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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: Mixed cryoglobulinemia is the most common HCV extrahepatic manifestation. We aimed to prospectively evaluate the cryoglobulinemic vasculitis (CV) clinical profile after a sustained virologic response (SVR) over a medium-term to long-term period. APPROACH AND RESULTS: Direct-acting antiviral-treated cryoglobulinemic patients, consecutively enrolled in the multicentric Italian Platform for the Study of Viral Hepatitis Therapy cohort, were prospectively evaluated. Cumulative incidence Kaplan-Meier curves were reported for response, clinical deterioration, relapse and relapse-free survival rates. Cox regression analysis evaluated factors associated with different outcomes. A clinical response was reported in at least one follow-up point for 373 of 423 (88%) patients with CV who achieved SVR. Clinical response increased over time with a 76% improvement rate at month 12 after the end of treatment. A full complete response (FCR) was reached by 164 (38.8%) patients in at least one follow-up point. CV clinical response fluctuated, with some deterioration of the initial response in 49.6% of patients (median time of deterioration, 19 months). In patients who achieved FCR and had an available follow-up (137 patients) a relapse was observed in 13% and it was transient in 66.7% of patients. The rate of patients without any deterioration was 58% and 41% at 12 and 24 months, respectively. After achieving SVR, a clinical nonresponse was associated with older age and renal involvement; a clinical deterioration/relapse was associated with high pretreatment rheumatoid factor values, and FCR was inversely associated with age, neuropathy, and high cryocrit levels. CONCLUSION: In patients with CV, HCV eradication may not correspond to a persistent clinical improvement, and clinical response may fluctuate. This implies an attentive approach to post-SVR evaluation through prognostic factors and tailored treatment.
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Deterioração Clínica , Crioglobulinemia , Hepatite C Crônica , Vasculite , Antivirais/uso terapêutico , Crioglobulinemia/tratamento farmacológico , Crioglobulinemia/etiologia , Hepacivirus , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Estudos Prospectivos , Recidiva , Resposta Viral Sustentada , Vasculite/tratamento farmacológicoRESUMO
To date, few reports have evaluated the pneumococcal vaccination status in cirrhotic patients. No data are available for European countries. We have explored this topic and the potential independent predictors motivating lack of vaccination in Italy. Between January 1st and June 30th 2022, 1419 cirrhotic patients of any etiology were consecutively enrolled in an observational, prospective study at 8 referral centers in Italy. Adjusted odds ratios (ORs) for the association with lack of vaccination were evaluated by multiple logistic regression analysis. Overall vaccine coverage was 17.9% (8.9% in patients < 65 years of age and 27.1% in those aged ≥ 65 years; p < 0.001). Among the 1165 unvaccinated patients, 1068 (91.7%) reported lack of information regarding vaccination as the reason for not having undergone vaccination. Independent predictors associated with lack of vaccination were age < 65 years (OR 3.39, CI 95% 2.41-4.76) and a higher number of schooling years (OR 2.14, CI 95% 1.58-2.91); alcoholic etiology resulted only marginally associated (OR 1.91, CI 95% 1.03-3.52). These findings establish evidence on how pneumococcal vaccination status in Italy is largely suboptimal among cirrhotic patients. These results raise concern, considering the severe outcomes of pneumococcal infection in patients with chronic liver diseases.
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Infecções Pneumocócicas , Vacinas Pneumocócicas , Idoso , Humanos , Itália/epidemiologia , Cirrose Hepática/complicações , Cirrose Hepática/epidemiologia , Infecções Pneumocócicas/epidemiologia , Infecções Pneumocócicas/prevenção & controle , Estudos Prospectivos , Vacinação , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Gambling Disorder (GD) is a behavioral addiction listed within the diagnostic category of substance-related and addictive disorders. Recently, transcranial magnetic stimulation (TMS), which non-invasively stimulates the brain and has neuromodulatory properties, has emerged as an innovative treatment tool for GD, thus offering a new option for the management of this complex disorder. The present review explored the efficacy of TMS as a possible non-pharmacological treatment for GD. METHODS: An exhaustive search was performed across the MEDLINE, Web of Science, and EMBASE databases using a specific search string related to GD and TMS. A total of 20 papers were selected for full-text examination, out of which eight fulfilled the inclusion criteria and were therefore systematically analyzed in the present review. RESULTS: This review included eight studies: three randomized-controlled trials (RCTs), three non-controlled studies, one case series, and one case report. Two cross-over RCTs described a decrease in craving after high-frequency (excitatory), repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) and the medial prefrontal cortex (PFC), respectively; another study applying low-frequency (inhibitory) rTMS on the right DLPFC did not find any positive effect on craving. Among uncontrolled studies, one demonstrated the beneficial effect of high-frequency rTMS over the left DLPFC, while another showed the efficacy of a continuous theta burst stimulation protocol directed over the pre-supplementary motor area, bilaterally. CONCLUSION: The included studies showed the promising effect of excitatory stimulation over the left PFC. However, further investigation is needed, particularly in terms of standardizing stimulation protocols and psychometric assessments.
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Jogo de Azar , Estimulação Magnética Transcraniana , Humanos , Estimulação Magnética Transcraniana/métodos , Jogo de Azar/terapia , Fissura/fisiologia , Córtex Pré-Frontal/fisiologia , Córtex Pré-Frontal Dorsolateral , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: limited evidence is available to guide hepatologists regarding endoscopic surveillance of oesophageal varices (EV) in Hepatitis C Virus (HCV)-positive cirrhotic patients achieving a sustained virologic response. To address these issues, we conducted a long-term prospective study on 427 HCV-positive cirrhotic patients successfully treated by Direct Antiviral Agents (DAAs). METHODS: Patients were divided into two groups according to their baseline Baveno VI status: Group 1 (92, 21.5%, favourable Baveno VI status) and Group 2 (335, 78.5%, unfavourable Baveno VI status). Each patient underwent baseline endoscopy and was endoscopically monitored for a median follow-up of 65.2 months according to Baveno VI recommendations. RESULTS: About 4.3% of Group 1 patients showed baseline EV compared with 30.1% of Group 2 patients (p < .0001). No patients belonging to Group 1 without baseline EV developed EV at follow-up endoscopy compared with 6.5% in Group 2 patients (p = .02); 69/107 (64.5%) patients with baseline EV showed small varices. During the endoscopic follow-up, EV disappeared/improved in 36 (33.6%), were stable in 39 (36.4%) and worsened in 32 (29.9%) patients, all belonging to Group 2 (p = .001). Improvement in Baveno VI status was observed in 118/335 (35.2%, p < .0001) of Group 2 patients and among those without pre-therapy EV, none developed EV throughout the follow-up. CONCLUSIONS: HCV-positive cirrhotic patients cured by DAAs showing baseline favourable Baveno VI status and no worsening during follow-up can safely avoid endoscopic screening and surveillance. Patients having unfavourable Baveno VI status without baseline EV who improve their status may suspend further endoscopic surveillance.
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Técnicas de Imagem por Elasticidade , Varizes Esofágicas e Gástricas , Hepatite C Crônica , Antivirais/uso terapêutico , Endoscopia Gastrointestinal , Varizes Esofágicas e Gástricas/etiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Cirrose Hepática , Estudos ProspectivosRESUMO
In the popular imaginary, cocoa-derived products, like chocolate, represent a panacea for mood and affectivity. However, whether this is a myth or a fact has yet to be clarified. A systematic review and meta-analysis were conducted according to the PRISMA guidelines to investigate the effect of cocoa-derived food on depressive and anxiety symptoms, positive and negative affect. We searched Web of KnowledgeTM and PsycINFO up to April 3, 2020. After screening 761 records, we selected nine studies. Two trials evaluated the long-term effects of cocoa consumption (>1 week), two studies the short-term effects (3 days), while five studies were conducted in acute (single administration). Random-effects meta-analyses found an overall significant effect of cocoa-rich products on depressive (Hedge's g = -0.42, 95% CI -0.67 to -0.17) and anxiety symptoms (Hedge's g = -0.49, 95% CI -0.78 to -0.19). Moreover, both positive (Hedge's g = 0.41, 95% CI 0.06 to 0.77) and negative affect (Hedge's g = -0.47, 95% CI -0.91 to -0.03) significantly improved. In all meta-analyses, the effect size was medium, while heterogeneity was low. Our findings suggest that the consumption of cocoa-rich products may improve affect and mood in the short term. However, given the short duration of trials, our results cannot be generalized to long-term intake of cocoa-derived food. Cautious interpretation is also needed due to the low number of participants and studies included in the meta-analyses.
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Cacau , Chocolate , Ansiedade , Depressão/prevenção & controle , HumanosRESUMO
We have evaluated flu vaccine coverage and variables associated with the lack of vaccination in cirrhotic subjects with particular attention to the cirrhosis etiology. Cirrhotic subjects consecutively referring to eight Italian centers were prospectively enrolled for a 6-month period in 2019. Subjects were asked if they had received a flu vaccine in the last 12 months. Multiple logistic regression analysis was performed to identify independent predictors of lack of vaccination. A total of 818 cases were recruited. The overall vaccine coverage was 39.6% (26.9% in those younger than 65 years and 51.9% in those older than 64 years; p < 0.001). Age < 65 years (odds ratio [OR] = 2.38; 95% confidence interval [CI] = 1.68-3.36), alcoholic etiology (OR = 2.40; 95% CI = 1.49-3.85), birth abroad (OR = 2.7; 95% CI = 1.10-6.61), and residence in South/Sardinia island (OR = 1.66; 95% CI = 1.14-2.42) all resulted independent predictors of the likelihood of lack of vaccination. The lack of information regarding the vaccine as the reason for no vaccination was reported by 71.4% of foreigners and by 34.7% of natives (p < 0.001). In conclusion, much work still should be done to improve coverage among groups at higher risk of lack of vaccination identified in this survey. The ongoing SARS-CoV-2 pandemic may represent one more alert for improving seasonal flu vaccine coverage to avoid further stress to the National Health System.
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COVID-19/epidemiologia , Vacinas contra Influenza/administração & dosagem , Influenza Humana/complicações , Cirrose Hepática/epidemiologia , Cobertura Vacinal/estatística & dados numéricos , Idoso , COVID-19/virologia , Feminino , Humanos , Influenza Humana/epidemiologia , Cirrose Hepática/etiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Pandemias , Prevalência , SARS-CoV-2/isolamento & purificação , Estações do Ano , Vacinação/estatística & dados numéricosRESUMO
BACKGROUND AND AIMS: Clearance of hepatitis C virus (HCV) is associated with improved glycometabolic control in patients with diabetes mellitus (DM) but whether this effect is maintained over the long term with a reduction in liver-related events (LRE) is still debated. To address these issues, we conducted a long-term prospective study on diabetic and non-diabetic patients with chronic hepatitis C cured by direct antiviral agents (DAAs). METHODS: Among 893 recruited patients, 15.7% were diabetic (Group 1) and 84.3% non-diabetic (Group 2); changes in fasting glucose (FG) and glycated haemoglobin (HbA1c) levels were assessed in Group 1 while the incidence of LRE was established in the whole cohort. Differences between groups were evaluated and independent predictors of unfavourable clinical outcome were established. RESULTS: After a mean follow up of 44.5 months, a significant reduction in FG and HbA1c values was found in Group 1. Death was reported in 5.7% of patients in Group 1 vs 1.6% in Group 2 (P = .003), hepatocellular carcinoma (HCC)-free survival was significantly lower in Group 2 (P = .015) as well as LRE-free survival in Group 1 cirrhotic patients (P = .0006). After adjustment for baseline variables, cirrhosis and albumin levels emerged as independent predictors of LRE; low albumin levels, DM and central obesity were associated with HCC risk in cirrhotic patients while insulin therapy emerged as unfavourable predictor among diabetics. CONCLUSIONS: SVR achieved by DAAs is associated with long-term improvement of glycometabolic control in diabetic patients, but among cirrhotics DM still exerts a detrimental effect on the liver.
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Carcinoma Hepatocelular , Diabetes Mellitus , Hepatite C Crônica , Neoplasias Hepáticas , Antivirais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Seguimentos , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Estudos ProspectivosRESUMO
BACKGROUND: HCV-related extra-hepatic complications include peripheral neuropathies, with important prevalence and impact. A recent metanalysis of previous intervention trials concluded for insufficient data to support evidence-based treatments for this complication. In this longitudinal study, we assessed for the first time prevalence and outcome of neuropathy in a cohort of patients with chronic HCV, before and after direct-acting antiviral agent (DAA) treatment. METHOD: Ninety-four patients (mean age 58.5 ± 9.9, infection duration 22.2 ± 6.3 years) without systemic and metabolic diseases, underwent neurological examination and electroneurography studies before (T0) and 10.4 ± 1.7 months after the end of DAA therapy (T1), and cryoglobulins (CG) assessment. Muscle strength was evaluated by Medical Research Council (MRC) score; neuropathic pain, sensory function, disability, quality of life were assessed by validated questionnaires (DN4, NPSI, SSS, INCAT and Euro-QoL). RESULTS: At T0, sensory-motor neuropathy was detected in 22 patients (23%), reflexes were depressed in 32 (34%) with no association with infection duration, viral load, age, CG. Neuropathic pain (DN4 ≥4) was present in 37 patients (39%). At T1, out of the 22 patients with altered electroneurography, 3 had died or developed HCC, 4 showed normal electroneurography, and nerve amplitude parameters tended to improve in the whole group. Only 11 patients (12%) had depressed reflexes and 10 (11%) DN4 ≥4 (P < .05 compared to T0). Scores for MRC, questionnaires and Euro-QoL improved significantly (P < .05). CONCLUSION: Our study confirms the high prevalence of clinical and subclinical peripheral sensory-motor neuropathy in patients with HCV infection and indicates improvement after eradication by DAA. These results support the need for larger intervention studies.
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Carcinoma Hepatocelular , Hepatite C Crônica , Hepatite C , Neoplasias Hepáticas , Doenças do Sistema Nervoso Periférico , Idoso , Antivirais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Hepatite C/tratamento farmacológico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Estudos Longitudinais , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/epidemiologia , Doenças do Sistema Nervoso Periférico/etiologia , Estudos Prospectivos , Qualidade de VidaRESUMO
The aim of this study is to provide updates on the characteristics of chronic HBsAg carriers in Italy before the advent of new drugs eliminating or functionally inactivating the genome HBV reservoirs. HBV endemicity has greatly decreased in Italy over the past decades. A not negligible number of chronic HBsAg carriers are still alive in the country. Chronic HBsAg carriers consecutively referring to 9 units in Italy were prospectively enrolled for a 6-month period in 2019. Multiple logistic regression analysis was performed to identify independent predictors of treatment. A total of 894 cases was recruited (sex ratio 1.6; mean age 53.7 ± 13.5 years). The proportion of subjects born abroad was 19.0%; only 1% of cases reported current heavy alcohol intake (> 4 units/day). Chronic HBV infection, chronic HBV hepatitis, and subjects with liver cirrhosis and/or HCC represented 24.8%, 55%, and 19.3% of cases, respectively. After exclusion of the 222 subjects with chronic HBV infection, the proportion of subjects under therapy was as high as 89.3%. A more severe liver disease (OR 2.52; 95% CI = 1.25-5.14) resulted an independent predictor of the likelihood of treatment; male sex was marginally associated (OR 1.67; 95% CI = 1.02-2.76) to the chance of treatment. People born abroad had same chance than Italians native to be treated (OR 2.12; 95% CI = 0.9-4.97). The high proportion of subjects under treatment and the absence of gender and ethnic barrier against treatment sound good news. These updated figures may represent reference data for evaluating the potential impact of forthcoming new therapy against HBV-related disease.
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Hepatite B Crônica/epidemiologia , Adulto , Idoso , Antivirais/uso terapêutico , Portador Sadio/epidemiologia , Feminino , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Hepatite B Crônica/tratamento farmacológico , Humanos , Incidência , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , MigrantesRESUMO
BACKGROUND: The development of direct-acting antivirals (DAA) for HCV has revolutionized the treatment of HCV, including its treatment in patients with HIV coinfection. The aim of this study was to compare the changes in liver function between coinfected and monoinfected patients with cirrhosis who achieved HCV eradication by DAA. METHODS: Patients with pre-treatment diagnosis of HCV liver cirrhosis, consecutively enrolled in the multicenter PITER cohort, who achieved a sustained virological response 12 weeks after treatment cessation (SVR12) were analysed. Changes in Child-Pugh (C-P) class and the occurrence of a decompensating event was prospectively evaluated after the end of DAA treatment. Cox regression analysis was used to evaluate factors independently associated with changes in liver function following viral eradication. RESULTS: We evaluated 1350 patients, of whom 1242 HCV monoinfected (median follow-up 24.7, range 6.8-47.5 months after viral eradication) and 108 (8%) HCV/HIV coinfected (median follow-up 27.1, range 6.0-44.6). After adjusting for age, sex, HCV-genotype, HBsAg positivity and alcohol use, HIV was independently associated with a more advanced liver disease before treatment (C-P class B/C vs A) (OR: 3.73, 95% CI:2.00-6.98). Following HCV eradication, C-P class improved in 17/20 (85%) coinfected patients (from B to A and from C to B) and in 53/82 (64.6%) monoinfected patients (from B to A) (p = 0.08). C-P class worsened in 3/56 coinfected (5.3%) (from A to B) and in 84/1024 (8.2%) monoinfected patients (p = 0.45) (from A to B or C and from B to C). Baseline factors independently associated with C-P class worsening were male sex (HR = 2.00; 95% CI = 1.18-3.36), platelet count < 100,000/µl (HR = 1.75; 95% CI 1.08-2.85) and increased INR (HR = 2.41; 95% CI 1.51-3.84). Following viral eradication, in 7 of 15 coinfected (46.6%) and in 61 of 133 (45.8%) monoinfected patients with previous history of decompensation, a new decompensating event occurred. A first decompensating event was recorded in 4 of 93 (4.3%) coinfected and in 53 of 1109 (4.8%) monoinfected patients (p = 0.83). CONCLUSIONS: Improvement of liver function was observed following HCV eradication in the majority of patients with cirrhosis; however viral eradication did not always mean cure of liver disease in both monoinfected and coinfected patients with advanced liver disease.
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Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Cirrose Hepática/virologia , Idoso , Coinfecção/tratamento farmacológico , Feminino , Infecções por HIV/tratamento farmacológico , Hepacivirus/genética , Hepatite C/complicações , Hepatite C/virologia , Humanos , Cirrose Hepática/tratamento farmacológico , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resposta Viral Sustentada , Resultado do TratamentoRESUMO
In Italy, HDV infection endemicity has greatly decreased overtime. Migratory flow may change this scenario as migrants often come from high HDV endemicity areas. Here, we studied characteristics of HDV infection in Italy, particularly addressed to the birth area of subjects. Chronic HBsAg carriers consecutively referring to 9 units in Italy prospectively enrolled for a six-month period in 2019 were tested for anti-HDV by ELISA. Multiple logistic regression analysis was performed to identify anti-HDV positivity independent predictors. A total of 894 HBsAg-positive subjects were enrolled. Of them, 786 (87.9%) were tested for anti-HDV. Anti-HDV overall prevalence was 9.9% (6.4% in Italian natives and 26.4% in non-natives; P < .001). HDV-RNA was checked in 63 (80.8%) of the 78 anti-HDV+ subjects, and 49 (77.8%) tested positive. Compared to non-natives, Italians were more likely males (male/female 1.6 vs 0.6; P < .05) and older (median age 57 years vs 46 years; P < .05). Multivariate analysis showed that non-natives (OR = 6.02; CI 95% = 3.06-11.84) and cirrhosis (OR 9.6; CI 95% = 5.39-17.30) were independently associated with anti-HDV positivity. A remarkable changing pattern in some characteristics of anti-HDV-positive subjects was observed over 1987-2019: a decreasing male/female ratio, an increasing mean age and proportion of cirrhotic subjects. Anti-HDV prevalence decreased from 7.4% to 6.4% among Italians, increasing from 12.2% to 26.4% among non-natives during 2001-2019. Hence, HDV infection in Italians is further decreasing and mostly affects old people and subjects with advanced disease reflecting a survival effect. Conversely, non-natives are sixfold more likely anti-HDV-positive with an increasing trend. Migratory flow may be a new challenge for HDV infection at the beginning of the third millennium.
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Emigrantes e Imigrantes , Hepatite D , Feminino , Anticorpos Anti-Hepatite , Hepatite D/epidemiologia , Vírus Delta da Hepatite/imunologia , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , PrevalênciaRESUMO
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
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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Antivirais/economia , Política de Saúde/economia , Hepatite C/tratamento farmacológico , Modelos Econômicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Análise Custo-Benefício , Hepatite C/economia , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND & AIMS: The non-invasive identification of steatohepatitis (NASH) in patients with Non-Alcoholic Fatty Liver Disease is an unmet need in clinical practice. Index of NASH (ION) is a new tool for the prediction of NASH. We aimed to externally validate ION and to compare it with CK-18. Since necroinflammation precedes fibrosis, we also tested ION in combination with non-invasive tools for fibrosis. METHODS: We analysed data from 292 Italian patients (169 Southern cohort, and 123 Northern cohort) with an histological diagnosis of NAFLD. The ION, FIB-4 and NFS scores were calculated according to published algorithms. Serum cytokeratin18-Aspartate396 levels and liver stiffness (LS) by Fibroscan were assessed within three months from liver biopsy. RESULTS: The diagnostic accuracy of ION for the identification of NASH was not as satisfactory as reported (area under the ROC curve, AUROC = 0.687 [95% CI = 0.62-0.75]). The proposed cut-off value ≥50 showed a poor sensitivity (Se) (28%) and a good specificity (Sp) (92%), with a positive predictive value (PPV) of 91% and a negative predictive value (NPV) of 30%. A new cut-off value >26 improved Se (73%) but decreased Sp (60%) (PPV of 84% and a NPV of 43%). ION performed slightly better in obese NAFLD (AUROC = 0.700). The combination of ION and markers of fibrosis did not improve the identification of advanced liver disease. CONCLUSIONS: ION is not feasible for the non-invasive diagnosis of NASH across different populations of NAFLD patients, mainly because its limited reproducibility in non-obese subjects.
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Cirrose Hepática/diagnóstico , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Índice de Gravidade de Doença , Adulto , Algoritmos , Biomarcadores/sangue , Técnicas de Imagem por Elasticidade , Feminino , Humanos , Itália , Queratina-18/sangue , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/patologia , Estudos Prospectivos , Curva ROC , Reprodutibilidade dos TestesRESUMO
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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Causas de Morte , Erradicação de Doenças/tendências , Hepatite C/epidemiologia , Mortalidade/tendências , Viremia/epidemiologia , Antivirais/uso terapêutico , Carcinoma Hepatocelular/mortalidade , Efeitos Psicossociais da Doença , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Humanos , Itália/epidemiologia , Cirrose Hepática/mortalidade , Neoplasias Hepáticas/mortalidade , Cadeias de Markov , Resposta Viral Sustentada , Viremia/diagnóstico , Viremia/tratamento farmacológico , Organização Mundial da SaúdeRESUMO
OBJECTIVES: In the setting of surveillance for hepatocellular carcinoma (HCC) detection, the use of serum biomarkers in addition to ultrasonography (US) is still a matter of debate. Hence, we performed a meta-analysis to evaluate the diagnostic accuracy of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein (AFP) alone or in combination for HCC detection in patients at risk of tumor development. MATERIALS AND METHODS: We performed a systematic search in PubMed and Scopus database for original articles published in English from 2011 to 2017, investigating the accuracy of PIVKA-II alone or in combination with AFP (reported as area under the curve [AUC]) for HCC detection among patients at risk of tumor development. Furthermore, we focused on studies in which serum PIVKA-II was assessed by highly sensitive chemiluminescence immunoassay (CLEIA). RESULTS: A total of 11 studies (873 patients with HCC and 1244 patients with advanced liver disease/cirrhosis) were included in the meta-analysis. The weighted summary AUC (sAUC) of PIVKA-II and AFP for the discrimination between patients with HCC and those without was 0.791 (0.746-0.837) and 0.767 (0.732-0.803), respectively. The combination of PIVKA-II + AFP results in a sAUC of 0.859 (0.837-0.882). The performance for HCC detection of PIVKA-II + AFP was significantly superior to each biomarker used alone (ΔsAUC = 0.068, p = .032 and ΔsAUC = 0.092, p < .001, respectively). CONCLUSION: In clinical practice, the use of PIVKA-II + AFP in addition to US examination may improve the effectiveness of surveillance among patients at risk for HCC development.
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Biomarcadores/análise , Carcinoma Hepatocelular/sangue , Cirrose Hepática/complicações , Neoplasias Hepáticas/sangue , Precursores de Proteínas/análise , Protrombina/análise , alfa-Fetoproteínas/análise , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Humanos , Técnicas Imunoenzimáticas , Neoplasias Hepáticas/patologia , LuminescênciaRESUMO
BACKGROUND & AIMS: Premenopausal women who are HCV positive (HCV+) have failing ovarian function, which is likely to impact their fertility. Thus, we investigated the reproductive history, risk of infertility, and pregnancy outcomes in women of childbearing age who were HCV+. METHODS: Three different groups were studied: (1) Clinical cohort: 100 women who were HCV+ and also had chronic liver disease (CLD), age matched with 50 women who were HBV+ with CLD and with 100 healthy women; all women were consecutively observed in three gastroenterology units in hospitals in Italy; (2) 1,998 women who were HCV+ and enrolled in the Italian Platform for the Study of Viral Hepatitis Therapies (PITER); (3) 6,085 women, who were mono-infected with HCV, and 20,415 women, who were HCV-, from a large de-identified insurance database from the USA. MEASUREMENTS: total fertility rate (TFR) defined as the average number of children that a woman would bear during her lifetime. To define the reproductive stage of each participant, levels of anti-Müllerian hormone (AMH) and 17ß-estradiol were measured. RESULTS: Clinical cohort: women who were either HCV+ or HBV+ had similar CLD severity and age at first pregnancy. Based on a multivariate analysis, women who were HCV+ had a higher risk of miscarriage than those who were HBV+ (odds ratio [OR] 6,905; 95% CI 1.771-26.926). Among women who were HCV+, incidence of miscarriage was correlated with median AMH level (1.0â¯ng/ml). Achieving a sustained virologic response (SVR) after antiviral treatment reduced the risk of miscarriage (OR 0.255; 95% CI 0.090-0.723). In the PITER-HCV cohort, miscarriage occurred in 42.0% of women (44.6% had multiple miscarriages). TFR for women who were HCV+ and between 15 and 49â¯years of age was 0.7 vs. 1.37 of Italian population of the same age range. In the US cohort: compared with women who were HCV-, women who were HCV+ positive were significantly more likely to have infertility (OR 2.439; 95% CI 2.130-2.794), premature birth (OR 1.34; 95% CI 1.060-1.690), gestational diabetes (OR 1.24; 95% CI 1.020-1.510), and pre-eclampsia (OR 1.206; 95% CI 0.935-1.556), and were less likely to have a live birth (OR 0.754; 95% CI 0.622-0.913). CONCLUSIONS: Ovarian senescence in women of childbearing age who are HCV+ is associated with a lower chance of live birth, greater risk of infertility, gestational diabetes, pre-eclampsia and miscarriage. Such risks could be positively influenced by successful HCV cure. LAY SUMMARY: Most new cases of HCV infection are among people who inject drugs, many of whom are young women in their childbearing years. Women of reproductive age who are HCV+ display markers of ovarian senescence. This is associated with an increased burden in terms of infertility and adverse pregnancy outcomes, including stillbirth, miscarriage, fewer live births, and gestational diabetes. Early viral suppression with therapy is likely to mitigate these risks.
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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.