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Objectives: To unravel the still unexplored HBV-replicative kinetics in antiHBc-positive/HBsAg-negative people-with-HIV (PWH) suspending TDF/TAF., Methods: 101 antiHBc-positive/HBsAg-negative PWH switching to TDF/TAF-sparing therapy were included. Serum HBV-DNA and HBV-RNA were quantified by droplet-digital-PCR at switching (T0), within 12-months (T1) and 12-24 months post-switch (T2)., Results: At T0, 33.7% had cryptic HBV-DNA (undetected by commercial assays, median[IQR]:2[1-5]IU/ml) and 22% were positive to HBV-RNA alone (median[IQR]:4[3-4]IU/ml), indicating an active HBV-reservoir despite HBsAg-negativity and TDF/TAF-pressure. Notably, antiHBs-titer<100mIU/ml independently correlated with cryptic HBV-DNA at T0 (OR[95%CI]:2.6[1.02-6.5], P=0.04). After TDF/TAF-withdrawal, the rate of PWH achieving HBV-DNA>10IU/ml increased from 12.9% at T1 to 42.6% at T2 (P<0.0001). Likewise, a rise from 2% to 11% was observed for HBV-DNA>100IU/ml (P=0.02); median(IQR) HBV-DNA: 579(425-770)IU/ml. Notably, HBV-DNA>10IU/ml at T2 occurred in 70% of PWH with cryptic HBV-DNA, in 38.5% with HBV-RNA alone and in 25% negative to both HBV-markers at T0 (P=0.01). Cryptic HBV-DNA at T0 and lower nadir CD4+T-cell-count independently predicted HBV-DNA>10IU/ml at T2 (OR[95%CI]:8.2[1.7-40.6], P=0.01; OR[95%CI]:8.1[1.3-52.1], P=0.03). Lastly, persistent HBV-DNA positivity was independently associated with a reduced CD4+T-cell recovery at T2 (OR[95%CI]:0.07[0.01-0.77], P=0.03)., Conclusions: This study underlines the importance to regularly monitor antiHBc-positive/HBsAg-negative PWH undergoing TDF/TAF-sparing regimen and the role of highly-sensitive HBV markers in optimizing their management., (Copyright © 2024. Published by Elsevier Ltd.)

Background and Aims: We aimed to characterize the epidemiologic and comorbidities profiles of patients with chronic Hepatitis D (CHD) followed in clinical practice in Italy and explored their interferon (IFN) eligibility., Methods: This was a cross-sectional study of the PITER cohort consisting of consecutive HBsAg-positive patients from 59 centers over the period 2019-2023. Multivariable analysis was performed by logistic regression model., Results: Of 5492 HBsAg-positive enrolled patients, 4152 (75.6%) were screened for HDV, 422 (10.2%) were anti-HDV positive. Compared with HBsAg mono-infected, anti-HDV positive patients were more often younger, non-Italians, with a history of drug use, had elevated alanine transaminase (ALT), cirrhosis, or hepatocellular carcinoma (HCC). Compared with Italians, anti-HDV positive non-Italians were younger (42.2% age ≤ 40 years vs. 2.1%; P < 0.001), more often females (males 43.0% vs. 68.6%; P < 0.001) with less frequent cirrhosis and HCC. HDV-RNA was detected in 63.2% of anti-HDV-positive patients, who were more likely to have elevated ALT, cirrhosis, and HCC. Extrahepatic comorbidities were present in 47.4% of anti-HDV positive patients and could affect the eligibility of IFN-containing therapies in at least 53.0% of patients in care., Conclusions: CHD affects young, foreign-born patients and older Italians, of whom two-thirds had cirrhosis or HCC. Comorbidities were frequent in both Italians and non-Italians and impacted eligibility for IFN., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Severe liver disease markers assessed before HCV eradication are acknowledged to usually improve after the SVR. We prospectively evaluated, in the PITER cohort, the long-term HCC risk profile based on predictors monitored after HCV eradication by direct-acting antivirals in patients with cirrhosis., Methods: HCC occurrence was evaluated by Kaplan-Meier analysis. Cox regression analysis identified the post-treatment variables associated with de-novo HCC; their predictive power was presented in a nomogram., Results: After the end of therapy (median follow-up:28.47 months), among 2064 SVR patients, 119 (5.8%) developed de-novo HCC. The HCC incidence was 1.90%, 4.21%, 6.47% at 12-, 24- and 36-months from end-of-therapy, respectively (incidence rate 2.45/100 person-years). Age, genotype 3, diabetes, platelets (PLT)≤120,000/µl and albumin ≤3.5g/dl levels were identified as pre-treatment HCC independent predictors. Adjusting for age, the post-treatment PLT≤120,000/µl (AdjHR 1.92; 95%CI:1.06-3.45) and albumin≤3.5g/dl (AdjHR 4.38; 95%CI 2.48-7.75) values were independently associated with HCC occurrence. Two different risk profiles were identified by combining long-term post-therapy evaluation of PLT ≤ vs. >120,000/µl and albumin ≤ vs. >3.5g/dl showing a significant different HCC incidence rate of 1.35 vs. 3.77/100 p-y, respectively., Conclusions: The nomogram score based on age, PLT and albumin levels after SVR showed an accurate prediction capability and may support the customizing management for early HCC detection., Competing Interests: Conflict of interest None declared., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: The study measures trends in the profile of patients with chronic hepatitis B virus linked to care in Italy., Methods: A cross-sectional, multicenter, observational cohort (PITER cohort) of consecutive patients with hepatitis B surface antigen (HBsAg) over the period 2019-2021 from 46 centers was evaluated. The reference was the MASTER cohort collected over the years 2012-2015. Standard statistical methods were used., Results: The PITER cohort enrolled 4583 patients, of whom 21.8% were non-Italian natives. Compared with those in MASTER, the patients were older and more often female. The prevalence of hepatitis B e antigen (HBeAg) declined (7.2% vs 12.3; P <0.0001) and that of anti-hepatitis D virus (HDV) remained stable (9.3% vs 8.3%). In both cohorts, about 25% of the patients had cirrhosis, and those in the PITER cohort were older. HBeAg-positive was 5.0% vs 12.6% (P <0.0001) and anti-HDV positive 24.8% vs 17.5% (P <0.0017). In the logistic model, the variables associated with cirrhosis were anti-HDV-positive (odds ratio = 10.08; confidence interval 7.63-13.43), age, sex, and body mass index; the likelihood of cirrhosis was reduced by 40% in the PITER cohort. Among non-Italians, 12.3% were HBeAg-positive (vs 23.4% in the MASTER cohort; P <0.0001), and 12.3% were anti-HDV-positive (vs 11.1%). Overall, the adherence to the European Association for the Study of the Liver recommendations for antiviral treatment increased over time., Conclusion: Chronic hepatitis B virus infection appears to be in the process of becoming under control in Italy; however, HDV infection is still a health concern in patients with cirrhosis and in migrants., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Liver transplantation (LT) represents the best therapeutic option for hepatocellular carcinoma (HCC) and end-stage liver disease (ESLD). Although HIV infection does not seem to lower survival rates, HCV and HCC recurrence appear more harmful., Aims: To compare the overall survival after LT; evaluate the impact of anti-HCV direct-acting agents (DAA); assess the rate of HCC recurrence in HIV-positive and negative patients., Methods: Subjects with HCV/HBV infection who underwent LT for HCC or ESLD from 2012 to 2019 were retrospectively evaluated., Results: Study population included 299 individuals, 31 (10.4%) were HIV-positive. Overall mortality was similar (16.1% versus 19.0%, p = 0.695). HCC recurrence was observed in 6 HIV-positive (19.4%) and in 17 negative subjects (6.3%, p = 0.022). Time to relapse was 831 days in HIV-positive and 315 days in negative patients (p = 0.046). Cox model found a significant role for HIV in univariate analysis but, after adjusting for variables, extra-hepatic tumor was the only factor associated to recurrence (aHR 56.379, p < 0.001)., Conclusions: Post-LT survival improved after DAA availability and HIV has no impact on mortality. A higher and delayed rate of HCC recurrence was observed in co-infected individuals: surveillance protocols should be strengthened along time in this population., Competing Interests: Declaration of Competing Interest none of the Authors has conflicts of interests to declare., (Copyright © 2022. Published by Elsevier Ltd.)

The vaccination campaign against Sars-CoV-2 commenced in Italy at the end of December 2020. The first ones to receive the immunization against the virus were the health workers and the residents of nursing homes, following which the vaccine would be available for the entire population, beginning with the most vulnerable individuals. SARS-CoV2 vaccines have been demonstrated to be safe for the general population, although no data for patients with liver diseases or those having undergone liver transplantation are available so far. The present position statement AISF is an attempt to suggest, based on the published data on the impact of Sars-Cov-2 infection in patients with chronic liver disease, a possible priority for vaccination for this category of patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: The MARS post-marketing, observational study evaluates glecaprevir/pibrentasvir in a large population of Italian patients who are infected with HCV., Patients and Methods: Achievement of SVR12 was the primary endpoint in the overall population and by subpopulations of interest (treatment-naïve and treatment-experienced patients, subjects infected with different HCV genotype/sub-genotype, cirrhotic and non-cirrhotic patients, patients with different severity of fibrosis, patients with an APRI score ≥1, subjects with comorbidities, HIV-coinfected patients, elderly patients and people who use drugs). Safety and quality of life (assessed by SF-36 and Work Productivity and Activity Impairment) were also evaluated., Results: The SVR12 rate was 99.4% (319/321; 95% CI: 97.8-99.8%) in the core population with sufficient follow-up (n = 321), 99.7% (289/290) in 8-week treated patients, and high (>96%) across subgroups. Only three patients (0.9%) had treatment-related adverse events that led to treatment discontinuation. In total, 30.1% of patients showed an improvement of ≥2.5 points in the Physical Component Summary of the SF-36 from baseline to the end of treatment, and this figure raised to 37.5% with the achievement of SVR12. Corresponding values for MCS were 42.2% and 42.8%, respectively., Conclusion: Glecaprevir/pibrentasvir is safe and effective across subpopulations who are underserved in clinical trials., Competing Interests: Declaration of Competing Interests None., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objective: To assess the efficacy of corticosteroids in patients with coronavirus disease 2019 (COVID-19)., Methods: A multicentre observational study was performed from 22 February through 30 June 2020. We included consecutive adult patients with severe COVID-19, defined as respiratory rate ≥30 breath per minute, oxygen saturation ≤93% on ambient air or arterial partial pressure of oxygen to fraction of inspired oxygen ≤300 mm Hg. We excluded patients being treated with other immunomodulant drugs, receiving low-dose corticosteroids and receiving corticosteroids 72 hours after admission. The primary endpoint was 30-day mortality from hospital admission. The main exposure variable was corticosteroid therapy at a dose of ≥0.5 mg/kg of prednisone equivalents. It was introduced as binomial covariate in a logistic regression model for the primary endpoint and inverse probability of treatment weighting using the propensity score., Results: Of 1717 patients with COVID-19 evaluated, 513 were included in the study, and of these, 170 (33%) were treated with corticosteroids. During hospitalization, 166 patients (34%) met the criteria of the primary outcome (60/170, 35% in the corticosteroid group and 106/343, 31% in the noncorticosteroid group). At multivariable analysis corticosteroid treatment was not associated with lower 30-day mortality rate (adjusted odds ratio, 0.59; 95% confidence interval (CI), 0.20-1.74; p 0.33). After inverse probability of treatment weighting, corticosteroids were not associated with lower 30-day mortality (average treatment effect, 0.05; 95% CI, -0.02 to 0.09; p 0.12). However, subgroup analysis revealed that in patients with PO2/FiO2 < 200 mm Hg at admission (135 patients, 52 (38%) treated with corticosteroids), corticosteroid treatment was associated with a lower risk of 30-day mortality (23/52, 44% vs. 45/83, 54%; adjusted odds ratio, 0.20; 95% CI, 0.04-0.90; p 0.036)., Conclusions: The effect of corticosteroid treatment on mortality might be limited to critically ill COVID-19 patients., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: We aimed to develop and validate a risk score to predict severe respiratory failure (SRF) among patients hospitalized with coronavirus disease-2019 (COVID-19)., Methods: We performed a multicentre cohort study among hospitalized (>24 hours) patients diagnosed with COVID-19 from 22 February to 3 April 2020, at 11 Italian hospitals. Patients were divided into derivation and validation cohorts according to random sorting of hospitals. SRF was assessed from admission to hospital discharge and was defined as: Spo 2 <93% with 100% Fio 2 , respiratory rate >30 breaths/min or respiratory distress. Multivariable logistic regression models were built to identify predictors of SRF, β-coefficients were used to develop a risk score. Trial Registration NCT04316949., Results: We analysed 1113 patients (644 derivation, 469 validation cohort). Mean (±SD) age was 65.7 (±15) years, 704 (63.3%) were male. SRF occurred in 189/644 (29%) and 187/469 (40%) patients in the derivation and validation cohorts, respectively. At multivariate analysis, risk factors for SRF in the derivation cohort assessed at hospitalization were age ≥70 years (OR 2.74; 95% CI 1.66-4.50), obesity (OR 4.62; 95% CI 2.78-7.70), body temperature ≥38°C (OR 1.73; 95% CI 1.30-2.29), respiratory rate ≥22 breaths/min (OR 3.75; 95% CI 2.01-7.01), lymphocytes ≤900 cells/mm 3 (OR 2.69; 95% CI 1.60-4.51), creatinine ≥1 mg/dL (OR 2.38; 95% CI 1.59-3.56), C-reactive protein ≥10 mg/dL (OR 5.91; 95% CI 4.88-7.17) and lactate dehydrogenase ≥350 IU/L (OR 2.39; 95% CI 1.11-5.11). Assigning points to each variable, an individual risk score (PREDI-CO score) was obtained. Area under the receiver-operator curve was 0.89 (0.86-0.92). At a score of >3, sensitivity, specificity, and positive and negative predictive values were 71.6% (65%-79%), 89.1% (86%-92%), 74% (67%-80%) and 89% (85%-91%), respectively. PREDI-CO score showed similar prognostic ability in the validation cohort: area under the receiver-operator curve 0.85 (0.81-0.88). At a score of >3, sensitivity, specificity, and positive and negative predictive values were 80% (73%-85%), 76% (70%-81%), 69% (60%-74%) and 85% (80%-89%), respectively., Conclusion: PREDI-CO score can be useful to allocate resources and prioritize treatments during the COVID-19 pandemic., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Daclatasvir (DCV) is a HCV NS5A inhibitor whose plasma exposure may be influenced by co-administration with inducers or inhibitors of CYP3A4 such as many antiretrovirals., Aims: Describe the use of different DCV dosages; assess if dose prescription complies with Summaries of Product Characteristics (SmPC); evaluate safety and efficacy of 60 versus 30/90 mg and adequate (i.e. concordant with SmPC) versus incorrect prescriptions., Methods: Retrospective analysis of patients included in ICONA/HepaICONA starting a DCV-including treatment. Incidence rates of liver adverse events (LAE) were calculated; Poisson regression model was used to identify factors associated with LAE., Results: 311 patients were included: 250 (80.4%) received DCV at a dosage of 60 mg, 52 (16.7%) 30 mg and 9 (2.9%) 90 mg. An inadequate dosage was used in 18 individuals (5.8%). No difference in SVR was observed (93.8% with 60 mg and 94.2% with 30/90 mg, p = 0.910; 93.5% with adequate and 100% with incorrect dosage, p = 0.277). There were 36 LAE with no differences in the two-paired groups. Decompensated liver disease was a risk factor for LAE (aRR = 2.37; p = 0.034), while HIV RNA < 50 copies/ml resulted protective (aRR = 0.22; p = 0.003)., Conclusions: DCV use resulted in high SVR rate regardless of dosage and correctness of prescription., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Sofosbuvir (SOF)-based regimens have been associated with renal function worsening in HCV patients with estimated glomerular filtration rate (eGFR) ≤ 45 ml/min, but further investigations are lacking., Aim: To assess renal safety in a large cohort of DAA-treated HCV patients with any chronic kidney disease (CKD)., Methods: All HCV patients treated with DAA in Lombardy (December 2014-November 2017) with available kidney function tests during and off-treatment were included., Results: Among 3264 patients [65% males, 67% cirrhotics, eGFR 88 (9-264) ml/min], CKD stage was 3 in 9.5% and 4/5 in 0.7%. 79% and 73% patients received SOF and RBV, respectively. During DAA, eGFR declined in CKD-1 (p < 0.0001) and CKD-2 (p = 0.0002) patients, with corresponding rates of CKD stage reduction of 25% and 8%. Conversely, eGFR improved in lower CKD stages (p < 0.0001 in CKD-3a, p = 0.0007 in CKD-3b, p = 0.024 in CKD-4/5), with 33-45% rates of CKD improvement. Changes in eGFR and CKD distribution persisted at SVR. Baseline independent predictors of CKD worsening at EOT and SVR were age (p < 0.0001), higher baseline CKD stages (p < 0.0001) and AH (p = 0.010 and p < 0.0001, respectively)., Conclusions: During DAA, eGFR significantly declined in patients with preserved renal function and improved in those with lower CKD stages, without reverting upon drug discontinuation., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: Sofosbuvir/velpatasivr/voxilaprevir (SOF/VEL/VOX) is approved for retreatment of patients with HCV and a previous failure on direct-acting antivirals (DAAs), however real-life data are limited. The aim of this study was to assess the effectiveness and safety of SOF/VEL/VOX in a real-life setting., Methods: All consecutive patients with HCV receiving SOF/VEL/VOX between May-October 2018 in 27 centers in Northern Italy were enrolled. Bridging fibrosis (F3) and cirrhosis (F4) were diagnosed by liver stiffness measurement: >10 and >13 kPa respectively. Sustained virological response (SVR) was defined as undetectable HCV-RNA 4 (SVR4) or 12 (SVR12) weeks after the end-of-treatment., Results: A total of 179 patients were included: median age 57 (18-88) years, 74% males, median HCV-RNA 1,081,817 (482-25,590,000) IU/ml. Fibrosis stage was F0-F2 in 32%, F3 in 21%, F4 in 44%. HCV genotype was 1 in 58% (1b 33%, 1a 24%, 1nc 1%), 2 in 10%, 3 in 23% and 4 in 9%; 82% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Patients received SOF/VEL/VOX for 12 weeks, ribavirin was added in 22% of treatment schedules. Undetectable HCV-RNA was achieved by 74% of patients at week 4 and by 99% at week 12. Overall, 162/179 (91%) patients by intention to treat analysis and 162/169 (96%) by per protocol analysis achieved SVR12, respectively; treatment failures included 6 relapsers and 1 virological non-responder. Cirrhosis (p = 0.005) and hepatocellular carcinoma (p = 0.02) were the only predictors of treatment failure. Most frequent adverse events included fatigue (6%), hyperbilirubinemia (6%) and anemia (4%)., Conclusions: SOF/VEL/VOX is an effective and safe retreatment for patients with HCV who have failed on a previous DAA course in a real-life setting., Lay Summary: This is the largest European real-life study evaluating effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in a large cohort of consecutive patients with hepatitis C virus infection and a prior direct-acting antiviral failure, who were treated within the NAVIGATORE Lombardia and Veneto Networks, in Italy. This study demonstrated excellent effectiveness (98% and 96% sustained virological response rates at week 4 and 12, respectively) and an optimal safety profile of SOF/VEL/VOX. Cirrhosis and hepatocellular carcinoma onset were the only features associated with treatment failure., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background and Aims: The efficacy and safety of glecaprevir/pibrentasvir (G/P) for patients infected with hepatitis C virus (HCV) have only been investigated in clinical trials, with no real-world data currently available. The aim of our study was to investigate the effectiveness and safety of G/P in a real-world setting., Methods: All patients with HCV consecutively starting G/P between October 2017 and January 2018 within the NAVIGATORE-Lombardia Network were analyzed. G/P was administered according to drug label (8, 12 or 16 weeks). Fibrosis was staged either histologically or by liver stiffness measurement. Sustained virological response (SVR) was defined as undetectable HCV-RNA 12 weeks after the end of treatment., Results: A total of 723 patients (50% males) were treated with G/P, 89% for 8 weeks. The median age of our cohort was 58 years, with a median body mass index of 23.9 kg/m 2 , and median liver stiffness measurement of 6.1 kPa; 84% were F0-2 and 16% were interferon-experienced. Median HCV-RNA was 1,102,600 IU/ml, and 49% of patients had HCV genotype 1 (32% 1b), 28% genotype 2, 10% genotype 3 and 13% genotype 4. The median estimated glomerular filtration rate was 90.2 ml/min, platelet count 209x10 3 /mm 3 and albumin 4.3 g/dl. The SVR rates were 94% in intention-to-treat and 99.3% in per protocol analysis (8-week vs. 12 or 16-week: 99.2% vs. 100%). Five patients failed therapy because of post-treatment relapse; a post-treatment NS5A resistance-associated substitution was detected in 1 case. SVR rates were lower in males (p = 0.002) and in HCV genotype-3 (p = 0.046) patients treated for 8 weeks, but independent of treatment duration, fibrosis stage, baseline HCV-RNA, HIV co-infection, chronic kidney disease stage and viral kinetics. Mild adverse events were reported in 8.3% of the patients, and 0.7% of them prematurely withdrew treatment. Three patients died of drug-unrelated causes., Conclusions: In a large real-world cohort of Italian patients, we confirmed the excellent effectiveness and safety of G/P administered for 8, 12 or 16 weeks., Lay Summary: A large number of patients with hepatitis C virus have been treated with glecaprevir/pibrentasvir (G/P) within the NAVIGATORE-Lombardia Network, in Italy. This is the first real-world study evaluating effectiveness and safety of G/P in patients with hepatitis C virus treated according to international recommendations. This study demonstrated excellent effectiveness (with sustained virological response rates of 99.3%) and safety profiles., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatitis C virus (HCV) infection is now considered a systemic disease due to the occurrence of extra-hepatic manifestations. Among these, the renal involvement is frequent. HCV infection, in fact, is strongly associated with proteinuria and chronic kidney disease (CKD) and negatively affects the prognosis of renal patients. In the last few years, availability of more specific and effective drugs against HCV has dramatically changed the clinical course of this disease. These drugs may provide further advantages in the CKD population as a whole by reducing progression of renal disease, mortality rate and by increasing the survival of graft in renal transplant recipients. The strict pathogenetic and prognostic link between HCV infection and CKD requires an ongoing relationship among the healthcare professionals involved in the treatment of both HCV infection and CKD. Therefore, Scientific Societies involved in the care of this high-risk population in Italy have organized a joint expert panel. The aim of the panel is to produce a position statement that can be used in daily clinical practice for the management of HCV infected patients across the whole spectrum of renal disease, from the conservative phase to renal replacement treatments (dialysis and transplantation). Sharing specific evidence-based expertise of different professional healthcare is the first step to obtain a common ground of knowledge on which to instate a model for multidisciplinary management of this high-risk population. Statements cover seven areas including epidemiology of CKD, HCV-induced glomerular damage, HCV-related renal risk, staging of liver disease in patients with CKD, prevention of transmission of HCV in hemodialysis units, treatment of HCV infection and management of HCV in kidney transplantation., (Copyright © 2018 Roberto Minutolo, Alessio Aghemo, Antonio Chirianni, Fabrizio Fabrizi, Loreto Gesualdo, Edoardo G. Giannini, Paolo Maggi, Vincenzo Montinaro, Ernesto Paoletti, Marcello Persico, Francesco Perticone, Salvatore Petta, Massimo Puoti, Giovanni Raimondo, Maria Rendina, Anna Linda Zignego, on behalf of the Italian Society of Nephrology (SIN), the Italian Association for the Study of the Liver (AISF), the Italian Society of Infectious and Tropical Disease (SIMIT), the Italian Society of Internal Medicine (SIMI). Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Glecaprevir plus pibrentasvir (G/P) is a pangenotypic, once-daily, ribavirin-free direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection. In nine phase II or III clinical trials, G/P therapy achieved rates of sustained virologic response 12 weeks after treatment (SVR12) of 93-100% across all six major HCV genotypes (GTs). An integrated efficacy analysis of 8- and 12-week G/P therapy in patients without cirrhosis with HCV GT 1-6 infection was performed., Methods: Data were pooled from nine phase II and III trials including patients with chronic HCV GT 1-6 infection without cirrhosis who received G/P (300 mg/120 mg) for either 8 or 12 weeks. Patients were treatment naïve or treatment experienced with peginterferon, ribavirin, and/or sofosbuvir; all patients infected with HCV GT 3 were treatment naïve. Efficacy was evaluated as the SVR12 rate., Results: The analysis included 2,041 patients without cirrhosis. In the intent-to-treat population, 943/965 patients (98%) achieved SVR12 when treated for eight weeks, and 1,060/1,076 patients (99%) achieved SVR12 when treated for 12 weeks; the difference in rates was not significant (p = 0.2). A subgroup analysis demonstrated SVR12 rates > 95% across baseline factors traditionally associated with lower efficacy. G/P was well tolerated, with one DAA-related serious adverse event (<0.1%); grade 3 laboratory abnormalities were rare., Conclusions: G/P therapy for eight weeks in patients with chronic HCV GT 1-6 infection without cirrhosis achieved an overall SVR12 rate of 98% irrespective of baseline patient or viral characteristics; four additional weeks of treatment did not significantly increase the SVR12 rate, demonstrating that the optimal treatment duration in this population is eight weeks., Lay Summary: In this integrated analysis of nine clinical trials, patients with chronic HCV genotype 1-6 infection without cirrhosis were treated for either 8 or 12 weeks with the direct-acting antiviral regimen glecaprevir/pibrentasvir (G/P). The cure rate was 98% and 99% following 8 and 12 weeks of treatment, respectively; the difference in rates was not significant (p = 0.2), nor was there a significant difference in the cure rates across the two treatment durations on the basis of baseline patient or viral characteristics. These results, along with a favourable safety profile, indicate that G/P is a highly efficacious and well-tolerated pangenotypic eight-week therapy for most patients with chronic HCV infection., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: To analyse the variation of hepatitis C virus (HCV) prevalence and genotype distribution and their determinants in people living with human immunodeficiency virus (HIV) who entered care between 1997 and 2015., Methods: HIV-infected patients enrolled in ICONA who were tested for HCV antibodies (HCV-Ab) were included., Results: Overall 3407 of 12 135 (28.1%) were HCV-Ab+; and 735 of 12 135 (6.1%) were HBsAg+. Among patients whose HCV genotype was known, the most represented were genotypes 1 and 3. The prevalence of HCV infection decreased from 49.2% (2565/5217) during 1997-2002 to 10.2% (556/5466) during 2009-2015. The frequency of genotype 1a increased from 29.0% (264/911) to 43.0% (129/300), whereas genotype 3 decreased from 38.5% (351/911) to 27.0% (81/300). Independent predictors of HCV-Ab+ status were being female (adjusted OR (AOR) 1.23, 95% CI 1.04-1.50, p = 0.01), risk category (versus injecting drug users: men who have sex with men AOR 0.01, 95% CI 0.01-0.01, p <0.001; heterosexuals AOR 0.01, 95% CI 0.01-0.01, p <0.001; other/unknown AOR 0.02, 95% CI 0.01-0.02, p <0.001), being cared for in Central Italy (versus being cared for in Northern Italy: AOR 0.85, 95% CI 0.73-0.98, p <0.001), being Italian-born (AOR 1.44, 95% CI 1.16-1.80, p = 0.001) and being enrolled in less recent calendar years (versus 1997-2002: 2009-2015 AOR 0.23, 95% CI 0.19-0.27, p <0.001; 2003-2008 AOR 0.49, 95% CI 0.41-0.61, p <0.001)., Conclusions: The prevalence of HCV infection in HIV-infected patients entering into care in Italy significantly declined in more recent calendar years. After adjusting for risk factors and calendar years, HCV co-infection was more frequent in females and in those born in Italy., (Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Scope: Hepatitis B virus (HBV) infection reactivation is associated with high morbidity and mortality in patients with haematologic malignancy and/or haematopoietic stem cell transplantation (HSCT). However, information on this issue is limited. The scope of this position paper is to provide recommendations on HBV screening, monitoring, prophylaxis, treatment and vaccination in the patients described above., Methods: These recommendations were developed from one meeting of experts attended by different Italian scientific societies as well as from a systematic literature review (of articles published through December 31, 2016) on HBV infection in haematologic patients and in patients who underwent haematopoietic stem cell transplantation published in the same issue of the journal. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess each recommendation's quality., Questions Addressed: These recommendations provide the answers to the following questions: (a) HBV screening and monitoring: Who should be screened before chemotherapy? Which screening tests should be used? Should HBV-DNA detection be used to monitor HBV reactivation before starting antivirals? What is the best timeline to monitor HBV reactivation? (b) Prophylaxis in HBsAg-positive patients: Which antiviral drugs should be used to treat HBsAg-positive patients? How long should antiviral prophylaxis be provided to HBsAg-positive patients? (c) Prophylaxis in patients with resolved HBV infection: Which patients with resolved HBV infection should receive antiviral prophylaxis? Which antiviral drug should be used? How long should antiviral prophylaxis be provided? (d) HBV infection management strategy in autologous (auto-HSCT) and allogeneic HSCT (allo-HSCT): Which HSCT recipients should receive antiviral prophylaxis? Which antiviral drug should be used? How long should antiviral prophylaxis be provided? (e) Choice of antiviral drugs in the treatment of HBV reactivation: Should third-generation anti-HBV drugs be preferred to first- or second-generation antiviral drugs in the treatment of HBV reactivation with or without hepatitis flare in haematologic patients? (f) Immunization against HBV in patients with haematologic malignancies and/or patients who underwent HSCT: Should these patients be vaccinated? Which HBV vaccination schedule should be adopted?, Recommendations: Haematologic patients should be screened for hepatitis B surface antigen (HBsAg) plus anti-hepatitis B core protein (HBc), and HBV DNA before chemotherapy. HBV DNA levels should be monitored monthly in all HBV-positive patients who do not receive prophylaxis. HBsAg-positive haematologic patients and those undergoing HSCT should receive third-generation antiviral therapy as prophylaxis. Anti-HBc-positive lymphoma patients and those receiving HSCT should receive antiviral prophylaxis. All HBV-negative haematologic patients should be vaccinated for HBV. The acquisition of data from well-designed studies is desirable in the near future., (Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The advent of safe and highly effective direct-acting antiviral agents (DAAs) has had huge implications for the hepatitis C virus (HCV) transplant field, and changed our management of both patients on the waiting list and those with HCV graft re-infection after liver transplantation (LT). When treating HCV infection before LT, HCV re-infection of the graft can be prevented in nearly all patients. In addition, some candidates show a remarkable clinical improvement and may be delisted. Alternatively, HCV infection can be treated post-LT either soon after the transplant, taking advantage of the removal of the infected native liver, or at the time of disease recurrence, as was carried out in the past. In either case, some DAAs have a limited use because of their drug to drug interactions with various immunosuppressants as well as the many other drugs liver transplant recipients are often prescribed. In addition, some DAAs should be avoided in case of severe renal failure, which is not an unusual complication after LT. The present document provides a series of consensus statements on the LT issues that have not been extensively addressed previously. These statements have been developed to support physicians and other stakeholders in charge of LT candidates and recipients when deciding to treat HCV, especially in difficult situations., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objective: To estimate the incidence of hepatitis C virus (HCV) seroconversion and the risk of severe fibrosis/cirrhosis in HCV seroconverters among persons with human immunodeficiency virus (HIV) infection., Methods: We analysed data on 4059 persons with HIV enrolled in a cohort study in Italy., Results: Incidence rate of seroconversion was 0.6/100 person-years overall, and drug users and men-who-have-sex-with-men were at highest risk. The cumulative risk of progression to severe fibrosis/cirrhosis was 30% by 10 years after seroconversion., Conclusions: New HCV infections have a rapidly progressive course in this population. Persons with HIV and HCV superinfection should be prioritized for treatment with anti-HCV direct-acting antivirals., (Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The prevalence and management of chronic hepatitis B virus (HBV) infection differ among European countries. The availability and reimbursement of diagnostics and drugs may also vary, determining distinct treatment outcomes. Herein, we analyse differences in medical facilities for the care of patients with chronic HBV infection across Europe. A survey was sent to the members of the ESCMID Study Group for Viral Hepatitis, all of whom are experts in chronic HBV infection management. The comprehensive survey asked questions regarding hepatitis B surface antigen (HBsAg) prevalence, the availability of diagnostics and drugs marketed, and distinct clinical practice behaviours in the management of chronic HBV infection. World Bank data were used to assess the economic status of the countries. With 16 expert physicians responding (69%), the HBsAg prevalence rates were <1% in France, Hungary, Italy, The Netherlands, Portugal, Spain, and the UK, intermediate (1-5%) in Turkey, Romania, and Serbia, and high (>5%) in Albania and Iran. Regarding the availability and reimbursement of HBV diagnostics (HBV DNA and liver stiffness measurement), HBV drugs (interferon, lamivudine, tenofovir, and entecavir), HBV prophylaxis, and duration of HBeAg-positive and HBeAg-negative HBV infection, the majority of high-income and middle-income countries had no restrictions; Albania, Iran and Serbia had several restrictions in diagnostics and HBV drugs. The countries in the high-income group were also the ones with no restrictions in medical facilities, whereas the upper-middle-income countries had some restrictions. The prevalence of chronic HBV infection is much higher in southern and eastern than in western European countries. Despite the availability of European guidelines, policies for diagnostics and treatment vary significantly across European countries., (Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Although interferon-free regimens are approved for patients co-infected with HIV and genotype-2 or genotype-3 hepatitis C virus (HCV), interferon-based regimens are still an option for those co-infected with HIV and HCV genotypes 1 or 4. These regimens are limited by clinically significant toxic effects and drug interactions with antiretroviral therapy. We aimed to assess the efficacy and safety of an interferon-free, all-oral regimen of sofosbuvir plus ribavirin in patients with HIV and HCV co-infection., Methods: We did this open-label, non-randomised, uncontrolled, phase 3 study at 45 sites in seven European countries and Australia. We enrolled patients (aged ≥18 years) co-infected with stable HIV and chronic HCV genotypes 1-4, including those with compensated cirrhosis. Once-daily sofosbuvir (400 mg) plus twice-daily ribavirin (1000 mg in patients with bodyweights <75 kg and 1200 mg in those with weights ≥75 kg) was given for 24 weeks to all patients except treatment-naive patients with genotype-2 HCV, who received a 12-week regimen. The primary efficacy endpoint was sustained virological response 12 weeks after treatment. We did analysis by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01783678., Findings: Between Feb 7, 2013, and July 29, 2013, we enrolled 275 eligible patients, of whom 262 (95%) completed treatment; 274 patients were included in the final analysis. Overall rates of sustained virological response 12 weeks after treatment were 85% (95% CI 77-91) in patients with genotype-1 HCV, 88% (69-98) in patients with genotype-2 HCV, 89% (81-94) in patients with genotype-3 HCV, and 84% (66-95) in patients with genotype-4 HCV. Response rates in treatment-naive patients with HCV genotypes 2 or 3 (89% [95% CI 67-99] and 91% [81-97], respectively) were similar to those in treatment-experienced patients infected with those genotypes (83% [36-100] and 86% [73-94], respectively). There was no emergence of sofosbuvir-resistance mutations in patients with HCV viral relapse. Six (2%) patients discontinued treatment because of adverse events. The most common adverse events were fatigue, insomnia, asthenia, and headache. Four (1%) patients had serious adverse events regarded as related to study treatment. Additionally, four (1%) patients receiving antiretroviral treatment had a transient HIV viral breakthrough; however, none required changes in antiretroviral regimen., Interpretation: Sofosbuvir and ribavirin provided high rates of sustained virological response after 12 weeks of treatment in treatment-naive and treatment-experienced patients co-infected with HIV and HCV genotypes 1-4. The characteristics of this interferon-free combination regimen make sofosbuvir plus ribavirin a useful treatment option for this patient population., Funding: Gilead Sciences., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Liver fibrosis is accelerated in patients co-infected with human immunodeficiency virus and hepatitis C viruses., Aims: We investigated the correlation between liver fibrosis, immune activation and microbial translocation., Methods: This cross-sectional study included patients with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) mono-infections, HIV/HCV co-infection, and healthy controls (20 subjects/group). Peripheral blood was analysed to determine the levels of Forkhead box 3 (Foxp3) T cells, TGF-β1, CD14 (soluble and surface isoforms), IL-17 and bacterial translocation products. These measurements were correlated to the severity of liver fibrosis, measured with the FIB-4 score and transient elastography., Results: Foxp3T cell levels were significantly elevated in HIV mono-infected and co-infected groups (p<0.0005). FIB-4 and liver stiffness values inversely correlated with TGF-β1 (p=0.0155 and p=0.0498). Bacterial DNA differed significantly in the HIV-positive compared to the other groups: HIV/HCV co-infected subjects had significantly higher serum levels of bacterial translocation products, CD14, and IL-17 levels (p<0.001)., Conclusions: Fibrosis stage in HIV/HCV co-infection may be influenced by immune activation due either by viral infections or to bacterial translocation., (Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Chronic infection with hepatitis C virus (HCV) may lead to B cell activation and transformation into non-Hodgkin lymphoma (NHL). Molecular mechanisms of B cell transformation by HCV are poorly understood. One of the most common lymphoproliferative disorders in HCV-infected patients is splenic marginal zone lymphoma (SMZL). A case of a 42-years old man, affected by HCV-related SMZL, effectively treated with an IFN-free, NS3-NS4A inhibitor-based regimen, is hereby described. The patient was treated for 16 weeks with faldaprevir, deleobuvir, and ribavirin, achieving a very rapid viral eradication without relevant toxicities. A rapid haematologic response was noted as well, with a statistically significant correlation between viral decay and lymphocyte improvement (coefficient r = 0.55, p = 0.042). The viral clearance led to SMZL cure, even without the use of IFN. Thus, the causative role, played by HCV in SMZL development, is once again reinforced, whereby the antiviral, rather than the anti-proliferative activity of IFN is indirectly proven. A regimen including DAAs should be considered when treating a HCV-related extra-hepatic disease., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

In the era of Directly Acting anti HCV Antivirals treatment of hepatitis C is successful in the majority of persons treated. However, treatment of persons with HIV or who inject drugs remains challenging because of special issues: drug-drug interactions with antiretroviral, psychiatric and drug substitution therapies, treatment adherence, impact of treatment on HIV disease course or on risk of bacterial infections. Sofosbuvir induced sustained virologic response in 91% of 23 HIV/HCV coinfected persons treated in combination with ribavirin and pegylated interferon, in 83% of 497 treated in combination with ribavirin and in all 50 patients infected with HCV GT1 treated in combination with ledipasvir and ribavirin. The rates of efficacy in HCV-HIV coinfected were almost the same as those observed in HCV monoinfected suggesting that the efficacy of sofosbuvir is not reduced by HIV coinfection. There are no data on the efficacy of sofosbuvir in injection drugs users. The pangenotypic activity, the high barrier to resistance, the modest potential for drug-drug interactions makes sofosbuvir a reference drug for the treatment of these two special populations., (Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. All rights reserved.)

The burden of infectious diseases both before and after liver transplantation is clearly attributable to the dysfunction of defensive mechanisms of the host, both as a result of cirrhosis, as well as the use of immunosuppressive agents. The present document represents the recommendations of an expert panel commended by the Italian Association for the Study of the Liver (AISF), on the prevention and management of infectious complications excluding hepatitis B, D, C, and HIV in the setting of liver transplantation. Due to a decreased response to vaccinations in cirrhosis as well as within the first six months after transplantation, the best timing for immunization is likely before transplant and early in the course of disease. Before transplantation, a vaccination panel including inactivated as well as live attenuated vaccines is recommended, while oral polio vaccine, Calmette-Guerin's bacillus, and Smallpox are contraindicated, whereas after transplantation, live attenuated vaccines are contraindicated. Before transplant, screening protocols should be divided into different levels according to the likelihood of infection, in order to reduce costs for the National Health Service. Recommended preoperative and postoperative prophylaxis varies according to the pathologic agent to which it is directed (bacterial vs. viral vs. fungal). Timing after transplantation greatly determines the most likely agent involved in post-transplant infections, and specific high-risk categories of patients have been identified that warrant closer surveillance. Clearly, specifically targeted treatment protocols are needed upon diagnosis of infections in both the pre- as well as the post-transplant scenarios, not without considering local microbiology and resistance patterns., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The statements produced by the consensus conference on infection in end-stage liver disease promoted by the Italian Association for the Study of the Liver, are here reported. The topics of epidemiology, risk factors, diagnosis, prophylaxis, and treatment of infections in patient with compensated and decompensated liver cirrhosis were reviewed by a scientific board of experts who proposed 26 statements that were graded according to level of evidence and strength of recommendation, and approved by an independent jury. Each topic was explored focusing on the more relevant clinical questions. By systematic literature search of available evidence, comparison and discussion of expert opinions, pertinent statements answering specific questions were presented and approved. Short comments were added to explain the basis for grading evidence particularly on case of controversial areas., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sustained virological response (SVR) to anti-hepatitis C virus (HCV) treatment is an outcome that can improve life expectancy in persons with human immunodeficiency virus (HIV) infection. Results of anti-HCV treatment are poor, and less than 50% of treated patients show SVR to peginterferon plus ribavirin combination therapy; in infections from HCV genotype 1 this proportion is less than 40%. Pilot studies have demonstrated that Boceprevir or Telaprevir in combination with peginterferon plus ribavirin are able to increase the SVR rate from 45% to 74% with Telaprevir, and from 26% to 61% with Boceprevir in persons never treated for hepatitis C. Interim data seem to indicate a high rate of HCV RNA undetectability on treatment also in patients without sustained response to peginterferon plus ribavirin. Both Telaprevir and Boceprevir have drug-drug interactions with antiretrovirals, and options for concurrent antiretroviral therapy are restricted. There are also several new anti-HCV drugs under study with the potential for more tolerable effective future regimens. The indication for treatment in a patient with HCV/HIV coinfection should take into account the priority of treatment, the probability of sustained response, the potential toxicities, the concurrent antiretroviral therapy options, the patient's motivation, and the sustainability of current and future therapies., (Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Hepatitis C virus (HCV) infected patients often take multiple co-medications to treat adverse events related to HCV therapy, or to manage other co-morbidities. Drug-drug interactions associated with this polypharmacy are relatively new to the field of HCV pharmacotherapy. With the advent of the direct-acting antivirals telaprevir and boceprevir, which are both substrates and inhibitors of the cytochrome P450 (CYP) 3A iso-enzyme, knowledge and awareness of drug-drug interactions have become a cornerstone in the evaluation of patients starting and continuing HCV combination therapy. In our opinion, an overview of conducted drug-drug interaction studies and a list of contraindicated medications is not enough for the clinical management of these drug-drug interactions. Knowledge of pharmacokinetic profiles and concentration-effect relationships is key for the interpretation of these data, and insight into how to manage these interactions (e.g., dose adjustments, safe alternatives and therapeutic drug monitoring) is of equal importance. This review provides a practical overview of the safe and effective management of these clinical challenges., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Vallecamonica-Sebino is a community in Northern Italy (99,776 inhabitants) with one of the highest mortality rates for primary liver cancer and cirrhosis in Italy, and voluntary screening for HCV and HBV is widespread. The aim of this study was to estimate the prevalence of chronic liver diseases and their aetiology in the area., Methods: We used the following sources of data, linked at an individual level: (1) hospital discharge data; (2) local Viral Hepatitis Services; (3) tests for anti-HCV antibodies and HBsAg from local laboratories; (4) Local Health Authority registry of chronic liver disease patients; (5) drug prescriptions for HBV and HCV treatment; (6) archives of Alcohol Units., Results: 3.5% of the residents had chronic liver disease, mainly chronic hepatitis (61.6%), followed by cirrhosis (14.0%) and alcoholic liver disease (11.2%). HCV was the main cause of chronic liver disease in females (46.3%) and males (29.8%), followed by alcohol abuse in males (22.9%) and HBV (10.9% males and 9.2% females). Prevalence of anti-HCV positivity was 3.2%, and increased with age to 8.8% in subjects aged 65 years and over., Conclusion: This study shows that an epidemiologic pattern of the prevalence of chronic liver diseases and their aetiology can be obtained using routinely collected data., (Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objective: The objective of this review was to define a core set of recommendations for the treatment of HCV-associated mixed cryoglobulinemia syndrome (MCS) by combining current evidence from clinical trials and expert opinion., Methods: Expert physicians involved in studying and treating patients with MCS formulated statements after discussing the published data. Their attitudes to treatment approaches (particularly those insufficiently supported by published data) were collected before the consensus conference by means of a questionnaire, and were considered when formulating the statements., Results: An attempt at viral eradication using pegylated interferon plus ribavirin should be considered the first-line therapeutic option in patients with mild-moderate HCV-related MCS. Prolonged treatment (up to 72 weeks) may be considered in the case of virological non-responders showing clinical and laboratory improvements. Rituximab (RTX) should be considered in patients with severe vasculitis and/or skin ulcers, peripheral neuropathy or glomerulonephritis. High-dose pulsed glucocorticoid (GC) therapy is useful in severe conditions and, when necessary, can be considered in combination with RTX; on the contrary, the majority of conference participants discouraged the chronic use of low-medium GC doses. Apheresis remains the elective treatment for severe, life-threatening hyper-viscosity syndrome; its use should be limited to patients who do not respond to (or who are ineligible for) other treatments, and emergency situations. Cyclophosphamide can be considered in combination with apheresis, but the data supporting its use are scarce. Despite the limited available data, colchicine is used by many of the conference participants, particularly in patients with mild-moderate MCS refractory to other therapies. Careful monitoring of the side effects of each drug, and its effects on HCV replication and liver function tests is essential. A low-antigen-content diet can be considered as supportive treatment in all symptomatic MCS patients. Although there are no data from controlled trials, controlling pain should always be attempted by tailoring the treatment to individual patients on the basis of the guidelines used in other vasculitides., Conclusion: Although there are few controlled randomised trials of MCS treatment, increasing knowledge of its pathogenesis is opening up new frontiers. The recommendations provided may be useful as provisional guidelines for the management of MCS., (Copyright © 2011. Published by Elsevier B.V.)

The Italian recommendations for the therapy of hepatitis B virus (HBV)-related disease were issued in 2008. Subsequently in 2008 the nucleotide analogue (NA) Tenofovir was approved for antiviral treatment. The introduction of this important new drug has called for the current guidelines update, which includes some additional revisions: (a) the indication for therapy is extended to mild liver fibrosis and the indication for treatment is graded as "possible", "optional" or "mandatory" according to the fibrosis stage; (b) two different treatment strategies are described: first line definite duration treatment with interferon, long-term treatment of indefinite duration with NA; (c) the indication to follow either strategy is also based on the stage of liver fibrosis; (d) virological monitoring is modified to include the definitions of failure and of sustained virological response to interferon therapy; (e) the recommendation to use HBV DNA assays with high sensitivity and wide linear ranges is underlined (f) guidelines on post-treatment follow-up after finite treatment with NA, potential side effects of therapy and non-virological monitoring are defined; (g) definitions and treatment of patients without optimal response to NA are reported; (f) treatment and monitoring of compensated or decompensated cirrhosis and hepatocellular carcinoma are updated., (Copyright © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Progression of chronic hepatitis C virus (HCV) infection to end-stage liver disease is accelerated in patients coinfected with human immunodeficiency virus (HIV). HCV/HIV-coinfected hemophiliacs are no exception. Although eradication of HCV with pegylated interferon (Peg-IFN) plus ribavirin (Rbv) is the only approach to halt the progression of liver disease, the rates of sustained virologic response (SVR) in coinfected patients are attenuated as compared with those in HCV-monoinfected patients. Nonetheless, in HCV-infected hemophiliacs, who are considered to constitute a difficult-to-treat population, current treatment strategies yielded rates of SVR similar to those obtained in non-hemophiliacs., Objectives and Patients: In this open-label, prospective, multicenter study, the efficacy and safety of therapy with Peg-IFNalpha2a plus Rbv was evaluated in 34 HCV/HIV-coinfected adult hemophiliacs naive to previous antiviral therapy., Methods: Peg-IFNalpha2a was administered at a dose of 180 mug subcutaneously once-weekly plus oral Rbv 1000-1200 mg day(-1) for 48 weeks, irrespective of HCV genotype., Results: All but one patient (3%) completed the study, 15 (44%) achieved an SVR, and 13 (38%) required dose reduction of either drug. A rapid virologic response (HCV-RNA clearance at week 4; P = 0.01), a complete early virologic response (HCV RNA clearance at week 12; P = 0.005) and absence of cirrhosis (P = 0.04) were independent predictors of SVR. During a median post-treatment follow-up of 3 years, a steady increase in CD4+ cell count and CD4+/CD8+ cell ratio was observed in SVR patients., Conclusions: These results strongly support the use of anti-HCV therapy in HCV/HIV-coinfected hemophiliacs.

Background/aims: The aims were to estimate among patients with hepatitis C virus (HCV) infection the prevalence of alcohol and coffee intake and smoking habit, the reliability of these self-reported data and the possible change of patients' habit after their first contact with a Viral Hepatitis Service., Methods: 229 patients were initially interviewed personally at the Viral Hepatitis Service and after 6 months they were re-interviewed by phone in regard to their alcohol, coffee drinking and smoking habits., Results: Alcohol drinkers were 55.5% of males and 35.3% of females. Most subjects drank coffee daily, both men (90.0%) and women (84.9%). The proportion of current smokers was higher in males (43.6%) than females (26.9%). We found a fair to good reliability of self-reported data regarding patients' habits, alcohol and coffee intake, and number of cigarettes smoked daily. We observed a statistically significant decrease in alcohol and coffee intake and cigarettes smoked between baseline and follow-up interviews., Conclusion: We found a fairly high proportion of HCV-infected patients who regularly drink alcohol and coffee beverages and smoke cigarettes, especially among males. The reliability of self-reported data on these habits seems satisfactory. More decisive action to modify these habits, especially alcohol intake, is required in these patients.

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.

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.

Hepatocellular carcinoma (HCC) resulting from chronic infection with hepatitis B or C virus (HBV, HCV) is a significant health problem. Concurrent infection with human immunodeficiency virus (HIV) may accelerate the progression from cirrhosis to HCC. Current guidelines advise screening patients with cirrhosis at 6-month intervals using ultrasonography and measurement of alpha-fetoprotein levels. In early-stage HCC, resection and liver transplantation are curative, as is percutaneous ethanol injection for small tumours in patients who are not candidates for surgery. HIV-infected patients do not qualify for liver transplantation. For late-stage HCC, chemoembolization can improve survival. Prevention of hepatitis and cirrhosis are key goals in reducing the impact of HCC. Numerous issues in HCC prevention, diagnosis, and management still remain to be resolved through large-scale, randomized clinical trials.

HIV co-infection influences the course and natural history of hepatitis B virus (HBV) infection by impairing the quantity and quality of the innate and adaptive immune response. The rates of spontaneous resolution after acute infection and spontaneous anti-HBe and anti-HBs seroconversions are decreased, and levels of HBV replication are increased in HIV-infected patients. A more rapid progression of liver fibrosis and a higher rate of cirrhosis decompensation (but not hepatocellular carcinoma) have been demonstrated in co-infected patients. The risk of HBV-associated end-stage liver disease and liver-related mortality may be increased by HIV co-infection. Antiretroviral therapy may trigger spontaneous anti-HBe and anti-HBs seroconversion and/or a better immune control of HBV replication by restoring adaptive immunity, but can also increase hepatitis flares. Reactivation of chronic hepatitis B has been observed after suspension of anti-retrovirals with anti-HBV activity or after occurrence of HBV resistance to lamivudine. Future research should focus on: the impact of HIV-induced changes in innate and adaptive immune response and modifications induced by anti-retroviral therapy that may impact on progression of advanced chronic hepatitis B; the association between HBV genotype and clinical course of disease; and the role of occult HBV infection as a co-factor with other causes of liver injury.

Background/aims: Interferon and ribavirin combination therapy for chronic hepatitis C induces a low response rate in human immunodeficiency virus (HIV) infected patients. To assess the impact of intensification of interferon administration and of the addition of amantadine on the efficacy and safety of standard anti-hepatitis C virus (HCV) treatment in HIV-infected patients., Methods: Multicentre, prospective, open-label, randomized, phase III clinical trial. Eighty co-infected patients were randomized to receive ribavirin 800-1,000 mg/day in combination with, group A: interferon alpha 2a 3MIU thrice weekly; group B: IFN alpha 2a 3MIU daily, plus amantadine 200 mg/day; treatment duration was 24-48 weeks according to HCV genotype., Results: Forty-one patients were randomized in group A and 39 in group B. Intention-to-treat analysis showed a sustained virological response, defined as HCV-RNA negativization, 6 months after stopping treatment in 22% of patients from group A and 13% from group B (P>0.05). The lack of a 2-log drop in HCV-RNA levels after 12 weeks of treatment showed a 100% predictive value of lack of sustained response., Conclusions: Amantadine addition and interferon intensification do not improve the low efficacy of combination of interferon alfa plus ribavirin in HIV/HCV co-infected patients. Patients with no early virologic response did not have any probability of sustained response.

Background/aims: To evaluate demographic characteristics, liver histology and virological features of hepatitis C virus (HCV) carriers with normal alanine transaminase (ALT) levels., Methods: A nationwide prospective study was started in 1997. Four Italian centres have participated in this study., Results: Eight hundred and eighty subjects entered the study. One hundred and eighty-nine (21.5%) were excluded during the follow-up because of ALT increase. Among the 691 patients with persistent ALT normality, 72% were females. An overall prevalence of genotype 2 was found (52%). Normal liver was found in 17% of the patients; 34% had minimal chronic hepatitis, 44% mild hepatitis, 4% moderate to severe hepatitis, and 1% had cirrhosis. Clinical and virological features did not differ between subjects with ALT flares and those with persistently normal ALT. Baseline ALT levels have no effects on liver histology and clinical outcome., Conclusions: Many HCV carriers have significant chronic liver damage, although in the majority of them liver lesions are minimal or mild. Up to 60% of HCV carriers in Italy harbour non-1 HCV types. Current definition of HCV carriers with persistently normal ALT levels, based upon three normal ALT values over a 6-month period, is not adequate to discriminate between carriers with persistent ALT normality and those with transient biochemical remission. Longer follow-ups are needed.