Direct-acting antivirals and hepatocellular carcinoma in chronic hepatitis C: A few lights and many shadows

With the introduction of direct-acting antiviral agents (DAA), the rate of sustained virological response (SVR) in the treatment of hepatitis C virus (HCV) has radically improved to over 95%. Robust scientific evidence supports a beneficial role of SVR after interferon therapy in the progression of cirrhosis, resulting in a decreased incidence of hepatocellular carcinoma (HCC). However, a debate on the impact of DAAs on the development of HCC is ongoing. This review aimed to analyse the scientific literature regarding the risk of HCC in terms of its recurrence and occurrence after the use of DAAs to eradicate HCV infection. Among 11 studies examining HCC occurrence, the de novo incidence rate ranged from 0 to 7.4% (maximum follow-up: 18 mo). Among 18 studies regarding HCC recurrence, the rate ranged from 0 to 54.4% (maximum "not well-defined" followup: 32 mo). This review highlights the major difficulties in interpreting data and reconciling the results of the included studies. These difficulties include heterogeneous cohorts, potential misclassifications of HCC prior to DAA therapy, the absence of an adequate control group, short follow-up times and different kinds of follow-up. Moreover, no clinical feature-based scoring system accounts for the molecular characteristics and pathobiology of the tumours. Nonetheless, this review does not suggest that there is a higher rate of de novo HCC occurrence or recurrence after DAA therapy in patients with previous HCV infection. \ua9 2018 The Author(s). Published by Baishideng Publishing Group Inc. All rights reserved

From current status to optimization of HCV treatment: Recommendations from an expert panel

Chronic hepatitis C virus (HCV) infection is a major public health problem at a global level, causing an enormous burden of hepatic and extra-hepatic morbidity and mortality. Treatment of chronic HCV (CHC) has been revolutionized in the last few years by the introduction of highly effective and well tolerated direct acting antiviral agents (DAAs) able to achieve >90% rates of sustained virological response (SVR) in many groups of patients, including those previously excluded from interferon-based regimens. For such reason interferon-free regimens are now the treatments of choice for all patients. Successful anti-HCV treatment can stop liver disease progression and can solve the HCV-related extra hepatic manifestations, eventually reducing both liver-related and overall mortality. Together with the rapidly accumulating data about the evolution of treatment landscape, different guidelines from national and international Liver Scientific Societies have been published until today. However, these recommendations may not be applied worldwide as, due to high treatment costs, most of them identify as priority groups only patients with advanced liver disease. Moreover some types of patients pose clinical management problems for which even the guidelines do not always provide useful answers. With the aim of treatment optimization by filling some of the gaps of the current guidelines and addressing the remaining unmet needs in practice, a group of Italian experts, experienced on treatment of HCV infection, met in Stresa in February 2016. The summary of all the considerations arising from this two-day meeting and the final statements are reported in this position paper

Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues

BACKGROUND & AIMS: In patients with chronic hepatitis B virus (HBV) infection, persistent exposure to high concentrations of antigen can disrupt T-cell functions. It is not clear to what extent long-term suppression of HBV by nucleos(t)ide analogues can restore antiviral T-cell functions. We compared HBV-specific T-cell responses of patients treated with nucleos(t)ide analogues with those detected in other conditions of HBV control. METHODS: We analyzed intracellular levels of interferon gamma, interleukin-2, and tumor necrosis factor α in HBV-specific T cells after 10 days of stimulation with peptides covering the overall HBV genotype D sequence and ex vivo with selected CD8 epitopes and the corresponding HLA-A2 dextramers. Findings from patients treated with nucleos(t)ide analogues who had complete (HBV DNA negative/antibody to hepatitis B surface antigen positive) or partial (HBV DNA negative/hepatitis B surface antigen positive) control of their infections were compared with those of patients with spontaneous or interferon alfa-induced resolution of acute or chronic infections, inactive HBV carriers, or untreated hepatitis B e antigen-negative patients with chronic infections. RESULTS: Although HBV-specific T cells from nucleos(t)ide analogue-treated patients with complete control of infection were dysfunctional ex vivo, they had efficient responses after in vitro expansion. These responses were comparable to those of patients who spontaneously resolved acute HBV infection. Nucleos(t)ide analogue-treated patients who were HBV DNA negative but hepatitis B surface antigen positive had lower levels of T-cell responses but responses greater than those of untreated patients with chronic infection. CONCLUSIONS: In vitro reactivity can be restored to T cells from patients with suppressed HBV infection following long-term treatment with nucleos(t)ide analogues, despite prolonged exposure to large loads of antigen. Immune therapies that increase the antiviral T-cell response might increase the likelihood of complete HBV control in patients undergoing long-term nucleos(t)ide analogue treatment. © 2012 AGA Institute

Reinfusion of highly purified CD133+ bone marrow-derived stem/progenitor cells in patients with end-stage liver disease: A phase I clinical trial

Background: Bone marrow stem/progenitor cells seem to be effective in liver regeneration after tissueinjury. Aim: To evaluate the feasibility and safety of the mobilization and reinfusion of CD133+stem/progenitorcells in patients with end-stage liver disease.Methods: Autologous CD133+stem/progenitor cells, mobilized with granulocyte-colony stimulating fac-tor, were collected by leukapheresis and reinfused at increasing doses through the hepatic artery startingfrom 5 × 104/kg up to 1 × 106/kg.Results: 16 subjects with Model for End-stage Liver Disease (MELD) score between 17 and 25 wereenrolled, 14 mobilized an adequate number of CD133+stem/progenitor cells and 12 were reinfused.No severe adverse events related to the procedure were reported. MELD score significantly worsenedduring mobilization in Child Turcotte Pugh-C patients. A significant improvement of liver function wasobserved 2 months after reinfusion (MELD 19.5 vs 16; P = 0.045). Overall, 5 patients underwent livertransplantation within 12 months from reinfusion and 2 died because of progressive liver failure.Conclusions: CD133+stem/progenitor cells reinfusion in patients with end-stage liver disease is feasi-ble and safe. A worsening of liver function was observed during mobilization in Child Turcotte Pugh-Cpatients. The temporary improvement of MELD score after reinfusion suggests that stem cells therapymay be a “bridge to transplant” approach for these patients

Treatment of Hepatitis C virus infection in Italy: A consensus report from an expert panel

Hepatitis C virus (HCV) infection remains one of the main causes of chronic liver disease worldwide. The advent of direct-acting antivirals (DAAs) has significantly improved the course of patients with chronic HCV infection (CHC), due to the ability of these drugs to achieve high rates of sustained virological response (SVR). These exceedingly high rates of SVR and the excellent safety data have been confirmed in real life practice. Evolving guidelines have been issued by national and international scientific societies in accordance with the progression of clinical knowledge and the availability of new DAAs. These recommendations, however, may not be applied universally because of delays in drugs reimbursability in different countries and because some National Health Systems identify only patients with advanced disease as a treatment priority. Italy in this regard is a prototype about DAAs treatment of CHC patients. With the aim to assess the Italian treatment experience with DAAs and to respond to unmet needs in treatment optimization of antiviral therapy in specific settings of CHC patients, a group of Italian experts met in Stresa in February 2017. The summary of the considerations arising from this two-day meeting and some statements regarding a few open issues are reported in this position paper

Recurrence of hepatocellular carcinoma after direct acting antiviral treatment for hepatitis C virus infection: Literature review and risk analysis

Although studies suggest decreased incident hepatocellular carcinoma (HCC) after treatment with direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection, data are conflicting regarding risk and aggressiveness of recurrence in patients who have a history of treated HCC. This review analyses data available in literature in order to elucidate the impact of DAAs on the risk of HCC recurrence after successful treatment of the tumor. Overall 24 papers were identified. The available data cannot be considered definitive, but the initial alarmist data indicating an increased risk of recurrence have not been confirmed by most subsequent studies. The suggested aggressive pattern (rapid growth and vascular invasion) of tumor recurrence after DAAs still remains to be confirmed. Several limitations of the available studies were highlighted, and should drive future researches. The time-to-recurrence should be computed since the last HCC treatment and results stratified for cirrhosis and sustained viral response. Any comparison with historical series is of limited interest because of a number of biases affecting these studies and differences between enrolled patients. Prospective intention-to-treat analyses will be probably the best contribution to drive clinical practice, provided that a randomized trial can be difficult to design

AISF position paper on HCV in immunocompromised patients

This report summarizes the clinical features and the indications for treating HCV infection in immunocompromised and transplanted patients in the Direct Acting Antiviral drugs era

Étonnante physique

International audienceDiscipline multimillénaire, la physique explore l’espace et le temps. De l’immensité des amas de galaxies à l’infinie petitesse des particules élémentaires, des échelles humaines – du mètre au centimètre – jusqu’au nanomonde, de l’extrême brièveté du mouvement de l’électron jusqu’au fond des âges d’où nous parviennent les premières lumières de l’Univers : les domaines couverts par cette discipline n’ont pas fini de nous étonner.Cette science est celle de l’expérimentation méthodique qui met au point des instruments originaux pour observer la matière, inerte ou vivante, en laboratoire ou à distance. Celle qui pose encore de grandes questions fondamentales. Mais aussi celle qui accompagne notre vie quotidienne avec ses développements dans les domaines des matériaux, de la santé, de l’énergie, du climat…Pour montrer toute sa richesse, cet ouvrage réunit 70 contributions de physiciennes et de physiciens récemment récompensés par une médaille du CNRS pour l’originalité et l’importance de leurs travaux. Abondamment illustré, accessible à tout amateur de science, Étonnante Physique lève un voile sur les recherches les plus actuelles

Étonnante physique

International audienceDiscipline multimillénaire, la physique explore l’espace et le temps. De l’immensité des amas de galaxies à l’infinie petitesse des particules élémentaires, des échelles humaines – du mètre au centimètre – jusqu’au nanomonde, de l’extrême brièveté du mouvement de l’électron jusqu’au fond des âges d’où nous parviennent les premières lumières de l’Univers : les domaines couverts par cette discipline n’ont pas fini de nous étonner.Cette science est celle de l’expérimentation méthodique qui met au point des instruments originaux pour observer la matière, inerte ou vivante, en laboratoire ou à distance. Celle qui pose encore de grandes questions fondamentales. Mais aussi celle qui accompagne notre vie quotidienne avec ses développements dans les domaines des matériaux, de la santé, de l’énergie, du climat…Pour montrer toute sa richesse, cet ouvrage réunit 70 contributions de physiciennes et de physiciens récemment récompensés par une médaille du CNRS pour l’originalité et l’importance de leurs travaux. Abondamment illustré, accessible à tout amateur de science, Étonnante Physique lève un voile sur les recherches les plus actuelles