Severe acute respiratory syndrome coronavirus-2-associated cholangiopathies.

PURPOSE OF REVIEW: SARS-CoV2 is a ß-coronavirus, isolated for the first time in Wuhan in December 2019. Bilateral interstitial pneumonia is the hallmark of this disease. Liver is the second viral target for frequency and AST and ALT elevation is a common finding. From February 2020, two different cholangiopathies have been reported in COVID-19 patients. The aim of this article is to review the cases so far described in order to share information and awareness about these new clinical entities. RECENT FINDINGS: SARS-CoV2 seems to trigger autoimmunity and two cases of primary biliary cholangitis (PBC) have been developed after viral infection while more than 30 patients have showed a rapidly progressing cholangiopathy with features of secondary sclerosing cholangitis (SSC). For what concerns SSC pathogenesis, a theory combining multiple hits is the most recognized. SUMMARY: Two different cholangiopathies have been reported in patients after severe-COVID-19. Attention should be paid to the development of cholestasis in ICU setting but above all after discharge and liver function tests should be, therefore, periodically performed. No treatment strategies are available and liver transplantation remains the last option in individuals with liver failure because of SSC. Other efforts are necessary to better understand the pathogenesis and to expand therapeutic options.

Quality of life in liver transplant recipients during the Corona virus disease 19 pandemic: A multicentre study.

BACKGROUND: Liver transplant recipients require specific clinical and psychosocial attention given their frailty. Main aim of the study was to assess the quality of life after liver transplant during the current pandemic. METHODS: This multicentre study was conducted in clinically stable, liver transplanted patients. Enrollment opened in June and finished in September 2021. Patients completed a survey including lifestyle data, quality of life (Short Form health survey), sport, employment, diet. To examine the correlations, we calculated Pearson coefficients while to compare subgroups, independent samples t-tests and ANOVAs. To detect the predictors of impaired quality of life, we used multivariable logistic regression analysis. RESULTS: We analysed data from 511 patients observing significant associations between quality of life's physical score and both age and adherence to Mediterranean diet (p < .01). A significant negative correlation was observed between mental score and the sedentary activity (p < .05). Female patients scored significantly lower than males in physical and mental score. At multivariate analysis, females were 1.65 times more likely to report impaired physical score than males. Occupation and physical activity presented significant positive relation with quality of life. Adherence to Mediterranean diet was another relevant predictor. Regarding mental score, female patients were 1.78 times more likely to show impaired mental score in comparison with males. Sedentary activity and adherence to Mediterranean diet were further noteworthy predictors. CONCLUSIONS: Females and subjects with sedentary lifestyle or work inactive seem to show the worst quality of life and both physical activity and Mediterranean diet might be helpful to improve it.

Predictors of solid extra-hepatic non-skin cancer in liver transplant recipients and analysis of survival: A long-term follow-up study.

INTRODUCTION AND OBJECTIVES: De novo malignancies represent an important cause of death for liver transplant recipients. Our aim was to analyze predictors of extra-hepatic non-skin cancer (ESNSC) and the impact of ESNSC on the long-term outcome. PATIENTS: We examined data from patients transplanted between 2000 and 2005 and followed-up in five Italian transplant clinics with a retrospective observational cohort study. Cox Regression was performed to identify predictors of ESNSC. A 1:2 cohort sub-study was developed to analyze the impact of ESNSC on 10-year survival. RESULTS: We analyzed data from 367 subjects (median follow-up: 15 years). Patients with ESNSC (n = 47) more often developed post-LT diabetes mellitus (DM) (57.4% versus 35,9%, p = 0.004). At multivariate analysis, post-LT DM independently predicted ESNSC (HR 1.929, CI 1.029-3.616, p = 0.040). Recipients with ESNSC showed a lower 10-year survival than matched controls (46,8% versus 68,1%, p = 0.023). CONCLUSIONS: Post-LT DM seems to be a relevant risk factor for post-LT ESNSC. ESNSC could have a noteworthy impact on the long-term survival of LT recipients.

Combined GS-4774 and Tenofovir Therapy Can Improve HBV-Specific T-Cell Responses in Patients With Chronic Hepatitis.

BACKGROUND & AIMS: One strategy to treat chronic hepatitis B virus (HBV) infection could be to increase the functions of virus-specific T cells. We performed a multicenter phase 2 study to evaluate the safety and efficacy of GS-4774, a yeast-based therapeutic vaccine engineered to express HBV antigens, given with tenofovir disoproxil fumarate (TDF) to untreated patients with chronic HBV infection. METHODS: We performed an open-label study at 34 sites in Canada, Italy, New Zealand, Romania, South Korea, and United States from July 2014 to August 2016. Adults who were positive for HB surface antigen (HBsAg) > 6 months and levels of HBV DNA ≥2000 IU/mL who had not received antiviral treatment for HBV within 3 months of screening were randomly assigned (1:2:2:2) to groups given oral TDF 300 mg daily alone (n = 27; controls) or with 2, 10, or 40 yeast units GS-4774 (n = 168), administered subcutaneously every 4 weeks until week 20 for a total of 6 doses. Blood samples were collected and analyzed and patients received regular physical examinations. Efficacy was measured by decrease in HBsAg from baseline to week 24. Specific responses to HBV (production of interferon gamma [IFNG], tumor necrosis factor [TNF], interleukin 2 [IL2], and degranulation) were measured in T cells derived from 12 HBeAg-negative patients with genotype D infections, after overnight or 10 days of stimulation of peripheral blood mononuclear cells with peptides from the entire HBV proteome. T-regulatory cells were analyzed for frequency and phenotype. Data from studies of immune cells were compared with data on reductions in HBsAg, HBV DNA, and alanine aminotransferase in blood samples from patients. RESULTS: GS-4774 was safe and well tolerated but did not produce significant decreases in levels of HBsAg. Production of IFNG, TNF, and IL2 increased significantly at weeks 24 and 48, compared with baseline, in HBV-specific CD8+ T cells from patients given GS-4774 but not from controls. GS-4774 had greater effects on CD8+ than CD4+ T cells, which were not affected at all or very weakly by TDF with or without GS-4774. GS-4774 did not affect responses of T cells to other viruses tested. HBV core peptides induced the greatest production of IFNG by T cells following overnight stimulation, whereas HBV envelope antigens did not induce a response. Following 10 days of stimulation, production of IFNG and TNF increased with time of exposure to GS-4774; the greatest levels of responses were to HBV envelope antigens followed by core and polymerase peptides. We observed a correlation in patients given GS-4774 between increased T-cell functions and reductions in numbers of T-regulatory cells. CONCLUSIONS: In a phase 2 study of patients with chronic HBV infection given TDF with or without GS-4774, we found that vaccination can increase production of IFNG, TNF, and IL2 by CD8+ T cells exposed to antigenic peptides, with little effect on CD4+ T cells. Although GS-4774 did not reduce levels of HBsAg in patients, its strong immune stimulatory effect on CD8+ T cells might be used in combination with other antiviral agents to boost the antivirus immune response. Clinicaltrials.gov no: NCT02174276.

Serum hepatitis B core-related antigen is an effective tool to categorize patients with HBeAg-negative chronic hepatitis B.

The discrimination between active chronic hepatitis B (CHB) and the clinically quiescent infection (CIB) is not always easy, as a significant portion of patients falls in a "grey" zone. Hepatitis B core-related antigen (HBcrAg) is a now quantifiable serological marker with potential applications in diagnosis and therapy monitoring. The aim of the present study was to evaluate the HBcrAg serum levels in HBeAg-negative HBV infection, and its ability in identifying the clinical profile, in comparison with HBsAg serum levels. HBcrAg was retrospectively assessed on serum samples from a population of treatment-naive HBeAg-negative patients by ChemiLuminescent Enzyme Immunoassay (CLEIA). HBsAg and HBV-DNA data were collected. Serological data were associated to clinical profile, defined in the subsequent follow-up of at least 1 year. In the overall population of 160 HBeAg-negative patients, HBcrAg results weakly correlated with qHBsAg levels (Spearman r = 0.471, P < 0.0001) and correlated closely with HBV-DNA (Spearman r = 0.746, P < 0.0001). HBcrAg levels were significantly higher in 85 CHB patients relative to 75 CIB carriers. A value of 2.5 logU/mL produced the optimal cut-off to identify CIB patients, with diagnostic accuracy comparable to HBsAg levels. In long-term clinical evaluation, a single measurement of HBcrAg at the established cut-off was optimally consistent with clinical outcome. Conversely, the HBsAg cut-off performed well in the true quiescent phase and less in more difficult-to-categorize patients. In conclusion, single-point use of HBcrAg serum levels provides an accurate identification of CIB and represents a useful tool for patient classification.

Worsening of Serum Lipid Profile after Direct Acting Antiviral Treatment.

INTRODUCTION: Host lipid metabolism influences viral replication and lifecycle of hepatitis C virus. Our aim was to evaluate changes in glucose and lipid metabolism of patients with chronic hepatitis C after therapy with direct acting antivirals (DAA). MATERIAL AND METHODS: We considered patients consecutively treated between January and November 2015 recording clinical data at baseline and week 24 of follow-up. Frozen serum samples were used for apolipoprotein A1 (apoA1), apolipoprotein B (apoB) and lipoprotein (a) [Lp(a)]. Wilcoxon test was utilized to estimate trends and Logistic Regression for predictors of lipid changes. RESULTS: We enrolled 100 patients, mostly cirrhotic (81%) and with genotype 1b (59%). Ninety-three patients achieved sustained virological response (SVR), while 7 relapsed. Homeostasis model assessment of insulin resistance declined (from 3 to 2.7, p < 0.001); non-high density lipoprotein (HDL) cholesterol increased from 102 ± 29 to 116 ± 35 (p < 0.001), and Lp(a) from 5.6 ± 6.5 to 9.8 ± 11.5 mg/dL (p < 0.001). Rise of low-density lipoprotein/HDL and apoB/apoA1 ratio were registered (from 1.79 ± 1.10 to 2.08 ± 1.05 and from 0.48 ± 0.18 to 0.53 ± 0.18 mg/dL, p < 0.001). We conducted a subanalysis on patients with relapse. In this subgroup, no change of lipid profile was recorded. At multivariate analysis emerged that the addition of ribavirin to DAA, represented an independent predictor of increased Lp(a) (OR 3.982, 95% CI 1.206-13.144, p = 0.023). CONCLUSION: DAA therapy led to reduction of insulin resistance. In contrast, pro-atherogenic lipid changes were observed in patients with SVR. Further studies will be necessary to evaluate the cardiovascular balance between amelioration of glucose metabolism and negative changes of lipid profile.

Vitamin E for the treatment of E-antigen-positive chronic hepatitis B in paediatric patients: results of a randomized phase 2 controlled study.

BACKGROUND & AIMS: The treatment of chronic hepatitis B infection (CHB) in children is still an area of great uncertainty. Vitamin E is an immunostimulating/antioxidant compound proven to be safe and effective for the treatment of adult CHB. The aim of this phase 2 controlled study was to evaluate the safety and efficacy of vitamin E for the treatment of paediatric HBeAg-positive CHB. METHODS: Forty-six children were randomized in a 1:1 ratio to receive vitamin E at a dose of 15 mg/kg/day (in galenic preparation) or no treatment for 12 months and were monitored for the subsequent 12 months. Clinical, biochemical, haematological and serovirological evaluations were carried out every 3 months. RESULTS: No significant side effects were associated with the vitamin E treatment. At the end of the study, anti-HBe seroconversion was obtained in 7 of 23 (30.4%) of vitamin E-treated versus 1 of 23 (4.3%) of the control patients (P = 0.05), while a virological response (≥2 log decrease in HBV-DNA from baseline) was observed in 9 of 23 (39.1%) vs. 2 of 23 (8.7%) respectively (P = 0.035). CONCLUSIONS: Vitamin E administration for the treatment of paediatric CHB at the tested dosage has no significant side effects and may induce anti-HBe seroconversion. Vitamin E could represent a tool for the treatment of paediatric CHB.

Tenofovir-induced Fanconi syndrome in a patient with chronic hepatitis B monoinfection.

 Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor indicated for treatment of patients with chronic hepatitis B virus (CHB) and human immunodeficiency virus (HIV) infections. Despite the good safety profile of the drug, Fanconi syndrome is a possible adverse reaction of TDF treatment, especially in HIV-infected patients. Only a few cases have been reported in patients with CHB-monoinfections. This report presents a case of a 58-year-old man with mild HBeAg-negative CHB who was exposed to TDF and developed drug-induced Fanconi syndrome. Renal dysfunction reverted after TDF discontinuation and a switch to entecavir, and viral replication remained suppressed. A literature review yielded six additional cases of TDF-induced Fanconi syndrome, all with risk factors for renal dysfunction despite the patients having normal glomerular filtration rates. We discuss the overall risk for Fanconi syndrome in CHB-monoinfected patients exposed to TDF and the importance of careful monitoring of glomerular and tubular functions even when pre-existing kidney disease is not present.

Increase of ribavirin dose improves sustained virological response in HCV-genotype 1 patients with a partial response to peg-interferon and ribavirin.

BACKGROUND AND AIM: In patients with chronic hepatitis C receiving Peg interferon/ribavirin (PEG-IFN/RBV) who do not achieve ≥ 2 log-reduction in HCV-RNA at week 12 (null responders, NR) and in those with ≥ 2 log-decrease but detectable at week 24 (partial responders, PR) the probability to achieve the sustained virological response (SVR) is almost null. The aim of this study was to investigate the efficacy of individualized schedule of progressively increased RBV doses in the setting of PEG-IFN/RBV treatment. MATERIAL AND METHODS: PR or NR to PEG-IFN/RBV instead of discontinuing treatment were enrolled to receive increasing doses of RBV until a target theoretical concentration ([tRBV]) of ≥ 15 µmol/L (by pharmacokinetic formula based on glomerular filtration rate). HCV-RNA was assessed every 4 weeks and, if detectable, RBV dose was gradually increased until negativization. Twelve weeks later, patients with detectable HCV-RNA discontinued therapy while those with undetectable HCV-RNA continued for further 48 weeks. RESULTS: Twenty genotype-1 patients (8 NR and 12 PR) were enrolled. After 12 weeks 9 (45%) were still HCV-RNA positive and were discontinued, while remaining 11 had undetectable HCV-RNA. One stopped treatment for side effects. Ten completed treatment. Five (all PR) achieved SVR. Side effects incidence was similar to that observed during PEG-IFN/RBV. CONCLUSIONS: In conclusion, RBV high doses, according to individualized schedule, increase SVR in PR on a similar extent to that of triple therapy but without increase of side effects. Such treatment should be considered in PR with no access or intolerant to protease inhibitors (PI).

Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B.

BACKGROUND & AIMS: A better understanding of the immunomodulatory effects of PegIFNα therapy could allow more rational optimisation of future therapeutic approaches in chronic HBV infection. In this study, we evaluated dynamic changes in the innate and adaptive arms of the immune system induced by PegIFNα. METHODS: PBMC were obtained from a cohort of patients with eAg-negative CHB before, during and after PegIFNα treatment. The number, phenotype and function of global and virus-specific T cells and NK cells were analyzed by flow cytometry and serum cytokines by ELISA or CBA. RESULTS: The absolute number of CD8 T cells was strikingly reduced on PegIFNα therapy (p<0.001), with a predominant loss of end-stage effectors, including CMV-specific CD8 T cells. There was no significant recovery of the exhausted HBV-specific CD8 T cell response. By contrast, PegIFNα was able to potently and cumulatively drive the proliferation and expansion in absolute numbers of CD56(bright) NK cell numbers (p<0.001), with induction of the pro-proliferative cytokine IL-15. Expanded CD56(bright) NK cells showed enhanced expression of activation markers and the activating receptor NKp46, accompanied by augmentation of TRAIL and IFN-γ expression (p<0.001). Peak virological response (temporal within individual patients and cross-sectional within the cohort) correlated with the degree of expansion of functional CD56(bright) NK cells. CONCLUSIONS: IFN-α mediates divergent effects on the innate and adaptive arms of the immune system in vivo. The efficacy of PegIFNα may be limited by its depleting effect on CD8 T cells; conversely, it can cumulatively drive proliferation, activation and antiviral potential of CD56(bright) NK cells.

Secondary Sclerosing Cholangitis After SARS-CoV2: ICU Ketamine Use or Virus-Specific Biliary Tropism and Injury in the Context of Biliary Ischemia in Critically Ill Patients?

Purpose: From the beginning of the Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV2) pandemic, different cases of a cholangiopathy with features of secondary sclerosing cholangitis in critically ill patients (SSC-CIP) have been reported. Patients developing it are generally recovering from severe Coronavirus disease 19 (COVID-19) and required intensive care unit (ICU) admission and mechanical ventilation. Many of them have been administered with ketamine during their ICU stay. The pathogenesis of this novel disease is still debated, and, since prognosis is poor, efforts are needed in order to better understand it. Patients and Methods: In this review, we focused our attention on COVID-19 SSC clinical, imaging, and histology findings in order to clarify the different pathogenetic options, particularly in regard of the ischemic-direct viral damage and ketamine-related theories, beginning with a recapitulation of SSC-CIP and ketamine-induced cholangiopathy in abusers. The research has been conducted using PubMed and Google Scholar databases. Key-words were "Secondary Sclerosing Cholangiopathy", "SSC-CIP", "Secondary Sclerosing Cholangiopathy in critically ill patients", "Ketamine and cholangiopathy", "Ketamine abusers and liver disease", "Ketamine-related cholangiopathy", "SARS-CoV2 infection and liver disease", "post Covid-19 secondary sclerosing cholangitis", "Covid-19 cholangiopathy". Results: Many authors, based on the clinical, histological, imaging, and prognostic features of the disease, have pointed out the similarities between post COVID-19 SSC and SSC-CIP; however, peculiar features in the former were not previously observed. Therefore, a direct viral cytopathic action and SARS-CoV2-related coagulopathy are considered the most likely causes. On the other hand, ketamine, with the available data, cannot be surely linked as the main determinant cause of cholangiopathy. Moreover, ketamine-induced cholangitis (KIC) presentation is different from post COVID-19 SSC. Its role as a cofactor precipitating the disease cannot be ruled out. Conclusion: Post COVID-19 SSC is a rare clinical entity following severe COVID-19 disease. The most accepted theory is that a sum of different insults determines the disease: biliary ischemia, direct viral damage, toxic bile, possibly worsened by ketamine and hyperinflammation due to the cytokine storm. Given the severe prognosis of the disease, with persistent cholangiopathy, organ failure, and orthotopic liver transplantation (OLT), further study on this novel clinical entity is needed.

Treatment Options for Hepatitis A and E: A Non-Systematic Review.

Hepatitis A and hepatitis E are relatively common causes of liver disease. Both viruses are mainly transmitted through the faecal-oral route and, consequently, most outbreaks occur in countries with poor sanitation. An important role of the immune response as the driver of liver injury is also shared by the two pathogens. For both the hepatitis A (HAV) and hepatitis E (HEV) viruses, the clinical manifestations of infection mainly consist of an acute disease with mild liver injury, which results in clinical and laboratory alterations that are self-limiting in most cases. However, severe acute disease or chronic, long-lasting manifestations may occur in vulnerable patients, such as pregnant women, immunocompromised individuals or those with pre-existing liver disease. Specifically, HAV infection rarely results in fulminant hepatitis, prolonged cholestasis, relapsing hepatitis and possibly autoimmune hepatitis triggered by the viral infection. Less common manifestations of HEV include extrahepatic disease, acute liver failure and chronic HEV infection with persistent viraemia. In this paper, we conduct a non-systematic review of the available literature to provide a comprehensive understanding of the state of the art. Treatment mainly consists of supportive measures, while the available evidence for aetiological treatment and additional agents in severe disease is limited in quantity and quality. However, several therapeutic approaches have been attempted: for HAV infection, corticosteroid therapy has shown outcome improvement, and molecules, such as AZD 1480, zinc chloride and heme oxygenase-1, have demonstrated a reduction in viral replication in vitro. As for HEV infection, therapeutic options mainly rely on the use of ribavirin, and some studies utilising pegylated interferon-alpha have shown conflicting results. While a vaccine for HAV is already available and has led to a significant reduction in the prevalence of the disease, several vaccines for HEV are currently being developed, with some already available in China, showing promising results.

Investigating Acute Hepatitis after SARS-CoV-2 Vaccination or Infection: A Genetic Case Series.

(1) Background: Despite the advantages of COVID-19 vaccination, rare cases of acute hepatitis developing after the administration of the COVID-19 vaccine or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported. The aim of the study is to describe a case series of patients who experienced the onset of acute hepatitis, with or without autoimmune features, following SARS-CoV-2 vaccination or infection and to hypothesize a genetic susceptibility in the pathogenesis. (2) Methods: A group of patients with acute onset hepatitis following SARS-CoV-2 vaccination or infection were evaluated in our hepatology outpatient clinic, where they underwent biochemical and autoimmune tests. Hepatitis A (HAV), B (HBV), and C virus (HCV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human immunodeficiency virus (HIV) infections were excluded. Patients with a diagnosis of autoimmune hepatitis (AIH) or drug-induced liver injury (DILI) underwent HLA typing and histological testing. (3) Results: Five patients experienced new-onset AIH after COVID-19 vaccination, one of which developed mild symptoms after vaccination that strongly worsened during subsequent SARS-CoV-2 infection. One patient had AIH relapse after COVID-19 vaccination while on maintenance immunosuppressive treatment. All of them had HLA DRB1 alleles known to confer susceptibility to AIH (HLA DRB1*03,*07,*13,*14), and in three of them, HLA DRB1*11 was also detected. Two patients developed acute hepatitis without autoimmune hallmarks which resolved spontaneously, both positive for HLA DRB1*11. (4) Conclusions: An association between AIH and COVID-19 vaccine or infection can be hypothesized in individuals with a genetic predisposition. In patients without autoimmune features and spontaneous improvement of hypertransaminasemia, the diagnosis of drug-induced liver injury (DILI) is probable. Further studies are needed to determine the presence of an actual association and identify a possible role of HLA DRB1*11 in the pathogenesis of acute liver injury after SARS-CoV2 vaccination or infection.

Virological Treatment Monitoring for Chronic Hepatitis B.

More than 250 million people worldwide are currently infected with hepatitis B, despite the effectiveness of vaccination and other preventive measures. In terms of treatment, new therapeutic approaches are rapidly developing, promising to achieve the elimination of infected cells and the complete cure of infection. The on-treatment monitoring of these innovative antiviral treatments will require the implementation of new virological tools. Therefore, new biomarkers are being evaluated besides the traditional virological and serological assays in order to obtain information on different steps of the viral replication cycle and to monitor response to therapy more accurately. The purpose of this work is to describe both standard and innovative tools for chronic hepatitis B treatment monitoring, and to analyse their potential and feasibility.

Vitamins in the treatment of chronic viral hepatitis.

Hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related chronic infections represent a major health problem worldwide. Although the efficacy of HBV and HCV treatment has improved, several important problems remain. Current recommended antiviral treatments are associated with considerable expense, adverse effects and poor efficacy in some patients. Thus, several alternative approaches have been attempted. To review the clinical experiences investigating the use of lipid- and water-soluble vitamins in the treatment of HBV- and HCV-related chronic infections, PubMed, the Cochrane Library, MEDLINE and EMBASE were searched for clinical studies on the use of vitamins in the treatment of HBV- and HCV-related hepatitis, alone or in combination with other antiviral options. Different randomised clinical trials and small case series have evaluated the potential virological and/or biochemical effects of several vitamins. The heterogeneous study designs and populations, the small number of patients enrolled, the weakness of endpoints and the different treatment schedules and follow-up periods make the results largely inconclusive. Only well-designed randomised controlled trials with well-selected endpoints will ascertain whether vitamins have any role in chronic viral hepatitis. Until such time, the use of vitamins cannot be recommended as a therapy for patients with chronic hepatitis B or C.

Hepatitis C: clinical management and debated issues.

Hepatitis C virus represents an important global health issue with 71 million of infected people in the word. Direct-acting antivirals are quite new molecules that hit specific Hepatitis C virus proteins useful for viral replication and assembly. Notably, Direct-acting antivirals bring to high sustained virological response rates showing also a great safety profile. This treatment revolution had an impact on transplantation world, in fact the number of liver transplants due to Hepatitis C virus-related cirrhosis and hepatocellular carcinoma is quickly decreasing. Even if this therapy has achieved excellent results in terms of morbility and mortality rates' reduction, there are some debated issues to consider. In the present review the main clinical challenges in every-day management of Hepatitis C virus patients treated with Direct-acting antivirals and the debated effects of viral clearance (metabolic, cardiovascular, immunologic and neoplastic) are discussed. The detection of barriers that can preclude the delivery of Hepatitis C virus care, is the most complex challenge for the scientific community. To obtain the Hepatitis C virus global eradication by 2030, as the World Health Organization has set, will be complex and laborious and will need a further multilevel effort.

Treatments for HBV: A Glimpse into the Future.

The hepatitis B virus is responsible for most of the chronic liver disease and liver cancer worldwide. As actual therapeutic strategies have had little success in eradicating the virus from hepatocytes, and as lifelong treatment is often required, new drugs targeting the various phases of the hepatitis B virus (HBV) lifecycle are currently under investigation. In this review, we provide an overview of potential future treatments for HBV.

Cognitive, neurological and psychiatric disorders occurring in Hepatitis C Virus infection.

Chronic Hepatitis C is associated with many extrahepatic manifestations. Central nervous system is frequently involved, but the pathophysiological mechanisms are not fully understood. Local and systemic inflammation, ischemia, immune-mediated phenomena have been described in this context. Clinical manifestations include cognitive alterations, stroke, depression and demyelinating phenomena. It is unclear if cognitive deficits can be improved or resolved with viral eradication and to understand this, could have important therapeutical implications.

Role of contrast-enhanced ultrasonography in primary hepatic lymphoma.

OBJECTIVE: Ultrasonography is the first examination performed for screening of hepatocellular carcinoma (HCC); contrast-enhanced ultrasonography (CEUS) can help discriminate between HCC and other lesions. Primary hepatic lymphoma (PHL), even if rare, should be considered in the differential diagnosis of focal liver lesions (FLLs). Few data are available in the literature about the role of CEUS in the diagnosis of PHL; we tried to determine whether CEUS could have a role in this setting. METHODS: we describe 2 cases of primary non-Hodgkin lymphoma of the liver associated with hepatitis B virus (HBV) infection. The first patient was a 62-year-old man who was an HBV-inactive carrier, and the second was a 58-year-old man with type 2 diabetes and chronic HBV hepatitis. RESULTS: in both cases, ultrasonography showed a hypoechoic liver lesion (4 and 3 cm, respectively) with irregular margins in segment 4 of the liver. On CEUS, these lesions were inhomogeneously hyperenhanced in the arterial phase and hypoenhanced in the portal and late phases. Contrast-enhanced computed tomography (CT) in both patients showed slight hyperenhancement in the arterial phase and hypoenhancement in the remaining phases. Needle biopsy showed marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type in both patients. CONCLUSIONS: Contrast-enhanced ultrasonography and CT did not help us differentiate PHL from HCC; in fact, in both cases we saw the characteristic findings of primary HCC. Primary hepatic lymphoma is a rare condition, but it should always be considered in the differential diagnosis of FLLs. We stress the important role of liver biopsy when imaging indicates HCC in patients without underlying cirrhosis.