Long-term outcomes of direct acting antivirals in post-transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis.

Long-term functional outcomes of sofosbuvir-based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post-transplant hepatitis C virus (HCV) recurrence. Seventy-three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24-week sofosbuvir with ribavirin±pegylated interferon or interferon-free sofosbuvir-based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82-112) weeks. Twelve of 73 (16.4%) died (10 non-FCH, 2 FCH) and two underwent re-LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non-FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow-up, MELD and Child-Turcotte-Pugh scores improved both in non-FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short-treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long-term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child-Turcotte-Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals-based treatments for severe post-transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long-term survival. The setting of severe HCV recurrence may require the identification of "too-sick-to-treat patients" to avoid futile treatments.

Defining the biology of intrahepatic cholangiocarcinoma: molecular pathways and early detection of precursor lesions.

Intrahepatic cholangiocarcinoma (ICC) is a rare malignant tumor of the biliary tract with growing incidence and dismal prognosis. It is responsible for 10-20% of primary liver cancer worldwide, but early diagnosis is still a challenge and few treatment options are available. Aim of this review is to summarize the current knowledge about biological features and arising molecular patterns of this disease. The identification of emerging biomarkers and early detection of precursor lesions shall play a key role in the perspective of future tailored targeted therapies.

Treatment of patients with chronic hepatitis C infection in Lombardia: a report by the Lombardia Hepatitis Network.

The arrival of potent directly acting antivirals (DAAs) for the treatment of chronic Hepatitis C virus (HCV) infection was a challenge for the regional health system of the Lombardia Region. Lombardia represents roughly 8% of the Italian territory but includes nearly 16% of the Italian population. In 2014, nearly 37,600 HCV patients were routinely followed-up in liver centers across the region; nearly 16,000 were classified as having advanced fibrosis or cirrhosis (Metavir F3-F4). The creation of a regional network was necessary to ensure uniformity in treatment access and treatment management. The first database analysis of the Lombardia Hepatitis Network was conducted in January 2016, and included data on 2432 patients who had received treatment from December 2014 to December 2015. The most prevalent HCV genotypes were HCV-1 found in 63% and HCV-3 found in 17%. Overall 90.4% patients achieved an SVR, SVR rates were 92.9% in HCV-1, 89.3% in HCV-2, 81.1% in HCV-3 and 88.9% in HCV-4.

Impact of eradicating hepatitis C virus on the work productivity of chronic hepatitis C (CH-C) patients: an economic model from five European countries.

CH-C negatively affects work productivity (WP), creating a large economic burden. The aim of this study was to model the impact of sustained virologic response (SVR) on WP in CHC genotype 1 (GT1) patients in five European countries (EU5). Work Productivity and Activity Index-Specific Health Problem questionnaire was administered to patients across the ION clinical trials (n = 629 European patients). The analysis modelled a population of GT1 CHC patients over one year, who had been either not treated or treated with LDV/SOF. Sensitivity analyses assessed the possibility that CHC patients' labour costs were lower than the general population's and presented results by fibrosis stage. Before initiation of treatment, EU patients with CHC GT1 exhibited absenteeism and presenteeism impairments of 3.54% and 9.12%, respectively. About 91.8% of EU patients in the ION trials achieved SVR and improved absenteeism and presenteeism impairments by 16.3% and 19.5%, respectively. Monetizing these data, treatment with LDV/SOF resulted in an annual productivity gain of €435 million and a weighted average per-employed patient (PEP) gain of €900 in the EU5. PEP gains from treatment are projected to be higher in cirrhotic than in noncirrhotic patients. If CHC patients are assumed to earn 20% less than the general population, gains of €348 million (€720 PEP) annually are projected. CHC results in a significant economic burden to European society. Due to improvements in WP, SVR with treatment could provide substantial economic gains, partly offsetting the direct costs related to its widespread use.

Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis.

BACKGROUND: Sorafenib has shown survival benefits in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A liver function. There are few prospective data on sorafenib in patients with HCC and CP class B. PATIENTS AND METHODS: A consecutive prospective series of 300 patients with CP class A or B HCC were enrolled in a dual-phase trial to determine survival and safety data according to liver function (class A or B) in patients receiving oral sorafenib 800 mg daily. [Results of this study were presented in part at the ASCO 2012 Gastrointestinal Cancers Symposium, 19-21 January 2012. J Clin Oncol 2012; 30 (Suppl 4): abstract 306.] RESULTS: Overall progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 3.9, 4.1 and 9.1 months, respectively. For patients with CP class A versus B status, PFS was 4.3 versus 2.1 months, TTP was 4.2 versus 3.8 months and OS was 10.0 versus 3. 8 months. Extrahepatic spread was associated with worse outcomes but taken together with CP class, liver function played a greater role in reducing survival. Adverse events for the two CP groups were similar. CONCLUSION: Although patients with HCC and CP class B liver function have poorer outcomes than those with CP class A function, data suggest that patients with CP class B liver function can tolerate treatment and may still benefit from sorafenib.

Folate in gastrointestinal health and disease.

OBJECTIVE: Folate has heterogeneous functions and is involved in several activities in both animal and human body. It is an important constituent of our organism, and its bioavailability is mainly dependent from the correct function of our gastrointestinal tract. Our aim is to describe what happens to folate homeostasis in gastrointestinal health and disease, analyzing the alterations of folate metabolism in some specific conditions of intestinal and liver impairment. DISCUSSION: Folate absorption and metabolization involve the small intestine and the liver; in conditions of gastrointestinal tract disease (i.e. celiac disease, liver disease) folate function may be compromised with important consequences on the whole organism. Moreover, folate deficiency may produce gastrointestinal alterations too. For this reason, the gastrointestinal tract could be the responsible but also the victim of folate deficiency. CONCLUSIONS: The presence of folate deficiency should always be assessed in patients with a gastrointestinal disease. Further studies are needed to assess the role of folates in gastrointestinal tract diseases and in other gynecologic, neurologic, psychiatric, cardiovascular, ophthalmic and neoplastic diseases. Folates supplementation could be considered, in the future, as an effective complimentary therapy in several pathologic conditions.

Comparison of peginterferon pharmacokinetic and pharmacodynamic profiles.

The pharmacokinetics and in dosing regimens of the currently available pegylated interferon (peginterferon) alfa molecules differ greatly, depending on the size and nature of their polyethylene glycol (PEG) moiety. Peginterferon alfa-2a has a branched 40 kDa PEG chain covalently attached to lysine residues and circulates as an intact molecule. On the other hand, peginterferon alfa-2b has a linear 12 kDa PEG chain covalently attached to interferon-a-2b via an unstable urethane bond that is hydrolysed after injection, releasing native interferon alfa-2b. The difference in pegylation between the two peginterferons has a significant impact on their pharmacokinetic properties. Data from comparative and non-comparative studies indicate that peginterferon alfa-2b has a shorter half-life in serum than peginterferon alfa-2a, and a significant proportion of patients receiving peginterferon alfa-2b may have trough concentrations below the limit of detection during the latter part of the 7-day dosing schedule. However, the pharmacodynamic parameters of the two drugs appear to be similar.

An infrequent cause of colonic stenosis.

We present the case of a young woman with intestinal endometriosis, in which colonic stenosis unusually represents the clinical onset; diagnostic workup allows to highlight the role of gastrointestinal ultrasounds that suggest the nature of the stenosis.

Viral kinetics during the first weeks of pegylated interferon and ribavirin treatment can identify patients at risk of relapse after its discontinuation: new strategies for such patients?

BACKGROUND: Pegylated interferon (PEG-IFN) and ribavirin is the most effective treatment for chronic hepatitis C virus (HCV) hepatitis, but the rate of sustained virological response (SVR) remains approximately 50%, and 15-20% of all treated patients have a virological relapse after completing the treatment. Studies on the SVR have failed to discriminate between non-responders and relapsers. AIMS: To identify the risk factors for relapse among patients with an end-of-treatment response (ETR). METHODS: We retrospectively analyzed 281 patients consecutively treated with PEG-IFN and ribavirin with a follow-up period of at least 24 weeks. The baseline details collected on each patient included demographic data, histological features, and biochemical profiles. RESULTS: Forty-six patients (16.4%) relapsed during the first 6 months of follow-up after discontinuing the therapy. Relapser patients were significantly older, had more steatosis, fibrosis, and showed significantly lower rapid virological response (RVR) rates compared with SVR patients. By logistic regression analysis, only the absence of RVR was found to be significantly associated with relapses in both subgroups of patients with genotypes 1 and 4 (p < 0.004) and those with genotypes 2 and 3 (p < 0.006). Severe fibrosis was also predictive of relapsing disease, but only for genotypes 2 and 3 patients (p < 0.003). During the treatment, serum HCV-RNA decreased more rapidly in patients with SVR compared to non-responder and relapser patients (p < 0.001). Interestingly, relapser patients exhibited an intermediate serum HCV-RNA decay during the first 4 weeks of therapy. CONCLUSION: Among HCV patients treated with PEG-IFN and ribavirin, the absence of RVR was the most important independent predictor of relapse, independent of the HCV genotype. In the subgroup of genotypes 2 and 3 patients, the severity of fibrosis was also an important factor associated with the relapse rate.

Management of hepatitis C virus infection recurrence after liver transplantation: an overview.

Hepatitis C virus (HCV) infection is the major indication for liver transplantation worldwide. Its recurrence is virtually universal. Once reinfection is established, progression to cirrhosis occurs in 25%-30% of recipients within 5 years. Several studies have attempted to identify the ideal antiviral treatment for liver transplant recipients. At present, the management of recurrent HCV infection in liver transplant recipients is based on widely accepted indications, which represent a reliable guide to identify the "ideal" candidate for therapy, when therapy should be started, and what is to be expected in terms of side effects and response to treatment.

The use of molecular assays in the management of viral hepatitis.

Molecular assays are instrumental in the clinical management of viral hepatitis. During the past years, a wide variety of molecular assays have been developed and implemented. This considerably improved the understanding of the natural history and pathogenesis of Hepatitis B virus (HBV), Hepatitis C virus (HCV) or Hepatitis delta virus (HDV) hepatitis, but also caused uncertainties in the selection of the most appropriate assays for clinical requirements. Indeed, a rational choice and application of these assays requires adequate knowledge of the performance of the single test. Moreover, the choice of the most accurate assay for patients' needs and physicians' objectives, needs to be oriented to specific contexts, such as diagnosis, management or treatment. In the past, a hurdle in the routine use of assays for hepatitis viruses nucleic acid quantification was represented by the availability of only "home brew" methods which lacked standardization. Major improvement in addressing the use of molecular assays for viral hepatitis has been derived from recent standardization procedures that allowed a comparison between different tests after results were given as International Units. In addition, it should be reminded that, before getting into the market, molecular assays should be approved by European regulation authorities and validated using internationally recognized standards. A subsequent clinical validation should address the diagnostic accuracy of the assay. These proceedings have the aim of identifying which molecular tests, among those currently available, meet clinical requirements for each specific application.

Hepatitis C infection in patients with chronic kidney disease.

The management of hepatitis C virus (HCV)-infected patients with chronic kidney disease (CKD) is complex and represents a particular concern since numerous issues, such as antiviral therapy in dialysis patients and post renal transplant, and prevention of HCV spread within dialysis units, remain unresolved. An enormous body of literature has been published on HCV in the CKD population; however, clinical evidence on important issues is mostly based on uncontrolled clinical trials or retrospective surveys. The aim of this paper is to provide a systematic review of the literature. Responses to the critical issues have been developed by a consensus of experts, endorsed by the Italian Association for the Study of the Liver (AISF) and some clinical recommendations have been added.

Management of hepatocellular carcinoma.

The aim of this review was to assess the correct clinical management of hepatocellular carcinoma (HCC). Following the diagnosis, the correct choice of treatment must take into account both the anatomical/biological features of HCC and the functional status of the underlying cirrhosis. As of today, only the application of the BCLC scoring system, which stratifies patients according to HCC staging and degree of liver disease in a process leading to a specific treatment, has shown the best results in terms of survival.

Combined double lung-liver transplantation for cystic fibrosis without cardio-pulmonary by-pass.

Sequential bilateral single lung-liver transplantation (SBSL-LTx) is a therapeutic option for patients with end stage lung and liver disease (ESLLD) due to cystic fibrosis (CF). A few cases have been reported, all of them were performed with the use of cardio-pulmonary by-pass (CPB). We performed SBSL-LTx in three young men affected by CF. All the recipients had respiratory failure and portal hypertension with hypersplenism. Along with lung transplants, two patients received a whole liver graft and one an extended right graft from an in situ split liver. During transplantation neither CPB nor veno-venous by-pass (VVB) were employed. Immunosuppression was based on basiliximab, tacrolimus, steroids and azathioprine. The three recipients are alive with a median follow-up of 670 days (range 244-1,533). Combined SBSL-LTx is a complex but effective procedure for the treatment of ESLLD due to CF, not necessarily requiring the use of CPB or VVB.

Prophylaxis and treatment of hepatitis B in immunocompromised patients.

The literature on hepatitis B virus (HBV) in immunocompromised patients is heterogeneous and referred mainly to the pre-antivirals era. Today a rational approach to the problem of hepatitis B in these patients provides for: (a) the evaluation of HBV markers and of liver condition in all subjects starting immunosuppressive therapies (baseline), (b) the treatment with antivirals (therapy) of active carriers, (c) the pre-emptive use of antivirals (prophylaxis) in inactive carriers, especially if they are undergoing immunosuppressive therapies judged to be at high risk, (d) the biochemical and hepatitis B surface antigen (HBsAg) monitoring (or universal prophylaxis, in case of high risk immunosuppression) in subjects with markers of previous contact with HBV (HBsAg negative and anti-HBc positive), in order to prevent reverse seroconversion. Moreover it is suggested a strict adherence to criteria of allocation based on the virological characteristics of both recipients and donors in the general setting of transplants and in liver transplantation the universal prophylaxis with nucleos(t)ides analogues (frequently combined with specific anti-HBV immunoglobulins) in HBsAg positive candidates and in HBsAg negative recipients of anti-HBc positive grafts.

Cyclosporin in steroid-resistant autoimmune hepatitis and HCV-related liver diseases.

Cyclosporin has been used for many years in transplantation, and in this field its role is widely documented. However, other fields of application merit to be investigated, including the role of cyclosporin in treating autoimmune hepatitis and its possible role as an antiviral agent in hepatitis C virus (HCV) infections in both immunocompetent patients and in recipients of orthotopic liver transplants. Cyclosporin A has given promising results in small studies, and experience in transplantation and other immunological disorders indicates that its side-effects can be adequately managed. Cyclosporin certainly deserves further clinical investigation for first-line therapy in autoimmune hepatitis. Cyclosporin A suppresses the HCV genome dose-dependently in vitro at clinically relevant concentrations (150-250 ng/mL). The maximum effect is similar to that obtained with IFN alpha, and the effects of these two agents are certainly additive, and possibly synergistic. The inhibitory action of cyclosporin A appears to be independent upon its immunosuppressive action. Analysis of indirect endpoints in clinical trials on cyclosporin A for immunosuppression in transplant recipients indicates that cyclosporin A treatment can delay recurrence of HCV. Small, open label studies suggest that the observed anti-HCV activity of cyclosporin A can be translated into a real clinical benefit; nevertheless, these findings need to be confirmed in randomized, controlled clinical trials.