic patients awaiting liver transplantation (LT). METHODS: Patients received PEG-IFN/ribavirin (RBV) for 48 weeks (W) and boceprevir from W4 to W48 or until LT. RESULTS: Fifty-one patients (80% males, median age: 56 years) were included. Fifty-seven percent had hepatocellular carcinoma and 43% end-stage liver disease. At enrolment, the median MELD score was 9 (range: 6-18); the Child-Pugh score was A in 65%, B in 35% and C in 2%. Therapy was discontinued because of severe adverse events (SAEs) in 39% of cases and virological inefficacy in 24%. 16% of patients had undetectable HCV RNA 24 weeks after the end of treatment (SVR24). LT was performed in 18 patients (35%). HCV RNA was undetectable in 16.6% at LT. Seven patients (14%) died and three deaths were attributed to treatment. SAEs (n=129) were observed in 84% of patients. Twenty-four percent of patients developed severe infections. Albumin<35g/L was independently associated with severe infection. Compared with baseline values, a significant decrease (P=0.02) of the physical dimension of health-related quality of life was observed between W4 and W24. The mean (95% CI) number of self-reported symptoms doubled during treatment (from 6.3 [4.8-7.7] to 11.8 [9.3-14.3]; P<0.001). CONCLUSIONS: The safety of the PEG-IFN/RBV/boceprevir combination is poor in patients awaiting LT, with a high risk of severe infection. Moreover, the limited efficacy confirms the indication for IFN-free combinations in these patients.

[Sofosbuvir and daclatasvir combination therapy in hemodialysis patient with liver transplantation]. / Association de sofosbuvir et daclatasvir chez un patient transplanté hépatique traité par hémodialyse.

We report a case of sustained remission of a liver transplant patient infected with hepatitis C virus (HCV) genotype 1 undergoing hemodialysis treatment. Oral treatment regimen of the HCV infection consists of a combination of sofosbuvir 400 mg after each hemodialysis session and daclatasvir 60 mg daily, for a period of 3 months. Laboratory testing indicate that the combination regimen was well-tolerated with no sign of drug-drug interaction. Confirmation of these clinical observations in large clinical studies may help improve morbidity and decrease mortality outcome in patients infected with HCV and undergoing hemodialysis treatment.

Sofosbuvir-based treatment of hepatitis C with severe fibrosis (METAVIR F3/F4) after liver transplantation.

Recurrence of hepatitis C virus (HCV) after liver transplantation (LT) can rapidly lead to liver graft cirrhosis and, therefore, graft failure and retransplantation or death. The aim of the present study was to assess efficacy and tolerance of sofosbuvir (SOF)-based regimens for the treatment of HCV recurrence in patients with severe fibrosis after LT. The Compassionate Use of Protease Inhibitors in Viral C Liver Transplantation (CULPIT) study is a prospective multicenter cohort including patients with HCV recurrence following LT treated with second generation direct antivirals. The present study focused on patients included between October 2013 and November 2014 and diagnosed with HCV recurrence and liver graft extensive fibrosis (METAVIR F3/F4). A SOF-based regimen was administered to 125 patients fulfilling inclusion criteria. The median delay from LT was 95.9 ± 69.6 months. The characteristics of patients were as follows: mean age, 59.4 ± 9.0 years; 78.4% male; infected by HCV genotype 1: 78.2%, mean HCV RNA: 6.1 ± 1.0 log10 IU/mL. Eighty patients had failed previous post-LT antiviral therapy (64.0%) including triple therapy with first generation protease inhibitors in 19 (15.2%) patients. The main combination regimen was SOF/daclatasvir (73.6%). Ribavirin was used in 60 patients. Sustained virological response 12 weeks after treatment was 92.8% (on an intention-to-treat basis); 7 patients with virological failure were observed. Serious adverse events occurred in 25.6% of the patients during antiviral treatment. During antiviral treatment and follow-up, 3 patients were retransplanted and 4 patients died. In conclusion, SOF-based antiviral treatment shows very promising results in patients with HCV recurrence and severe fibrosis after LT. Liver Transplantation 22 1367-1378 2016 AASLD.

Transjugular intrahepatic porto-systemic shunt is a risk factor for liver dysplasia but not hepatocellular carcinoma: a retrospective study of explanted livers.

BACKGROUND: Conflicting data exist regarding the risk for hepatocellular carcinoma after transjugular intrahepatic porto-systemic shunt (TIPS) insertion in cirrhotic patients. METHODS: We retrospectively analysed histopathological data from 214 patients who were transplanted in our Institution including 68 patients who underwent TIPS placement before transplantation. Pathological lesions from explanted livers, including incidental hepatocellular carcinoma, small cell dysplasia and large cell dysplasia were recorded. RESULTS: Pathological lesions were found in 36.4% of explanted livers. TIPS insertion was an independent risk factor for pathological lesion (HR = 2.11, p < 0.05), concurrently with age (HR = 1.10 per year, p < 0.001) and viral aetiology of cirrhosis (HR = 3.05, p < 0.001). When considering the different type of lesions, TIPS insertion was not associated with an increased risk for hepatocellular carcinoma but was an independent risk factor for liver dysplasia (HR = 2.15, p = 0.042). CONCLUSION: Although a direct relationship between TIPS insertion and hepatocellular carcinoma risk was not demonstrated in this study, the increased frequency of liver dysplasia observed in TIPS-bearing explanted livers deserves further prospective investigations with adequate follow-up.

Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: a multicenter experience.

BACKGROUND & AIMS: Protease inhibitors (PI) with peginterferon/ribavirin have significantly improved SVR rates in HCV G1 patients. Their use to treat HCV recurrence after liver transplantation (LT) is a challenge. METHODS: This cohort study included 37 liver transplant recipients (male, 92%, age 57 ± 11 years), treated with boceprevir (n=18) or telaprevir (n=19). The indication for therapy was HCV recurrence (fibrosis stage ≥F2 (n=31, 83%) or fibrosing cholestatic hepatitis (n=6, 16%). RESULTS: Eighteen patients were treatment-naive, five were relapsers and fourteen were non-responders to dual therapy after LT. Twenty-two patients received cyclosporine and fifteen tacrolimus. After 12 weeks of PI therapy, a complete virological response was obtained in 89% of patients treated with boceprevir, and 58% with telaprevir (p=0.06). The end of treatment virological response rate was 72% (13/18) in the boceprevir group and 40% (4/10) in the telaprevir group (p=0.125). A sustained virological response 12 weeks after treatment discontinuation was observed in 20% (1/5) and 71% (5/7) of patients in the telaprevir and boceprevir groups, respectively (p=0.24). Treatment was discontinued in sixteen patients (treatment failures (n=11), adverse events (n=5)). Infections occurred in ten patients (27%), with three fatal outcomes (8%). The most common adverse effect was anemia (n=34, 92%), treated with erythropoietin and/or a ribavirin dose reduction; thirteen patients (35%) received red blood cell transfusions. The cyclosporine dose was reduced by 1.8 ± 1.1-fold and 3.4 ± 1.0-fold with boceprevir and telaprevir, respectively. The tacrolimus dose was reduced by 5.2 ± 1.5-fold with boceprevir and 23.8±18.2-fold with telaprevir. CONCLUSIONS: Our results suggest that triple therapy is effective in LT recipients, particularly those experiencing a severe recurrence. The occurrence of anemia and drug-drug interactions, and the risk of infections require close monitoring.

Assessment of chronic rejection in liver graft recipients receiving immunosuppression with low-dose calcineurin inhibitors.

BACKGROUND & AIMS: Calcineurin inhibitors represent the cornerstone immunosuppressants after liver transplantation despite their side effects. As liver graft is particularly well tolerated, low doses may be proposed. The aim of this study was to assess the prevalence of chronic rejection in patients with low calcineurin inhibitors regimen and to compare their characteristics with patients under standard doses. METHODS: All patients with liver transplantation between 1997 and 2004 were divided into two groups. Low-dose patients (n=57) had tacrolimus baseline levels <5ng/ml or cyclosporine levels <50ng/ml at t0 or <100ng/ml at t+2h and were prospectively proposed a liver biopsy, searching for chronic rejection according to Banff criteria. The remaining patients constituted the standard-doses group (n=40). RESULTS: Among the low-dose group, 36 patients in the low-dose group were assessed by biopsy. No chronic rejection was found. Fifty-six percent had only calcineurin inhibitors and 8% received other immunosuppressants only. The median time between liver transplantation and biopsy was 90 months (64-157) and between IS regimen decrease and biopsy was 41 months (11-115). Liver tests were normal in 72% of the patients. Low-dose patients had more often hepatitis B (p=0.045), less past acute rejection episodes (p=0.028), and better renal function (p=0.040). Decrease of calcineurin inhibitors failed in 15% of standard-dose patients without impacting the graft function. In the low-dose group, co-prescription of other immunosuppressants facilitated the decrease (p=0.051). CONCLUSIONS: The minimization, or even cessation, of calcineurin inhibitors may be an achievable goal in the long term for most of the liver graft recipients.

[Pancreatic tuberculosis: an unusual cause of obstructive jaundice accessible to endoscopic management]. / Tuberculose céphalopancréatique: une cause rare d'ictère obstructif accessible à un traitement conservateur.

Tuberculosis of the pancreas is unusual and often secondary to generalized tuberculosis. In most cases clinical presentation is obstructive jaundice due to pancreatic mass lesion. Although diagnosis is usually obtained after resection of the mass lesion, endoscopic procedures might avoid non-necessary surgical procedure. We report a clinical case of pancreatic tuberculosis diagnosed by endoscopic ultrasound guided fine needle aspiration biopsy and treated by biliary stenting.

Independent prospective multicenter validation of biochemical markers (fibrotest-actitest) for the prediction of liver fibrosis and activity in patients with chronic hepatitis C: the fibropaca study.

OBJECTIVES: Fibrotest (FT) and Actitest (AT) are biochemical markers of fibrosis and activity for use as a non-invasive alternative to liver biopsy in patients with chronic hepatitis C virus (HCV). The aim of this study was to perform an external validation of FT and AT and to study the discordances between FT/AT and liver biopsy in patients with chronic hepatitis C. METHODS: A total of 519 consecutive patients with chronic HCV were prospectively included in five centers, with liver biopsy and biochemical markers taken at the same day. Fifteen patients were excluded because their biopsies could not be interpreted. Diagnostic accuracies were assessed by receiver operating characteristic (ROC) curve analysis. RESULTS: Median biopsy size was 15 mm (range: 2-58), with 9 portal tracts (1-37) and 1 fragment (1-12). 46% (230/504) were classified F2-F4 in fibrosis and 39% A2-A3 in activity. FT area under ROC curve for diagnosis of activity (A2-A3), significant fibrosis (F2-F4), and severe fibrosis (F3-F4) were 0.73 [0.69-0.77], 0.79 [0.75-0.82], and 0.80 [0.76-0.83], respectively. Among the 92 patients (18%) with 2 fibrosis stages of discordance between FT and biopsy, the discordance was attributable to FT in 5% of cases, to biopsy in 4%, and undetermined in 9%. CONCLUSIONS: This prospective independent and multicenter study confirms the diagnostic value of FT and AT found in the princeps study and suggests that FT and AT can be an alternative to biopsy in most patients with chronic HCV.

Accuracy of hyaluronic acid level for predicting liver fibrosis stages in patients with hepatitis C virus.

BACKGROUND: In patients with chronic hepatitis C virus, liver biopsy is the gold standard for assessing liver disease stage; nevertheless, it is prone to complications, some of them serious. Non-invasive methods have been proposed as surrogate markers for liver fibrosis. It was shown that serum hyaluronic acid (HA) level increases with the development for liver fibrosis. The aim of this study was to evaluate the diagnostic value of HA as well as to determine the HA level cut-off for predicting the presence or absence of fibrosis, severe fibrosis, and cirrhosis. RESULTS: 405 patients with chronic hepatitis C were prospectively included with biomarker measurement and liver biopsy done the same day: 151 in the training set (only biopsy lengths of 25 mm or more) and 254 in the validation set. For the discrimination of significant fibrosis, severe fibrosis, and cirrhosis in the training set, the areas under curve (AUCs) were 0.75 +/- 0.03, 0.82 +/- 0.02, and 0.89 +/- 0.03, respectively. Absence of significant fibrosis, severe fibrosis, and cirrhosis can be predicted by HA levels of 16, 25, and 50 microg/l, respectively (with negative predictive values of 82%, 89%, and 100%, in the same order). Presence of significant fibrosis, severe fibrosis, and cirrhosis can be predicted by HA levels of 121, 160, and 237 microg/l, respectively (with positive predictive values of 94%, 100%, and 57%, in the same order). CONCLUSION: In the validation set, HA was accurate in predicting significant fibrosis, severe fibrosis, and cirrhosis with AUCs of 0.73, 0.77, and 0.97, respectively. Moreover, accurate HA level cut-offs were defined for predicting significant fibrosis, severe fibrosis, and cirrhosis. Thus, the study supports that HA level may be clinically useful as a non-invasive marker for liver fibrosis and/or cirrhosis.

Effect of ischemia-reperfusion on Na+, K+-ATPase expression in human liver tissue allograft: image analysis by confocal laser scanning microscopy.

We have analyzed the effect of ischemia-reperfusion on expression of hepatic Na+,K+-ATPase on bile canalicular (BCM) and basolateral membranes (BLM) in human liver allografts using confocal laser scanning microscopy imaging. Na+, K+-ATPase, an integral membrane enzyme, plays a key role in the physiology and structure of hepatocytes, where it maintains the electrochemical gradients for Na+ and K+ across the cell membrane. The concentrations of these ions as well as their gradients regulate the active transport across the plasma membrane for bile acid and water from sinusoidal to canalicular membranes. In addition, Na+,K+-ATPase is also involved in cellular structure because of its close relationship with submembrane microfilaments and its implication in tight junction assembly. Therefore, Na+,K+-ATPase appears as an indicator of tissue viability and hepatic functionality during liver transplantation. Its localization and its function in BCM are still controversial. As in previous studies, we found an enzyme expression in both BLM and BCM. We show that ischemia induced a decrease in Na+,K+-ATPase expression only in BCM. This result could be explained by the differences in biochemical membrane environment between basolateral and bile canalicular Na+,K+-ATPase. Membrane lipid fluidity, which is more elevated in BLM than in BCM, could protect the enzyme during ischemia. After reperfusion, Na+,K+-ATPase expression was strongly decreased in both BCM and BLM. This alteration following reperfusion is probably due to multiple factors: direct alteration of the enzyme catalytic subunit and modification of its environment and membrane lipid fluidity by free radicals and changes in ATP levels and ionic distribution. This important decrease in Na+,K+-ATPase expression of both BLM and BCM could disturb not only hepatic secretory function but also cellular volume and structure during the postoperative period.

The antibody response to hepatitis B virus vaccination is negatively influenced by the hepatitis C virus viral load in patients with chronic hepatitis C: a case-control study.

The purpose of this work was to evaluate in a case-control study the immunogenicity of a recombinant hepatitis B virus (HBV) vaccine in patients with chronic hepatitis C. Seventy-seven patients with histologically proven chronic hepatitis C without cirrhosis were included in a prospective trial and matched for sex and age to 231 healthy adult subjects. Recombinant HBV vaccine was administered at a dose of 20 microg at months 0, 1 and 2. The definition of 'responder to vaccination' was anti-HBs titre > 10 mIU/ml after the three injections. Forty-nine (63.6%) chronic hepatitis C patients were responders to vaccination, compared with 217 (93.9%) controls (P < 0.0001). After the three injections, anti-HBs titres were 156 +/- 260 and 615 +/- 435 mIU/ml (P < 0.0001), respectively. Chronic hepatitis C patients who were non-responders to vaccination had significantly higher viral load than responders to vaccination. Moreover, a negative correlation was observed between viral load and anti-HBs concentration (r = -0.36, P = 0.003). No significant side effects were observed. There was no effect of vaccination on alanine aminotransferase (ALT) levels and hepatitis C virus (HCV) viral load during or after vaccination. In multivariate analysis, the main predictive factors of response to HBV vaccine were absence of anti-HCV antibodies (OR = 7.65, P < 0.0001), weight < 75 kg (OR = 1.99, P < 0.035), and age < 50 years (OR = 1.58, P < 0.082). Our results suggest that viral load seems to negatively influence the response to HBV vaccine.