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Micro-RNAs (miRNAs) are involved in the modulation of viral replication and host immune antiviral response. Using next-generation sequencing, we investigated the miRNome profile of circulating extracellular vesicles in 20 patients with chronic hepatitis D virus (HDV) infection undergoing pegylated interferon alpha (Peg-IFNα) treatment. Circulating miRNAs' expression was analysed according to virologic response (i.e., HDV RNA clearance maintained at least 6 months after the end of therapy). Overall, 8 patients (40%) achieved a virologic response to Peg-IFNα treatment. At baseline, 14 miRNAs were differentially expressed between responders and non-responders; after 6 months of Peg-IFNα treatment, 7 miRNAs (miR-155-5p, miR-1246, miR-423-3p, miR-760, miR-744-5p, miR-1307-3p and miR-146a-5p) were consistently de-regulated. Among de-regulated miRNAs, miR-155-5p showed an inverse correlation with HDV RNA (at baseline: rs = -0.39, p = 0.092; at 6 months: rs = -0.53, p = 0.016) and hepatitis B surface antigen (HBsAg) (at baseline: rs = -0.49, p = 0.028; at 6 months: rs-0.71, p < 0.001). At logistic regression analysis, both miR-155-5p (at baseline: OR = 4.52, p = 0.022; at 6 months: OR = 5.30, p = 0.029) and HDV RNA (at baseline: OR = 0.19, p = 0.022; at 6 months: OR = 0.38, p = 0.018) resulted significantly associated to virologic response. Considering that Peg-IFNα still has a relevant role in the treatment of patients with chronic hepatitis D infection, the assessment of EV miR-155-5p may represent an additional valuable tool for the management of HDV patients undergoing Peg-IFNα treatment.
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BACKGROUND AND AIMS: Chronic hepatitis delta represents a major global health burden. Clinical features of hepatitis D virus (HDV) infection vary largely between different regions worldwide. Treatment approaches are dependent on the approval status of distinct drugs and financial resources. METHODS: The Hepatitis Delta International Network (HDIN) registry involves researchers from all continents (Wranke, Liver International 2018). We here report long-term follow-up data of 648 hepatitis D patients recruited by 14 centres in 11 countries. Liver-related clinical endpoints were defined as hepatic decompensation (ascites, encephalopathy and variceal bleeding), liver transplantation, hepatocellular carcinoma or liver-related death. RESULTS: Patient data were available from all continents but Africa: 22% from Eastern Mediterranean, 32% from Eastern Europe and Central Asia, 13% from Central and Southern Europe, 14% from South Asia (mainly Pakistan) and 19% from South America (mainly Brazil). The mean follow-up was 6.4 (.6-28) years. During follow-up, 195 patients (32%) developed a liver-related clinical event after 3.5 (±3.3) years. Liver cirrhosis at baseline and a detectable HDV RNA test during follow-up were associated with a worse clinical outcome in multivariate regression analysis while patients receiving interferon alfa-based therapies developed clinical endpoints less frequently. Patients from South Asia developed endpoints earlier and had the highest mortality. CONCLUSIONS: The HDIN registry confirms the severity of hepatitis D and provides further evidence for HDV viraemia as a main risk factor for disease progression. Hepatitis D seems to take a particularly severe course in patients born in Pakistan. There is an urgent need to extend access to antiviral therapies and to provide appropriate education about HDV infection.
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The European Liver and Intestine Transplant Association, ELITA, promoted a Consensus Conference involving 20 experts across the world which generated updated guidelines on HBV prophylaxis in liver transplant candidates and recipients. This study explores the economic impact associated with the implementation of the new ELITA guidelines. To this aim, a condition-specific cohort simulation model has been developed to compare new and historical prophylaxis, including only pharmaceutical cost and using the European perspective. The target population simulated in the model included both prevalent and incident cases, and consisted of 6,133 patients after the first year, that increased to 7,442 and 8,743 patents after 5 and 10 years from its implementation. The ELITA protocols allowed a cost saving of around 235.65 million after 5 years and 540.73 million after 10 years; which was mainly due to early HIBG withdrawal either after the first 4 weeks or after the first year post Liver Transplantation (LT) depending on the virological risk at transplantation. Results were confirmed by sensitivity analyses. The money saved by the implementation of the ELITA guidelines would allow healthcare decision makers and budget holders to understand where costs could be reduced and resources re-allocated to different needs.
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Hepatite B , Transplante de Fígado , Humanos , Antivirais/uso terapêutico , Hepatite B/prevenção & controle , Quimioterapia CombinadaRESUMO
The hepatitis D virus (HDV) is unique in animal virology. It is the smallest of human pathogens, re- quires the HBsAg capsid of the hepatitis B virus (HBV) to assembly into infectious virions, and parasitizes the transcriptional machinery of the host. Hepatitis D is ubiquitous but prevalence varies throughout the world. It is the most severe form of chronic viral liver disorder. Vaccination against the HBV has decreased the circulation of HDV in industrialized countries but Hepatitis D remains a significant medical issue in many areas of the developing world.
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Hepatite A , Hepatite B , Hepatite D , Animais , Hepatite B/prevenção & controle , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/genética , Hepatite D/epidemiologia , Vírus Delta da Hepatite/genética , Humanos , RNA ViralRESUMO
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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Antivirais/farmacologia , Hepatite D Crônica , Coinfecção/epidemiologia , Europa (Continente)/epidemiologia , Hepatite D Crônica/epidemiologia , Hepatite D Crônica/terapia , Hepatite D Crônica/transmissão , Hepatite D Crônica/virologia , Humanos , Avaliação das NecessidadesRESUMO
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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Hepatite D Crônica , Hepatite D , África/epidemiologia , Ásia/epidemiologia , Hepatite D/diagnóstico , Hepatite D/epidemiologia , Vírus Delta da Hepatite , Humanos , PrevalênciaRESUMO
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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Hepatite D Crônica/tratamento farmacológico , Biomarcadores , Ensaios Clínicos como Assunto , Antígenos de Superfície da Hepatite B/análise , Hepatite D Crônica/patologia , Humanos , Lipopeptídeos/uso terapêutico , Fígado/patologia , Ácidos Nucleicos/uso terapêutico , Piperidinas/uso terapêutico , Polímeros/uso terapêutico , Piridinas/uso terapêutico , RNA Viral/análise , Resultado do TratamentoRESUMO
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 in silico 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.IMPORTANCE 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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Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Antígenos HLA-B/imunologia , Hepatite D/imunologia , Vírus Delta da Hepatite/imunologia , Antígenos da Hepatite delta/imunologia , Sequência de Aminoácidos , Substituição de Aminoácidos , Linfócitos T CD8-Positivos/metabolismo , Epitopos de Linfócito T/metabolismo , Antígenos HLA-B/genética , Antígenos HLA-B/metabolismo , Hepatite D/genética , Hepatite D/virologia , Vírus Delta da Hepatite/genética , Antígenos da Hepatite delta/metabolismo , Humanos , Mutação , Homologia de SequênciaRESUMO
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-log10 and ≥1-log10 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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Antivirais/administração & dosagem , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Nucleosídeos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adulto , Esquema de Medicação , Quimioterapia Combinada , Feminino , Genótipo , Vírus da Hepatite B/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Resultado do TratamentoRESUMO
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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Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/complicações , Hepatite D/complicações , Vírus Delta da Hepatite/genética , Cirrose Hepática/virologia , Adolescente , Adulto , Feminino , Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/genética , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/imunologia , Hepatite C/epidemiologia , Hepatite D/epidemiologia , Hepatite D/imunologia , Humanos , Cirrose Hepática/epidemiologia , Masculino , Pessoa de Meia-Idade , Uzbequistão/epidemiologia , Adulto JovemRESUMO
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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Transtorno do Espectro Autista/genética , Duodenite/dietoterapia , Duodenite/genética , Duodeno/patologia , Dor Abdominal/etiologia , Adolescente , Transtorno do Espectro Autista/complicações , Caseínas/administração & dosagem , Doença Celíaca/dietoterapia , Doença Celíaca/genética , Criança , Pré-Escolar , Constipação Intestinal/etiologia , Dieta Livre de Glúten , Duodenite/complicações , Duodenite/patologia , Feminino , Genótipo , Antígenos HLA-DQ/genética , Humanos , Síndromes de Malabsorção/etiologia , MasculinoRESUMO
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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Antivirais/uso terapêutico , Hepatite D Crônica/tratamento farmacológico , Vírus Delta da Hepatite/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Animais , Antivirais/efeitos adversos , DNA Viral/genética , Farmacorresistência Viral , Hepatite D Crônica/diagnóstico , Hepatite D Crônica/virologia , Vírus Delta da Hepatite/genética , Vírus Delta da Hepatite/patogenicidade , Humanos , Resposta Viral Sustentada , Resultado do Tratamento , Carga ViralRESUMO
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 68.2â¯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: R2â¯=â¯0.9998; lower limit of quantitation and detection of 2.4 and 0.8â¯copies/105â¯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 13â¯copies/105â¯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, pâ¯=â¯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, pâ¯=â¯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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DNA Viral/análise , Anticorpos Anti-Hepatite B/sangue , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Vírus da Hepatite B , Hepatite B Crônica , Hepatite B/diagnóstico , Transplante de Fígado/métodos , Fígado/virologia , Idoso , DNA Circular/análise , Feminino , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Masculino , Reação em Cadeia da Polimerase/métodos , Reprodutibilidade dos Testes , Doadores de TecidosRESUMO
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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Antivirais/uso terapêutico , Glicemia/análise , Diabetes Mellitus Tipo 2/patologia , Hemoglobinas Glicadas/análise , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
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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Antivirais/administração & dosagem , Carcinoma Hepatocelular/epidemiologia , Hepatite D/epidemiologia , Vírus Delta da Hepatite/genética , Neoplasias Hepáticas/epidemiologia , Adolescente , Adulto , Idoso , Carcinoma Hepatocelular/cirurgia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Heterogeneidade Genética , Antígenos de Superfície da Hepatite B/sangue , Hepatite D/complicações , Hepatite D/tratamento farmacológico , Humanos , Lactente , Internacionalidade , Fígado/patologia , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Adulto JovemRESUMO
UNLABELLED: Surrogate indexes of insulin resistance and insulin sensitivity are widely used in nonalcoholic fatty liver disease (NAFLD), although they have never been validated in this population. We aimed to validate the available indexes in NAFLD subjects and to test their ability to predict liver damage also in comparison with the NAFLD fibrosis score. Surrogate indexes were validated by the tracer technique (6,6-D2 -glucose and U-(13) C-glucose) in the basal state and during an oral glucose tolerance test. The best-performing indexes were used in an independent cohort of 145 nondiabetic NAFLD subjects to identify liver damage (fibrosis and nonalcoholic steatohepatitis). In the validation NAFLD cohort, homeostasis model assessment of insulin resistance, insulin to glucose ratio, and insulin sensitivity index Stumvoll had the best association with hepatic insulin resistance, while peripheral insulin sensitivity was most significantly related to oral glucose insulin sensitivity index (OGIS), insulin sensitivity index Stumvoll, and metabolic clearance rate estimation without demographic parameters. In the independent cohort, only oral glucose tolerance test-derived indexes were associated with liver damage and OGIS was the best predictor of significant (≥F2) fibrosis (odds ratio = 0.76, 95% confidence interval 0.61-0.96, P = 0.0233) and of nonalcoholic steatohepatitis (odds ratio = 0.75, 95% confidence interval 0.63-0.90, P = 0.0021). Both OGIS and NAFLD fibrosis score identified advanced (F3/F4) fibrosis, but OGIS predicted it better than NAFLD fibrosis score (odds ratio = 0.57, 95% confidence interval 0.45-0.72, P < 0.001) and was also able to discriminate F2 from F3/F4 (P < 0.003). CONCLUSION: OGIS is associated with peripheral insulin sensitivity in NAFLD and inversely associated with an increased risk of significant/advanced liver damage in nondiabetic subjects with NAFLD.
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Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Adulto , Feminino , Humanos , Hepatopatias/etiologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND & AIMS: Several studies have shown that new direct-acting antivirals maintain their efficacy in liver transplant (LT) recipients with severe hepatitis C virus (HCV) recurrence. We determined the clinical impact of sofosbuvir/ribavirin in LT through the changes in liver function and fibrosis state at 24 and 48 weeks after treatment. METHODS: Between June 2014 and July 2015, 126 patients (30 F3, 96 F4 Metavir stage) were enrolled to receive sofosbuvir + ribavirin (24 weeks, 118 patients) or sofosbuvir + simeprevir + ribavirin (12 weeks, 8 patients); treatment was initiated at a median time of 4.3 years from LT. Median follow-up after therapy completion was 461 days. RESULTS: All 30 F3 patients achieved a sustained virological response at week 24 after treatment (SVR24) and showed a distinct amelioration of the AST-to-platelet ratio index (APRI), FIB-4 and liver stiffness at elastography by week 24 post-therapy, which were maintained at week 48. Of the 96 F4 cirrhotic patients, 72 (75%) achieved SVR24 accompanied by significant improvement of liver function, which was maintained at week 48 (Child B-C 22% baseline, 11% week 24, 7% week 48); APRI, FIB-4 and liver stiffness further improved significantly between weeks 24 and 48 of follow-up. Among the 77 responders (27 F3, 50 F4) who underwent elastography at baseline and at the end of follow-up, 39 (50.6%; 18 F3, 21 F4) exhibited a regression in fibrosis stage. CONCLUSION: At about 1 year from the completion of successful sofosbuvir-based therapy, patients with post-LT HCV and severe fibrosis experienced a long-term liver function improvement accompanied by a regression of fibrosis stage in half of them.