Search

Ivan Gentile,1 Antonio Riccardo Buonomo,1 Emanuela Zappulo,1 Giuseppina Minei,1 Filomena Morisco,2 Francesco Borrelli,1 Nicola Coppola,3 Guglielmo Borgia1 1Section of Infectious Diseases, 2Section of Gastroenterology, Department of Clinical Medicine and Surgery, University of Naples Federico II, 3Section of Infectious Diseases, Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy Abstract: According to the World Health Organization, approximately 150 million people worldwide are chronic carriers of hepatitis C virus (HCV). HCV infection can evolve into cirrhosis of the liver and its complications, which are ultimately responsible for more than 350,000 deaths every year. Antiviral therapy, when successful, is able to decrease the rate of progression and increase survival. Two types of therapies are currently available, ie, interferon-based therapies and interferon-free ones. The latter have several advantages in terms of safety and tolerability, and could be used even in the most advanced stages of the disease. However, their use is restricted to some viral genotypes (genotype 2 and 3) and they are expensive. Several molecules are in an advanced phase of development. This review deals with the pharmacokinetics, pharmacodynamics, tolerability, and safety of asunaprevir, an inhibitor of HCV nonstructural 3 protease. Asunaprevir exerts optimal in vitro activity particularly against HCV genotypes 1 and 4, and its pharmacokinetic profile enables twice daily administration. The drawback of asunaprevir, and of all protease inhibitors, is its low barrier to resistance. Consequently, it is used in association with other drugs to prevent resistance. Specifically, when combined with daclatasvir, an NS5A inhibitor, asunaprevir results in a very high rate of viral eradication in both treatment-naïve and treatment-experienced patients, with a sustained virological response rate of 80%–90%. Tolerability is fair; in fact, asunaprevir is associated with a transient increase in aminotransferase levels, which is mild in most cases. In conclusion, asunaprevir is a good candidate component of interferon-free combinations and may revolutionize the treatment of chronic HCV infection in the near future. Keywords: NS3, interferon, ribavirin, interferon-free, daclatasvir, sofosbuvir

Clinically significant portal hypertension (CSPH) in patients with advanced chronic liver disease (ACLD) is high-risk condition for liver-related events (LRE). According with BAVENO VII, non-invasive tests (NIT) should be preferred to rule in or out for CSPH to avoid endoscopy. The novel score HVPG-3Parameters gave a prediction of HVPG showing good accuracy in CSPH prediction. Aim is to evaluate the ability of HVPG-3P in PH and LRE prediction. A retrospective study was conducted in two different Italian centers: University of Naples and University of Marche. In 10 years, consecutive compensated-ACLD patients who underwent upper-GI endoscopy for PH assessment were enrolled. NIT (FIB-4,ANTICIPATE,PLT/spleen-diameter ratio and HVPG-3P) were calculated. During the follow-up any LRE were recorded. Two-hundred and ninety-one ACLD subjects (with no differences between centers) were recruited (62.1% males, mean age 60 years). Mean LSM was 23.6±11.7kPa; HVPG-3P was 13.3±2.0mmHg, ANTICIPATE was 1.0±1.6, FIB-4 was 5.0±3.2, platelets/spleen-diameter ratio was 906.5±568.2. One-hundred and forty-two (48,9%) subjects showed PH endoscopic signs. They had higher LSM (26.6±12.4vs20.8±10.3kPa, p=0.00002), HVPG-3P (14.2±1.6vs12.4±2.0mmHg, p<0.001), ANTICIPATE (1.66±1.4vs0.31±1.5, p<0.001), FIB-4 (5.87±3.28vs4.13±2.84, p=0.001) and lower platelets/spleen-diameter ratio (652.4±323.6vs1148.6±641.8, p<0.0001) compared to subjects without PH endoscopic signs. During a median follow-up of 41.5months (IQR 17.8-74.0) LRE occurred in a median of 18.9months (IQR 7.5-37) in 126/291 (43.2%). Patients who experienced LRE showed higher LSM (26.0±12.3 vs21.9±11.0kPa, p=0.003), HVPG-3P (14.1±1.7vs12.6±2.0mmHg, p<0.0001), ANTICIPATE (1.54±1.57vs0.55±1.56, p<0.0001), FIB-4 (6.02±3.36vs4.19±2.79, p<0.0001) and lower platelets/spleen-diameter ratio (694.9±385.7vs1068.0±630.0, p<0.0001). The HVPG-3P seems to have a good performance in PH and LRE prediction (considering the results from Random Forest model: MDA 4.52 and 6.55, higher than the majority of variables). HVPG-3P is a simple tool for non-invasive prediction of PH and could be used to stratify the risk of LRE in patients with ACLD. However, this score needs to be validated in larger cohorts. [ABSTRACT FROM AUTHOR]

Background and aims: Retreatment with a combination of α interferon (IFN) plus ribavirin of patients with chronic hepatitis C who did not respond to IFN monotherapy has not been assessed [...]

The efficacy of systemic therapy for unresectable advanced hepatocellular carcinoma (aHCC) has not been proven in patients with Child-Pugh (C-P) B cirrhosis. Nevertheless, in real-world these patients are treated with tyrosine-kinase inhibitors (TKIs) since their toxicity is similar to that observed in C-P A patients and, off-label, with Metronomic Capecitabine (MC) in patients not amenable to TKIs. This study aimed to compare Sorafenib and MC's outcomes versus best supportive care (BSC) in C-P B-HCC patients. Between 2008 and 2020, among 774 consecutive C-P B patients with aHCC not amenable/responding to locoregional treatments extracted from the ITA.LI.CA database, 410 underwent Sorafenib, 62 MC, and 302 BSC. The propensity score matching method was used to correct the baseline unbalanced prognostic factors, with a 1:1 allocation of Sorafenib vs BSC, MC vs BSC, and Sorafenib vs MC patients, and Kaplan-Meier method and Log-rank test were used to define overall survival (OS) and differences. in the unmatched population median OS (95% CI) was 9.9 (8.3-11.4) months in Sorafenib, 8.0 (0.4-15.7) months in MC, and 3.9 (3.1-4.8) months in BSC-treated patients (p<0.001 for Sorafenib vs BSC and for MC vs BSC; p=0.812 for Sorafenib vs MC). In Sorafenib vs BSC-matched patients (135 couples) median OS was 7.3 (4.8-9.7) vs 3.9 (2.6-5.2) months (p<0.001). Independent predictors of survival were ECOG-Performance Status >1 [HR: 1.61 (1.22-2.13)], tumour size [HR: 1.04 (1.01-1.07)] macrovascular invasion [HR: 1.48 (1.12-1.96)], AFP >400 ng/mL [HR: 1.52 (1.14-2.04)], treatment-naïve [HR: 1.54 (1.15-2.07)] and Sorafenib [HR: 0.51 (0.38-0.68)]. In MC vs BSC matched patients (40 couples) median OS was 9.0 (0.2-17.8) vs 3.0 (2.2-3.8) months (p<0.001). In Sorafenib vs MC-matched patients (55 couples) the median OS did not differ (p=0.283). C-P B patients with aHCC undergoing BSC have poor survival. Both Sorafenib and MC treatment improve their prognosis. [ABSTRACT FROM AUTHOR]

In Italy, the prevalence of HDV infection in HBsAg carriers is about 9.9% (6.4% in Italian natives and 26.4% in immigrants). However, the actual prevalence is probably underestimated because the anti-HDV test is not performed routinely in all HBsAg carriers. The HDV causes a rapidly progressive liver disease and as new antiviral therapies are coming, it is fundamental to known the exact HDV prevalence. The aim of this study was to assess the real HDV prevalence in the AOU Federico II. From April 2021 to July 2022, reflex test for the detection of total HDV antibodies was performed in all HBsAg positive subjects observed at AOU Federico II. Demographic, clinical and laboratory data were collected. Liver fibrosis was evaluated with FIB-4. Sera were evaluated with ADVIA Centaur HBsAgII Qualitative, Liaison Murex HBsAg Quantitative and Liaison Murex Total Anti-HDV Qualitative. Of 365 HBsAg carriers, 46 (12.6%) resulted positive for total anti-HDV. The majority of them (89.2%) were Italian natives and only 5 (10.8%) of them were immigrants. Twenty-one (45.6%) were males with a median age of 62.2 years. Thirty-five (76%) patients were already aware of HBV/HDV coinfection. HDV-RNA was performed in 18 (39.1%) subjects and resulted detectable in 15 (83.3%) of them, with a median HDV-RNA level of 84.300 [25th – 75th percentiles: 1.685-547.796] IU/ml. Twenty (43.5%) anti-HDV positive subjects had advanced liver fibrosis. Our data showed that the HDV prevalence is higher than expected, demonstrating that the reflex test in HBsAg carriers could be a useful approach to identify the real prevalence of HDV infection. Moreover, the HDV-RNA is performed only in the minority of the anti-HDV positive subjects. In this setting, due to the forthcoming approval of specific anti-HDV drugs, a reflex test for HDV-RNA should be implemented to identify viremic patients needing antiviral treatment. [ABSTRACT FROM AUTHOR]

Introduction: All types of local ablation therapy (TACE, TAE, PEI, RFA, MCT, etc) produce necrosis of hepatocellular carcinomas (HCC) but the size and pattern of necrosis and possible prognostic significance [...]

Background It is unclear whether the efficacy and long-term outcome of treating patients with hepatitis C virus (HCV)-positive cirrhosis with the new protease inhibitors will extend to those with Child C cirrhosis. Aim To assess the effectiveness of the interferon-free regimens in Child C cirrhotic patients with HCV infection. Methods A systematic Medline search was conducted to retrieve studies describing the treatment of Child C patients with direct-acting agents. Citations from identified studies were cross-referenced and abstracts from European Association for the Study of the Liver ( EASL) and American Association for the Study of Liver Disease ( AASLD) meetings were checked. Extracted data were evaluated using a meta-analysis to calculate a weighted response rate. Results Seven full-text records and two conference abstracts were retained for analysis from the 649 records identified. Data from an Italian real-life trial were also interrogated. Information on treatment outcome was available for 228 of the 240 Child C patients evaluated in the 10 trials. Overall, the weighted mean sustained virological response (SVR12) was 74.9% (95% CI: 65.6-82.4%). Neither duration of treatment (24 or 12 weeks), nor addition of ribavirin influenced these rates. The weighted SVR12 was 65.4% (95% CI: 46.8-80.2) after sofosbuvir/simeprevir, 76.0% (95% CI: 54.4-89.3%) after sofosbuvir/daclatasvir and 83.0% (95% CI: 73.4-89.6) after sofosbuvir/ledipasvir. Some studies did not provide information on the rate of post-treatment relapse or functional improvement. However, in those studies that did provide such data, a relapse was documented in 12.1% of patients and an improvement of ≥2 points on the model for end-stage liver disease ( MELD) score in 61.1% of patients. Conclusion The improvement in MELD scores strongly suggests HCV-positive patients with Child C cirrhosis should be treated with these agents. [ABSTRACT FROM AUTHOR]

Emerging reports suggest a relationship between thyroid hormones (TH) signalling pathways and liver diseases, including hepatocellular carcinoma (HCC). Although it has been proven that the expression of deiodinases type 1 and 3 (D1-3) changes during induced liver injury, their role is still poorly understood in hepatocarcinogenesis. We aimed to evaluate the role of deiodinases and their regulation in liver carcinogenesis. This is a proof of knowledge introductory to an ongoing monocentric prospective study. We enrolled 19 patients underwent liver surgery for HCC (10 cases) or for other non-neoplastic liver diseases in non-cirrhotic context (9 controls). We evaluated genes and protein expression of the main TH metabolism factors (D1, Monocarboxylate transporter-MCT8, Thyroid receptors-TR alpha and beta and Kruppel-like factor-KLF-9), with RT-PCR and Western blot analysis in HCC, cirrhotic tissue and healthy liver samples. RT -PCR analysis showed a progressive statistically significant decrease of D1 (p=0.004), MCT-8 (p=0.001) and TRα (p=0.02) mRNA expression from healthy liver to HCC. The expression of KLF9, involved in cell differentiation and proliferation, decreased accordingly (p=0.03). Western Blot analysis showed a decreased expression of D1 protein in all cirrhotic samples (p=0.01), while D3 increased in 50% of HCC (p=0.02). Among HCC patients, D3 expression was associated with more severe liver stiffness (32 kPa, IQR:23.47-35.5, p=0.002) and high BMI (p=0.004). A statistically significant overall survival (OS) difference between D3 positive and D3 negative HCC patients was observed (log rank p=0.003), with a median OS of 17.9 (IQR:15.5-18.7) months for D3 positive vs 41.3 (IQR:35.1-43.8) months in D3 negative. Furthermore, a shorter Progression Free Survival and an increased recurrence rate was observed in D3 positive patients, even if not statistically significant. These preliminary data showed that D3 expression could define a more severe phenotype of HCC and it could be used in clinical practice as negative prognostic biomarker. [ABSTRACT FROM AUTHOR]

Several studies showed that patients with liver cirrhosis have an immune dysregulation leading to poor immunological response to vaccination. However, in literature there are few data about the response to SARS-CoV-2 vaccination in patients with chronic liver disease (CLD). Aims of the study are (is) the evaluation of safety and immunogenicity of booster dose in patients with CLD. From September 2021 to April 2022, all consecutive outpatients with CLD who completed the primary vaccination course and the booster dose for anti-SARS-CoV-2 vaccination were enrolled. Blood samples were collected 12-16 weeks after second dose and after booster dose. Collected samples were analyzed for detecting anti-Spike protein IgG using LIAISON TrimericS IgG chemiluminescent assay (Diasorin, Italy). We enrolled 340 patients (187 Males, mean age:64.32±17.34years). Stratified by the presence of cirrhosis, 249 had CLD and 91 were cirrhotic whose 57 (62.24%) had portal hypertension. At the end of the primary vaccination course, 60 patients (17.65%) did not develop a protective antibody titer, with no statistically significant differences between the two groups (19.7% in cirrhotic vs 16.8% in non-cirrhotic; p=0.076). The majority of them (53/60 patients; 88.3%) developed a protective titer after booster dose, without differences between cirrhotics and non-cirrhotics (p=0.089). At multivariate analysis, factors associated with a higher humoral response after booster dose were young age (p=0.0098); porto-sinusoidal vascular disorder (p=0.005), none or a single comorbidity rather than two or more (p=0.05) and Spikevax booster dose compared with Comirnaty (p=0.001). Moreover, the antibody titer is inversely related to age (p=0.000). In a large cohort of patients with CLD booster dose of anti-Sars-CoV-2 vaccine has an excellent immunogenicity and leads to an adequate antibody response even in those who had not produced a protective titer after the primary vaccination course. Cirrhosis is not associated with a reduced humoral response. [ABSTRACT FROM AUTHOR]

Osteoporosis is a complication of chronic liver disease, with impact on morbidity, quality of life, and survival. The progress of medicine and the new therapies stretched the disease's natural history and improved the survival of patients with liver disease. So, it is fundamental to make better the quality of life and to prevent complications. Metabolic bone disorders are common complications of chronic liver disease (CLD). Patients with CLD have an increased risk of bone fractures, with significant impact on morbidity, quality of life, and even on survival. Bone diseases, including osteomalacia, osteoporosis, and osteopenia, are frequently observed in many types of liver disease. The pathogenesis of damage and the mechanisms of bone loss are different in relation to the specific liver disease. The relevance of these conditions induced many authors to create a new nosographic entity known as 'hepatic osteodystrophy', although this term is rarely used anymore and it is now commonly referred to as osteopenia or osteoporosis associated with chronic liver disease. This review is based on the personal experiences of the authors and upon research done of the available literature on this subject matter. The authors searched the PubMed database for publications containing the term 'liver disease' in combination with 'bone disease', 'hepatic osteodistrophy', 'osteoporosis', 'osteopenia', 'osteomalacia', and 'fractures'. They selected publications from the past 10 years but did not exclude older seminal publications, especially for colestatic liver diseases. This review of literature shows that osteoporosis crosses all CLD. It is important to underline that the progress of medicine and the new therapies stretched the disease's natural history and improved the survival of patients with CLD. It is fundamental to make better the quality of life and it is mandatory to prevent complications and in particular the osteoporotic ones, especially fractures. [ABSTRACT FROM AUTHOR]

Background: Although liver transplantation (LT) for hepatocellular carcinoma (HCC) can be curative a 25% recurrence by 5 years is limiting. Aim: Evaluate predictive factors for HCC recurrence after LT. Patients [...]

Introduction: Older age is not considered a contraindication for liver transplantation, but age related morbidity may be a cause of mortality. Aim: To evaluate survival and the incidence of main [...]

Abstract: Aim of this study was to investigate the anti-HBs antibody persistence and immune memory to hepatitis B virus in adult celiacs vaccinated as adolescents and the effect of a booster administration in non-protected individuals. Eleven years after primary vaccination, the proportion of vaccinees with titres ≥10mIU/ml and antibody geometric mean concentrations (GMCs) were lower among celiac patients than among controls (68.6% vs 91.7%, p <0.01; GMCs 29.38mIU/ml vs 250.6mIU/ml, p <0.001). Participants with anti-HBs below 10mIU/ml received a booster dose and were retested 2 weeks later to assess the anamnestic response. Post-booster anti-HBs levels were still <10mIU/ml in 71.4% celiacs and 25% controls (p <0.01). Our findings indicate that the prevalence of seroprotective levels of anti-HBs detected eleven years after primary immunization as well as the frequency of response to a booster dose of vaccine are lower in celiac patients compared to healthy controls. [ABSTRACT FROM AUTHOR]

Abstract: Background: Hepatitis C virus (HCV) infection is often clinically silent in haemodialysed (HD) patients and their immune response may modulate liver damage in HCV infection. IL-10 and TGF-β1 could play a role in this setting as, IL-10 down-regulates hepatic fibrosis, while TGF-β1 is a pro-fibrotic cytokine. Aim: To evaluate the role of IL-10 and TGF-β1 in HD/HCV+ patients. Patients: 71 HD/HCV+ patients (58 with normal [HD/HCV-N] and 13 with high serum transaminases [HD/HCV-H]), 40 non-uremic patients with chronic hepatitis C (HCV+), 56 HD anti-HCV− patients and 20 healthy volunteers (H). Methods: IL-10 and TGF-β1 serum levels were assessed using ELISA tests. Liver histology was assessed by Ishak''s score. Results: IL-10 serum levels were significantly higher in HD patients, both HCV+ (3.7±0.4pg/ml; p <0.01) and HCV− (3.8±0.8pg/ml; p <0.05) than in non-uremic HCV patients (2.3±0.4pg/ml). Among the HD/HCV+ patients, IL-10 serum levels were similar in HD/HCV-N and in HD/HCV-H patients. Among the HD/HCV+ patients, IL-10 serum levels were similar in those with moderate histological damage compared to those with mild damage. TGF-β1 serum levels were significantly lower in HD patients, both HCV+ (4.6±0.9ng/ml) and HCV− (6.0±0.9ng/ml) than in non-uremic HCV+ patients (8.1±1.1ng/ml; p <0.001 and p <0.01, respectively), but similar to the values found in H (5.3±0.9ng/ml; p =n.s.). No correlation was seen between IL-10 and TGF-β1 serum levels in any of the groups considered. Conclusions: Patients on haemodialysis treatment to have high levels of IL-10, which remain high even when patients are anti-HCV+, whereas the opposite is true of TGF-β1. The cytokine pattern observed in HD patients is compatible with the hypothesis explaining the relatively benign evolution of HCV-related liver disease in HD patients, and has a pathophysiological role. [Copyright &y& Elsevier]