Publications by authors named "Mario Rizzetto"

227 Publications

Endpoints and New Options for Treatment of Chronic Hepatitis D.

Hepatology 2021 Jul 31. Epub 2021 Jul 31.

Department of Medical Sciences, University of Torino, Torino, Italy.

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http://dx.doi.org/10.1002/hep.32082DOI Listing
July 2021

2020 position statement and recommendations of the European Liver and Intestine Transplantation Association (ELITA): management of hepatitis B virus-related infection before and after liver transplantation.

Aliment Pharmacol Ther 2021 09 19;54(5):583-605. Epub 2021 Jul 19.

Valencia, Spain.

Background: Prophylaxis of HBV recurrence is critical after liver transplantation in HBV patients. Despite new prophylactic schemes, most European LT centres persist on a conservative approach combining hepatitis B immunoglobulin (HBIG) and nucleos(t)ides analogues (NA).

Aim: This setting prompted the European Liver Intestine Transplantation Association (ELITA) to look for a consensus on the prevention of HBV recurrence.

Methods: Based on a 4-round Delphi process, ELITA investigated 16 research questions and established 50 recommendations.

Results: Prophylaxis should be driven according to 3 simplified risk groups: Low and high virological risk patients, with undetectable and detectable HBV DNA pre-LT, respectively, and special populations (HDV, HCC, poorly adherent patients). In low-risk patients, short-term (4 weeks) combination of third-generation NA+ HBIG, or third generation NA monotherapy can be considered as prophylactic options. In high-risk patients, HBIG can be discontinued once HBV DNA undetectable. Combined therapy for 1 year is advised. HBV-HCC patients should be treated according to their virological risk. In HDV/HBV patients, indefinite dual prophylaxis remains the gold standard. Full withdrawal of HBV prophylaxis following or not HBV vaccination should only be attempted in the setting of clinical trials. Organs from HBsAg+ve donors may be considered after assessment of risks, benefits, and patient consent. They should not be used if HDV is present. In poorly adherent patients, dual long-term prophylaxis is recommended. Budget impact analysis should be taken into account to drive prophylactic regimen.

Conclusions: These ELITA recommendations should stimulate a more rational and homogeneous approach to HBV prophylaxis across LT programs.
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http://dx.doi.org/10.1111/apt.16374DOI Listing
September 2021

Forty-Five Years after the Discovery of the Hepatitis D Virus: Where Do We Stand?

Viruses 2021 03 26;13(4). Epub 2021 Mar 26.

Department of Tropical and Infectious Diseases, Policlinico Umberto I, University of Rome, 00161 Rome, Italy.

The discovery of the Australia Antigen in the mid-1960s led, in a few years, to the identification of the virus of Hepatitis B [...].
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http://dx.doi.org/10.3390/v13040555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066537PMC
March 2021

The changing context of hepatitis D.

J Hepatol 2021 05 20;74(5):1200-1211. Epub 2021 Jan 20.

Division of Gastroenterology and Hepatology, Geneva University Hospitals, Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland.

The global epidemiology of hepatitis D is changing with the widespread implementation of vaccination against hepatitis B. In high-income countries that achieved optimal control of HBV, the epidemiology of hepatitis D is dual, consisting of an ageing cohort of domestic patients with advanced liver fibrosis who represent the end stage of the natural history of HDV, and of a younger generation of immigrants from endemic countries who account for the majority of new infections. As observed in Europe in the 1980s, the distinctive clinical characteristic of chronic hepatitis D in endemic countries is the accelerated progression to cirrhosis and hepatocellular carcinoma. Despite some recent progress, the therapeutic management of HDV remains unsatisfactory, as most patients are not cured of HDV with currently available medicines. This review article describes the current epidemiology and clinical features of chronic hepatitis D, based on the literature published in the last 10 years.
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http://dx.doi.org/10.1016/j.jhep.2021.01.014DOI Listing
May 2021

The medical impact of hepatitis D virus infection in Asia and Africa; time for a reappraisal.

Liver Int 2021 01 23;41(1):16-19. Epub 2020 Nov 23.

Department of Medicine, Aga Khan University, Karachi, Pakistan.

Although hepatitis D is believed to be an important medical problem in Africa and many areas of Asia, the geographical distribution and prevalence rates of infection with the hepatitis D virus (HDV) vary considerably, are often inconsistent and sometimes conflicting. Discrepancies may depend on methodological problems, primarily on different modalities of patients' recruitment; these are analysed in this mini-review, in order to provide a uniform clinical approach when testing patients with chronic HDV disease.
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http://dx.doi.org/10.1111/liv.14729DOI Listing
January 2021

The Discovery of the Hepatitis D Virus: Three Princes of Serendip and the Recognition of Autoantibodies to Liver-Kidney Microsomes.

Authors:
Mario Rizzetto

Clin Liver Dis (Hoboken) 2020 Oct 7;16(Suppl 1):1-11. Epub 2020 Oct 7.

Division of Gastroenterology University of Turin Turin Italy.

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http://dx.doi.org/10.1002/cld.1033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538916PMC
October 2020

Analytical and clinical evaluation of a novel assay for anti-HBc IgG measurement in serum of subjects with overt and occult HBV infection.

Diagn Microbiol Infect Dis 2020 Apr 9;96(4):114985. Epub 2020 Jan 9.

Department of Medical Sciences, University of Turin, Gastroenterology Division of Città della Salute e della Scienza of Turin, University Hospital, Turin, Italy.

Objectives: We assessed the analytical and clinical performance of the Lumipulse® G HBcAb-N (Fujirebio, Japan) assay for IgG antibodies to hepatitis B core antigen (anti-HBc IgG) measurement in serum of subjects with overt and occult HBV infection (OBI).

Materials/methods: Serum anti-HBc IgG was assessed in 181 anti-HBc-positive subjects: 119 chronic hepatitis B (CHB) patients in different infection phases and 62 subjects (35 CHB and 27 OBI) with available liver specimens for HBV covalently-close-circular (ccc) DNA analysis.

Results: The anti-HBc IgG assay showed a linear dynamic range (R = 0.9967); lower limit of detection and quantitation were 0.5 IU/mL and 0.8 IU/mL. Reproducibility was 4.9% and accuracy 98.7%. Anti-HBc IgG levels varied according to HBV infection phase, linearly declined during antiviral treatment and resulted correlated to intrahepatic HBV cccDNA (r = 0.752, P < 0.001).

Conclusions: The quantitative anti-HBc IgG assay exhibited appropriate analytical performance and may represent a diagnostic complement in CHB patients and OBI subjects.
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http://dx.doi.org/10.1016/j.diagmicrobio.2020.114985DOI Listing
April 2020

The medical impact of hepatitis D virus infection in Uzbekistan.

Liver Int 2019 11 20;39(11):2077-2081. Epub 2019 Sep 20.

Research Institute of Virology, Tashkent, Uzbekistan.

Background & Aims: The hepatitis B virus (HBV) is endemic in Uzbekistan but the medical impact of infection with the HBV-dependent hepatitis D virus (HDV) is unknown in the Country. An Hepatology Center was recently established at the Institute of Virology in Tashkent, which has set up a database enlisting patients with chronic viral liver disorders from all over Uzbekistan; it provides an observatory on the current scenario of viral hepatitis in the Country.

Methods: The prevalence of HBV monoinfection, hepatitis C virus (HCV) infection and HDV superinfection on hepatitis B surface antigen (HBsAg)-positive cirrhosis was determined in 6589 patients with viral cirrhosis collected in the last 3 years.

Results: Of 1089, 1150 and 1455 carriers of the HBsAg with cirrhosis recruited in 2016, 2017 and 2018, 834 (76.5%), 926 (80.5%) and 1224 (84%) respectively, had antibody to the HDV. In 2016, 2017 and 2018, the prevalence of HDV infection has been 41%, 45% and 49.1% respectively, largely exceeding the prevalence of HBV monoinfection (12.5%, 11% and 9.3% respectively) and surpassing the prevalence of HCV in 2017 and 2018 (44% and 41.5% respectively). The median age of the patients with HDV cirrhosis was 39 years, distinctly lower than that of HBV and HCV patients (46 and 55).

Conclusions: Superinfection with the HDV is present in over 80% of the HBsAg-positive cirrhosis in Uzbekistan. The HDV appears to be the major cause of advanced viral liver disease and of juvenile cirrhosis in the Country.
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http://dx.doi.org/10.1111/liv.14243DOI Listing
November 2019

HLA-DQ Genotyping, Duodenal Histology, and Response to Exclusion Diet in Autistic Children With Gastrointestinal Symptoms.

J Pediatr Gastroenterol Nutr 2019 07;69(1):39-44

Division of Gastroenterology and Hepatology, Città Della Salute e Della Scienza di Torino Hospital.

Objectives: A correlation between autism spectrum disorders (ASDs) and gastrointestinal (GI) problems, and a possible link between gluten consumption and ASD have been increasingly reported. Gluten/casein-free diet (GCFD) is often undertaken, with conflicting results. This study aimed at evaluating the distribution of human leukocyte antigen (HLA)-DQ2/DQ8 typing among patients with ASD with GI symptoms, together with its correlation with duodenal histology and response to GCFD.

Methods: Between 2002 and 2015 all patients with ASD with GI symptoms referred to our outpatient clinic, displaying clinical, laboratory, or ultrasound findings suggestive of organic disease, underwent endoscopy, celiac disease (CD) serum antibodies testing and HLA-DQ2/DQ8 genotyping. Patients were prescribed a 6-month GCFD, and then clinically reassessed.

Results: Among 151 enrolled patients, 134 (89%) were negative for CD-specific antibodies; 72 (48%) were positive for HLA-DQ2/DQ8; and 56 (37%) showed duodenal microscopic inflammation. Clinical improvement was observed in non-CD patients irrespective of the rigorous or partial adherence to the diet, being the difference nonstatistically significant. Response to diet was related to the presence of histological duodenal alterations at baseline (odds ratio 11.323, 95% confidence interval 1.386-92.549 for Marsh 2 pattern), but not to HLA-DQ2/DQ8 positivity (odds ratio 1.120, 95% confidence interval 0.462-2.716).

Conclusions: Our data suggest that children with ASD with GI symptoms have a high prevalence of duodenal intraepithelial lymphocytic infiltration, which seems to be linked to a mechanism other than autoimmune response to gluten consumption. Alteration of duodenal histology, but not the HLA-DQ2/DQ8 status, was associated with clinical response to the diet.
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http://dx.doi.org/10.1097/MPG.0000000000002293DOI Listing
July 2019

Clinical outcomes in chronic hepatitis C long-term responders to pre-direct antiviral agents: a single-center retrospective study.

Minerva Med 2019 Oct 6;110(5):401-409. Epub 2019 May 6.

Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy.

Background: Obesity, type 2 diabetes (T2D), dyslipidemia, arterial hypertension as well as hepatic steatosis (HS) are common conditions that can affect clinical outcomes of patients with chronic hepatitis C (CHC) who achieved sustained virologic response (SVR). The aim of this study was to assess the impact of metabolic cofactors on the occurrence of clinical events during follow-up (FU) in a group of CHC long-term responders (LTRs) to interferon- (IFN) based therapy.

Methods: A total of 5172 medical records of CHC patients enrolled from 1990 to 2011 were examined; 1034 of 5172 (20%) patients were treated with IFN-based therapy and 382 of 1034 (37%) of them achieved SVR. A total of 188 (49%) LTRs underwent liver biopsy before antiviral treatment. Data on liver and cardiometabolic events such as cirrhosis and its complications, hepatocellular carcinoma, coronary artery disease, arterial hypertension, impaired fasting glucose (IFG)/type 2 diabetes (T2D) and dyslipidemia, were collected over time.

Results: The mean age of the whole cohort was 46±12 years and 114/188 (61%) patients were males. HS was found in 82 of 188 (43.6%) patients and most of them were infected by HCV genotype 3a. The prevalence of obesity, IFG/T2D, dyslipidemia and arterial hypertension was 4.3%, 6.9%, 37.2%, and 5.9%, and was similarly distributed among patients with and without HS. Cirrhosis was histologically diagnosed in 18 of 188 (9.6%) patients. After a median follow-up of 11 years (range 3-21 years), the cumulative incidence of cardiovascular events, IFG/T2D and dyslipidemia was higher in CHC-LTRs who had HS at baseline compared to those without HS (1.2%, 2.3%, and 3.0% vs. 0.4%, 0.8%, and 2.5%, respectively). At multivariable Cox regression analysis, HS was significantly associated to the development of cardiovascular events and IFG/T2D (HR=5.2, 95% CI: 1.3-20.7, P=0.019, and HR=2.6, 95% CI: 1.1-6.2, P=0.027, respectively).

Conclusions: In CHC-LTRs, HS at baseline may predispose to the development of cardiovascular events and T2D during follow-up emphasizing the importance of an accurate counseling in order to prevent extra-hepatic complications.
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http://dx.doi.org/10.23736/S0026-4806.19.06108-1DOI Listing
October 2019

Treating chronic hepatitis delta: The need for surrogate markers of treatment efficacy.

J Hepatol 2019 05 27;70(5):1008-1015. Epub 2018 Dec 27.

Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.

Chronic hepatitis delta represents the most severe form of chronic viral hepatitis. The current treatment of hepatitis delta virus (HDV) infection consists of the use of interferons and is largely unsatisfactory. Several new compounds are currently in development for the treatment of HDV infection. However, surrogate markers that can be used to develop clinical endpoints in HDV infection are not well defined. In the current manuscript, we aimed to evaluate the existing data on treatment of HDV infection and to suggest treatment goals (possible "trial endpoints") that could be used across different clinical trials.
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http://dx.doi.org/10.1016/j.jhep.2018.12.022DOI Listing
May 2019

Ombitasvir/paritaprevir/ritonavir plus ribavirin for 24 weeks in patients with HCV GT4 and compensated cirrhosis (AGATE-I Part II).

Health Sci Rep 2019 Mar 1;2(3):e92. Epub 2019 Mar 1.

AbbVie, Inc Chicago Illinois.

Background And Aims: AGATE-I Part I previously reported high sustained virologic response rates in hepatitis C genotype 4 patients with cirrhosis, with 12 and 16 weeks' treatment with a combination of two direct-acting antivirals, ombitasvir and paritaprevir (codosed with ritonavir), plus ribavirin. Part II, reported here, extended the trial to include a 24-week treatment arm to fully assess treatment duration in patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis.

Methods: Enrollment took place between June and November of 2015. Treatment-naive and interferon-experienced patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis were enrolled into Arm C; patients previously treated with a sofosbuvir-based regimen were enrolled into Arm D. All patients received a 24-week treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin. The primary outcome was the proportion of patients with a sustained virologic response (hepatitis C virus RNA < 25 IU/mL) at posttreatment week 12 in the intention-to-treat population. The safety population included all patients who received at least one dose of study drug.

Results: In total, 64 patients were enrolled into AGATE-I Part II. Sustained virologic response at posttreatment week 12 was achieved in 57 of 61 patients (93.4%; 97.5% confidence interval, 92.6-97.7) in Arm C and 3 of 3 patients (100%) in Arm D. Two patients were missing SVR12 data, and two prematurely discontinued treatment. The most common adverse events for Arm C were fatigue (16 [26%]) and asthenia (15 [25%]). Results were comparable with those reported in Part I.

Conclusions: AGATE-I Part II indicates that extending treatment beyond 12 weeks in genotype 4-infected patients with compensated cirrhosis does not offer additional benefit.
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http://dx.doi.org/10.1002/hsr2.92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427060PMC
March 2019

Quantitation of anti-HBe antibodies in anti-HBc-positive liver donors.

J Hepatol 2019 04 24;70(4):793-795. Epub 2018 Dec 24.

Department of Medical Sciences, University of Turin, Gastroenterology Division of Città della Salute e della Scienza of Turin, University Hospital, Turin, Italy.

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http://dx.doi.org/10.1016/j.jhep.2018.11.023DOI Listing
April 2019

Add-on peginterferon alfa-2a to nucleos(t)ide analogue therapy for Caucasian patients with hepatitis B 'e' antigen-negative chronic hepatitis B genotype D.

J Viral Hepat 2019 01 11;26(1):118-125. Epub 2018 Dec 11.

Clinical and Research Center Humanitas, Rozzano, Italy.

Nucleos(t)ide analogues (NAs) and peginterferon have complementary effects in chronic hepatitis B, but it is unclear whether combination therapy improves responses in genotype D-infected patients. We conducted an open-label study of peginterferon alfa-2a 180 μg/wk added to ongoing NA therapy in hepatitis B e antigen (HBeAg)-negative, genotype D-infected patients with hepatitis B virus DNA <20 IU/mL. The primary endpoint was proportion of patients with ≥50% decline in serum HBsAg by the end of the 48-week add-on phase. Seventy patients received treatment, 11 were withdrawn at week 24 for no decrease in HBsAg, and 14 withdrew for other reasons. Response rate (per-protocol population) was 67.4% (29/43) at week 48 (95% confidence interval [CI]: 51, 81) and 50.9% (28/55) at week 96 (95% CI: 38, 66). Median serum HBsAg decreased throughout peginterferon alfa-2a treatment and was significantly lower than baseline at weeks 48, 72 and 96 (P < 0.001). Decreases in HBsAg of ≥0.5-log and ≥1-log were documented in 19 (44.2%) and 6 (14.0%) patients at week 48 and 6 (10.9%) and 17 (30.9%) patients at week 96. The proportion of patients with HBsAg <1000, <500, <100 and <10 IU/mL at ≥1 timepoint during treatment was 78.6% (n = 44), 57.1% (n = 32), 21.4% (n = 12) and 7.1% (n = 4). Interferon gamma-induced protein 10 increased from baseline up to week 48, with week 12 levels significantly associated with response at week 48. Addition of peginterferon alfa-2a to ongoing NA therapy significantly decreased HBsAg levels in HBeAg-negative patients with genotype D infection (ClinicalTrials.gov NCT01706575).
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http://dx.doi.org/10.1111/jvh.12999DOI Listing
January 2019

Amino Acid Substitutions within HLA-B*27-Restricted T Cell Epitopes Prevent Recognition by Hepatitis Delta Virus-Specific CD8 T Cells.

J Virol 2018 07 13;92(13). Epub 2018 Jun 13.

Center for Integrated Protein Science Munich at the Department of Biosciences, Technische Universität München, Freising, Germany.

Virus-specific CD8 T cell response seems to play a significant role in the outcome of hepatitis delta virus (HDV) infection. However, the HDV-specific T cell epitope repertoire and mechanisms of CD8 T cell failure in HDV infection have been poorly characterized. We therefore aimed to characterize HDV-specific CD8 T cell epitopes and the impacts of viral mutations on immune escape. In this study, we predicted peptide epitopes binding the most frequent human leukocyte antigen (HLA) types and assessed their HLA binding capacities. These epitopes were characterized in HDV-infected patients by intracellular gamma interferon (IFN-γ) staining. Sequence analysis of large hepatitis delta antigen (L-HDAg) and HLA typing were performed in 104 patients. The impacts of substitutions within epitopes on the CD8 T cell response were evaluated experimentally and by studies. We identified two HLA-B*27-restricted CD8 T cell epitopes within L-HDAg. These novel epitopes are located in a relatively conserved region of L-HDAg. However, we detected molecular footprints within the epitopes in HLA-B*27-positive patients with chronic HDV infections. The variant peptides were not cross-recognized in HLA-B*27-positive patients with resolved HDV infections, indicating that the substitutions represent viral escape mutations. Molecular modeling of HLA-B*27 complexes with the L-HDAg epitope and its potential viral escape mutations indicated that the structural and electrostatic properties of the bound peptides differ considerably at the T cell receptor interface, which provides a possible molecular explanation for the escape mechanism. This viral escape from the HLA-B*27-restricted CD8 T cell response correlates with a chronic outcome of hepatitis D infection. T cell failure resulting from immune escape may contribute to the high chronicity rate in HDV infection. Hepatitis delta virus (HDV) causes severe chronic hepatitis, which affects 20 million people worldwide. Only a small number of patients are able to clear the virus, possibly mediated by a virus-specific T cell response. Here, we performed a systematic screen to define CD8 epitopes and investigated the role of CD8 T cells in the outcome of hepatitis delta and how they fail to eliminate HDV. Overall the number of epitopes identified was very low compared to other hepatotropic viruses. We identified, two HLA-B*27-restricted epitopes in patients with resolved infections. In HLA-B*27-positive patients with chronic HDV infections, however, we detected escape mutations within these identified epitopes that could lead to viral evasion of immune responses. These findings support evidence showing that HLA-B*27 is important for virus-specific CD8 T cell responses, similar to other viral infections. These results have implications for the clinical prognosis of HDV infection and for vaccine development.
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http://dx.doi.org/10.1128/JVI.01891-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002722PMC
July 2018

Quantitation of HBV cccDNA in anti-HBc-positive liver donors by droplet digital PCR: A new tool to detect occult infection.

J Hepatol 2018 08 3;69(2):301-307. Epub 2018 Apr 3.

Department of Medical Sciences, University of Turin, Gastroenterology Division of Città della Salute e della Scienza of Turin, University Hospital, Turin, Italy.

Background & Aims: The accurate diagnosis of occult hepatitis B virus (HBV) infection (OBI) requires the demonstration of HBV DNA in liver biopsies of hepatitis B surface antigen-negative individuals. However, in clinical practice a latent OBI is deduced by the finding of the antibody to the hepatitis B core antigen (anti-HBc). We investigated the true prevalence of OBI and the molecular features of intrahepatic HBV in anti-HBc-positive individuals.

Methods: The livers of 100 transplant donors (median age 68.2 years; 64 males, 36 females) positive for anti-HBc at standard serologic testing, were examined for total HBV DNA by nested-PCR and for the HBV covalently closed circular DNA (HBV cccDNA) with an in-house droplet digital PCR assay (ddPCR) (Linearity: R = 0.9998; lower limit of quantitation and detection of 2.4 and 0.8 copies/10 cells, respectively).

Results: A total of 52% (52/100) of the individuals studied were found to have OBI. cccDNA was found in 52% (27/52) of the OBI-positive, with a median 13 copies/10 cells (95% CI 5-25). Using an assay specific for anti-HBc of IgG class, the median antibody level was significantly higher in HBV cccDNA-positive than negative donors (17.0 [7.0-39.2] vs. 5.7 [3.6-9.7] cut-off index [COI], respectively, p = 0.007). By multivariate analysis, an anti-HBc IgG value above 4.4 COI was associated with the finding of intrahepatic HBV cccDNA (odds ratio 8.516, p = 0.009); a lower value ruled out its presence with a negative predictive value of 94.6%.

Conclusions: With a new in-house ddPCR-based method, intrahepatic HBV cccDNA was detectable in quantifiable levels in about half of the OBI cases examined. The titer of anti-HBc IgG may be a useful surrogate to predict the risk of OBI reactivation in immunosuppressed patients.

Lay Summary: The covalently closed circular DNA (cccDNA) form of the hepatitis B virus (HBV) sustains the persistence of the virus even decades after resolution of the symptomatic infection (occult HBV infection). In the present study we developed a highly sensitive method based on droplet digital PCR technology for the detection and quantitation of HBV cccDNA in the liver of individuals with occult HBV infection. We observed that the amount of HBV cccDNA may be inferred from the titer in serum of the IgG class antibody to the hepatitis B core antigen. The quantitation of this antibody may represent a surrogate to determine which patients are at the highest risk of HBV reactivation following immunosuppressive therapies.
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http://dx.doi.org/10.1016/j.jhep.2018.03.021DOI Listing
August 2018

Declining prevalence and increasing awareness of HCV infection in Italy: A population-based survey in five metropolitan areas.

Eur J Intern Med 2018 07 21;53:79-84. Epub 2018 Feb 21.

Department of Medical Sciences, University of Torino, Department of Gastroenterology and Hepatology, Azienda Ospedaliera Città della Salute e della Scienza, Torino, Italy.

Background: Data on the prevalence of hepatitis C virus (HCV) infection in Italy are outdated and usually derived from studying residents in small towns.

Methods: To assess prevalence of and risk factors for HCV infection among Italian residents in 5 metropolitan areas, subjects ≥20 years of age were randomly selected from the list of the general practitioners' registers in 2015. Anti-HCV was tested by a salivary test; HCV-RNA, HCV genotypes, and ALT were determined in positive individuals. Logistic regression analysis evaluated independent risk factors for HCV.

Results: Of the 4907 enrolled subjects, 112 (2.3%) tested anti-HCV positive. The prevalence of HCV increased with age, from 0.2% in subjects born after the year 1984, to 4.2% in those born before the year 1935 (P < 0.01). The birth-cohort prevalence peaked (7.0%) in elderly. Serum HCV-RNA was detected in 1.7% of the whole population. Nearly 80% of anti-HCV subjects were aware of their status. Age > 70 years, low education level, past use of glass syringes, blood transfusion, intravenous drug use, and cohabitation with an anti-HCV positive subject predicted the HCV positivity.

Interpretation: In metropolitan areas in Italy, HCV is prevalent in elderly, reflecting a cohort effect determined by modalities of viral transmission no longer operative. The impact of the infection will further diminish in the years to come due to the natural depletion of the reservoir of the virus. This age pattern and the high proportion of subjects aware of their status do not warrant a policy of screening.
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http://dx.doi.org/10.1016/j.ejim.2018.02.015DOI Listing
July 2018

Targeting Hepatitis D.

Authors:
Mario Rizzetto

Semin Liver Dis 2018 02 22;38(1):66-72. Epub 2018 Feb 22.

Division of Gastroenterology, University of Torino, Torino, Italy.

New therapeutic strategies to treat chronic hepatitis D are directed to deprive the hepatitis D virus (HDV) of functions necessary to complete its life cycle that are provided by the hepatitis B virus (HBV) and by the host. Current options are (1) the block by the synthetic peptide Myrcludex B of HBV surface antigen (HBsAg) entry into cells through the inhibition of the sodium taurocholate cotransporting receptor; (2) the inhibition with lonafarnib of the farnesylation of the large HD antigen, required for virion assembly; (3) the presumed reduction by the nucleic acid polymer REP 2139 of the release of the HBsAg and subviral HBV particles necessary for HD virion morphogenesis. Lonafarnib and Myrcludex in monotherapy reduced serum HDV-RNA but did not reduce the HBsAg and HD viremia rebounded after therapy; they may provide additional efficacy to pegylated interferon alpha (Peg IFN-α) therapy. Treatment with REP-2139 in combination with Peg IFN-α induced a sustained clearance both of the HDV-RNA and HBsAg in 5 of 12 patients, providing the best interim results so far obtained in the therapy of chronic hepatitis D.
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http://dx.doi.org/10.1055/s-0037-1621711DOI Listing
February 2018

Are immunoglobulins against the HBsAg still needed in liver transplantation for hepatitis D?

Hepatology 2018 06 25;67(6):2475-2476. Epub 2018 Apr 25.

Gastrohepatology Unit, AOU Città della Salute e della Scienza di Torino, University of Torino, Turin, Italy.

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http://dx.doi.org/10.1002/hep.29796DOI Listing
June 2018

Clinical and virological heterogeneity of hepatitis delta in different regions world-wide: The Hepatitis Delta International Network (HDIN).

Liver Int 2018 05 26;38(5):842-850. Epub 2017 Oct 26.

Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Background & Aims: Chronic hepatitis D (delta) is a major global health burden. Clinical and virological characteristics of patients with hepatitis D virus (HDV) infection and treatment approaches in different regions world-wide are poorly defined.

Methods: The Hepatitis Delta International Network (HDIN) registry was established in 2011 with centres in Europe, Asia, North- and South America. Here, we report on clinical/ virological characteristics of the first 1576 patients with ongoing or past HDV infection included in the database until October 2016 and performed a retrospective outcome analysis. The primary aim was to investigate if the region of origin was associated with HDV replication and clinical outcome.

Results: The majority of patients was male (n = 979, 62%) and the mean age was 36.7 years (range 1-79, with 9% of patients younger than 20 years). Most patients were HBeAg-negative (77%) and HDV-RNA positive (85%). Cirrhosis was reported in 48.7% of cases which included 13% of patients with previous or ongoing liver decompensation. Hepatocellular carcinoma (HCC) developed in 30 patients (2.5%) and 44 (3.6%) underwent liver transplantation. Regions of origin were independently associated with clinical endpoints and detectability of HDV RNA. Antiviral therapy was administered to 356 patients with different treatment uptakes in different regions. Of these, 264 patients were treated with interferon-a and 92 were treated with HBV-Nucs only.

Conclusions: The HDIN registry confirms the severity of hepatitis delta but also highlights the heterogeneity of patient characteristics and clinical outcomes in different regions. There is an urgent need for novel treatment options for HDV infection.
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http://dx.doi.org/10.1111/liv.13604DOI Listing
May 2018

Significant improvement of glycemic control in diabetic patients with HCV infection responding to direct-acting antiviral agents.

J Med Virol 2018 02 14;90(2):320-327. Epub 2017 Nov 14.

Gastroenterology Unit, Department of Medical Sciences, AOU Città della Salute e della Scienza di Torino, University of Turin, Torino, Italy.

Many studies showed insulin resistance amelioration in HCV-patients achieving Sustained Virologic Response (SVR) but results on glycemic control in diabetic patients are unclear. This study aimed to assess fasting glucose (FG) and glycated hemoglobin (HbA1c) values before and after therapy with direct-acting antivirals (DAAs) in HCV-patients with type 2 diabetes mellitus (T2DM). Of the 122 consecutively recruited patients with chronic hepatitis C and T2DM, 110 patients were treated with DAAs and 12 remained untreated. Clinical, biochemical, virological, and metabolic features were collected both at baseline and at 12 weeks after the end of therapy (EOT) or after a comparable period of time in untreated patients. A total of 101 patients obtained a SVR (Group 1), while nine were relapsers. Group 2 (21 patients) was composed by the nine relapsers and the 12 untreated patients. A significant reduction of mean FG (134.3 ± 41.32 mg/dL vs 152.4 ± 56.40 mg/dL, P = 0.002) and HbA1c values (46.51 ± 16.15 mmoL/moL vs 52.15 ± 15.43 mmoL/moL, P <  0.001) was found in Group 1 but not in Group 2 (140.6 ± 47.87 mg/dL vs. 145.31 ± 30.18 mg/dL, P = 0.707, and 55.31 ± 20.58 mmoL/moL vs. 53.38 ± 9.49 mmoL/moL, P = 0.780). In Group 1, 20.7% of patients could reduce or suspend their antidiabetic therapy compared to none in Group 2 (P = 0.03), despite the significant weight increase observed in Group 1. SVR induced a significant amelioration of glycemic control in diabetic HCV-patients, despite a significant weight increase; larger prospective studies are needed to verify whether these results are maintained over the long-term.
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http://dx.doi.org/10.1002/jmv.24954DOI Listing
February 2018

Investigational drugs in development for Hepatitis D.

Authors:
Mario Rizzetto

Expert Opin Investig Drugs 2017 Sep 28;26(9):999-1005. Epub 2017 Jul 28.

a Department of Medicine , University of Torino , Torino , Italy.

Introduction: Treatment of chronic hepatitis D still relies on Interferon. To improve efficacy, new therapeutic strategies are in development which aim to deprive the Hepatitis D Virus (HDV) of functions of the Hepatitis B Virus and of the host required for its life-cycle. Areas covered: The therapeutic options are; 1) The inhibition of the farnesylation of the large HD-protein permissive of virion assembly with Lonafarnib, 2) The blocking of HBsAg entry into cells with Myrcludex B via the inhibition of the Sodium Taurocholate Cotransporting Receptor, to prevent the spreading of HDV to uninfected hepatocytes, 3) The reduction of subviral HBsAg particles by REP 2139, leading to diminished virion morphogenesis . Expert opinion: Lonafarnib and Myrcludex reduced serum HVD-RNA; neither diminished serum HBsAg. NAP REP-2139 diminished both HDV-RNA and HBsAg in serum; a full report is awaited. In combination with Peg-Interferon, these new drugs may provide additional efficacy.
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http://dx.doi.org/10.1080/13543784.2017.1357695DOI Listing
September 2017

Risk of hepatocellular carcinoma in HBV cirrhotic patients assessed by the combination of miR-122, AFP and PIVKA-II.

Panminerva Med 2017 Dec 23;59(4):283-289. Epub 2017 Jun 23.

Department of Medical Sciences, University of Turin, Turin, Italy.

Background: Reliable biomarkers for early detection of hepatocellular carcinoma (HCC) in patients with cirrhosis are lacking. We evaluated the use of miR-122, alpha-fetoprotein (AFP) and protein induced by vitamin k absence/antagonist II (PIVKA-II) for HCC risk prediction in patients with HBV-related cirrhosis under surveillance.

Methods: We first analyzed a group of 63 patients with HBV-related liver cirrhosis of whom 33 had HCC. Then we performed a retrospective analysis on another group of 13 cirrhotic patients who developed HCC during surveillance, of whom serial serum samples were available (at time of HCC diagnosis [T0], 6-9 months [T-1] and 12-18 months [T-2] before HCC detection). Serum miR-122 levels were assessed by quantitative real time-PCR, whereas AFP and PIVKA-II were measured by fully automated chemiluminescent enzyme immunoassay.

Results: Serum levels of miR-122, AFP and PIVKA-II were different between patients with cirrhosis and those with HCC (P=0.024, P<0.001 and P<0.001, respectively). Areas under the curve (AUC) were 0.675 for miR-122, 0.791 for AFP and 0.846 for PIVKA-II, while their combination improved the discrimination power between cirrhosis and HCC (AUC=0.918). In the longitudinal study, we found a significant variation overtime for the biomarkers combination (P=0.011) but not for each single biomarker (miR-122, P=0.163; AFP, P=0.170; PIVKA-II, P=0.447). Combined miR-122+AFP+PIVKA-II adjusted Hazard Ratio for HCC development was 10.63, 95% confidence interval 1.87-60.28 (P<0.001).

Conclusions: In HBV-related cirrhosis, the combination of miR-122, AFP and PIVKA-II enables the identification of patients at higher risk of HCC development that could benefit from closer monitoring.
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http://dx.doi.org/10.23736/S0031-0808.17.03353-5DOI Listing
December 2017

Persistence of Virologic Response after Liver Transplant in Hepatitis C Patients Treated with Ledipasvir / Sofosbuvir Plus Ribavirin Pretransplant.

Ann Hepatol 2017 May - Jun;16(3):375-381

Department for Gastroenterology and Hepatology, University Hospital Zurich, Switzerland.

Introduction: Recurrence of HCV infection in patients with chronic hepatitis C virus (HCV) at the time of liver transplantation is nearly universal and reduces the likelihood of graft and patient survival.

Materials And Methods: We evaluated outcomes of 17 patients (16 with HCV genotype 1 and 1 with genotype 4) who received up to 12 or 24 weeks of ledipasvir/sofosbuvir plus ribavirin prior to or up to the time of liver transplant in the SOLAR-1 and SOLAR-2 trials. In all patients, HCV RNA was < 15 IU/mL prior to transplant. At screening, 6 patients were Child-Pugh-Turcotte (CPT) class B and 11 were CPT class C. Seven patients underwent transplant prior to completing assigned treatment, with 4 treated for < 12 weeks. The primary endpoint was posttransplant virologic response 12 weeks after transplant (pTVR12) in patients with HCV RNA < 15 IU/mL at their last measurement prior to transplant.

Results: Overall, 94% (16/17) achieved pTVR12. All who achieved pTVR12 received at least 11 weeks of treatment. The single patient who did not achieve pTVR12 discontinued study drug on day 21 and underwent liver transplant the following day. The patient had HCV RNA < 15 IU/mL at post-transplant week 2 but died 15 days post-transplant because of multi-organ failure and septic shock.

Conclusion: Among a small population of HCV patients with decompensated cirrhosis, virologic response to ledipasvir / sofosbuvir plus ribavirin prior to liver transplantation was maintained after transplantation, even if treatment was stopped early. Administration of ledipasvir / sofosbuvir plus ribavirin before liver transplant can prevent post-transplant HCV recurrence.
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http://dx.doi.org/10.5604/16652681.1235480DOI Listing
October 2017

Screening and management of viral hepatitis and hepatocellular carcinoma in Mongolia: results from a survey of Mongolian physicians from all major provinces of Mongolia.

BMJ Open Gastroenterol 2016 10;3(1):e000119. Epub 2016 Nov 10.

Division of Gastroenterology and Hepatology, Stanford University, Stanford, California, USA; Center for Innovation in Global Health, Stanford University, Stanford, California, USA.

Background: According to Globocan, Mongolia has the highest worldwide hepatocellular carcinoma (HCC) incidence (78.1/100 000, 3.5× higher than China).

Aims And Methods: We conducted an anonymous survey of physicians from major provinces who attended an educational liver symposium, analysing their demography, practice, knowledge, perceptions and proposed solutions. Multivariate logistic regression was used to estimate OR relating demography and practice factors with higher provider knowledge and improvement.

Results: Of the 121 attendees, 44-95 (36-79%) responded to each question. Most were female (87%), young (79% age <50), subspecialists (81%), university-affiliated (74%), and practised in urban areas (61%). The mean pretest and post-test scores per physician were 60.4±20.4 and 65.6±21.3, with no observed significant predictors for baseline knowledge or improvement. Most (>80%) noted that <50% of patients who need hepatitis or HCC screening receive it. The main perceived barriers to screening were inability to pay for tests, lack of guidelines and poor patient awareness. Hepatitis treatment rates were low; 83% treated hepatitis C virus in <10 patients in the past year, and 86% treated hepatitis B virus in <10 patients/month. Treatment barriers were multifactorial, with cost as a principal barrier. Proposed solutions were universal screening policies (46%), removal of financial barriers (28%) and provider education (20%).

Conclusions: Physicians from major regions of Mongolia noted low screening for viral hepatitis, even lower treatment rates, financial barriers and the need for increased educational efforts. We advocate broad-based medical education tailored to local needs and based on needs assessment and outcome measurements.
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http://dx.doi.org/10.1136/bmjgast-2016-000119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5128837PMC
November 2016

Etiology of chronic liver diseases in the Northwest of Italy, 1998 through 2014.

World J Gastroenterol 2016 Sep;22(36):8187-93

Giorgio Maria Saracco, Department of Oncology, University of Turin, 10123 Turin, Italy.

Aim: To assess the etiology of chronic liver diseases (CLD) from 1998 to 2014 at the outpatient clinic of Gastroenterology of the main hospital in Northwest of Italy among those dedicated to hepatology.

Methods: A random sample of charts of patients referred to for increased liver enzymes between January 1998 and December 2006, and between January 2012 and December 2014 were reviewed. Etiology search included testing for hepatitis B virus (HBV), hepatitis C virus (HCV), autoimmune hepatitis, primary biliary cirrhosis, Wilson's disease and hereditary hemocromatosis. A risky alcohol consumption was also considered. Non-alcoholic fatty liver disease (NAFLD) was diagnosed in patients with histological and/or ultrasound evidence of steatosis/steatohepatitis, and without other causes of CLD.

Results: The number of patients included was 1163. Of them, 528 (45%) had positivity for HCV and 85 (7%) for HBV. Among the virus-free patients, 417 (36%) had metabolic disorders whereas the remaining had history of alcohol abuse, less prevalent causes of CLD or concomitant conditions. In comparison to 1998-2000 (41%), a reduction of HCV alone-related cases was detected during the periods 2001-2003 (35%, OR = 0.75, 95%CI: 0.53-1.06), 2004-2006 (33%, OR = 0.70, 95%CI: 0.50-0.97) and 2012-2014 (31%, OR = 0.64, 95%CI: 0.46-0.91). On the contrary, in comparison to 1998-2000 (31%), metabolic-alone disorders increased in the period 2004-2006 (39%, OR = 1.37, 95%CI: 0.99-1.91) and 2012-2014 (41%, OR = 1.53, 95%CI: 1.09-2.16). The other etiologies remained stable. The increase of incidence of metabolic-alone etiology during the period 2004-2006 and 2012-2014 tended to be higher in older patients (≥ 50 years) compared to younger (P = 0.058).

Conclusion: In the Northwest of Italy, during this study period, the prevalence of HCV infection decreased notably whereas that of NAFLD increased.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037087PMC
http://dx.doi.org/10.3748/wjg.v22.i36.8187DOI Listing
September 2016

Hepatitis B core-related antigen kinetics in chronic hepatitis B virus genotype D-infected patients treated with nucleos(t)ide analogues or pegylated-interferon-α.

Hepatol Res 2017 Jul 27;47(8):747-754. Epub 2016 Sep 27.

Department of Medical Sciences, University of Turin, Turin, Italy.

Aim: The aim of this study was to evaluate the correlation between hepatitis B core-related antigen (HBcrAg) and hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HBsAg) levels, and to investigate HBcrAg kinetics during nucleos(t)ide analogue (NA) or pegylated-interferon (PEG-IFN)-α treatment in a cohort of chronic hepatitis B (CHB) genotype D patients.

Methods: One hundred thirty eight sequential serum samples were collected from 28 hepatitis B e antigen-negative CHB genotype D patients (20 men and 8 women; median age, 54 years [range, 47-58 years]) who underwent NA (n = 20) or PEG-IFN-α (n = 8) treatment. Serum HBcrAg levels were determined by chemiluminescent enzyme immunoassay. Longitudinal analysis was carried out at 6, 12, 24, and 36 months after NA treatment initiation and at 6, 12, and 18 months and at follow-up month 6 after PEG-IFN-α treatment.

Results: Basal HBcrAg levels were 4.7 ± 1.8 Log U/mL and 3.3 ± 1.6 Log U/mL in NA- and PEG-IFN-α-treated patients, respectively. Hepatitis B core-related antigen showed a moderate correlation with HBV DNA (r = 0.498, P < 0.0001) and no correlation with HBsAg (r = 0.192, P = 0.0669). In serial serum samples, a significant HBcrAg reduction was observed only in patients receiving NA (P = 0.019). In these patients, we observed a group (n = 12) with an early HBcrAg decline to undetectable levels between months 6-12, whereas the other group (n = 8) still had detectable HBcrAg at month 36 (4.4 ± 0.6 Log U/mL), independently from HBV DNA and HBsAg kinetics.

Conclusions: Serum HBcrAg correlates with HBV DNA levels, most likely through expression of viral replication activity. We observed two different HBcrAg kinetics in NA-treated patients, suggesting different relapse risk related to NA cessation. Further studies on larger patient cohorts will elucidate the role of HBcrAg in the safe discontinuation of NA in CHB genotype D patients.
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http://dx.doi.org/10.1111/hepr.12811DOI Listing
July 2017

[Chronic hepatitis B: standard of therapy and perspectives].

Authors:
Mario Rizzetto

Recenti Prog Med 2016 Jul;107(7):355-9

Cattedra di Gastroenterologia, Istituto di Medicina Interna, Università di Torino.

Infection with the hepatitis B virus (HBV) has much diminished in Italy in the last 25 years; at present, all Italian nationals aged under 36 years are protected from HBV by vaccinal immunity. The problem of the infection has shifted to the immigrants from countries where HBV is still endemic; in this population the prevalence of the infection is high, up to 10% of the immigrants. In the next 5 years the prevalence of HBV is bound to further diminish in the domestic population, for the increment of the age of the subjects protected by mandatory HBV vaccination and for the natural exhaustion of the elderly cohorts of HBsAg carriers which represent the last domestic reservoir of the infection. Most likely, instead, the problem in immigrants will become more important, forcing new strategies to the approach and containment of HBV. Therapy of hepatitis B is not satisfactory; it allows the control of HBV replication and related disease but is not capable of clearing the virus; eradication of the HBsAg is achieved only in few patients. The future target are therapies aimed at eradicating the HBV, not only at containing its replication and disease expression. A miriad new drugs acting directly against functions necessary to the life cycle of the HBV are under study; it is unlikely, however, that they will enter clinical trials in the few years. More promising in the short term, it is the development of prodrugs of antivirals currently in use, of which tenofovir alafenamide (TAF), the prodrug of tenofovir, is the prototype, entering soon into therapeutic routine.
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http://dx.doi.org/10.1701/2318.24926DOI Listing
July 2016

Myrcludex B, a novel therapy for chronic hepatitis D?

J Hepatol 2016 09;65(3):465-6

IRCCS "Casa Sollievo Sofferenza" Hospital, Gastroenterology Unit, San Giovanni Rotondo (FG), Italy.

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http://dx.doi.org/10.1016/j.jhep.2016.06.014DOI Listing
September 2016
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