Camille Besch

Multicentre experience using daclatasvir and sofosbuvir to treat hepatitis C recurrence – The ANRS CUPILT study

BACKGROUND & AIMS HCV recurrence remains a major issue in the liver transplant field, as it has a negative impact on both graft and patient survival. The purpose of this study was to investigate the efficacy and safety of treating HCV recurrence with sofosbuvir (SOF) and daclatasvir (DCV) combination therapy. METHODS From October 2013 to March 2015, 559 liver recipients were enrolled in the prospective multicentre France REcherche Nord&Sud Sida-hiv Hépatites (ANRS) Compassionate use of Protease Inhibitors in viral C Liver Transplantation cohort. We selected 137 patients with an HCV recurrence receiving SOF and DCV, whatever the genotype or fibrosis stage. The use of ribavirin and the duration of therapy were at the investigators discretion. The primary efficacy end point was a sustained virological response (SVR) 12weeks after the end of treatment. RESULTS The SVR rate 12weeks after completing treatment was 96% under the intention-to treat analysis and 99% when excluding non-virological failures. Only two patients experienced a virological failure. The serious adverse event (SAE) rate reached 17.5%. Four patients (3%) stopped their treatment prematurely because of SAEs. Anaemia was the most common AE, with significantly more cases in the ribavirin group (56% vs. 18%; p<0.0001). A slight but significant reduction in creatinine clearance was reported. No clinically relevant drug-drug interactions were noted, but 52% of patients required a change to the dosage of immunosuppressive drugs. CONCLUSIONS Treatment with SOF plus DCV was associated with a high SVR12 and low rates of serious adverse events among liver recipients with HCV recurrence. LAY SUMMARY The recurrence of hepatitis C used to be the first cause of graft failure in infected liver transplanted recipients. Our study demonstrates the great efficacy of one combination of new all-oral direct-acting antiviral, sofosbuvir and daclatasvir, to treat the recurrence of hepatitis C on the graft. Ninety-six per cent of recipients were cured. The safety profile of this combination seemed to be good, especially no relevant drug-drug interaction with immunosuppressive drugs.

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.

Liver transplantation in critically ill patients: Preoperative predictive factors of post-transplant mortality to avoid futility

The allocation of liver transplants to patients with acute liver failure (ALF) and acute‐on‐chronic liver failure (ACLF) with multi‐organ failure who are admitted in ICU remains controversial due to their high post‐transplant mortality rate and the absence of identified mortality risk factors.

Acute Liver Failure/injury Related to Drug Reaction With Eosinophilia and Systemic Symptoms: Outcomes and Prognostic Factors

Background Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare severe adverse drug-induced reaction with multiorgan involvement. The outcome and prediction of those patients who develop severe acute liver injury (sALI) or acute liver failure (ALF) remain little known. Methods A multicenter retrospective study of patients admitted with a diagnosis of DRESS-related sALI or ALF. Histological review was performed on liver core biopsies from native livers. Results Sixteen patients (11 women, 5 men; mean age, 39±17.2 years) were classified as having definite (n=13) or probable (n=3) DRESS. At admission, 3 patients had hepatic encephalopathy; median levels of prothrombin time, INR, and total bilirubin were, respectively, 33% (Q1-Q3, 21-41), 2.74 (1.98-4.50), and 94 &mgr;mol/L (Q1-Q3, 39.5-243.5). Nine patients received corticosteroid therapy. Overall, 9 patients improved spontaneously and 7 worsened (liver transplantation [LT] (n=5), deceased (n=2)). Transplantation-free and post-LT survival was 56% and 60%, respectively. After LT, DRESS recurrence was observed in 3 of 5 patients. Systemic corticosteroid therapy was not significantly associated with a clinical improvement. In the multivariate analysis, factor V level less than 40% at day 0 and factor V levels of 40% or greater at admission but decreasing at day 2 were associated with worse outcome. Pathological findings (n=7) revealed atypical lymphoid infiltrates, Kupffer cell hyperplasia with erythrophagocytosis, and an inconstant presence of eosinophils. Conclusions The spontaneous prognosis of patients with sALI/ALF due to DRESS is poor and was not improved by corticosteroid therapy. Histology is helpful to establish diagnosis. Dynamic variables regarding factor V values are predictive of a poor outcome.

12 Weeks of a Ribavirin‐Free Sofosbuvir and Nonstructural Protein 5A Inhibitor Regimen Is Enough to Treat Recurrence of Hepatitis C After Liver Transplantation

Sofosbuvir (SOF) combined with nonstructural protein 5A (NS5A) inhibitors has demonstrated its efficacy in treating a recurrence of hepatitis C virus (HCV) after liver transplantation (LT). However, the duration of treatment and need for ribavirin (RBV) remain unclear in this population. Our aim was to determine whether LT recipients could be treated with an SOF + NS5A inhibitor‐based regimen without RBV for 12 weeks post‐LT. Between October 2013 and December 2015, 699 LT recipients experiencing an HCV recurrence were enrolled in the multicenter ANRS CO23 CUPILT cohort. We selected patients receiving SOF and NS5A inhibitor ± RBV and followed for at least 12 weeks after treatment discontinuation. The primary efficacy endpoint was a sustained virological response 12 weeks after the end of treatment (SVR12). Among these 699 patients, 512 fulfilled the inclusion criteria. Their main characteristics were: 70.1% genotype 1, 18.2% genotype 3, 21.1% cirrhosis, and 34.4% previously treated patients. We identified four groups of patients according to their treatment and duration: SOF + NS5A without RBV for 12 (156 patients) or 24 (239 patients) weeks; SOF + NS5A + RBV for 12 (47 patients) or 24 (70 patients) weeks. SVR12 values reached 94.9%, 97.9%, 95.7%, and 92.9%, respectively (P = 0.14). Only 20 patients experienced a treatment failure. Under multivariate analysis, factors such as fibrosis stage, previous treatment, HCV genotype, and baseline HCV viral load did not influence SVR12 rates in the four groups (P = 0.21). Hematological adverse events (AEs) were more common in the RBV group: anemia (P < 0.0001) and blood transfusion (P = 0.0001). Conclusion: SOF + NS5A inhibitors without RBV for 12 weeks constituted reliable therapy for recurrent HCV post‐LT with an excellent SVR12 whatever the fibrosis stage, HCV genotype, and previous HCV treatment. (Hepatology 2018; 00:000‐000).

Safety of sofosbuvir-based regimens after liver transplantation: longitudinal assessment of renal function in the prospective ANRS CO23 CUPILT study

In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir‐based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable.

Impact of real-time metabolomics in liver transplantation: Graft evaluation and donor-recipient matching

BACKGROUND & AIMS There is an emerging need to assess the metabolic state of liver allografts especially in the novel setting of machine perfusion preservation and donor in cardiac death (DCD) grafts. High-resolution magic-angle-spinning nuclear magnetic resonance (HR-MAS-NMR) could be a useful tool in this setting as it can extemporaneously provide untargeted metabolic profiling. The purpose of this study was to evaluate the potential value of HR-MAS-NMR metabolomic analysis of back-table biopsies for the prediction of early allograft dysfunction (EAD) and donor-recipient matching. METHOD The metabolic profiles of back-table biopsies obtained by HR-MAS-NMR, were compared according to the presence of EAD using partial least squares discriminant analysis. Network analysis was used to identify metabolites which changed significantly. The profiles were compared to native livers to identify metabolites for donor-recipient matching. RESULTS The metabolic profiles were significantly different in grafts that caused EAD compared to those that did not. The constructed model can be used to predict the graft outcome with excellent accuracy. The metabolites showing the most significant differences were lactate level >8.3 mmol/g and phosphocholine content >0.646 mmol/g, which were significantly associated with graft dysfunction with an excellent accuracy (AUROClactates = 0.906; AUROCphosphocholine = 0.816). Native livers from patients with sarcopenia had low lactate and glycerophosphocholine content. In patients with sarcopenia, the risk of EAD was significantly higher when transplanting a graft with a high-risk graft metabolic score. CONCLUSION This study underlines the cost of metabolic adaptation, identifying lactate and choline-derived metabolites as predictors of poor graft function in both native livers and liver grafts. HR-MAS-NMR seems a valid technique to evaluate graft quality and the consequences of cold ischemia on the graft. It could be used to assess the efficiency of graft resuscitation on machine perfusion in future studies. LAY SUMMARY Real-time metabolomic profiles of human grafts during back-table can accurately predict graft dysfunction. High lactate and phosphocholine content are highly predictive of graft dysfunction whereas low lactate and phosphocholine content characterize patients with sarcopenia. In these patients, the cost of metabolic adaptation may explain the poor outcomes.

Hepatocellular Carcinoma Spreading Through the Round Ligament

A 70-year-old man with a previous past medical history significant for alcoholic cirrhosis was referred to our unit for the treatment of multifocal hepatocellular carcinoma (HCC). An abdominal magnetic resonance imaging (MRI) showed five nodules of HCC ranging from 2 to 5 cm in diameter involving the right and left liver lobes. Biologic data and clinical status classed the patients as Child-Pugh A 6. There was minimal portal hypertension with grade 1 oesophageal varices, no previous history of liver decompensation and serum alphafetoprotein was elevated at 50 μg/l (normal values < 13 μg/ l). After multidisciplinary discussion, the patient was treated by sequential (right-liver first) transarterial chemoembolization (TACE) in order to downstage HCC. Following TACE, alpha-fetoprotein dropped within normal values and MRI showed complete tumoral necrosis. The patient was then followed up radiologically and clinically in outpatient clinic and liver transplantation (LT) work-up was considered after 1 year of clinical remission. Fourteen months after TACE, serum alpha-fetoprotein level increased to 56μg/l and abdominal MRI showed a non hypervascularized recurrent noudule 1, 5 cm in size in the segment 4 inferior close to the segmental portal pedicle and 4, 5 cm exophytic nodule under the left liver lobe (Fig. 1). The abdominal examination found a round, mobile nodule on the epigastrium. Complete work-up did not found any recurrence into the chest and bone. In order to rule out the presence of a peritoneal implant, the patient underwent explorative laparoscopy which found HCC spreading through the round ligament (RL). The RL was excised and pathology confirmed HCC diffusion through the RL (Fig. 2). The patient was delisted from LT and treated by sorafenib®. The round ligament of the liver connects the umbilical portion of the left portal vein to the umbilicus. RL is a fibrous cord which originates from the involution of the umbilical vein which transfers oxygenated blood from the placenta into the growing foetus. Under increased intrahepatic pressures the round ligament reopens allowing a wide communication between the portal and systemic circulation such as seen in cirrhotic patients with portal hypertension. Tumoral spreading through the RL and umbilical metastases represents rare manifestations of digestive cancers. Spreading to the umbilicus can arise from cutaneous lymphatics by retrograde lymphatic flow, by direct peritoneal implantation from the anterior peritoneal surface and by arterial embolization from distant sites. The final localization of tumoral disease at the umbilicus is known as the sister Mary Joseph’s nodule. However because of his vascular structure, the RL can also be the source of tumoral diffusion directly from the liver. HCC has an elevated propensity toward diffusion through portal system into the same liver segment and toward the main portal branches. In the presence of portal hypertension and reopened umbilical vein, HCC invading a segmental branch of the umbilical left portal vein can spread through the RL such as in the present case. Considering the RL as a major branch of the portal system, invasion form HCC should be considered such as macrovascular invasion and precludes the performance of LT. * Pietro Addeo pietroad@hotmail.com

Interleukin 6 at reperfusion: A potent predictor of hepatic and extrahepatic early complications after liver transplantation

Ischemia‐reperfusion injury impacts early liver graft function. Interleukin 6 (IL‐6) as early as at reperfusion has shown to predict in‐hospital complications, but its impact on vascular complications and long‐term outcomes is not ascertained.

Direct-acting antiviral agent-based regimen for HCV recurrence after combined liver-kidney transplantation: Results from the ANRS CO23 CUPILT study

Hepatitis C virus (HCV) infection is associated with reduced patient survival following combined liver‐kidney transplantation (LKT). The aim of this study was to assess the efficacy and safety of second‐generation direct‐acting antivirals (DAAs) in this difficult‐to‐treat population. The ANRS CO23 “Compassionate use of Protease Inhibitors in Viral C Liver Transplantation” (CUPILT) study is a prospective cohort including transplant recipients with recurrent HCV infection treated with DAAs. The present work focused on recipients with recurrent infection following LKT. The study population included 23 patients. All patients received at least one NS5B inhibitor (sofosbuvir) in their antiviral regimen an average of 90 months after LKT. Ninety‐six percent of recipients achieved a sustained virological response (SVR) at week 12 (SVR12). In terms of tolerance, 39% of recipients presented with at least one serious adverse event. None of the patients experienced acute rejection during therapy and there were no deaths during follow‐up. The glomerular filtration rate (GFR) decreased significantly from baseline to the end of therapy. However, this study did not show that the decline in GFR persisted over time or that it was directly related to DAAs. The DAA‐based regimen is well tolerated with excellent results in terms of efficacy. It will become the gold standard for the treatment of recurrent HCV following LKT.