Publications by authors named "Antonio Craxí"

288 Publications

Addressing HCV Elimination Barriers in Italy: Healthcare Resource Utilization and Cost Impact Using 8 Weeks' Glecaprevir/Pibrentasvir Therapy.

Infect Dis Ther 2021 Mar 3. Epub 2021 Mar 3.

GI and Liver Unit, PROMISE, University of Palermo, Palermo, Italy.

Introduction: In Italy, hepatitis C virus (HCV) elimination is achievable; however, barriers remain to achieving the World Health Organization's elimination targets, and have become more pronounced with the spread of COVID-19. Glecaprevir/pibrentasvir (G/P) is a direct-acting antiviral therapy for HCV, approved for 8-week treatment in patients without cirrhosis, and with compensated cirrhosis (CC). Previously, 12 weeks of therapy was recommended for patients with CC. Shortened treatment may reduce the burden on healthcare resources, allowing more patients to be treated. This study presents the benefits that 8-week vs 12-week treatment with G/P may have in Italy.

Methods: A multicohort Markov model was used to assess the collective number of healthcare visits and time on treatment with 8-week vs 12-week G/P in the HCV-infected population of Italy from 2019 to 2030, using healthcare resource data from post-marketing observational studies of G/P. Increased treatment capacity and downstream clinical and economic benefits were also assessed assuming the reallocation of saved healthcare visits to treat more patients.

Results: Modeled outcomes showed that by 2030, 8-week treatment saved 27,006 years on therapy compared with 12-week treatment, with 21,065 fewer hepatologist visits. Reallocating these resources to treat more patients could increase capacity to treat 5064 (1.4%) more patients with 8 weeks of G/P, all with CC. This increased treatment capacity would further avoid 2257 cases of end-stage liver disease, 893 liver-related deaths, and provide net savings to the healthcare system of nearly €70 million.

Conclusion: The modeled comparisons between 8- and 12-week treatment with G/P show that shorter treatment duration can lead to greater time and resource savings, both in terms of healthcare visits and downstream costs. These benefits have the potential to enable the treatment of more patients to overcome elimination barriers in Italy through programs aimed to engage and treat targeted HCV populations.
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http://dx.doi.org/10.1007/s40121-021-00410-0DOI Listing
March 2021

Estimated prevalence of undiagnosed HCV infected individuals in Italy: A mathematical model by route of transmission and fibrosis progression.

Epidemics 2021 Feb 11;34:100442. Epub 2021 Feb 11.

Gastroenterology and Liver Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy.

Background: The universal treatment of diagnosed patients with chronic HCV infection has been widely conducted in Italy since 2017. However, the pool of individuals diagnosed but yet to be treated in Italy has been estimated to end around 2025, leaving a significant proportion of infected individuals undiagnosed/without care. Estimates of this population are currently unknown.

Methods: A probabilistic modelling approach was applied to estimate annual historical HCV incident cases by their age-group (0-100 years) distribution from available literature and Italian National database (1952 to October 2019). Viraemic infection rates were modelled on the main infection routes in Italy: people who inject drugs (PWID), tattoos, sexual transmission, glass syringe use, blood transfusion and vertical transmission. Annual liver fibrosis stage transition probabilities were modelled using a Markov model. The number of HCV viraemic asymptomatic (fibrosis stage F0-F3:potentially undiagnosed/unlinked to care) and symptomatic (fibrosis stage F4: potentially linked to care) individuals was estimated.

Results: By October 2019, total viraemic HCV individuals in Italy (excluding treated patients since 1992) were estimated to be 410,775 (0.68 % of current population of Italy; 95 % CI: 0.64-0.71%, based on the current Italian population), of which 281,809 (0.47 %; 95 % CI:0.35-0.60%) were fibrosis stage F0-F3. Among different high risk groups in stage F0-F3, the following distribution was estimated: PWID; 52.0 % (95 % CI:37.9-66.6 %), tattoo; 28.8 % (95 % CI:23-32.3 %), sexual transmission; 12.0 % (95 % CI:9.6-13.7 %), glass syringe and transfusion; 6.4 % (95 % CI:2.4-17.8 %), and vertical transmission; 0.7 % (95 % CI:0.4-1.2 %).

Conclusion: Under the assumption that most untreated HCV-infected individuals with stage F0-F3 are undiagnosed, more than 280,000 individuals are undiagnosed and/or unlinked to care in Italy. Marked heterogeneity across the major routes of HCV transmission was estimated. This modelling approach may be a useful tool to characterise the HCV epidemic profile also in other countries, based on country specific epidemiology and HCV main transmission routes.
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http://dx.doi.org/10.1016/j.epidem.2021.100442DOI Listing
February 2021

Guidelines Have a Key Role in Driving HCV Elimination by Advocating for Simple HCV Care Pathways.

Adv Ther 2021 Feb 16. Epub 2021 Feb 16.

Department of Gastroenterology and Hepatology, CHU Pontevedra and IIS Galicia Sur, Pontevedra, Spain.

The availability of pangenotypic direct-acting antivirals for treatment of hepatitis C (HCV) has provided an opportunity to simplify patient pathways. Recent clinical practice guidelines have recognised the need for simplification to ensure that elimination of HCV as a public health concern remains a priority. Despite the move towards simplified treatment algorithms, there remains some complexity in the recommendations for the management of genotype 3 patients with compensated cirrhosis. In an era where additional clinical trial data are not anticipated, clinical guidance should consider experience gained in real-world settings. Although more experience is required for some pangenotypic therapeutic options, on the basis of published real-world data, there is already sufficient evidence to consider a simplified approach for genotype 3 patients with compensated cirrhosis. The coronavirus disease 2019 (COVID-19) pandemic has highlighted the need to minimise the need for complex patient pathways and clinical practice guidelines need to continue to evolve in order to ensure that patient outcomes remain optimised.
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http://dx.doi.org/10.1007/s12325-021-01636-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884205PMC
February 2021

The impact of direct acting antivirals on hepatitis C virus disease burden and associated costs in four european countries.

Liver Int 2021 Feb 2. Epub 2021 Feb 2.

Center for Global Health, Istituto Superiore di Sanità, Rome, Italy.

Background And Aims: We assessed the clinical and economic impact of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) in England, Italy, Romania and Spain.

Methods: An HCV progression Markov model was developed considering DAA eligibility and population data during the years 2015-2019. The period of time to recover the investment in DAAs was calculated as the cost saved by avoiding estimated clinical events for 1000 standardized treated patients. A delayed treatment scenario because of coronavirus disease (COVID-19) was also developed.

Results: The estimated number of avoided hepatocellular carcinoma, decompensated cirrhosis and liver transplantations over a 20-year time horizon was: 1,057 in England; 1,221 in Italy; 1,211 in Romania; and 1,103 in Spain for patients treated during 2015-2016 and 640 in England; 626 in Italy; 739 in Romania; and 643 in Spain for patients treated during 2017-2019. The cost-savings ranged from € 45 to € 275 million. The investment needed to expand access to DAAs in 2015-2019 is estimated to be recovered in 6.5 years in England; 5.4 years in Italy; 6.7 years in Romania; and 4.5 years in Spain. A delay in treatment because of COVID-19 will increase liver mortality in all countries.

Conclusion: Direct-acting antivirals have significant clinical benefits and can bring substantial cost-savings over the next 20 years, reaching a Break-even point in a short period of time. When pursuing an exit strategy from strict lockdown measures for COVID-19, providing DAAs should remain high on the list of priorities in order to maintain HCV elimination efforts.
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http://dx.doi.org/10.1111/liv.14808DOI Listing
February 2021

Resistance analysis and treatment outcomes in hepatitis C virus genotype 3-infected patients within the Italian network VIRONET-C.

Liver Int 2021 Jan 26. Epub 2021 Jan 26.

Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy.

Aim: This study aimed to investigate the role of resistance-associated substitutions (RASs) to direct-acting-antivirals (DAAs) in HCV genotype 3 (GT3).

Methods: Within the Italian VIRONET-C network, a total of 539 GT3-infected patients (417 DAA-naïve and 135 DAA-failures, of them, 13 at both baseline and failure) were analysed. Sanger sequencing of NS3/NS5A/NS5B was performed following home-made protocols.

Results: The majority of patients were male (79.4%), 91.4% were injection drug users, 49.3% were cirrhotic and 13.9% were HIV co-infected. Phylogenetic analysis classified sequences as GT3a-b-g-h (98%-0.4%-0.2%-1.2%) respectively. Overall, 135 patients failed a DAA regimen: sofosbuvir (SOF)/daclatasvir (DCV) or velpatasvir (VEL)±ribavirin (RBV) (N = 91/15) and glecaprevir (G)/pibrentasvir (P) (N = 9). Moreover, 14.8% of patients were treated with suboptimal regimens for GT3: 3D ± RBV (Paritaprevir/r + Ombitasvir+Dasabuvir, N = 15), SOF + Simeprevir (SIM) (N = 1) or SOF/Ledipasvir (LDV) ± RBV (N = 4). RAS prevalence was 15.8% in DAA-naïve patients. At failure, 81.5% patients showed at least one RAS: 11/25 (44.0%) in NS3, 109/135 (80.7%) in NS5A, 7/111 (6.3%) in NS5B SOF-failures. In NS5A-failures, Y93H RAS was the most prevalent (68.5% vs 5.1% DAA-naïve, P < .001) followed by A30K (12.7% vs 2.8% in DAA-naïve, P < .001). Analysing baseline samples, a higher prevalence of NS5A-RASs was observed before treatment in DAA-failures (5/13, 38.5%) vs DAA-naïves (61/393, 15.5%, P = .04). Regarding 228 DAA-naïve patients with an available outcome, 93.9% achieved a SVR. Interestingly, patients with baseline Y93H and/or A30K had SVR rate of 72.2% vs 95.7% for patients without NS5A-RASs (P = .002).

Conclusions: In this real-life GT3 cohort, the majority of failures harboured resistant variants carrying NS5A-RASs, the most frequent being Y93H. The presence of natural NS5A-RASs before treatment was associated with failure. Further analyses are needed to confirm this observation, particularly for the new current regimens.
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http://dx.doi.org/10.1111/liv.14797DOI Listing
January 2021

Absolute targets for HCV elimination and national health policy paradigms: Foreseeing future requirements.

Liver Int 2021 Jan 23. Epub 2021 Jan 23.

Humanitas University and Humanitas Clinical and Research Center IRCCS, Rozzano, Italy.

The World Health Organization (WHO) targets for eliminating HCV by 2030 may be overambitious for many high-income countries. Recent analyses (ie, data from 2017 to 2019) show that only 11 countries are on track for meeting WHO's elimination targets. For a country to be truly on track, it is important that the majority of infected individuals be identified and treated. There is still a need for country and population-specific evaluations within the different HCV screening and treatment strategies available, in order to assess their cost-effectiveness and sustainability and support an evidence-based policy for HCV elimination. Any health policy model is affected by the diversity and quality of the available data and by gaps in data. Given the differences among countries, comparing progress based on fixed global targets will not necessarily be suitable in the same measure for each country. In a recent document, the European Collaborators of Polaris Observatory provide insight into the limitations of the current WHO targets. The absolute targets identified by each country in accordance with the measures set by WHO would be essential in reaching the HCV elimination. All analytic models to assess the progress towards HCV elimination are based on projections to 2030 not including the impact of the COVID-19 pandemic on hepatitis-related services. With specific regard to the achievement of WHO hepatitis elimination goals, all measures that will be put in place during and after COVID-19 pandemic could be transferred in increasing diagnosis and linkage to care of people with hepatitis.
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http://dx.doi.org/10.1111/liv.14796DOI Listing
January 2021

Progression-Free Survival Early Assessment Is a Robust Surrogate Endpoint of Overall Survival in Immunotherapy Trials of Hepatocellular Carcinoma.

Cancers (Basel) 2020 Dec 30;13(1). Epub 2020 Dec 30.

Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy.

Background: Radiology-based outcomes, such as progression-free survival (PFS) and objective response rate (ORR), are used as surrogate endpoints in oncology trials. We aimed to assess the surrogacy relationship of PFS with overall survival (OS) in clinical trials of systemic therapies targeting advanced hepatocellular carcinoma (HCC) by novel meta-regression methods.

Methods: A search of databases (PubMed, American Society of Clinical Oncology (ASCO), and European Society for Medical Oncology (ESMO) Meeting Libraries, Clinicaltrials.gov) for trials of systemic therapies for advanced HCC reporting both OS and PFS was performed. Individual patient data were extracted from PFS and OS Kaplan-Meier curves. Summary median PFS and OS data were obtained from random-effect model. The surrogate relationships of median PFS, first quartile (Q1), third quartile (Q3), and restricted mean survival time (RMST) for OS were evaluated by the coefficient of determination R. Heterogeneity was explored by meta-regression.

Results: We identified 49 trials, 11 assessing immune-checkpoint inhibitors (ICIs) and 38 multikinase inhibitors (MKIs). Overall, the correlation between median PFS and median OS was weak (R = 0.20. 95% Confidence Intervals [CI]-0.02;0.42). Surrogacy robustness varied between treatment classes and PFS endpoints. In ICI trials only, the correlations between Q1-PFS and Q1-OS and between 12-month PFS-RMST and 12-month OS-RMST were high (R = 0.89, 95%CI 0.78-0.98, and 0.80, 95% CI 0.63-0.96, respectively). Interaction -values obtained by meta-regression confirmed the robustness of results.

Conclusions: In trials of systemic therapies for advanced HCC, the surrogate relationship of PFS with OS is highly variable depending on treatment class (ICI or MKI) and evaluation time-point. In ICI trials, Q1-PFS and 12-month PFS-RMST are robust surrogate endpoints for OS.
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http://dx.doi.org/10.3390/cancers13010090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796103PMC
December 2020

Reply to: correspondence on "Hepatic benefits of HCV cure".

J Hepatol 2020 Dec 17. Epub 2020 Dec 17.

GI & Liver Unit, Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.12.015DOI Listing
December 2020

Genetic variation in the TLL1 gene is not associated with fibrosis in patients with metabolic associated fatty liver disease.

PLoS One 2020 11;15(12):e0243590. Epub 2020 Dec 11.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia.

Metabolic associated fatty liver disease (MAFLD) is the most prevalent liver disease in Western nations, with high heritability. A recent study of Japanese patients with the disease suggested that TLL1 rs17047200 is associated with fibrosis; whether a similar association is observed in Caucasian patients with MAFLD is unknown. We investigated the association of the TLL1 rs17047200 polymorphism with liver fibrosis in a cohort of Caucasian patients with MAFLD (n = 728). We also investigated whether TLL1 expression is altered during liver injury in humans, in murine models of fibrosis, and in in-vitro. While TLL1 expression is upregulated in the liver of humans with MAFLD and in mice, the rs17047200 variant was not associated with fibrosis or any other histological features, or with hepatic TLL1 expression. In conclusion, the TLL1 rs17047200 variant is not a risk variant for fibrosis in Caucasian patients with MAFLD. However, TLL1 could be involved in the pathogenesis of liver fibrosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243590PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732106PMC
January 2021

Metabolic comorbidities and male sex influence steatosis in chronic hepatitis C after viral eradication by direct-acting antiviral therapy (DAAs): Evaluation by the controlled attenuation parameter (CAP).

Dig Liver Dis 2020 Nov 17. Epub 2020 Nov 17.

Unit of Internal Medicine and Metabolic Disease, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Italy; Department of Pathophysiology and Transplantation, University of Milan, Italy.

Background: Chronic hepatitis C (CHC) is associated with hepatic steatosis, related to both a direct viral action and metabolic features. Vice-versa data on hepatic steatosis after viral eradication by direct-acting antiviral agents (DAA) are undefined although the presence of metabolic alterations could strongly influence the occurrence of steatosis as in NAFLD. The controlled attenuation parameter (CAP) (FibroscanⓇ) allows the qualitative and quantitative evaluation of fatty liver.

Aim: to evaluate in patients with CHC whether hepatic steatosis diagnosed by CAP modifies after DAAs-induced sustained virologic response (SVR).

Methods: Data were collected the day of DAAs therapy starting and six months after SVR. CAP ≥ 248 dB/m defined the presence of steatosis.

Results: 794 CHC SVR patients referring to 2 Italian Units were enrolled. Mean age was 64 ± 16 ys, 50% males, BMI 25.4 ± 4 kg/m, genotype type-1 in 73%, type-3 in 8%. Prevalence of hepatic steatosis at baseline was 32% by US and 46% by CAP. De novo steatosis developed in 125 (29%), resolution in 122 (30%). At multivariate analysis de novo steatosis was independently associated with male sex (OR 1.7, CI 95% 1.09-2.67; p = 0.02) and baseline BMI (for unit increase OR 1.19, CI 95%1.11-1.29; p < 0.001). Baseline BMI (for unit increase OR 0.47, CI 95% 0.25-0.89; p = 0.02) and triglycerides (for unit increase OR 0.93, CI 95% 0.87-0.99; p = 0.03) prevented steatosis resolution after therapy.

Conclusions: after SVR de novo steatosis and resolution of baseline steatosis are closely related to the presence of metabolic comorbidities.
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http://dx.doi.org/10.1016/j.dld.2020.11.001DOI Listing
November 2020

SARS-CoV-2 infection in patients with a normal or abnormal liver.

J Viral Hepat 2021 01 1;28(1):4-11. Epub 2020 Dec 1.

Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel coronavirus causing coronavirus disease 19 (COVID-19), with an estimated 22 million people infected worldwide so far although involving primarily the respiratory tract, has a remarkable tropism for the liver and the biliary tract. Patients with SARS-CoV-2 infection and no antecedent liver disease may display evidence of cytolytic liver damage, proportional to the severity of COVID-19 but rarely of clinical significance. The mechanism of hepatocellular injury is unclear and possibly multifactorial. The clinical impact of SARS-CoV-2 infection in patients with underlying chronic liver disease, a cohort whose global size is difficult to estimate, has been assessed appropriately only recently and data are still evolving. Patients with cirrhosis are at higher risk of developing severe COVID-19 and worse liver-related outcomes as compared to those with non-cirrhotic liver disease. OLT patients have an intermediate risk. Specific interventions in order to reduce the risk of transmission of infection among this high-risk population have been outlined by international societies, together with recommendations for modified treatment and follow-up regimens during the COVID-19 pandemic. When a vaccine against SARS-CoV-2 becomes available, patients with fibrotic liver disease and those with OLT should be considered as prime targets for prophylaxis of COVID-19, as all other highly susceptible subjects.
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http://dx.doi.org/10.1111/jvh.13440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753389PMC
January 2021

Luigi Pagliaro, 1931-2020.

Authors:
Antonio Craxì

Dig Liver Dis 2021 Jan 10;53(1):141-142. Epub 2020 Nov 10.

Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.dld.2020.10.027DOI Listing
January 2021

PCSK9 rs11591147 R46L loss-of-function variant protects against liver damage in individuals with NAFLD.

Liver Int 2021 Feb 2;41(2):321-332. Epub 2020 Nov 2.

Sezione di Gastroenterologia e Epatologia, PROMISE, University of Palermo, Palermo, Italy.

Background And Aims: The proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis, and its inhibition represents an effective therapy to lower low-density lipoprotein cholesterol (LDL-C) levels. In this study, we examined the impact of the PCSK9 rs11591147 loss-of-function (LOF) variant on liver damage in a multicenter collection of patients at risk of nonalcoholic steatohepatitis (NASH), in clinical samples and experimental models.

Methods: We considered 1874 consecutive individuals at risk of NASH as determined by histology. The SNP rs11591147, encoding for the p.R46L variant of PCSK9, was genotyped by TaqMan assays. We also evaluated 1) PCSK9 mRNA hepatic expression in human liver, and 2) the impact of a NASH-inducing diet in mice with hepatic overexpression of human PCSK9.

Results: Carriers of PCSK9 rs11591147 had lower circulating LDL-C levels and were protected against nonalcoholic fatty liver disease (NAFLD) (OR: 0.42; 95% CI: 0.22-0.81; P = .01), NASH (OR: 0.48; 95% CI: 0.26-0.87; P = .01) and more severe fibrosis (OR: 0.55; 95% CI: 0.32-0.94; P = .03) independently of clinical, metabolic and genetic confounding factors. PCSK9 hepatic expression was directly correlated with liver steatosis (P = .03). Finally, liver-specific overexpression of human PCSK9 in male mice drives NAFLD and fibrosis upon a dietary challenge.

Conclusions: In individuals at risk of NASH, PCSK9 was induced with hepatic fat accumulation and PCSK9 rs11591147 LOF variant was protective against liver steatosis, NASH and fibrosis, suggesting that PCSK9 inhibition may be a new therapeutic strategy to treat NASH.
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http://dx.doi.org/10.1111/liv.14711DOI Listing
February 2021

SARS-CoV-2 Viral Load, IFNλ Polymorphisms and the Course of COVID-19: An Observational Study.

J Clin Med 2020 Oct 15;9(10). Epub 2020 Oct 15.

Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, 90127 Palermo, Italy.

The course of SARS-CoV-2 infection ranges from asymptomatic to a multiorgan disease. In this observational study, we investigated SARS-CoV-2 infected subjects with defined outcomes, evaluating the relationship between viral load and single nucleotide polymorphisms of genes codifying for IFNλs (interferon). The study enrolled 381 patients with laboratory-confirmed SARS-CoV-2 infection. For each patient, a standardized form was filled including sociodemographic variables and clinical outcomes. The host's gene polymorphisms (IFNL3 rs1297860 C/T and INFL4 rs368234815 TT/ΔG) and RtReal-Time PCR cycle threshold (PCR Ct) value on SARS-CoV-2 were assessed on nasal, pharyngeal or nasopharyngeal swabs. Higher viral loads were found in patients aged > 74 years and homozygous mutant polymorphisms DG in IFNL4 (adj-OR = 1.16, 95% CI = 1.01-1.34 and adj-OR = 1.24, 95% CI = 1.09-1.40, respectively). After adjusting for age and sex, a statistically significantly lower risk of hospitalization was observed in subjects with higher RtReal-Time PCR cycle threshold values (adj-OR = 0.95, 95% CI = 0.91, 0.99; = 0.028). Our data support the correlation between SARS-CoV-2 load and disease severity, and suggest that IFNλ polymorphisms could affect the ability of the host to modulate viral infection without a clear impact on the outcome of COVID-19.
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http://dx.doi.org/10.3390/jcm9103315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602550PMC
October 2020

Tailored screening and dedicated funding for direct acting antiviral drugs: how to keep Italy on the road to hepatitis C virus elimination?

Ann Ist Super Sanita 2020 Jul-Sep;56(3):325-329

Dipartimento Biomedico di Medicina Interna e Specialistica, Università degli Studi di Palermo, Palermo, Italy.

Background And Aims: Hepatitis C virus (HCV) elimination for Italy is an ambitious, but achievable goal. In Italy, there is political will, which aims to achieve the World Health Organization (WHO) elimination goals recognizing the need to identify undiagnosed individuals in key high-risk groups and in the general population, however there is concern regarding HCV treatment implementation in Italian Regions.

Methods: A modelling analysis was conducted, using the "Italy Polaris" model, to forecast the impact of different HCV treatment rates in achieving the HCV elimination goals in Italy. The model assessed two treatment scenarios: 2018 Scenario and 2019 Scenario, using the annually HCV treatment rate in Italy.

Results: Considering a high treatment rate, as assumed by the 2018 Scenario, all HCV elimination targets would be achieved. Considering the 2019 Scenario, in which a decreasing number of newly diagnosed individuals and as consequence, a decline in the number of treated patients, were assumed, only the 65% HCV mortality reduction would be an achievable goal in Italy. The other elimination targets could be achievable over 7 years later than the year 2030.

Conclusions: Establishing an ad hoc fund for DAAs for each Italian Region, binding resources both for case finding, through active screening and activities for rapid linkage to care and treatment, is of paramount importance, in order to keep Italy on track to achieve the WHO elimination targets by 2030.
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http://dx.doi.org/10.4415/ANN_20_03_10DOI Listing
September 2020

Effectiveness and safety of glecaprevir/pibrentasvir in chronic hepatitis C patients: Results of the Italian cohort of a post-marketing observational study.

Dig Liver Dis 2020 Sep 8. Epub 2020 Sep 8.

Dipartimento di Medicina Sperimentale e Clinica, Centro Interdipartimentale di Epatologia Università di Firenze e C.R.I.A. MASVE AOU Careggi, Firenze, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.dld.2020.08.007DOI Listing
September 2020

PNPLA3 rs738409 C>G Variant Predicts Fibrosis Progression by Noninvasive Tools in Nonalcoholic Fatty Liver Disease.

Clin Gastroenterol Hepatol 2020 Sep 6. Epub 2020 Sep 6.

Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy.

Liver fibrosis is the main predictor of events in patients with nonalcoholic fatty liver disease (NAFLD), and its evolution is characterized by a nonlinear trend mostly affected by metabolic risk factors, severity of liver inflammation and steatosis, and weight loss. The rs738409 C>G common variant in PNPLA3 gene has been associated with severity of fibrosis and risk of liver-related events in NAFLD. Noninvasive tests as Fibrosis-4 (FIB-4) and liver stiffness measurement (LSM) are useful to rule-out advanced fibrosis and they could be reliable to predict fibrosis progression. We aimed to evaluate in patients with NAFLD whether PNPLA3 rs738409 C>G variant impacts on fibrosis progression, noninvasively assessed by FIB-4 and LSM.
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http://dx.doi.org/10.1016/j.cgh.2020.09.009DOI Listing
September 2020

Genetic susceptibility of increased intestinal permeability is associated with progressive liver disease and diabetes in patients with non-alcoholic fatty liver disease.

Nutr Metab Cardiovasc Dis 2020 10 27;30(11):2103-2110. Epub 2020 Jun 27.

University Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medicine and Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Background And Aim: Increased intestinal permeability plays a key role in the pathogenesis of fat deposition in the liver. The aim of our study was to assess whether a single nucleotide polymorphism of protein tyrosine phosphatase non-receptor type 2 (PTPN2) (rs2542151 T→G), involved in intestinal permeability, may be associated with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM).

Methods And Results: We recruited a prospective cohort of NAFLD subjects and matched controls. Clinical data, PTPN2 genotype and laboratory data were collected for each patient. Results were stratified according to liver histology and diabetes. We enrolled 566 cases and 377 controls. PTPN2 genotype distribution did not significantly differ between patients and controls. In the entire population, patients with PTPN2 rs2542151 T→G (dominant model) have a higher prevalence of diabetes; 345 patients (60.9%) underwent liver biopsy: 198 (57.4%) had steatohepatitis and 75 (21.7%) had advanced fibrosis. At multiple logistic regression analysis PTPN2 rs2542151 T→G was associated with T2DM (OR 2.14, 95% CI 1.04-4.40, P = 0.03). Patients who underwent liver biopsy, rs2542151 T→G of PTPN2 was independently associated with severe steatosis (OR 2.00, 95% CI 1.17-3.43, p = 0.01) and severe fibrosis (OR 2.23, 95% CI 1.06-4.72, P = 0.03).

Conclusion: Our study shows that NAFLD patients with rs2542151 T→G of PTPN2 have a higher severity of fatty liver disease and a higher prevalence of T2DM. These results suggest that individual genetic susceptibility to intestinal permeability could play a role in liver disease progression.
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http://dx.doi.org/10.1016/j.numecd.2020.06.013DOI Listing
October 2020

EASL Recognition Awardee 2020: Prof. Giovanna Fattovich.

Authors:
Antonio Craxi

J Hepatol 2020 Sep;73(3):484-486

Department of Internal Medicine, University of Palermo, Palermo, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.02.003DOI Listing
September 2020

Hepatic benefits of HCV cure.

J Hepatol 2020 Dec 7;73(6):1548-1556. Epub 2020 Aug 7.

GI & Liver Unit, Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo.

Direct-acting antiviral (DAA)-induced HCV clearance conceivably leads to improved outcomes at all stages of liver disease. However, available data suggest that the maximum measurable benefit is obtained by treating patients before they reach the stage of compensated advanced chronic liver disease (cACLD). Ideally, all patients with chronic hepatitis C should be treated before they develop advanced fibrosis or cirrhosis, since even if sustained virologic response (SVR) reduces the risk of hepatic events (e.g. decompensation and hepatocellular carcinoma [HCC]) and improves survival, further progression of liver disease and adverse outcomes, including hepatic deaths, cannot be entirely avoided. The hepatic venous pressure gradient (HVPG) correlates closely with the stage of liver disease. Measurements of HVPG in patients with severe fibrosis or cirrhosis treated with DAAs show that those with the highest degree of portal hypertension have the lowest probability of a meaningful reduction of portal pressure after SVR, and remain at significant risk of decompensation. Reduced liver stiffness is commonly observed in patients with cACLD but its role in predicting prognosis is yet to be demonstrated. In patients with decompensated cirrhosis, prevention of further decompensation and of HCC is only weakly associated with SVR. Overall, the main clinical predictors of a high risk of HCC in patients who obtain SVR on DAAs are all indexes strongly reflecting advanced fibrosis and impaired hepatic function. Long-term follow-up of large real-life cohorts of patients treated at all stages of liver disease, but mainly those with mild to moderate fibrosis, will be needed to confirm the impact of SVR among diverse HCV-infected populations and, more importantly, to better stratify patients at higher risk of complications in order to define their correct surveillance.
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http://dx.doi.org/10.1016/j.jhep.2020.08.006DOI Listing
December 2020

Impact of COVID-19 on global HCV elimination efforts.

J Hepatol 2021 01 7;74(1):31-36. Epub 2020 Aug 7.

Gastroenterology and Hepatology Unit, Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.

Background & Aims: Coronavirus disease 2019 (COVID-19) has placed a significant strain on national healthcare systems at a critical moment in the context of hepatitis elimination. Mathematical models can be used to evaluate the possible impact of programmatic delays on hepatitis disease burden. The objective of this analysis was to evaluate the incremental change in HCV liver-related deaths and liver cancer, following a 3-month, 6-month, or 1-year hiatus in hepatitis elimination programs.

Methods: Previously developed models were adapted for 110 countries to include a status quo or 'no delay' scenario and a '1-year delay' scenario assuming significant disruption in interventions (screening, diagnosis, and treatment) in the year 2020. Annual country-level model outcomes were extracted, and weighted averages were used to calculate regional (WHO and World Bank Income Group) and global estimates from 2020 to 2030. The incremental annual change in outcomes was calculated by subtracting the 'no-delay' estimates from the '1-year delay' estimates.

Results: The '1-year delay' scenario resulted in 44,800 (95% uncertainty interval [UI]: 43,800-49,300) excess hepatocellular carcinoma cases and 72,300 (95% UI: 70,600-79,400) excess liver-related deaths, relative to the 'no-delay' scenario globally, from 2020 to 2030. Most missed treatments would be in lower-middle income countries, whereas most excess hepatocellular carcinoma and liver-related deaths would be among high-income countries.

Conclusions: The impact of COVID-19 extends beyond the direct morbidity and mortality associated with exposure and infection. To mitigate the impact on viral hepatitis programming and reduce excess mortality from delayed treatment, policy makers should prioritize hepatitis programs as soon as it becomes safe to do so.

Lay Summary: COVID-19 has resulted in many hepatitis elimination programs slowing or stopping altogether. A 1-year delay in hepatitis diagnosis and treatment could result in an additional 44,800 liver cancers and 72,300 deaths from HCV globally by 2030. Countries have committed to hepatitis elimination by 2030, so attention should shift back to hepatitis programming as soon as it becomes appropriate to do so.
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http://dx.doi.org/10.1016/j.jhep.2020.07.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411379PMC
January 2021

Reduced incidence of type 2 diabetes in patients with chronic hepatitis C virus infection cleared by direct-acting antiviral therapy: A prospective study.

Diabetes Obes Metab 2020 12 6;22(12):2408-2416. Epub 2020 Sep 6.

Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy.

Aim: To assess the effect of hepatitis C virus (HCV) eradication on type 2 diabetes mellitus (T2DM). incidence.

Methods: A prospective multicentre case-control study was performed, which included 2426 patients with HCV, 42% of whom had liver fibrosis stage F0-F2 and 58% of whom had liver fibrosis stage F3-F4. The study population consisted of a control group including 1099 untreated patients and 1327 cases treated with direct-acting antivirals (DAAs). T2DM incidence was assessed during a median (interquartile range) follow-up period of 30 (28-42) months. Risk factors for T2DM were assessed using a Cox regression model (relative risk [RR], hazard ratio [HR], Kaplan-Meier analysis). Insulin sensitivity was evaluated by homeostatic model assessment (HOMA) and changes by repeated-measures ANOVA. Factors independently associated with T2DM were assessed by multivariate analysis.

Results: The absolute incidence of T2DM for controls and cases was 28 and 7/1000 person-years, respectively (P = 0.001). In cases compared to controls, HCV clearance reduced the RR and HR of T2DM by 81% and 75% to 93%, respectively (P = 0.001). It was calculated that, for every 15 patients who obtained HCV clearance, one case of T2DM was saved. HCV clearance was associated with significant reductions in HOMA-insulin resistance and HOMA-β-cell function and an increase in HOMA-insulin sensitivity, as assessed in 384 patients before and after HCV clearance. At multivariate analysis, HCV clearance emerged as independently associated with a reduced T2DM risk.

Conclusion: The results showed that HCV clearance by DAA treatment reduces T2DM incidence probably by restoring the HCV-induced alteration of glucose homeostasis mechanisms.
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http://dx.doi.org/10.1111/dom.14168DOI Listing
December 2020

Primary biliary cholangitis management: controversies, perspectives and daily practice implications from an expert panel.

Liver Int 2020 11 16;40(11):2590-2601. Epub 2020 Sep 16.

Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

Primary biliary cholangitis (PBC) is a rare progressive immune-mediated liver disease that, if not adequately treated, may culminate in end-stage disease and need for transplantation. According to current guidelines, PBC is diagnosed in the presence of antimitochondrial antibodies (AMA) or specific antinuclear antibodies, and of a cholestatic biochemical profile, while biopsy is recommended only in selected cases. All patients receive ursodeoxycholic acid (UDCA) in first line; the only registered second-line therapy is obeticholic acid (OCA) for UDCA-inadequate responders. Despite the recent advances in understanding PBC pathogenesis and developing new treatments, many grey areas remain. Six Italian experts selected the following topics as the most urgent to address in PBC management: diagnosis and natural history of PBC: as a portion of the subjects with isolated AMA, normal alkaline phosphatase (ALP) levels and no symptoms of liver disease could have PBC by histology, defining how to manage and follow this population is crucial; role of liver biopsy: recent evidence suggests that biopsy may provide relevant information for risk stratification and prediction of UDCA response, possibly facilitating personalized approaches; risk stratification: the tools for risk stratification are well established, but some issues (eg bile acid dosage in routine practice) remain controversial; and therapy: those in more advanced stages of development are nuclear receptor modulators and fibrates, but more data are needed to plan personalized strategies. In this manuscript, for each topic, current evidence, controversies and future perspectives are summarized with the possible implications for clinical practice.
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http://dx.doi.org/10.1111/liv.14627DOI Listing
November 2020

Optimizing Sequential Systemic Therapies for Advanced Hepatocellular Carcinoma: A Decision Analysis.

Cancers (Basel) 2020 Jul 31;12(8). Epub 2020 Jul 31.

Department of Health Promotion Sciences Maternal and Infant Care, Section of Gastroenterology & Hepatology, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy.

An optimal sequential systemic therapy for advanced hepatocellular carcinoma (HCC) has not been discovered. We developed a decision model based on available clinical trials to identify an optimal risk/benefit strategy for sequences of novel systemic agents. A Markov model was built to simulate overall survival (OS) among patients with advanced HCC. Three first-line (single-agent Sorafenib or Lenvatinib, and combination of Atezolizumab plus Bevacizumab) followed by five second-line treatments (Regorafenib, Cabozantinib, Ramucirumab, Nivolumab, Pembrolizumab) were compared in fifteen sequential strategies. The likelihood of transition between states (initial treatment, cancer progression, death) was derived from clinical trials. Life-year gained (LYG) was the main outcome. Rates of severe adverse events (SAEs) (≥grade 3) were calculated. The innovative measure, called incremental safety-effectiveness ratio (ISER), of the two best sequential treatments was calculated as the difference in probability of SAEs divided by LYG. Lenvatinib followed by Nivolumab (median OS, 27 months) was the most effective sequence, producing a LYG of 0.75, while Atezolizumab plus Bevacizumab followed by Nivolumab was the safest sequence (SAEs 40%). Accordingly, the net health benefit assessed by ISER favored Lenvatinib followed by Nivolumab, compared to Atezolizumab plus Bevacizumab, followed by Nivolumab in 52% of cases. : Further sequential clinical trials or large-scale real-world studies may prove useful to evaluate the net health benefit of the best sequential treatment for advanced HCC.
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http://dx.doi.org/10.3390/cancers12082132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464739PMC
July 2020

Hepatitis C virus eradication by direct antiviral agents abates oxidative stress in patients with advanced liver fibrosis.

Liver Int 2020 11 4;40(11):2820-2827. Epub 2020 Aug 4.

Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy.

Background And Aims: HCV eradication improves non-hepatic outcomes such as cardiovascular diseases, although without clearly defined mechanisms. In this study we aimed to assess whether improvement of carotid atherosclerosis may be linked to a reduction in systemic oxidative stress after viral clearance.

Methods: We studied a retrospective cohort of 105 patients (age 62.4 ± 11.2 years; 62 men) with F3/F4 fibrosis, characterized by carotid ultrasonography at baseline and at sustained virologic response (SVR) follow-up. Levels of 8-iso-prostaglandin F (F -isoprostanes) and other oxidative stress markers were measured on frozen sera. Association between change (denoted as Δ) in oxidative stress markers (exposures) and change in carotid intima-media thickness (cIMT) (outcome) was examined using multiple linear regression.

Results: Subclinical atherosclerosis, defined as the presence of carotid plaque and/or cIMT ≥ 0.9, was present in 72% of the cohort. All patients achieved SVR that led to reduction in cIMT (0.92 ± 0.20 vs 0.83 ± 0.21 mm, P < .001). HCV eradication markedly decreased serum levels of F -isoprostanes (620.5 [143.2; 1904.1] vs 119.51 [63.2; 400.6] pg/mL, P < .0001), lipid hydroperoxides (13.8 [6.3; 20.7] vs 4.9 [2.3; 9.6] nmol/μl, P < .0001) and 8-hydroxy-2'-deoxyguanosine (558.9 [321.0; 6301.2] vs 294.51 [215.31; 408.95] pg/mL, P < .0001), whereas increased serum GPx activity (10.44 [4.6; 16.3] vs 13.75 [9.42; 20.63] nmol/min/mL, P = .001). By multiple linear regression analysis ΔcIMT was independently associated with ΔF -isoprostanes (β: 1.746 [0.948; 2.543]; P < .0001) after adjustment for age, baseline F -isoprostanes and baseline IMT.

Conclusions: Besides association of lipid peroxidation with severity of liver disease, the reduction in F -isoprostanes may be involved in the improvement of atherosclerosis after HCV eradication.
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http://dx.doi.org/10.1111/liv.14608DOI Listing
November 2020

Monitoring Occurrence of Liver-Related Events and Survival by Transient Elastography in Patients With Nonalcoholic Fatty Liver Disease and Compensated Advanced Chronic Liver Disease.

Clin Gastroenterol Hepatol 2020 Jul 2. Epub 2020 Jul 2.

Centre d'Investigation de la Fibrose Hépatique, INSERM U1053, Hôpital Haut-Lévêque, Bordeaux University Hospital, Pessac, France.

Background & Aims: Patients with advanced fibrosis related to nonalcoholic fatty liver disease (NAFLD) are at risk of developing hepatic and extrahepatic complications. We investigated whether, in a large cohort of patients with NAFLD and compensated advanced chronic liver disease, baseline liver stiffness measurements (LSMs) and their changes can be used to identify patients at risk for liver-related and extrahepatic events.

Methods: We performed a retrospective analysis of consecutive patients with NAFLD (n = 1039) with a histologic diagnosis of F3-F4 fibrosis and/or LSMs>10 kPa, followed for at least 6 months, from medical centers in 6 countries. LSMs were made by FibroScan using the M or XL probe and recorded at baseline and within 1 year from the last follow-up examination. Differences between follow up and baseline LSMs were categorized as: improvement (reduction of more than 20%), stable (reduction of 20% to an increase of 20%), impairment (an increase of 20% or more). We recorded hepatic events (such as liver decompensation, ascites, encephalopathy, variceal bleeding, jaundice, or hepatocellular carcinoma [HCC]) and overall and liver-related mortality during a median follow-up time of 35 months (interquartile range, 19-63 months).

Results: Based on Cox regression analysis, baseline LSM was independently associated with occurrence of hepatic decompensation (hazard ratio [HR], 1.03; 95% CI, 1.02-1.04; P < .001), HCC (HR, 1.03; 95% CI, 1.00-1.04; P = .003), and liver-related death (HR, 1.02; 95% CI, 1.02-1.03; P = .005). In 533 patients with available LSMs during the follow-up period, change in LSM was independently associated with hepatic decompensation (HR, 1.56; 95% CI, 1.05-2.51; P = .04), HCC (HR, 1.72; 95% CI, 1.01-3.02; P = .04), overall mortality (HR, 1.73; 95% CI, 1.11-2.69; P = .01), and liver-related mortality (HR, 1.96; 95% CI, 1.10-3.38; P = .02).

Conclusions: In patients with NAFLD and compensated advanced chronic liver disease, baseline LSM and change in LSM are associated with risk of liver-related events and mortality.
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http://dx.doi.org/10.1016/j.cgh.2020.06.045DOI Listing
July 2020

Will the COVID-19 pandemic affect HCV disease burden?

Dig Liver Dis 2020 09 29;52(9):947-949. Epub 2020 May 29.

Gastroenterology and Liver Unit, PROMISE, University of Palermo, Palermo, Italy.

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http://dx.doi.org/10.1016/j.dld.2020.05.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256501PMC
September 2020

Extrahepatic Manifestations of Chronic Viral C Hepatitis.

Gastroenterol Clin North Am 2020 06 29;49(2):347-360. Epub 2020 Mar 29.

Sezione di Gastroenterologia e Epatologia, PROMISE, Università di Palermo, Italia.

Hepatits C virus (HCV) infection has been largely associated with extrahepatic comorbidities such as diseases related to dysregulation of the immune system, neuropsychiatric disorders, and cardiometabolic alterations. These clinical consequences, together with experimental evidence, suggest a potential (in)direct effect of HCV, contributing to the pathogenesis of these diseases. Various studies have reported a positive effect of viral eradication on occurrence and outcomes of extrahepatic diseases. These observations and the availability of safe and effective direct antiviral agents further underline the need to search for virological eradication in all infected individuals independent of the severity of the liver disease.
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http://dx.doi.org/10.1016/j.gtc.2020.01.012DOI Listing
June 2020

Optimization of hepatitis C virus screening strategies by birth cohort in Italy.

Liver Int 2020 07 2;40(7):1545-1555. Epub 2020 Apr 2.

Centre for Economic and International Studies, Faculty of Economics, University of Rome Tor Vergata, Rome, Italy.

Background And Aims: Cost-effective screening strategies are needed to make hepatitis C virus (HCV) elimination a reality. We determined if birth cohort screening is cost-effective in Italy.

Methods: A model was developed to quantify screening and healthcare costs associated with HCV. The model-estimated prevalence of undiagnosed HCV was used to calculate the antibody screens needed annually, with a €25 000 cost-effectiveness threshold. Outcomes were assessed under the status quo and a scenario that met the World Health Organization's targets for elimination of HCV. The elimination scenario was assessed under five screening strategies.

Results: A graduated birth cohort screening strategy (graduated screening 1: 1968-1987 birth cohorts, then expanding to 1948-1967 cohorts) was the least costly. This strategy would gain approximately 144 000 quality-adjusted life years (QALYs) by 2031 and result in an 89.3% reduction in HCV cases, compared to an 89.6%, 89.0%, 89.7% and 88.7% reduction for inversed graduated screening, 1948-77 birth cohort, 1958-77 birth cohort and universal screening, respectively. Graduated screening 1 yielded the lowest incremental cost-effectiveness ratio (ICER) of €3552 per QALY gained.

Conclusions: In Italy, a graduated screening scenario is the most cost-effective strategy. Other countries could consider a similar birth cohort approach when developing HCV screening strategies.
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http://dx.doi.org/10.1111/liv.14408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384106PMC
July 2020

Impact of hepatitis C virus clearance by direct-acting antiviral treatment on the incidence of major cardiovascular events: A prospective multicentre study.

Atherosclerosis 2020 03 21;296:40-47. Epub 2020 Jan 21.

Division of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy.

Background And Aims: HCV is associated with an increased risk of cardiovascular events (CV). Whether HCV clearance by direct-acting antivirals (DAA) reduces incident CV disease is poorly understood. We investigate whether HCV eradication reduces CV events.

Methods: In a prospective multicentre study, 2204 HCV patients (F0-F2:29.5%, F3-F4: 70.5%) were enrolled. Males were 48%, median age was 68 (59-74) years and BMI 25.9 (23.1-28); 24.7% were smokers, 18% had diabetes, 13.2% had cholesterol levels >200 mg/dl and 9.1% took statins, 44% had hypertension. During an overall median follow-up of 28 (24-39) months, incident CV events, such as ischemic heart disease (IHD) and ischemic cerebral stroke (ICS), were recorded. An overall of 2204 patients were evaluated as control group and 1668 patients after HCV elimination were followed as a case group. Factors associated with CV events were evaluated by uni- and multi-variate analyses.

Results: Incident CV rates per 100 patient years in pre-treatment and untreated controls and treated cases were 1.12, 1.14 and 0.44 (p = 0.0001 vs. controls), respectively, and a decreased of relative risk (RR = 0.379; p = 0.0002) was observed. CV risk was 2.0-3.5 times lower then in controls (HR 3.671; 95%C.I.:1.871-7.201; p < 0.001). The calculated number of patients to be treated to get a benefit in a patient was 55.26. The annual incidence reduction of CV events was 0.68%. HCV clearance was independently associated with CV events reduction (OR, 4.716; 95% C.I.:1.832-12.138; p = 0.001).

Conclusions: HCV clearance by DAA reduces CV events (IHD and ICS) with both clinical and socio-economic benefits.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.01.010DOI Listing
March 2020