Trends in liver transplantation for primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis is a cholestatic disease with a low prevalence in Italy. Indications for liver transplantation and the time of listing are not stated. AIM: We performed a national survey to investigate the listing criteria, comorbidities, and outcomes. METHODS: In April 2022, we surveyed liver transplantation in primary sclerosing cholangitis nationwide for the last 15 years. RESULTS: From 2007 to 2021, 445 patients were included on waiting lists, and 411 had undergone liver transplants. The median age at transplantation was 46 years (males 63.9%); 262 patients (59%) presented an inflammatory bowel disease. Transplants increased over the years, from 1.8 % in 2007 to 3.0 % in 2021. Cholangitis (51%) and hepatic decompensation (45%) were the main indications for listing. The disease recurred in 81 patients (20%). Patient survival after the first transplant was 94 %, 86% and 84% at one, five, and ten years. Twenty-four died in the first year (50% surgical complications, 25% infections); 33 between one to five years (36% recurrence, 21% cholangiocarcinoma recurrence) and nine after five years (56% de novo cancer, 44% recurrence). CONCLUSIONS: Primary sclerosing cholangitis has been an increasing indication for transplantation in Italy. Cholangitis and decompensation were the main indications for listing. Recurrence and cancer were the leading causes of death.

Superiority of the new sex-adjusted models to remove the female disadvantage restoring equity in liver transplant allocation.

BACKGROUND AND AIMS: Model for End-stage Liver Disease (MELD) and MELDNa are used worldwide to guide graft allocation in liver transplantation (LT). Evidence exists that females are penalized in the present allocation systems. Recently, new sex-adjusted scores have been proposed with improved performance respect to MELD and MELDNa. GEMA-Na, MELD 3.0, and sex-adjusted MELDNa were developed to improve the 90-day dropout prediction from the list. The present study aimed at evaluating the accuracy and calibration of these scores in an Italian setting. METHODS: The primary outcome of the present study was the dropout from the list up to 90 days because of death or clinical deterioration. We retrospectively analysed data from 855 adults enlisted for liver transplantation in the Lazio region (Italy) (2012-2018). Ninety-day prediction of GEMA-Na, MELD 3.0 and sex-adjusted MELDNa with respect to MELD and MELDNa was analysed. Brier score and Brier Skill score were used for accuracy, and the Greenwood-Nam-D'Agostino test was used to evaluate the calibration of the models. RESULTS: GEMA-Na (concordance = .82, 95% CI = .75-.89), MELD 3.0 (concordance = .81, 95% CI = .74-.87) and sex-adjusted MELDNa (concordance = .81, 95% CI = .74-.88) showed the best 90-day dropout prediction. GEMA-Na showed a higher increase in accuracy with respect to MELD (p = .03). No superiority was shown with respect to MELDNa. All the tested scores showed a good calibration of the models. Using GEMA-Na instead of MELD would potentially save one in nine dropouts and could save one dropout per 285 patients listed. CONCLUSIONS: Validation and reclassification of the sex-adjusted score GEMA-Na confirm its superiority in predicting short-term dropout also in an Italian setting when compared with MELD.

"Real world" efficacy of bulevirtide in HBV/HDV-related cirrhosis including people living with HIV: Results from the compassionate use programme at INMI Spallanzani in Rome, Italy.

OBJECTIVES: We describe the preliminary results of bulevirtide compassionate use in patients with hepatitis B and delta virus (HBV/HDV)-related cirrhosis and clinically significant portal hypertension, including those living with HIV. METHODS: We conducted a prospective observational study of consecutive patients. Clinical evaluation, liver function tests, bile acid levels, HDV-RNA, HBV-DNA, hepatitis B surface antigen, and liver and spleen stiffness were assessed at baseline and after treatment months 1, 2, 3, 4, 6, 9, and 12. HIV-RNA and CD4+/CD8+ count were assessed in people living with HIV. The first drug injection was administered under nurse supervision, and counselling was provided and adherence reviewed at each visit. RESULTS: In total, 13 patients (61.5% migrants) were enrolled. The median treatment duration was 11 months. At month 6, mean alanine aminotransferase (ALT) levels fell by 64.5% and mean liver and spleen stiffness decreased by 8.6 and 0.9 kPa, respectively. The mean baseline HDV-RNA was 3.34 log IU/mL and 5.10 log IU/mL in people without and with HIV (n = 5) (p = 0.28), respectively. A similar mean decline was observed in both groups: -2.06 log IU/mL and -1.93 log IU/mL, respectively (p = 0.87). A combined response (undetectable HDV RNA or ≥ -2 log IU/mL decline vs. baseline, with ALT normalization) was achieved in 66% of subjects without and in 60% of patients with HIV. Patients with HIV showed persistently undetectable HIV-RNA and a progressive increase in CD4+/CD8+ cells during treatment. No patient discontinued bulevirtide because of adverse effects. CONCLUSIONS: Preliminary results suggest that bulevirtide is feasible and well-tolerated in populations with difficult-to-treat conditions, such as those with HIV/HBV/HDV co-infection and migrants, when special attention is given to patient education. HDV-RNA decline during treatment was similar in people living with and without HIV.

Humoral Immune Response after COVID-19 mRNA Vaccination in Patients with Liver Cirrhosis: A Prospective Real-Life Single Center Study.

Coronavirus-disease-2019 (COVID-19) mRNA vaccination effectively reduces mortality and morbidity in cirrhotic patients, but the immunogenicity and safety of vaccination have been partially characterized. The study aimed to evaluate humoral response, predictive factors, and safety of mRNA-COVID-19 vaccination in cirrhotic patients compared to healthy subjects. A prospective, single-center, observational study enrolled consecutive cirrhotic patients who underwent mRNA-COVID-19 vaccination from April to May 2021. Anti-spike-protein (anti-S) and nucleocapsid-protein (anti-N) antibodies were evaluated before the first (T0) and the second (T1) doses and 15 days after completing the vaccination. An age and sex-matched healthy reference group was included. The incidence of adverse events (AEs) was assessed. In total, 162 cirrhotic patients were enrolled, 13 were excluded due to previous SARS-CoV-2 infection; therefore, 149 patients and 149 Health Care Workers (HCWs) were included in the analysis. The seroconversion rate was similar in cirrhotic patients and HCWs at T1 (92.5% vs. 95.3%, p = 0.44) and T2 (100% in both groups). At T2, anti-S-titres were significantly higher in cirrhotic patients compared to HCWs (2776.6 vs. 1756 BAU/mL, p < 0.001]. Male sex (ß = -0.32 [-0.64, -0.04], p = 0.027) and past-HCV-infection (ß = -0.31 [-0.59, -0.04], p = 0.029) were independent predictors of lower anti-S-titres on multiple-gamma-regression-analysis. No severe AEs occurred. The COVID-19-mRNA vaccination induces a high immunization rate and anti-S-titres in cirrhotic patients. Male sex and past-HCV infection are associated with lower anti-S-titres. The COVID-19-mRNA vaccination is safe.

Lymphofollicular lesions associated with monkeypox (Mpox) virus proctitis.

In the recent 2022 monkeypox (Mpox) global outbreak, cases have been mostly documented among men who have sex with men. Proctitis was reported in almost 14% of cases. In this study, four Mpox-confirmed cases requiring hospitalizations for severe proctitis were characterized by clinical, virological, microbiological, endoscopic, and histological aspects. The study showed the presence of lymphofollicular lesions associated with Mpox virus rectal infection for the first time.

Third dose of SARS-CoV2 mRNA vaccination produces robust persistent cellular and humoral immune responses in liver transplant recipients.

Weaker responses have been described after two doses of anti-SARS-CoV2 vaccination in liver transplant recipients (LTRs). At the Italian National Institute for Infectious Diseases, 122 LTRs (84% males, median age 64 years) were tested for humoral and cell-mediated immune response after a third doses of anti-SARS-CoV2 mRNA vaccines. Humoral response was measured by quantifying anti-receptor binding domain and neutralizing antibodies; cell-mediated response was measured by quantifying IFN-γ after stimulation of T cells with SARS-CoV-2-specific peptides. Humoral and cellular responses improved significantly compared to the second vaccine dose; 86.4% of previous non-responders to the first 2 vaccine doses (N = 22) became responders. Mycophenolate mofetil-containing regimens were not associated with lower response rates to a third vaccine; shorter time since transplantation (<6 years) was associated with lower humoral and cellular responses to third vaccine. Protective antibodies against Omicron variant were detected in 60% of patients 12 weeks after third vaccine dose.

Coordinated cellular and humoral immune responses after two-dose SARS-CoV2 mRNA vaccination in liver transplant recipients.

Limited data are available on risks and benefits of anti-SARS-CoV2 vaccination in solid organ transplant recipients, and weaker responses have been described. At the Italian National Institute for Infectious Diseases, 61 liver transplant recipients underwent testing to describe the dynamics of humoral and cell-mediated immune response after two doses of anti-SARS-CoV2 mRNA vaccines and compared with 51 healthy controls. Humoral response was measured by quantifying both anti-spike and neutralizing antibodies; cell-mediated response was measured by PBMC proliferation assay with IFN-γ and IL-2 production. Liver transplant recipients showed lower response rates compared with controls in both humoral and cellular arms; shorter time since transplantation and multi-drug immunosuppressive regimen containing mycophenolate mofetil were predictive of reduced response to vaccination. Specific antibody and cytokine production, though reduced, were highly correlated in transplant recipients.

High prevalence of asymptomatic SARS-CoV-2 infection in a cohort of liver transplant recipients in central Italy.

Asymptomatic subjects account for 25 to 45% of SARS-CoV-2 infections, and in particular, subjects on mild immunosuppressive therapy may have symptoms masked and could spread virus for an extended period of time. To determine the cumulative incidence of symptomatic and asymptomatic SARS-CoV-2 infections and associated risk factors, we conducted a prospective clinical and serological survey in a cohort of 278 liver transplant recipients (LTRs) from Central Italy. Three different serology tests were performed every 4 months in 259 LTRs between April 2020 and April 2021: one based on raw extract of whole SARS-CoV-2 virus and two on specific viral antigens (nucleoprotein and receptor binding domain) to detect specific IgG, IgM and IgA. Hundred fifteen LTRs who reported symptoms or close contact with a SARS-CoV-2-positive subject, or had a positive serological result underwent molecular testing by standard screening procedures (RT-PCR on naso-pharyngeal swab). Thirty-one past or active SARS-CoV-2 infections were identified: 14 had positive molecular test (64% symptomatic), and 17 had positive serology only (18% symptomatic). SARS-CoV-2 infection was not statistically related to gender, age, obesity, diabetes, renal impairment, type of anti-rejection therapy or time from transplant. Asymptomatic SARS-CoV-2 cases (61.3%) were more frequent in males and in those with glomerular filtrate rate >50 ml/min. Overall, the addition of repeated serology to standard diagnostic molecular protocols increased detection of SARS-CoV-2 infection from 5.1% to 10.9%. Anti-SARS-CoV-2 seroprevalence among our LTRs (11.2%) is comparable to the general population of Central Italy, considered a medium-impact area. Only one asymptomatic subject (6%) was found to carry SARS-CoV-2 in respiratory tract at the time of serological diagnosis.

Sarco-Model: A score to predict the dropout risk in the perspective of organ allocation in patients awaiting liver transplantation.

BACKGROUND & AIMS: Sarcopenia in liver transplantation (LT) cirrhotic candidates has been connected with higher dropouts and graft losses after transplant. The study aims to create an 'urgency' model combining sarcopenia and Model for End-stage Liver Disease Sodium (MELDNa) to predict the risk of dropout and identify an appropriate threshold of post-LT futility. METHODS: A total of 1087 adult cirrhotic patients were listed for a first LT during January 2012 to December 2018. The study population was split into a training (n = 855) and a validation set (n = 232). RESULTS: Using a competing-risk analysis of cause-specific hazards, we created the Sarco-Model2 . According to the model, one extra point of MELDNa was added for each 0.5 cm2 /m2 reduction of total psoas area (TPA) < 6.0 cm2 /m2 . At external validation, the Sarco-Model2 showed the best diagnostic ability for predicting the risk of 3-month dropout in patients with MELDNa < 20 (area under the curve [AUC] = 0.93; P = .003). Using the net reclassification improvement, 14.3% of dropped-out patients were correctly reclassified using the Sarco-Model2 . As for the futility threshold, transplanted patients with TPA < 6.0 cm2 /m2 and MELDNa 35-40 (n = 16/833, 1.9%) had the worse results (6-month graft loss = 25.5%). CONCLUSIONS: In sarcopenic patients with MELDNa < 20, the 'urgency' Sarco-Model2 should be used to prioritize the list, while MELDNa value should be preferred in patients with MELDNa ≥ 20. The Sarco-Model2 played a role in more than 30% of the cases in the investigated allocation scenario. In sarcopenic patients with a MELDNa value of 35-40, 'futile' transplantation should be considered.

Anti-HEV IgG Avidity Testing: Utility for Diagnosing Acute and Resolved Genotype 3 Infections.

European Association of the Study of the Liver (EASL) guidelines specify HEV RNA, as well as anti-HEV IgG and IgM as positive markers for acute HEV infection. HEV RNA assay sensitivity limitations may lead to false negative test results in patients with low levels of viremia. Moreover, anti-HEV IgM positivity is not a reliable indicator for distinguishing between acute and resolved infections given the ability of this antibody to persist several months after a resolved infection. Our study aims were to assess HEV IgG avidity for diagnosing acute and resolved infections, regardless of the anti-HEV IgM serostatus, and examine assay reliability when evaluating different genotype 3 (GT3) HEV subtypes. Patient serum samples (n = 104) were tested for HEV IgG avidity by utilizing the DIA.PRO kit on a DSX automated instrument. Among patients identified with acute HEV infections, 32 were infected with GT3: GT3c (n = 5), GT3e (n = 8), 3f (n = 17) and GT3-unsubtyped (n = 2). Avidity sensitivity was 91.2% and specificity was 100%. For patients with long-lasting anti-HEV IgM persistence, an Avidity Index >70% was observed. Thus, the DIA.PRO avidity assay may be utilized to distinguish between recently acquired and resolved HEV GT3 infections. However, for equivocal results (Avidity Index > 40-70%), HEV RNA molecular testing will be required to confirm a recent infection.

Cumulative incidence of solid and hematological De novo malignancy after liver transplantation in a multicentre cohort.

BACKGROUND: Recent innovations in the field of liver transplantation have led to a wealth of new treatment regimes, with potential impact on the onset of de novo malignancies (DNM). The aim of this multicenter cohort study was to provide contemporary figures for the cumulative incidences of solid and hematological DNM after liver transplantation. METHODS: We designed a retrospective cohort study including patients undergoing LT between 2000 and 2015 in three Italian transplant centers. Cumulative incidence was calculated by Kaplan-Meyer analysis. RESULTS: The study included 789 LT patients with a median follow-up of 81 months (IQR: 38-124). The cumulative incidence of non-cutaneous DNM was 6.2% at 5-years, 11.6% at 10-years and 16.3% at 15-years. Post-Transplant Lymphoproliferative Disorders (PTLD) were demonstrated to have a cumulative incidence of 1.0% at 5-years, 1.6% at 10-years and 2.2% at 15-years. Solid Organ Tumors (SOT) demonstrated higher cumulative incidences - 5.3% at 5-years, 10.3% at 10-years and 14.4% at 15-years. The most frequently observed classifications of SOT were lung (rate 1.0% at 5-years, 2.5% at 10-years) and head & neck tumors (rate 1.3% at 5-years, 1.9% at 10-years). CONCLUSIONS: Lung tumors and head & neck tumors are the most frequently observed SOT after LT.

The impact of the coronavirus disease 2019 pandemic on a central Italy transplant center.

Coronavirus disease 2019 (COVID-19) is challenging health care systems worldwide, raising the question of reducing the transplant program due to the shortage of intensive care unit beds and to the risk of infection in donors and recipients.We report the positive experience of a single Transplant Center in Rome, part of the National Institute for Infectious Diseases Lazzaro Spallanzani, one of the major national centers involved in the COVID-19 emergency.

Daclatasvir, sofosbuvir with or without ribavirin for 24 weeks in hepatitis C genotype 3 cirrhosis: A real-life study.

INTRODUCTION AND AIM: Cirrhotic patients with hepatitis C virus genotype 3 infection show unsatisfactory outcomes after 12 weeks' treatment with direct antiviral agents. The National Italian Drug Agency allows 24 weeks of therapy in difficult-to-treat patients, including genotype 3 cirrhotics. Aim of this study was to evaluate efficacy and safety of a 24-week course of sofosbuvir plus daclatasvir±ribavirin in this population. MATERIALS AND METHODS: 106 consecutive cirrhotics (70.8% males, mean age 55.3±7.6 years) in 8 tertiary hepatology centers received sofosbuvir plus daclatasvir for 24 weeks. Ribavirin was administered in 85 (80.2%) based expected tolerability, at a mean dose of 964±202mg/day. Baseline Child-Pugh class was A 91.5%, B 6.6%, C 1.9%; mean baseline MELD was 8.5±2.7. RESULTS: All patients completed 12-week follow-up post-treatment, and 104 (98.1%) obtained sustained virological response (100% in ribavirin -treated patients vs. 90.4% without ribavirin; p=0.04). No worsening in renal and liver function was observed, no serious adverse events occurred. Two virological failures showed resistance associated variants (Y93H and S282T). CONCLUSION: An extended 24-week treatment with sofosbuvir plus daclatasvir+ribavirin obtained 100% efficacy in genotype 3 hepatitis C cirrhosis, with very limited side effects. The role of ribavirin seems crucial in this setting and should be administered if clinically feasible.

Daclatasvir-based regimens in HCV cirrhosis: experience from the Italian early access program.

We reported the efficacy and safety data for daclatasvir (DCV)-based all-oral antiviral therapy in patients treated in the Italian compassionate-use program. 275 patients were included (202 male-73.5%, mean age: 57.4 years, 62 HIV-coinfected, 94 with recurrence of hepatitis C post-OLT). Forty-nine patients (17.8%) had Child-Pugh B, Genotype(G) distribution was: G1a:72 patients (26.2%), G1b:137 (49.8%); G3:40 (14.5%) and G4:26 (9.5%). Patients received DCV with sofosbuvir(SOF) (n = 221, 129 with ribavirin(RBV) or with simeprevir (SMV) or asunaprevir (ASU) (n = 54, 19 with RBV) for up to 24 weeks. Logistic regression was used to identify baseline characteristics associated with sustained virological response at week 12 post-treatment (SVR12). Liver function changes between baseline and follow up were assessed in 228 patients. 240 patients achieved SVR12 (87.3%), post transplant and HIV co-infected patients were equally distributed among SVR and no SVR (35% vs 34.3%; p = 0.56 and 24.2% vs 11.4%, p = 0.13, respectively). SVR rate was significantly higher with the combination DCV + SOF compared with DCV + SIM or ASU (93.2% vs 63.0%, p < 0.0001). Bilirubin value (OR: 0.69, CI95%: 0.54-0.87, p = 0.002) and regimen containing SOF (OR: 9.99, CI95%: 4.09-24.40; p < 0.001) were independently related with SVR. Mean albumin and bilirubin values significantly improved between baseline and follow-up week 12. DCV-based antiviral therapy was well tolerated and resulted in a high SVR when combined with SOF either in pre-transplant and in OLT patients and in "difficult to treat" HCV genotypes. Regimens containing DCV in combination with NS3 protease inhibitors obtained suboptimal results.

Pitfalls in the reporting of upper endoscopy features in cirrhotic patients.

BACKGROUND: Upper endoscopy is the main tool for the accurate assessment of the risk of bleeding in cirrhotic patients. AIM: To evaluate the diagnostic accuracy of upper endoscopy, in cirrhotic subjects, during common clinical practice. METHODS: 120 endoscopic reports produced in different hospitals in our region were retrospectively and randomly selected. After a general evaluation, aimed at assessing the description of various endoscopic features, reports were evaluated by four expert endoscopists and four expert hepatologists. Experts were asked to fill in a questionnaire for each single endoscopic procedure, regarding the diagnostic accuracy of the report. RESULTS: Endoscopic reports lacked descriptions of the size of esophageal varices and red signs in 14% and 29% of cases respectively. Presence (or absence) of gastric varices or portal hypertensive gastropathy were not reported in 62% and 34% of cases respectively. According to expert endoscopists 41% of the reports were incomplete, while, according to hepatologists, reports were incomplete and inadequate for clinical purposes in 36% of cases. CONCLUSION: Our study clearly evidenced a significant lack of information in reports on upper endoscopy in cirrhotic patients, and supports the prompt adoption of corrective strategies.

Lack of reduction in serum alpha-fetoprotein during treatment with direct antiviral agents predicts hepatocellular carcinoma development in a large cohort of patients with hepatitis C virus-related cirrhosis.

Risk of hepatocellular carcinoma (HCC) in hepatitis C virus cirrhotic patients treated with direct-acting antiviral agents (DAA) is still debating. We investigated it in a large cohort. The cohort comprised 1045 cirrhotic patients who completed treatment with DAA, with a median follow-up of 17.3 months after end of treatment (EOT), including 943 patients without history of HCC and 102 previously treated for HCC. The majority were men (59.9%), with compensated cirrhosis (88.8%), genotype 1b (44.7%). Univariate, multivariate analysis and Kaplan-Meier curves were performed to detect predictors of HCC in patients with and without reduction in alpha-fetoprotein (AFP) during treatment. SVR12 was 95.6%. HCC developed in 95 (9.9%), including 54 of 943 (5.7%) occurrent and 41 of 102 (39%) recurrent tumours. De novo were more often unifocal (P = 0.01) and curable (P = 0.03). AFP decreased from 16.1 ± 36.2 mg/dL (baseline) to 11.4 ± 55 mg/dL (EOT). At univariate analysis, predictors were a previous HCC, older age, higher model for end-stage liver disease, prolonged INR, lower platelets, baseline and EOT AFP, virological failure and no reduction in AFP during treatment. Kaplan-Meier curves showed lower incidence of HCC in patients showing any reduction in AFP (P = 0.001). Those with AFP <6 ng/mL had the lowest risk (P = 0.0002). At logistic regression, platelets (P = 0.009, OR 0.99 CI: 0.99-1.00), previous HCC (P < 0.000 01, OR: 10.76, 95% CI: 5.89-19.34) and no reduction in AFP during treatment (P = 0.0005, OR: 2.98, CI: 1.60-5.54) were independent predictors of HCC. In conclusion, risk of HCC after DAA treatment remains substantial. It is higher among patients with previous HCC, low platelets and without reduction in AFP during treatment.

Significance of detectable HCV RNA below the limit of quantification in patients treated with DAAs using standard and ultrasensitive protocols.

Predictive factors of HCV relapse after treatment with DAAs are poorly understood. In this study, we aimed to assess whether the residual viral load positivity observed during or at the end of treatment (EOT) has an impact on viral outcome. Blood samples were collected from 337 patients with genotypes (GT) 1a, 1b, 2, 3, and 4 HCV chronic infection, treated with DAAs to determine HCV RNA load by the Abbott RealTime HCV (ART) assay at treatment week (W) 4, at EOT, and 4, 12, 24 weeks after discontinuation. EOT and other samples with "detected <12/mL" (DNQ) were retested by an ultrasensitive protocol (USP) to confirm the result. Frequency of DNQ was analyzed in subgroups of patients and clinical conditions to assess potential correlations. At W4, 22% and 30.9% of the samples were undetectable and DNQ by ART assay, respectively, but no correlation for achieving SVR was found. In contrast, an HCV RNA cut-off of ≥50/mL at W4 was a significant predictor of therapy failure (P = 0.036, univariate analysis). At EOT, DNQ was associated to 12W treatment duration (P < 0.001) and GT1a infection (P = 0.036). Overall, 20/41 (48.8%) of DNQ samples at EOT or post-treatment W4, were confirmed by USP but only in a single case the patient experienced viral relapse. HCV RNA at W4 can predict SVR, irrespective to genotype or DAA regimen. HCV RNA DNQ at EOT is associated to shorter treatment duration and to GT1a, but is not a predictor of therapy failure.

Sofosbuvir plus daclatasvir with or without ribavirin is safe and effective for post-transplant hepatitis C recurrence and severe fibrosis and cirrhosis: A prospective study.

BACKGROUND: In 2012, an Italian Named Patient Program began for hepatitis C virus (HCV)-infected liver transplant (LT) recipients with advanced fibrosis, before approval of direct antiviral agents (DAA), to benefit severely ill patients. The aim of this "real-life" study was to assess treatment efficacy and safety with an extended course of daclatasvir (DCV) plus sofosbuvir (SOF) with or without ribavirin (RBV). METHODS: All HCV LT recipients with severe fibrosis in 15 Italian transplant centers were treated with DCV+SOF±RBV for 24 weeks; sustained virological response was assessed at 12 weeks post-treatment (SVR12). RESULTS: Eighty-seven patients were enrolled (75.9% males, mean age 58.4 ± 7.2 years, 83.9% genotype 1, 81.6% cirrhosis); 52 (59.8%) received RBV. Overall, 79 obtained SVR12 (90.8%): 100% in F3 and 88.7% in cirrhotics (91.5% in Child-Pugh A, 83.3% in Child-Pugh B and C). According to the treatment group, SVR was 80% in DCV + SOF group and 98.1% in SOF + DCV + RBV. Two virological relapses occurred during follow-up in cirrhotic patients who received DCV + SOF. Four cirrhotic patients in DCV + SOF group and 1 in DCV + SOF + RBV group died on treatment. CONCLUSION: An extended course of SOF plus DCV for 24 weeks, with or without RBV, is effective and well tolerated for the treatment of post-LT HCV recurrence with severe fibrosis.

Characterization of Naturally Occurring NS5A and NS5B Polymorphisms in Patients Infected with HCV Genotype 3a Treated with Direct-Acting Antiviral Agents.

Hepatitis C virus (HCV) genotype (GT)3 is associated with increased risk of steatosis, development of cirrhosis and hepatocellular carcinoma. Limited data are available regarding genetic variability and use of direct-acting antiviral agents in these patients. non-structural protein 5A (NS5A) and non-structural protein 5B (NS5B) sequencing was performed on 45 HCV GT3-infected Italian patients subsequently treated with sofosbuvir ± daclatasvir (SOF ± DCV). Novel GT3a polymorphisms were observed by Sanger sequencing in three NS5A (T79S, T107K, and T107S) and three NS5B (G166R, Q180K, and C274W) baseline sequences in patients who achieved sustained virological response (SVR). Baseline NS5A resistance-associated substitutions A30K and Y93H were detected in 9.5% of patients; one patient with A30K did not achieve SVR. Phylogenetic analyses of sequences showed no distinct clustering. Genetic heterogeneity of NS5A and NS5B was evaluated using ultra-deep pyrosequencing (UDPS) in samples longitudinally collected in patients not achieving SVR. Some novel NS5A and NS5B polymorphisms detected at baseline may not impact treatment outcome, as they were not enriched in post-failure samples. In contrast, the novel L31F NS5A variant emerged in one treatment failure, and I184T, G188D and N310S, located on the same NS5B haplotype, became predominant after failure. These findings suggest a potential impact of these novel substitutions on the treatment outcome; however, their significance requires further investigation.

The Italian compassionate use of sofosbuvir observational cohort study for the treatment of recurrent hepatitis C: clinical and virological outcomes.

Direct antivirals are available for treating recurrent hepatitis C (RHC). This study reported outcomes of 424 patients with METAVIR F3-F4 RHC who were treated for 24 weeks with sofosbuvir/ribavirin and followed for 12 weeks within the Italian sofosbuvir compassionate use program. In 55 patients, daclatasvir or simeprevir were added. Child-Pugh class and model of end stage liver disease (MELD) scores were evaluated at baseline and 36 weeks after the start of therapy. The sustained viral response (SVR) was 86.7% (316/365) in patients who received sofosbuvir/ribavirin and 98.3% (58/59) in patients who received a second antiviral (P < 0.01). In patients treated with sofosbuvir/ribavirin, a significant difference in SVR was observed between patients diagnosed with METAVIR F4 (211/250; 84.4%), METAVIR F3 (95/105; 90.5%) and fibrosing cholestatic hepatitis (10/10; 100%) (P = 0.049). A significant association was found between patients who worsened from Child-Pugh class A and who experienced viral relapse (4/26 vs. 8/189, P = 0.02). In patients with a baseline MELD score <15, a significant association was found between maintaining a final MELD score <15 and the achievement of SVR (187/219 vs. 6/10, P = 0.031). This real-world study indicates that sofosbuvir/ribavirin treatment for 24 weeks was effective, and the achievement of SVR was associated with a reduced probability of developing worsening liver function.