Publications by authors named "Luchino Chessa"

30 Publications

  • Page 1 of 1

Natural killer-cell immunoglobulin-like receptors trigger differences in immune response to SARS-CoV-2 infection.

PLoS One 2021 5;16(8):e0255608. Epub 2021 Aug 5.

Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.

Background: The diversity in the clinical course of COVID-19 has been related to differences in innate and adaptative immune response mechanisms. Natural killer (NK) lymphocytes are critical protagonists of human host defense against viral infections. It would seem that reduced circulating levels of these cells have an impact on COVID-19 progression and severity. Their activity is strongly regulated by killer-cell immuno-globulin-like receptors (KIRs) expressed on the NK cell surface. The present study's focus was to investigate the impact of KIRs and their HLA Class I ligands on SARS-CoV-2 infection.

Methods: KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 396 Sardinian patients with SARS-CoV-2 infection. Comparisons were made between 2 groups of patients divided according to disease severity: 240 patients were symptomatic or paucisymptomatic (Group A), 156 hospitalized patients had severe disease (Group S). The immunogenetic characteristics of patients were also compared to a population group of 400 individuals from the same geographical areas.

Results: Substantial differences were obtained for KIR genes, KIR haplotypes and KIR-HLA ligand combinations when comparing patients of Group S to those of Group A. Patients in Group S had a statistically significant higher frequency of the KIR A/A haplotype compared to patients in Group A [34.6% vs 23.8%, OR = 1.7 (95% CI 1.1-2.6); P = 0.02, Pc = 0.04]. Moreover, the KIR2DS2/HLA C1 combination was poorly represented in the group of patients with severe symptoms compared to those of the asymptomatic-paucisymptomatic group [33.3% vs 50.0%, OR = 0.5 (95% CI 0.3-0.8), P = 0.001, Pc = 0.002]. Multivariate analysis confirmed that, regardless of the sex and age of the patients, the latter genetic variable correlated with a less severe disease course [ORM = 0.4 (95% CI 0.3-0.7), PM = 0.0005, PMC = 0.005].

Conclusions: The KIR2DS2/HLA C1 functional unit resulted to have a strong protective effect against the adverse outcomes of COVID-19. Combined to other well known factors such as advanced age, male sex and concomitant autoimmune diseases, this marker could prove to be highly informative of the disease course and thus enable the timely intervention needed to reduce the mortality associated with the severe forms of SARS-CoV-2 infection. However, larger studies in other populations as well as experimental functional studies will be needed to confirm our findings and further pursue the effect of KIR receptors on NK cell immune-mediated response to SARS-Cov-2 infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255608PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341547PMC
August 2021

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology.

J Hepatol 2021 Jul 30. Epub 2021 Jul 30.

Gastroenterology Unit, ASL Latina, Department of Translational and Precision Medicine, "Sapienza" University of Rome, Italy.

Background & Aims: Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model.

Methods: In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses.

Results: In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD.

Conclusions: In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed.

Lay Summary: While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.
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http://dx.doi.org/10.1016/j.jhep.2021.07.018DOI Listing
July 2021

COVID-19: Considerations about immune suppression and biologicals at the time of SARS-CoV-2 pandemic.

World J Clin Cases 2021 Jul;9(20):5352-5357

Department of Medical Sciences and Public Health, University of Cagliari, Monserrato 09042, Cagliari, Italy.

The extent of the profound immunological and nonimmunological responses linked to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is currently being investigated worldwide due to the large burden associated with death due to SARS-CoV-2 and the short-term consequences of coronavirus disease 2019 (COVID-19). It has been hypothesized that patients on immunosuppressive treatments, including biologics, may have an augmented risk of being infected by SARS-CoV-2; however, there are currently no definitive data about biological drugs and COVID-19 in immune-mediated inflammatory diseases. Current epidemiological models developed to understand how long the COVID-19 epidemic may last are not conclusive and range from sustained epidemics to complete elimination. Nevertheless, even in the best-case scenario of apparent elimination, there is concordance about a possible contagion resurgence as late as 2024. Therefore, knowledge of the impact of SARS-CoV-2 on immune-mediated diseases and among patients treated with biologicals, together with the results of novel and promising COVID-19 treatment strategies targeting the virus and the host immune response (or both), will help us to best manage our patients during this pandemic over the next few years.
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http://dx.doi.org/10.12998/wjcc.v9.i20.5352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281435PMC
July 2021

The COVID-19 incidence in Italian regions correlates with low temperature, mobility and PM10 pollution but lethality only with low temperature.

J Public Health Res 2021 06 7. Epub 2021 Jun 7.

Colorectal Surgery Unit, Department of Surgical Science, University of Cagliari.

Background: The aim was to verify whether the density of particulate matter (PM10), the climate, and the mobility of people can influence the pandemic in the 19 regions and in the two autonomous Italian provinces as incidence rate and lethality.

Design And Methods: The incidence rates per 100,000 inhabitants and the case fatality ratio (CFR) (dependent variables) in all Italian regions were calculated in January 2021 at John Hopkins University Coronavirus Center. The independent variables were: -Minimum average temperatures in the same month (January) of 2020, -Average pollution of PM10 in the air in each region in the last year available reported on a 0-10 scale to 0 = total absence of PM10 to 10 maximum pollutions. -Number of places in hotels occupied per inhabitants in 2020. Linear regression and Multiple Regression Analysis were carried out.

Results: The spread of the COVID-19 in the Italian regions seems to be related to pollution of PM10, the number of beds occupied in hotels (as an index of mobility and temperature (indirect correlation). On the contrary, the CFR correlates inversely with temperature but not with pollution. Measuring the concomitant effect of two independent variables by means of Multiple Regression Analysis, temperature and pollution show a synergistic effect on COVID-19 incidence.

Conclusions: The study seems to confirm the literature on the influence of temperature on the lethality of COVID-19 but adds the new results of an inverse relationship between the spread of the virus and low temperature in regions between the Mediterranean area (which includes southern Italy and Sicily and Sardinia islands) and the cold European temperate zone which includes the northern regions under the Alps. A new date also concerns the summation effect of the risk between cold weather and PM10 air pollution was found. Due to several methodic weakness the study has an exploratory than conclusive relevance.
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http://dx.doi.org/10.4081/jphr.2021.2303DOI Listing
June 2021

Real-world experience with obeticholic acid in patients with primary biliary cholangitis.

JHEP Rep 2021 Apr 27;3(2):100248. Epub 2021 Jan 27.

Medical Team Torino, Turin, Italy.

Background & Aims: Obeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions.

Methods: Patients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical response according to ; the secondary endpoint was the biochemical response according to , defined as normal levels of bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) at 12 months. Safety and tolerability were also assessed.

Results: We analysed 191 patients until at least 12 months of follow-up. Median age was 57 years, 94% female, 61 (32%) had cirrhosis, 28 (15%) had histologically proven overlap with autoimmune hepatitis (PBC-AIH). At 12 months, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed. Response rates were 42.9% according to , and 11% by . Patients with cirrhosis had lower response than patients without cirrhosis (29.5% 49.2%,  = 0.01), owing to a higher rate of OCA discontinuation (30% 12%,  = 0.004), although with similar ALP reduction (29.4% 34%,  = 0.53). Overlap PBC-AIH had a similar response to pure PBC (46.4% 42.3%,  = 0.68), with higher ALT reduction at 6 months (-38% -29%,  = 0.04). Thirty-three patients (17%) prematurely discontinued OCA because of adverse events, of whom 11 experienced serious adverse events. Treatment-induced pruritus was the leading cause of OCA discontinuation (67%).

Conclusions: Effectiveness and safety of OCA under real-world conditions mirror those in the Poise trial. Patients with cirrhosis had lower tolerability. Overlap PBC-AIH showed higher ALT reduction at 6 months compared with patients with pure PBC.

Lay Summary: Obeticholic acid (OCA) was shown to be effective in more than one-third of patients not responding to ursodeoxycholic acid in a real-world context in Italy. Patients with cirrhosis had more side effects with OCA, and this led to suspension of the drug in one-third of patients. OCA was also effective in patients who had overlap between autoimmune hepatitis and primary biliary cholangitis.
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http://dx.doi.org/10.1016/j.jhepr.2021.100248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930359PMC
April 2021

Review article: safety of new biologic agents for inflammatory bowel disease in the liver.

Eur J Gastroenterol Hepatol 2021 05;33(5):623-630

Gastroenterology Unit, Department of Surgery, 'G. Brotzu' Hospital, Piazzale Alessandro Ricchi, Cagliari, Italy.

New biologic agents (vedolizumab, ustekinumab and tofacitinib) represent an effective treatment for inflammatory bowel diseases and have been recently approved. However, with a rapidly evolving complement of advanced targeted therapies, new concerns about their potentially undesirable effects on liver function emerge. In particular, little is known about safety data in patients with hepatitis B virus, hepatitis C virus chronic infections, cirrhosis and in transplanted patients who are accumulating. In addition, these new agents have also been associated with drug-induced liver injury. Limited data on the efficacy of vedolizumab in patients with primary sclerosing cholangitis are also available. This article reviews available data about hepatic safety concerns in patients receiving vedolizumab, ustekinumab and tofacitinib with and without preexistent hepatic diseases.
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http://dx.doi.org/10.1097/MEG.0000000000002076DOI Listing
May 2021

Human Leukocyte Antigen Complex and Other Immunogenetic and Clinical Factors Influence Susceptibility or Protection to SARS-CoV-2 Infection and Severity of the Disease Course. The Sardinian Experience.

Front Immunol 2020 4;11:605688. Epub 2020 Dec 4.

Liver Unit, Department of Internal Medicine, University Hospital of Cagliari, Cagliari, Italy.

Aim: SARS-CoV-2 infection is a world-wide public health problem. Several aspects of its pathogenesis and the related clinical consequences still need elucidation. In Italy, Sardinia has had very low numbers of infections. Taking advantage of the low genetic polymorphism in the Sardinian population, we analyzed clinical, genetic and immunogenetic factors, with particular attention to HLA class I and II molecules, to evaluate their influence on susceptibility to SARS-CoV-2 infection and the clinical outcome.

Method And Materials: We recruited 619 healthy Sardinian controls and 182 SARS-CoV-2 patients. Thirty-nine patients required hospital care and 143 were without symptoms, pauci-symptomatic or with mild disease. For all participants, we collected demographic and clinical data and analyzed the HLA allele and haplotype frequencies.

Results: Male sex and older age were more frequent in hospitalized patients, none of whom had been vaccinated during the previous seasonal flu vaccination campaignes. Compared to the group of asymptomatic or pauci-symptomatic patients, hospitalized patients also had a higher frequency of autoimmune diseases and glucose-6-phosphate-dehydrogenase (G6PDH) deficiency. None of these patients carried the beta-thalassemia trait, a relatively common finding in the Sardinian population. The extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 [OR 0.1 (95% CI 0-0.6), Pc = 0.015] was absent in all 182 patients, while the HLA-C*04:01 allele and the three-loci haplotype HLA-A*30:02, B*14:02, C*08:02 [OR 3.8 (95% CI 1.8-8.1), Pc = 0.025] were more frequently represented in patients than controls. In a comparison between in-patients and home care patients, the HLA-DRB1*08:01 allele was exclusively present in the hospitalized patients [OR > 2.5 (95% CI 2.7-220.6), Pc = 0.024].

Conclusion: The data emerging from our study suggest that the extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 has a protective effect against SARS-CoV-2 infection in the Sardinian population. Genetic factors that resulted to have a negative influence on the disease course were presence of the HLA-DRB1*08:01 allele and G6PDH deficiency, but not the beta-thalassemic trait. Absence of influenza vaccination could be a predisposing factor for more severe disease.
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http://dx.doi.org/10.3389/fimmu.2020.605688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746644PMC
December 2020

Gastrointestinal coronavirus disease 2019: epidemiology, clinical features, pathogenesis, prevention, and management.

Expert Rev Gastroenterol Hepatol 2021 Jan 24;15(1):41-50. Epub 2020 Nov 24.

Colorectal Surgery Unit, Department of Surgical Science, University of Cagliari , Cagliari, Italy.

Introduction: The new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the etiologic agent of coronavirus disease 2019. Some authors reported pieces of evidence that patients with SARS-CoV-2 infection could have direct involvement of the gastrointestinal tract, and in symptomatic cases, gastrointestinal symptoms (diarrhea, nausea/vomiting, abdominal pain) could be very common.

Area Covered: In this article, we reviewed current-published data of the gastrointestinal aspects involved in SARS-CoV-2 infection, including prevalence and incidence of specific symptoms, the presumptive biological mechanism of GI infection, prognosis, clinical management, and public health-related concerns on the possible risk of oral-fecal transmission.

Expert Opinion: Different clues point to direct virus infection and replication in mucosal cells of the gastrointestinal tract. In vitro studies showed that SARS-CoV-2 could enter into the gastrointestinal epithelial cells by the Angiotensin-Converting enzyme two membrane receptor. These findings, coupled with the identification of viral RNA found in stools of patients, clearly suggest that direct involvement of the gastrointestinal tract is very likely. This can justify most of the gastrointestinal symptoms but also suggest a risk for an oral-fecal route for transmission, additionally or alternatively to the main respiratory route.
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http://dx.doi.org/10.1080/17474124.2020.1821653DOI Listing
January 2021

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 2021 May 8;53(5):612-619. Epub 2020 Sep 8.

Medical Department, AbbVie S.r.l., 00144 Roma, Italy.

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
May 2021

Advanced liver disease outcomes after hepatitis C eradication by human immunodeficiency virus infection in PITER cohort.

Hepatol Int 2020 May 11;14(3):362-372. Epub 2020 Apr 11.

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

Background: Liver disease progression after Hepatitis C Virus (HCV) eradication following direct-acting antiviral (DAA) treatment in the real-life setting according to Human Immunodeficiency Virus (HIV) coinfection was evaluated.

Methods: Patients consecutively enrolled in PITER between April 2014 and June 2019 and with at least 12-weeks follow-up following treatment were analysed. Cox regression analysis were used to evaluate HIV coinfection and factors independently associated with liver disease outcomes following viral eradication in DAA treated patients with pre-treatment liver cirrhosis.

Results: 93 HIV/HCV coinfected and 1109 HCV monoinfected patients were evaluated during a median follow-up of 26.7 (range 6-44.6) and 24.6 (range 6.8-47.3) months, respectively. No difference in the cumulative HCC incidence and hepatic decompensation was observed between coinfected and monoinfected patients. Age (Hazard Ratio [HR] = 1.08; 95% CI 1.04-1.13), male sex (HR = 2.76; 95% CI 1.28-5.96), lower albumin levels (HR = 3.94; 95% CI 1.81-8.58), genotype 3 (HR = 5.05; 95% CI 1.75-14.57) and serum anti-HBc positivity (HR = 1.99, 95% CI 1.01-3.95) were independently associated with HCC incidence. Older age (HR = 1.03; 95% CI 1.00-1.07), male sex (HR = 2.13; 95% CI 1.06-4.26) and lower albumin levels (HR = 3.75; 95% CI 1.89-7.46) were independently associated with the appearance of a decompensating event after viral eradication.

Conclusion: Different demographic, clinical and genotype distribution between HIV coinfected vs those monoinfected, was observed in a representative cohort of HCV infected patients in Italy. Once liver cirrhosis is established the disease progression is decreased, but still persists regardless of viral eradication in both coinfected and monoinfected patients. In patients with cirrhosis, HIV coinfection was not associated with a higher probability of liver complications, after viral eradication.
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http://dx.doi.org/10.1007/s12072-020-10034-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220859PMC
May 2020

Entropy of human leukocyte antigen and killer-cell immunoglobulin-like receptor systems in immune-mediated disorders: A pilot study on multiple sclerosis.

PLoS One 2019 17;14(12):e0226615. Epub 2019 Dec 17.

Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.

Background: Entropy is a thermodynamic variable statistically correlated with the disorder of a system. The hypothesis that entropy can be used to identify potentially unhealthy conditions was first suggested by Schrödinger, one of the founding fathers of quantum mechanics. Shannon later defined entropy as the quantity of information stored in a system. Shannon's entropy has the advantage of being adaptable across a variety of disciplines, including genetic studies on complex immunogenetic systems such as the human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptor (KIR) systems.

Methods: In our study, entropy associated to the HLA and KIR systems was compared between a cohort of 619 Sardinian healthy controls and a group of 270 patients affected by multiple sclerosis (MS), the latter stratified into 81 patients with primary progressive multiple sclerosis (PPMS) and 189 patients with relapsing remitting multiple sclerosis (RRMS).

Results: The entropy associated to HLA four-loci haplotypes (A, B, C, DR) and combinations of two inhibitory KIR genes was significantly higher in patients affected by RRMS than in healthy controls. No significant differences were observed for patients with PPMS. By calculating the total HLA and KIR entropy ratio in each subject, it was possible to determine the individual risk of developing MS, particularly RRMS.

Conclusions: In addition to the standard statistical methods used to evaluate immunogenetic parameters associated to immune-mediated disease, the analysis of entropy measures the global disorder status deriving from these parameters. This innovative approach may represent a useful complementary tool to the risk assessment of immune-mediated disorders. Improved risk assessment is particularly important for family members of patients with MS. However, further investigation is warranted to confirm our findings and to evaluate the validity of the entropy-based method in other types of immune-mediated disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226615PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917289PMC
April 2020

Rate of non-response to ursodeoxycholic acid in a large real-world cohort of primary biliary cholangitis patients in Italy.

Scand J Gastroenterol 2019 Oct 28;54(10):1274-1282. Epub 2019 Sep 28.

Department of Infectious Diseases, D. Cotugno Hospital, Napoli, Italy.

Response to ursodeoxycholic acid (UDCA) is crucial for the prediction of primary biliary cholangitis (PBC) prognosis, and different response criteria were validated and proposed by reference centers for PBC. To date, rates of non-response to UDCA from real-world series are lacking. Hepatology/Gastroenterology centers belonging to 'Club Epatologi Ospedalieri' (CLEO) and 'Associazione Italiana Gastroenterologi Ospedalieri' (AIGO) were invited to participate in the study, and asked to extract all patients followed for PBC, without any selection or exclusion, and fill in the database provided. Thirty-four centers were enrolled throughout Italy, for a total of 713 patients. None of these centers, except one, had a hepatology outpatient clinic devoted to the care of patients with autoimmune liver diseases. After excluding 79 cases of PBC/autoimmune hepatitis overlaps, 634 patients were analyzed: mean age, 64.4 ± 12.0 years; 91.2% females; F/M 10.3/1. For patients with at least 1 year of UDCA treatment (583), rates of non-response to UDCA were evaluated according to the Paris-I/-II, Toronto and GLOBE criteria, and compared with those in the original cohorts: 27% vs 39% in Paris-I cohort; 39.6% vs 52% in Paris-II; 20.1% vs 43.5% in Toronto; 15.7% vs 30% in GLOBE (age-specific cutoffs). Mean alkaline phosphatase levels on UDCA treatment, and the age-adjusted prevalence of F3/F4 fibrosis, appeared lower in this PBC population than in reference cohorts. A mean ∼15% better response to UDCA is observed in a real-world PBC population, probably due to migration of some of most severe/advanced cases to PBC referral centers.
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http://dx.doi.org/10.1080/00365521.2019.1669702DOI Listing
October 2019

HepaDisk - A new quality of life questionnaire for HCV patients.

Dig Liver Dis 2019 07 23;51(7):1008-1015. Epub 2018 Dec 23.

Cronic Infectious Diseases Unit, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.

Background: Since most patients with hepatitis C virus (HCV) infection now receive treatment irrespective of liver disease severity, special attention to patient quality of life (QoL), including psycho-social aspects, is required. No QoL questionnaire is specific for patients with HCV.

Aims: To develop and validate a short Italian questionnaire (HepaDisk) assessing the QoL of patients affected by HCV with intuitive graphic results that is understandable by patients and physicians.

Methods: A questionnaire, drafted by a steering committee, underwent a Delphi survey. A multicenter, observational study was conducted to validate the developed HepaDisk versus other tools (CLDQ-I, SF-36, WPAI:HCV), and to evaluate its correlation with disease severity in Italian patients with HCV.

Results: The 10-item questionnaire was validated in 214 patients. HepaDisk showed a high correlation with CLDQ overall score and WPAI:HCV activity impairment (Spearman's rank correlation: 0.651 and 0.595, respectively) and a lower correlation with SF-36. Strong internal consistency (Cronbach coefficient: 0.912), good test-retest reliability (Pearson's correlation coefficient: 0.789; 95% CI, 0.714-0.865), and responsiveness to changes among improved patients were demonstrated.

Conclusion: HepaDisk is a reliable and user-friendly tool that can monitor disease impact on patient QoL over time, providing a visual representation easily understandable by both patients and physicians.
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http://dx.doi.org/10.1016/j.dld.2018.12.009DOI Listing
July 2019

Impact of direct-acting antiviral drugs for chronic hepatitis C on mood: Preliminary results from a longitudinal study.

Gen Hosp Psychiatry 2019 Jan - Feb;56:50-51. Epub 2018 Nov 14.

Department of Medical Sciences and Public Health, University of Cagliari, Italy.

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http://dx.doi.org/10.1016/j.genhosppsych.2018.10.008DOI Listing
May 2019

Bone mass preservation with high-dose cholecalciferol and dietary calcium in HIV patients following antiretroviral therapy. Is it possible?

HIV Clin Trials 2018 10 16;19(5):188-196. Epub 2018 Nov 16.

a Department of Medical Sciences and Internal Medicine , University Hospital, University of Cagliari , Cagliari , Italy.

Objective: To evaluate whether treatment with 100,000 IU/month (equivalent to 3200 IU/day) of cholecalciferol and 1 g/day of dietary calcium supplementation in HIV patients following different cART regimens yields normal levels of vitamin D3 and PTH as well as whether changes in bone mineral density are clinically significant.

Methods: Consecutive HIV patients following different cART regimens received 100,000 IU/month (equivalent to 3200 IU/day) of cholecalciferol and 1 g/day of dietary calcium supplementation. The participants underwent BMD assessment via dual energy X-ray absorptiometry of the spine and hip at baseline (T0) and after 24 months (T1). Levels of 25(OH) vitamin D3 and parathyroid hormone (PTH) were assessed at T0 and T1. Quantitative variables were assessed with a paired t-test, independent t-test or analysis of variance, as appropriate. A chi-squared analysis was used to assess the association between qualitative variables. A p-value <0.05 was considered significant. Patients were divided into three groups depending on the cART regimen.

Results: A total of 79 patients were included (40 males, 51% and 39 females, 49%), with a mean age of 46.6 (SD ±11.2) years, a baseline CD4 count of 649 cells/µl and a mean 25 hydroxycholecalciferol (25(OH) D3) value of 25 + 10 ng/ml. After 24 months, the 25(OH) D3 increased to 40 + 11 ng/ml. The initial BMDs at T0 were estimated as 0.919 (±0.27) and 0.867 (±0.14) g/cm at the spine and hip, respectively. After 24 months, the BMD was 0.933 (±0.15) g/cm at the spine and 0.857 (±0.14) g/cm at the hip. Based on a BMD change exceeding 3%, a worsening was observed in 23% of patients at the spine and 27% at the hip, whereas stability or improvement was demonstrated in 77% of patients at the spine and 73% at the hip. Subgrouping patients based on antiretroviral therapy indicated that, at T1, there was a statistically significant increase in vitamin D3 concentration in all patients, while PTH concentration was not significantly reduced in patients taking tenofovir or efavirenz. BMD stability or improvement was demonstrated in 77% of patients at the spine and 73% at the hip after 24 months. The multivariate analysis confirms a decrease in vitamin D3 and an increase in PTH levels in smokers, as well higher vitamin D3 concentrations in males and lower spine BMDs in menopausal females.

Conclusion: The proposed protocol of cholecalciferol and dietary calcium supplementation is safe and valid for correcting vitamin D abnormalities in almost all patients as well as reducing PTH levels in a high percentage of patients; however, it is not sufficient for normalization, particularly in patients exposed to tenofovir or efavirenz. At the spine, no significant BMD change was found in any of the therapy groups. At the hip, our data confirm a modest negative effect on bone mass caused by tenofovir and efavirenz.
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http://dx.doi.org/10.1080/15284336.2018.1525841DOI Listing
October 2018

Forecasting Hepatitis C liver disease burden on real-life data. Does the hidden iceberg matter to reach the elimination goals?

Liver Int 2018 12 10;38(12):2190-2198. Epub 2018 Aug 10.

Internal Medicine, Villa Sofia-Cervello Hospital, Palermo, Italy.

Background & Aims: Advances in direct-acting antiviral treatment of HCV have reinvigorated public health initiatives aimed at identifying affected individuals. We evaluated the possible impact of only diagnosed and linked-to-care individuals on overall HCV burden estimates and identified a possible strategy to achieve the WHO targets by 2030.

Methods: Using a modelling approach grounded in Italian real-life data of diagnosed and treated patients, different linkage-to-care scenarios were built to evaluate potential strategies in achieving the HCV elimination goals.

Results: Under the 40% linked-to-care scenario, viraemic burden would decline (60%); however, eligible patients to treat will be depleted by 2025. Increased case finding through a targeted screening strategy in 1948-1978 birth cohorts could supplement the pool of diagnosed patients by finding 75% of F0-F3 cases. Under the 60% linked-to-care scenario, viraemic infections would decline by 70% by 2030 but the patients eligible for treatment will run out by 2028. If treatment is to be maintained, a screening strategy focusing on 1958-1978 birth cohorts could capture 55% of F0-F3 individuals. Under the 80% linked-to-care scenario, screening limited in 1968-1978 birth cohorts could sustain treatment at levels required to achieve the HCV elimination goals.

Conclusion: In Italy, which is an HCV endemic country, the eligible pool of patients to treat will run out between 2025 and 2028. To maintain the treatment rate and achieve the HCV elimination goals, increased case finding in targeted, high prevalence groups is required.
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http://dx.doi.org/10.1111/liv.13901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282782PMC
December 2018

Multicenter prospective study of angiogenesis polymorphism validation in HCC patients treated with sorafenib. An INNOVATE study protocol.

Tumori 2018 Dec 9;104(6):476-479. Epub 2018 May 9.

21 University Hospital of Modena, Modena - Italy.

Introduction: Although sorafenib is the upfront standard of care for advanced hepatocellular carcinoma (HCC), molecular predictors of efficacy have not been identified yet. In the ALICE-1 study, rs2010963 of VEGF-A and VEGF-C proved to be independent predictive factors for progression-free survival (PFS) and overall survival (OS) in multivariate analysis. The ALICE-1 study results were confirmed in the ALICE-2 study, in which VEGF and VEGFR SNPs were analyzed. In the ePHAS study we analyzed the SNPs of eNOS. In univariate analysis, patients homozygous for an eNOS haplotype (HT1: T-4b at eNOS-786/eNOS VNTR) had significantly shorter median PFS and OS than those with other haplotypes. These data were confirmed in the validation set.

Methods: This nonpharmacological, interventional, prospective multicenter study aims to determine whether eNOS, HIF-1, VEGF, Ang2 and VEGFR polymorphisms play a role in predicting the objective response rate, PFS, and OS of advanced HCC patients treated with sorafenib. The study will involve 160 advanced HCC patients with Child-Pugh class A disease. The primary aim is to validate the prognostic or predictive roles of eNOS, Ang2, HIF-1, VEGF and VEGFR polymorphisms in relation to the clinical outcome (PFS) of HCC patients treated with sorafenib.

Conclusions: Overall, our data may suggest that polymorphism analysis of the VEGF, VEGFR-2, HIF and eNOS genes can identify HCC patients who are more likely to benefit from sorafenib.
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http://dx.doi.org/10.5301/tj.5000704DOI Listing
December 2018

Incidence of DAA failure and the clinical impact of retreatment in real-life patients treated in the advanced stage of liver disease: Interim evaluations from the PITER network.

PLoS One 2017 4;12(10):e0185728. Epub 2017 Oct 4.

University of Salerno, Salerno, Italy.

Background: Few data are available on the virological and clinical outcomes of advanced liver disease patients retreated after first-line DAA failure.

Aim: To evaluate DAA failure incidence and the retreatment clinical impact in patients treated in the advanced liver disease stage.

Methods: Data on HCV genotype, liver disease severity, and first and second line DAA regimens were prospectively collected in consecutive patients who reached the 12-week post-treatment and retreatment evaluations from January 2015 to December 2016 in 23 of the PITER network centers.

Results: Among 3,830 patients with advanced fibrosis (F3) or cirrhosis, 139 (3.6%) failed to achieve SVR. Genotype 3, bilirubin levels >1.5mg/dl, platelet count <120,000/mm3 and the sofosbuvir+ribavirin regimen were independent predictors of failure by logistic regression analysis. The failure rate was 7.6% for patients treated with regimens that are no longer recommended or considered suboptimal (sofosbuvir+ribavirin or simeprevir+sofosbuvir±ribavirin), whereas 1.4% for regimens containing sofosbuvir combined with daclatasvir or ledipasvir or other DAAs. Of the patients who failed to achieve SVR, 72 (51.8%) were retreated with a second DAA regimen, specifically 38 (52.7%) with sofosbuvir+daclatasvir, 27 (37.5%) with sofosbuvir+ledipasvir, and 7 (9.7%) with other DAAs ±ribavirin. Among these, 69 (96%) patients achieved SVR12 and 3 (4%) failed. During a median time of 6 months (range: 5-14 months) between failure and the second DAA therapy, the Child-Pugh class worsened in 12 (16.7%) patients: from A to B in 10 patients (19.6%) and from B to C in 2 patients (10.5%), whereas it did not change in the remaining 60 patients. Following the retreatment SVR12 (median time of 6 months; range: 3-12 months), the Child-Pugh class improved in 17 (23.6%) patients: from B to A in 14 (19.4%) patients, from C to A in 1 patient (1.4%) and from C to B in 2 (2.9%) patients; it remained unchanged in 53 patients (73.6%) and worsened in 2 (2.8%) patients. Of patients who were retreated, 3 (4%) had undergone OLT before retreatment (all reached SVR12 following retreatment) and 2 (2.8%) underwent OLT after having achieved retreatment SVR12. Two (70%) of the 3 patients who failed to achieve SVR12 after retreatment, and 2 (2.8%) of the 69 patients who achieved retreatment SVR12 died from liver failure (Child-Pugh class deteriorated from B to C) or HCC complications.

Conclusions: Failure rate following the first DAA regimen in patients with advanced disease is similar to or lower than that reported in clinical trials, although the majority of patients were treated with suboptimal regimens. Interim findings showed that worsening of liver function after failure, in terms of Child Pugh class deterioration, was improved by successful retreatment in about one third of retreated patients within a short follow-up period; however, in some advanced liver disease patients, clinical outcomes (Child Pugh class, HCC development, liver failure and death) were independent of viral eradication.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185728PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5627924PMC
November 2017

Modeling cost-effectiveness and health gains of a "universal" versus "prioritized" hepatitis C virus treatment policy in a real-life cohort.

Hepatology 2017 12 30;66(6):1814-1825. Epub 2017 Oct 30.

University of Milan, Milan, Italy.

We evaluated the cost-effectiveness of two alternative direct-acting antiviral (DAA) treatment policies in a real-life cohort of hepatitis C virus-infected patients: policy 1, "universal," treat all patients, regardless of fibrosis stage; policy 2, treat only "prioritized" patients, delay treatment of the remaining patients until reaching stage F3. A liver disease progression Markov model, which used a lifetime horizon and health care system perspective, was applied to the PITER cohort (representative of Italian hepatitis C virus-infected patients in care). Specifically, 8,125 patients naive to DAA treatment, without clinical, sociodemographic, or insurance restrictions, were used to evaluate the policies' cost-effectiveness. The patients' age and fibrosis stage, assumed DAA treatment cost of €15,000/patient, and the Italian liver disease costs were used to evaluate quality-adjusted life-years (QALY) and incremental cost-effectiveness ratios (ICER) of policy 1 versus policy 2. To generalize the results, a European scenario analysis was performed, resampling the study population, using the mean European country-specific health states costs and mean treatment cost of €30,000. For the Italian base-case analysis, the cost-effective ICER obtained using policy 1 was €8,775/QALY. ICERs remained cost-effective in 94%-97% of the 10,000 probabilistic simulations. For the European treatment scenario the ICER obtained using policy 1 was €19,541.75/QALY. ICER was sensitive to variations in DAA costs, in the utility value of patients in fibrosis stages F0-F3 post-sustained virological response, and in the transition probabilities from F0 to F3. The ICERs decrease with decreasing DAA prices, becoming cost-saving for the base price (€15,000) discounts of at least 75% applied in patients with F0-F2 fibrosis.

Conclusion: Extending hepatitis C virus treatment to patients in any fibrosis stage improves health outcomes and is cost-effective; cost-effectiveness significantly increases when lowering treatment prices in early fibrosis stages. (Hepatology 2017;66:1814-1825).
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http://dx.doi.org/10.1002/hep.29399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765396PMC
December 2017

The prevalence of bright liver echo pattern in patients with chronic hepatitis C: correlation with steatosis and fibrosis.

J Ultrasound 2016 5;19(2):91-8. Epub 2014 Jul 5.

Liver Unit, Department of Medical Sciences, Policlinico Universitario, University of Cagliari, SS 554 Bivio Sestu, 09042 Monserrato, Cagliari Italy.

Purpose: To evaluate the prevalence of bright liver echo pattern (BLP) on ultrasonography and its correlation with liver steatosis (LS), and fibrosis in patients with chronic hepatitis C. The usefulness of detecting skip areas for steatosis diagnosis has also been evaluated.

Methods: The study included 88 patients with chronic hepatitis C (55 men, 33 women, average age 45.7 ± 11.2 years). Ultrasound examination was performed in all patients before liver biopsy. The presence of BLP was assessed and graded from 1 to 3. Hypoechogenic areas (skip areas) around the gallbladder or near the portal vein were also evaluated. Hepatic fibrosis was assessed using the Ishak fibrosis score. Steatosis was graded as follows: 1, 2, 3 (<30, 30-70, >70 % of hepatocytes affected, respectively).

Results: Fifty-three of the 88 patients (60 %) showed BLP (40 grade 1, 13 grades 2 or 3). Skip areas were found in 14 patients (16 %). Histological steatosis was observed in 40 patients (45 %) and in 10 of them (25 %) was grades 2 and 3 (4 and 6 patients, respectively). As regards fibrosis, 2 patients showed F0, 34 F1, 28 F2, 20 F3, 4 F4, none of them F5 and F6. BLP of grades 2 or 3 and presence of skip areas were strongly correlated with LS (P = 0.00007 and P = 0.00003, respectively). No correlation was found between BLP and fibrosis. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of BLP for LS were 75, 50, 56, 68 and 61 %, respectively. When BLP of grades 2 and 3 and LS of 30 % or more were correlated, the sensitivity, specificity, PPV, NPV and accuracy of BLP were 72, 96, 61, 96 and 90 %, respectively. As regards skip areas the sensitivity, specificity, PPV, NPV and accuracy for LS were 35, 100, 100, 64 and 70 %, respectively.

Conclusions: In a well-defined group of patients with chronic hepatitis C, the detection of BLP grades 2 and 3 has a good sensitivity and high specificity for high grades of steatosis. A high specificity but low sensitivity for liver steatosis was also found for skip areas, whereas mild fibrosis does not seem to correlate with the hyperechogenicity of the liver.
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http://dx.doi.org/10.1007/s40477-014-0114-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879006PMC
July 2016

Exploring the Role of Killer Cell Immunoglobulin-Like Receptors and Their HLA Class I Ligands in Autoimmune Hepatitis.

PLoS One 2016 8;11(1):e0146086. Epub 2016 Jan 8.

Medical Genetics, R. Binaghi Hospital, ASL 8, Cagliari, Italy.

Background: Natural killer cells are involved in the complex mechanisms underlying autoimmune diseases but few studies have investigated their role in autoimmune hepatitis. Killer immunoglobulin-like receptors are key regulators of natural killer cell-mediated immune responses.

Methods And Findings: KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 114 patients diagnosed with type 1 autoimmune hepatitis and compared with a group of 221 healthy controls. HLA Class I and Class II antigen frequencies were compared to those of 551 healthy unrelated families representative of the Sardinian population. In our cohort, type 1 autoimmune hepatitis was strongly associated with the HLA-B18, Cw5, DR3 haplotype. The KIR2DS1 activating KIR gene and the high affinity HLA-C2 ligands were significantly higher in patients compared to controls. Patients also had a reduced frequency of HLA-Bw4 ligands for KIR3DL1 and HLA-C1 ligands for KIR2DL3. Age at onset was significantly associated with the KIR2DS1 activating gene but not with HLA-C1 or HLA-C2 ligand groups.

Conclusions: The activating KIR gene KIR2DS1 resulted to have an important predictive potential for early onset of type 1 autoimmune hepatitis. Additionally, the low frequency of the KIR-ligand combinations KIR3DL1/HLA-Bw4 and KIR2DL3/HLA-C1 coupled to the high frequency of the HLA-C2 high affinity ligands for KIR2DS1 could contribute to unwanted NK cell autoreactivity in AIH-1.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146086PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712907PMC
June 2016

Can antiretroviral therapy modify the clinical course of HDV infection in HIV-positive patients?

Antivir Ther 2015 27;20(7):671-9. Epub 2014 Oct 27.

Center for the Study of Liver Diseases, Department of Medical Sciences 'Mario Aresu', University of Cagliari, Cagliari, Italy.

Background: Infection with hepatitis delta virus (HDV) affects approximately 6-14.5% of patients coinfected with HIV-1 and HBV, showing a more aggressive clinical course compared with an HIV-negative population. There is no universally approved treatment for chronic hepatitis D (CHD) in HIV-infected patients. Antiretroviral therapy (ART) containing tenofovir has been recently associated with HDV suppression. Our aim was to evaluate whether the outcome of CHD in HIV-infected patients can be favourably influenced by ART including reverse transcriptase inhibitors.

Methods: The clinical course of four HBV/HDV/HIV-coinfected patients receiving ART were retrospectively examined.

Results: HDV RNA became undetectable in all patients after a variable period of ART along with the disappearance of hepatitis B surface antigen in two of them, and an increase in CD4(+) T-cell count. In all patients, virological changes were associated with improved liver function tests and clinical features.

Conclusions: We suggest that ART regimens including drugs active against HBV could have beneficial effects on the clinical course of CHD in patients with HIV-1 by favouring immunological reconstitution.
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http://dx.doi.org/10.3851/IMP2911DOI Listing
November 2016

Absence of activating killer immunoglobulin-like receptor genes combined with hepatitis C viral genotype is predictive of hepatocellular carcinoma.

Hum Immunol 2013 Oct 10;74(10):1288-94. Epub 2013 Jun 10.

Centro Regionale Trapianti, Ospedale R. Binaghi - ASL 8, 09126 Cagliari, Italy. Electronic address:

Killer immunoglobulin-like receptors and their human leukocyte antigen class I ligands have a critical role in natural killer cell response to viral pathogens and tumors. To investigate whether killer immunoglobulin-like receptor genes could influence the chronic course of hepatitis C virus infection and/or progression to hepatocellular carcinoma we retrospectively analyzed a cohort of 228 patients transplanted for hepatitis C virus-induced cirrhotic end stage liver disease, combined or not with hepatocellular carcinoma. We found that patients completely lacking activating killer immunoglobulin-like receptor genes had a high risk of developing hepatocellular carcinoma. Hepatitis C viral genotype and viral load are other risk factors that can influence the course of chronic hepatitis C virus infection. In our study, the risk conferred by hepatitis C viral genotypes was enhanced in patients lacking activating killer immunoglobulin-like receptors. These results point to an important role for activating killer immunoglobulin-like receptors in the control of hepatitis C virus infection and progression to hepatocellular carcinoma. In clinical practice, assessment of killer immunoglobulin-like receptor and hepatitis C viral genotype combinations should allow for more accurate monitoring of patients with chronic hepatitis C virus infection.
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http://dx.doi.org/10.1016/j.humimm.2013.05.007DOI Listing
October 2013

Association of chronic hepatitis C with recurrent brief depression.

J Affect Disord 2012 Dec 18;141(2-3):361-6. Epub 2012 May 18.

Department of Public Health, University of Cagliari, Italy.

Background: Depressive syndromes, including recurrent brief depression (RBD), have frequently been observed in association with chronic diseases characterized by immune activation, such as autoimmune thyroiditis or celiac disease. However, the association of RBD with chronic hepatitis C (CHC), a disease with an increased incidence of major depressive disorders, is unknown.

Methods:

Cases: 135 (83 males, 52 females) consecutive treatment-naïve patients with CHC.

Exclusion Criteria: previous treatment with IFN-alpha, co-infection with hepatitis C virus (HCV) and hepatitis B virus, infection with human immunodeficiency virus (HIV), drug or alcohol abuse, or malignancy.

Controls: 540 (332 males, 208 females) subjects without evidence of hepatitis, randomly extracted from the database of a previous epidemiological study. The psychiatric diagnosis was based on the Composite International Diagnostic Interview Simplified (CIDI-S), containing a specific section on RBD.

Results: A significantly higher rate of RBD was observed among both male and female patients with CHC (n=21, 15.5%) as compared to controls (n=34, 6.3%) (OR=2.6, CI 95% from 1.37 to 4.93).

Conclusion: The present study provides the first evidence of an association between CHC and RBD, independent of treatment with IFN-alpha and not influenced by substance or alcohol abuse. The results are similar to those found in other conditions with immune activation. RBD may be another expression of mood disorders in such conditions.
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http://dx.doi.org/10.1016/j.jad.2012.03.020DOI Listing
December 2012

Association of chronic hepatitis C with major depressive disorders: irrespective of interferon-alpha therapy.

Clin Pract Epidemiol Ment Health 2007 Oct 23;3:22. Epub 2007 Oct 23.

Department of Public Health, University of Cagliari, Italy.

Background: Mood and anxiety symptoms in chronic hepatitis C (CHC) may be related to the patient awareness of the diagnosis and prognosis, to side effects induced by interferon (IFN)-alpha treatment, as well as to substance abuse. However, the observation of metabolic alterations in patients with CHC has led to hypothesize a direct effect of hepatitis C virus (HCV) on brain function. This study was aimed at elucidating whether CHC is associated with specific anxiety or mood disorders independently of confounding factors.

Methods: Patient cohort: consecutive patients, 135 with CHC and 76 with chronic hepatitis B (CHB).

Exclusion Criteria: previous treatment with IFN-alpha, co-infection with HCV and hepatitis B virus, infection with human immunodeficiency virus, drug or alcohol abuse, or malignancies.

Controls: subjects without evidence of hepatitis randomly extracted from the database of a previous epidemiological study; they were divided into two groups of 540 (332 males) and 304 (220 males) as controls for patients with CHC and CHB, respectively. The psychiatric diagnosis was formulated by means of the Composite International Diagnostic Interview Simplified carried out by a physician according to DSM-IV criteria.

Results: A higher lifetime prevalence of major depressive disorder (MDD) was observed among CHC compared to CHB or controls. The risk of MDD was not statistically different between CHB and controls. Both the CHC and CHB groups showed a significantly higher frequency of panic disorder when compared to controls. No statistical differences were observed in the prevalence of general anxiety disorder and social phobia when CHC or CHB were compared to controls.

Conclusion: The present study provides the first evidence of an association between CHC and MDD, diagnosed on the basis of well-defined international criteria. This association is independent of treatment with IFN-alpha and is not influenced by substance or alcohol abuse. By contrast, anxiety disorders do not appear to be specifically associated with CHC.
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http://dx.doi.org/10.1186/1745-0179-3-22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2203967PMC
October 2007

Severe autoimmune hemolytic anemia in a patient with chronic hepatitis C during treatment with peginterferon alfa-2a and ribavirin.

Haematologica 2006 Jun;91(6 Suppl):ECR26

Department of Medical Sciences, University of Cagliari, Italy.

Peginterferon (Peg-IFN) alfa in combination with ribavirin represents the gold standard treatment for chronic hepatitis C, but is associated with various side effects, especially hematological abnormalities. We report here a case of severe autoimmune hemolytic anemia (AIHA) complicated by symptomatic myocardial ischemia in a patient with chronic hepatitis C during combination therapy. The worsening hemolysis after ribavirin withdrawal and exclusion of other causes implicated Peg-IFN alfa as the cause of AIHA. Our study demonstrates that in patients without preexisting immunological abnormalities Peg-IFN can de novo induce autoimmune complications that, albeit rarely, may be life-threatening.
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June 2006

[Interferon-alpha-induced psychiatric side effects in patients with chronic viral hepatitis: a prospective, observational, controlled study].

Epidemiol Psichiatr Soc 2005 Jul-Sep;14(3):145-53

Clinica Psichiatrica, Università degli Studi di Cagliari, Cagliari, Italy.

Aims: Patients with chronic viral hepatitis suffer from a high prevalence of psychiatric problems. Furthermore, the treatment for chronic viral hepatitis, with interferon (IFN) alpha, induces the occurrence of further psychopathological symptoms. The authors examined whether patients with a pre-existing psychiatric diagnosis had more severe IFN alpha-induced psychiatric adverse effects, and whether they were more likely to interrupt the IFN alpha therapy, compared with control patients with no pre-existing psychiatric diagnosis. They also examined the psychopharmacological management of the interferon-alpha-induced psychiatric side effects.

Methods: The authors studied prospectively 60 patients with chronic hepatitis B or C in Cagliari, Italy. Patients underwent psychiatric assessment before starting interferon alpha and monthly throughout the therapy.

Results: After adjusting for the baseline psychopathology, there was no statistically significant difference in interferon-alpha-induced psychiatric adverse effects between patients with a pre-existing psychiatric diagnosis and controls. There was also no evidence that psychiatric cases were more likely than controls to interrupt the IFN alpha therapy because of psychiatric side effects. Moreover, there was no difference in the psychiatric adverse effects severe enough to require psychopharmacological treatment. Finally, psychopharmacological management successfully treated psychiatric symptoms induced by the IFN alpha.

Conclusions: Patients with a pre-existing psychiatric diagnosis do not have a specific vulnerability to interferon-alpha-induced psychiatric adverse effects.
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http://dx.doi.org/10.1017/s1121189x00006394DOI Listing
December 2005

Long-term benefit of interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis.

Gastroenterology 2004 Jun;126(7):1740-9

Dipartimento di Scienze Mediche, Università di Cagliari, SS 554 Bivio Sestu, 09042 Cagliari, Italy.

Background & Aims: Little is known about the long-term effects of interferon alpha on clinical outcome and survival of patients with chronic hepatitis D.

Methods: Thirty-six patients with chronic hepatitis D who participated in a randomized controlled trial of a 48-week course of high (9 million units) or low (3 million units) doses of interferon alpha or no treatment were followed for an additional 2 to 14 years.

Results: Long-term survival was significantly longer in the high-dose group than in untreated controls (P = 0.003) or in the low-dose group (P = 0.019) but did not differ between patients treated with 3 million units and controls. Among surviving patients at 12 years of follow-up, a biochemical response was present in 7 of 12 treated with 9 million units, in 2 of 4 who received 3 million units, and in none of 3 controls. Long-term alanine aminotransferase (ALT) normalization correlated with improved hepatic function and loss of IgM antibody to hepatitis delta antigen (anti-HD). Patients in the high-dose group had a sustained decrease in HDV replication (P = 0.008), leading to clearance of HDV RNA and, eventually, hepatitis B virus (HBV) in some patients, as well as a dramatic improvement in liver histology with respect to activity grade (P = 0.0004) and fibrosis stage (P = 0.007). Strikingly, we documented an absence of fibrosis in the final biopsy of 4 patients with a long-term biochemical response and an initial diagnosis of active cirrhosis.

Conclusions: High doses of interferon alpha-2a significantly improved the long-term clinical outcome and survival of patients with chronic hepatitis D, even though the majority had active cirrhosis before the onset of therapy.
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http://dx.doi.org/10.1053/j.gastro.2004.03.017DOI Listing
June 2004

Early changes in hepatitis C viral quasispecies during interferon therapy predict the therapeutic outcome.

Proc Natl Acad Sci U S A 2002 Mar;99(5):3081-6

Department of Medical Sciences, University of Cagliari, 09124 Cagliari, Italy.

Despite recent treatment advances, the majority of patients with chronic hepatitis C fail to respond to antiviral therapy. Although the genetic basis for this resistance is unknown, accumulated evidence suggests that changes in the heterogeneous viral population (quasispecies) may be an important determinant of viral persistence and response to therapy. Sequences within hepatitis C virus (HCV) envelope 1 and envelope 2 genes, inclusive of the hypervariable region 1, were analyzed in parallel with the level of viral replication in serial serum samples obtained from 23 patients who exhibited different patterns of response to therapy and from untreated controls. Our study provides evidence that although the viral diversity before treatment does not predict the response to treatment, the early emergence and dominance of a single viral variant distinguishes patients who will have a sustained therapeutic response from those who subsequently will experience a breakthrough or relapse. A dramatic reduction in genetic diversity leading to an increasingly homogeneous viral population was a consistent feature associated with viral clearance in sustained responders and was independent of HCV genotype. The persistence of variants present before treatment in patients who fail to respond or who experience a breakthrough during therapy strongly suggests the preexistence of viral strains with inherent resistance to IFN. Thus, the study of the evolution of the HCV quasispecies provides prognostic information as early as the first 2 weeks after starting therapy and opens perspectives for elucidating the mechanisms of treatment failure in chronic hepatitis C.
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http://dx.doi.org/10.1073/pnas.052712599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC122476PMC
March 2002
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