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Plasma cell-free DNA (cfDNA) is a noninvasive biomarker for cell death of all organs. Deciphering the tissue origin of cfDNA can reveal abnormal cell death because of diseases, which has great clinical potential in disease detection and monitoring. Despite the great promise, the sensitive and accurate quantification of tissue-derived cfDNA remains challenging to existing methods due to the limited characterization of tissue methylation and the reliance on unsupervised methods. To fully exploit the clinical potential of tissue-derived cfDNA, here we present one of the largest comprehensive and high-resolution methylation atlas based on 521 noncancer tissue samples spanning 29 major types of human tissues. We systematically identified fragment-level tissue-specific methylation patterns and extensively validated them in orthogonal datasets. Based on the rich tissue methylation atlas, we develop the first supervised tissue deconvolution approach, a deep-learning-powered model, cfSort, for sensitive and accurate tissue deconvolution in cfDNA. On the benchmarking data, cfSort showed superior sensitivity and accuracy compared to the existing methods. We further demonstrated the clinical utilities of cfSort with two potential applications: aiding disease diagnosis and monitoring treatment side effects. The tissue-derived cfDNA fraction estimated from cfSort reflected the clinical outcomes of the patients. In summary, the tissue methylation atlas and cfSort enhanced the performance of tissue deconvolution in cfDNA, thus facilitating cfDNA-based disease detection and longitudinal treatment monitoring.
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Ácidos Nucleicos Livres , Aprendizado Profundo , Humanos , Ácidos Nucleicos Livres/genética , Metilação de DNA , Biomarcadores , Regiões Promotoras Genéticas , Biomarcadores Tumorais/genéticaRESUMO
INTRODUCTION: Indeterminate liver nodules (ILNs) are frequently encountered on diagnostic imaging after positive hepatocellular carcinoma (HCC) surveillance results, but their natural history remains unclear. METHODS: We conducted a multicenter retrospective cohort study among patients with ≥1 newly detected LI-RADS 3 (LR-3) lesion ≥1 cm or LI-RADS 4 (LR-4) lesion of any size (per LI-RADS v2018) between January 2018 and December 2019. Patients were followed with repeat imaging at each site per institutional standard of care. Multivariable Fine-Gray models were used to evaluate associations between potential risk factors and patient-level time-to-HCC diagnosis, with death and liver transplantation as competing risks. RESULTS: Of 307 patients with ILNs, 208 had LR-3 lesions, 83 had LR-4 lesions, and 16 had both LR-3 and LR-4 lesions. HCC incidence rates for patients with LR-3 and LR-4 lesions were 110 (95% CI 70-150) and 420 (95% CI 310-560) per 1,000 person-year, respectively. In multivariable analysis, incident HCC among patients with LR-3 lesions was associated with older age, thrombocytopenia (platelet count ≤150 ×10 9 /L), and elevated serum alpha-fetoprotein levels. Among those with LR-4 lesions, incident HCC was associated with a maximum lesion diameter >1 cm. Although most patients had follow-up computed tomography or magnetic resonance imaging, 13.7% had no follow-up imaging and another 14.3% had follow-up ultrasound only. DISCUSSION: ILNs have a high but variable risk of HCC, with 4-fold higher risk in patients with LR-4 lesions than those with LR-3 lesions, highlighting a need for accurate risk stratification tools and close follow-up in this population.
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BACKGROUND AND AIMS: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC. APPROACH AND RESULTS: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations ( E pCAM + CD63 + , C D147 + CD63 + , and G PC3 + CD63 + HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort ( n = 106) and an independent validation cohort ( n = 72).Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99). CONCLUSION: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes.
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Carcinoma Hepatocelular , Vesículas Extracelulares , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Biomarcadores Tumorais/análise , Vesículas Extracelulares/química , Proteínas de Membrana , Eletrocardiografia , GlipicanasRESUMO
BACKGROUND & AIMS: HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase II trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically- suppressed patients on NrtIs. METHODS: Non-cirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B e antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks. RESULTS: Of 73 patients enrolled, 47 were HBeAgâpositive and 26 were HBeAg negative. In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline achieved undetectable HBV DNA at Week 24 in the VBR+NrtI vs. PBO+NrtI group. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported. CONCLUSIONS: In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone. CLINICAL TRIALS NUMBER: NCT03576066. LAY SUMMARY: Core inhibitors represent a novel approach for the treatment of chronic hepatitis B virus (HBV) infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated.
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Hepatite B Crônica , Antivirais/efeitos adversos , DNA Viral , Antígenos de Superfície da Hepatite B , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , HumanosRESUMO
BACKGROUND & AIMS: Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor that interferes with multiple aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV. METHODS: HBeAg-positive, treatment-naïve patients without cirrhosis were randomised 1:1 in a double-blind manner to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV 0.5 mg for 24 weeks. The primary endpoint was change in mean log10 HBV DNA from Baseline to Week 12 and 24. RESULTS: All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At Week 12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log10 IU/ml HBV DNA (-4.45 [1.03]) vs. PBO+ETV (-3.30 [1.18]; p = 0.0077). At Week 24, VBR+ETV led to a greater reduction from Baseline in log10 IU/ml HBV DNA (-5.33 [1.59]) vs. PBO+ETV (-4.20 [0.98]; p = 0.0084). Greater mean reductions in pregenomic RNA were observed at Week 12 and 24 in patients receiving VBR+ETV vs. PBO+ETV (p <0.0001 and p <0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. The safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious adverse events, or evidence of drug-induced liver injury. CONCLUSIONS: In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV, with a favourable safety and tolerability profile. CLINICAL TRIAL NUMBER: NCT03577171 LAY SUMMARY: Hepatitis B is a long-lasting viral infection of the liver. Current treatments can suppress hepatitis B virus but do not offer the opportunity of cure, hence, new treatment approaches are required. Herein, we show that the combination of the novel core inhibitor vebicorvir with an existing antiviral (entecavir) in treatment-naïve patients chronically infected with hepatitis B virus demonstrated greater antiviral activity than entecavir alone. Additionally, vebicorvir was safe and well tolerated. Thus, further studies evaluating its potential role in the treatment of chronic hepatitis B are warranted.
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Antivirais , Hepatite B Crônica , Humanos , Antivirais/efeitos adversos , DNA Viral , Guanina/análogos & derivados , Antígenos E da Hepatite B , Vírus da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Inibidores da Transcriptase Reversa/uso terapêutico , RNA , Resultado do Tratamento , Quimioterapia Combinada/efeitos adversos , Método Duplo-CegoRESUMO
Numerous studies in hepatocellular carcinoma (HCC) have proposed tissue-based gene signatures for individualized prognostic assessments. Here, we develop a novel circulating tumor cell (CTC)-based transcriptomic profiling assay to translate tissue-based messenger RNA (mRNA) signatures into a liquid biopsy setting for noninvasive HCC prognostication. The HCC-CTC mRNA scoring system combines the NanoVelcro CTC Assay for enriching HCC CTCs and the NanoString nCounter platform for quantifying the HCC-CTC Risk Score (RS) panel in enriched HCC CTCs. The prognostic role of the HCC-CTC RS was assessed in The Cancer Genome Atlas (TCGA) HCC cohort (n = 362) and validated in an independent clinical CTC cohort (n = 40). The HCC-CTC RS panel was developed through our integrated data analysis framework of 8 HCC tissue-based gene signatures and identified the top 10 prognostic genes (discoidin domain receptor tyrosine kinase 1 [DDR1], enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase [EHHADH], androgen receptor [AR], lumican [LUM], hydroxysteroid 17-beta dehydrogenase 6[HSD17B6], prostate transmembrane protein, androgen induced 1 [PMEPA1], tsukushi, small leucine rich proteoglycan [TSKU], N-terminal EF-hand calcium binding protein 2 [NECAB2], ladinin 1 [LAD1], solute carrier family 27 member 5 [SLC27A5]) highly expressed in HCC with low expressions in white blood cells. The panel accurately discriminated overall survival in TCGA HCC cohort (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.4-2.9). The combined use of the scoring system and HCC-CTC RS panel successfully distinguished artificial blood samples spiked with an aggressive HCC cell type, SNU-387, from those spiked with PLC/PRF/5 cells (P = 0.02). In the CTC validation cohort (n = 40), HCC-CTC RS remained an independent predictor of survival (HR, 5.7; 95% CI, 1.5-21.3; P = 0.009) after controlling for Model for End-Stage Liver Disease score, Barcelona Clinic Liver Cancer stage, and CTC enumeration count. Our study demonstrates a novel interdisciplinary approach to translate tissue-based gene signatures into a liquid biopsy setting. This noninvasive approach will allow real-time disease profiling and dynamic prognostication of HCC.
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Carcinoma Hepatocelular , Doença Hepática Terminal , Neoplasias Hepáticas , Transplante de Fígado , Células Neoplásicas Circulantes , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Células Neoplásicas Circulantes/metabolismo , Prognóstico , RNA Mensageiro/genética , Índice de Gravidade de DoençaRESUMO
Hepatitis B virus reactivation (HBVr) can occur spontaneously, but more often occurs when a patient is in an immunocompromised state or on immunosuppressive therapy. HBVr can lead to clinical hepatitis, acute liver failure, and even death. HBVr is preventable with screening of at-risk patients and initiation of prophylactic antiviral therapy for appropriate candidates. Screening for hepatitis B virus is recommended for all patients who plan to initiate immunosuppressive therapy. An individual's serological profile, underlying disease, and planned type of immunosuppression contribute to their risk of HBVr. This review serves to summarize the major society guidelines regarding screening, management of, and monitoring for HBVr in individuals on anticancer therapy and immunosuppressive therapy.
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Hepatite B , Ativação Viral , Antivirais/efeitos adversos , Hepatite B/diagnóstico , Hepatite B/tratamento farmacológico , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B , Humanos , Imunossupressores/uso terapêuticoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) accounts for 90% of primary hepatic malignancies. With the exception of chronic hepatitis B (CHB), other etiologies of chronic liver disease require progression to cirrhosis before HCC development. Case reports have described HCC in noncirrhotic patients with hepatitis C (HCV) and nonalcoholic fatty liver disease. GOAL: The aim of this study was to determine the prevalence of patients without cirrhosis and CHB who developed HCC among a large cohort of HCC patients and to identify independent variables that are associated with no cirrhosis among patients with HCC. STUDY: From 2005 to 2015, hepatobiliary cancer patients seen in our liver cancer and liver transplant clinics were evaluated. Patients were included if above18 years old and had histologically confirmed HCC from liver biopsy, resection specimen, or explanted livers. Patients with CHB, non-HCC tumors, or missing paired tumor and nontumor liver histology were excluded. Demographic information, pertinent laboratory values, and comorbid conditions were recorded. Potential predictors were evaluated using both backward stepwise logistic regression model and classification tree model. RESULTS: Of the 1927 patients screened, 545 HCC patients (411 transplanted, 43 resected, 74 transarterial chemoembolization/radiofrequency ablation, 17 untreated) included, 29 (5.3%) patients had no cirrhosis histologically. Eleven patients had HCV, 3 had alcoholic liver disease, 3 had nonalcoholic fatty liver, and 12 had cryptogenic liver disease. Logistic regression models show that patients with hyperlipidemia and elevated serum alanine aminotransferase are more likely to develop HCC without cirrhosis (odds ratio, 1.73 and 0.40; P<0.05). CONCLUSIONS: This large cohort, histology-confirmed case-controlled study shows that patients with nonalcoholic fatty liver disease and hyperlipidemia with elevated serum alanine aminotransferase (most likely nonalcoholic steatohepatitis) are significantly associated with the development of HCC in the absence of cirrhosis.
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Carcinoma Hepatocelular/epidemiologia , Hiperlipidemias/epidemiologia , Neoplasias Hepáticas/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Idoso , Alanina Transaminase/sangue , Carcinoma Hepatocelular/etiologia , Estudos de Casos e Controles , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Hiperlipidemias/complicações , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Fatores de RiscoRESUMO
BACKGROUND: Limited data exist with regard to treatment outcomes in Asian Americans with chronic hepatitis C (CHC). We evaluated sofosbuvir (SOF)-based regimens in a national cohort of Asian Americans. METHODS: Eligible Asian Americans patients with CHC who had posttreatment follow-up of 24 weeks for SOF -based therapies from December 2013 to June 2017 were enrolled from 11 sites across the United States. The primary endpoint was sustained virologic response (SVR) rates at posttreatment weeks 12 and 24. Secondary endpoints were to evaluate safety by tolerability and adverse events (AEs). RESULTS: Among 231 patients screened, 186 were enrolled. At baseline, 31% (57/186) patients were cirrhotic, 34% (63/186) were treatment experienced. Most of the subjects (42%, 79/186) received ledispavir/SOF therapy. The overall SVR12 was 95%, ranging from 86% in genotype (GT) 1b on SOF+ribavirin to 100% in GT 1b patients on ledipasvir/SOF at subgroup analyses. SVR12 was significantly lower in cirrhotic than in noncirrhotic patients [88% (50/57) vs. 98% (126/129), P<0.01]. Stratified by GT, SVR12 were: 96% (43/45) in GT 1a; 93% (67/72) in GT 1b; 100% (23/23) in GT 2; 90% (19/21) in GT 3; 100% (1/1) in GT 4; 83% (5/6) in GT 5; and 100% (16/16) in GT 6. Cirrhotic patients with treatment failure were primarily GT 1, (GT 1a, n=2; GT 1b, n=4) with 1 GT 5 (n=1). Patients tolerated the treatment without serious AEs. Late relapse occurred in 1 patient after achieving SVR12. CONCLUSIONS: In Asian Americans with CHC, SOF-based regimens were well tolerated without serious AEs and could achieve high SVR12 regardless of hepatitis C viral infection GT.
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Antivirais/administração & dosagem , Asiático , Hepatite C Crônica/tratamento farmacológico , Sofosbuvir/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzimidazóis/administração & dosagem , Estudos de Coortes , Quimioterapia Combinada , Feminino , Fluorenos/administração & dosagem , Seguimentos , Genótipo , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ribavirina/administração & dosagem , Resposta Viral Sustentada , Resultado do Tratamento , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/análogos & derivados , Adulto JovemRESUMO
BACKGROUND: The use of direct acting agents has changed the management paradigm of hepatitis C (HCV) in liver transplant (LT) recipients. However, the appropriate antiviral regimen in LT recipients on hemodialysis (HD) remains unclear. METHODS: We retrospectively evaluated the safety and efficacy of sofosbuvir-based LT recipients on HD followed at the University of California Los Angeles. RESULTS: Twelve LT recipients on HD were treated for recurrent HCV with sofosbuvir-based therapy. Indications for antiviral therapy included fibrosing cholestatic hepatitis, symptomatic cryoglobulinemia, and recurrent HCV. The causes of renal failure included hepatorenal syndrome, acute tubular necrosis and cryoglobulinemia. Of those who were not on dialysis at the time of transplantation, the mean creatinine (±SD) was 1.7 (±0.8) mg/dL. The mean age (±SD) of the cohort was 62.2 (±6.0) years. Most recipients were male (67%) and infected with genotype 1 (83%). Baseline alanine aminotransferase, total bilirubin, hemoglobin and HCV RNA values (±SD) were 53.2 (±59.4) IU/L, 3.2 (±5.5) mg/dL, 10.5 (±1.8) g/dL, and 30,499,500 (±29,655,754) IU/mL. HCV RNA levels were undetectable in all recipients at the end of therapy. The trough mean (±SD) hemoglobin of patients on treatment and on HD was 8.4 (±2.3). The sustained viral response was 58% (7/12), and the overall patient survival was 42%. All the deaths occurred a mean (±SD) after 5.4 (±3.6) months after treatment was completed. CONCLUSIONS: All patients achieved viral suppression from therapy, and over half the recipients achieved a sustained virological response. A high mortality underscores the necessity of starting antiviral treatment sooner in LT recipients and the need for larger cohort studies.
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Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Transplante de Fígado , Complicações Pós-Operatórias/tratamento farmacológico , Diálise Renal , Sofosbuvir/uso terapêutico , Idoso , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/virologia , Diálise Renal/métodos , Estudos Retrospectivos , Resposta Viral SustentadaRESUMO
BACKGROUND & AIMS: GS-4774 is a heat-inactivated, yeast-based, T-cell vaccine designed to elicit hepatitis B virus (HBV)-specific T-cell responses. We evaluated the safety, tolerability and efficacy of GS-4774 in patients with chronic HBV infection. METHODS: In this phase II study, 178 patients with chronic HBV infection and no cirrhosis who were virally suppressed on an oral antiviral (OAV) for ⩾1year were randomized (1:2:2:2) to continue OAV alone or receive OAV plus GS-4774 2, 10, or 40 yeast units (YU) subcutaneously every 4weeks until week 20. OAV was continued for the remainder of the study. Efficacy was measured by decline in serum hepatitis B surface antigen (HBsAg) from baseline to week 24. RESULTS: Baseline characteristics were similar across groups (mean age, 45-50years; male, 62-74%; Asian, 68-80%; hepatitis B e antigen (HBeAg)-positive, 24-26%; mean HBsAg, 2.5-3.1log10IU/ml). There were no significant differences between groups in mean HBsAg declines from baseline to week 24 or 48. Five HBeAg-positive patients receiving GS-4774 experienced HBeAg loss vs. none in the control group. Three GS-4774 40 YU-treated patients had HBsAg declines ⩾0.5log10IU/ml, but no patient experienced loss of serum HBsAg. No virologic breakthrough occurred. Injection site reactions were the most frequent adverse event (AE), and there were no treatment discontinuations. CONCLUSIONS: GS-4774 was well tolerated, but did not provide significant reductions in serum HBsAg in virally suppressed patients with chronic hepatitis B. Efficacy of GS-4774 in treatment-naïve patients remains to be determined. LAY SUMMARY: GS-4774 is a therapeutic vaccine designed to improve the immune response against hepatitis B virus (HBV) in patients who already have chronic infection with HBV. In this study, GS-4774 was safe and well tolerated in patients with chronic HBV infection receiving oral antiviral therapy, but did not result in a clinical benefit. Combination approaches with other agents, and evaluation in other populations of patients with HBV are ongoing to determine if GS-4774 might have a therapeutic benefit. CLINICAL TRIAL REGISTRATION NUMBER: NCT01943799.
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Hepatite B Crônica , Antivirais , DNA Viral , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Despite widespread use of transjugular intrahepatic portosystemic shunt (TIPS) for treatment of portal hypertension, a paucity of nationwide data exists on predictors of the economic impact related to TIPS. AIMS: Using the National Inpatient Sample (NIS) database from 2001 to 2012, we aimed to evaluate factors contributing to hospital cost of patients admitted to US hospitals for TIPS. METHODS: Using the NIS, we identified a discharge-weighted national estimate of 61,004 TIPS procedures from 2001 to 2012. Through independent sample analysis, we determined profile factors related to increases in hospital costs. RESULTS: Of all TIPS cases, the mean charge adjusted for inflation to the year 2012 is $125,044 ± $160,115. The mean hospital cost adjusted for inflation is $44,901 ± $54,565. Comparing pre- and post-2005, mean charges and cost have increased considerably ($98,154 vs. $142,652, p < 0.001 and $41,656 vs. $46,453, p < 0.001, respectively). Patients transferred from a different hospital, weekend admissions, Asian/Pacific Islander patients, and hospitals in the Northeastern and Western region had higher cost. Number of diagnoses and number of procedures show positive correlations with hospital cost, with number of procedures exhibiting stronger relationships (Pearson 0.613). Comorbidity measures with highest increases in cost were pulmonary circulation disorders ($32,157 increase, p < 0.001). CONCLUSION: The cost of the TIPS procedure is gradually rising for hospitals. Alongside recent healthcare reform through the Affordable Care Act, measures to reduce the economic burden of TIPS are of increasing importance. Data from this study are intended to aid physicians and hospitals in identifying improvements that could reduce hospital costs.
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Custos Hospitalares , Hospitalização/economia , Hipertensão Portal/cirurgia , Derivação Portossistêmica Transjugular Intra-Hepática/economia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/estatística & dados numéricos , Criança , Pré-Escolar , Comorbidade , Custos e Análise de Custo , Bases de Dados Factuais , Emergências , Etnicidade/estatística & dados numéricos , Feminino , Hospitais de Ensino/estatística & dados numéricos , Humanos , Hipertensão Portal/economia , Lactente , Recém-Nascido , Pneumopatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Havaiano Nativo ou Outro Ilhéu do Pacífico/estatística & dados numéricos , New England/epidemiologia , Estados do Pacífico/epidemiologia , Transferência de Pacientes/estatística & dados numéricos , Circulação Pulmonar , Fatores Sexuais , Estados Unidos/epidemiologia , População Branca/estatística & dados numéricos , Adulto JovemRESUMO
Background. Patient race and ethnicity have historically impacted HCV treatment response. This phase 3 study evaluated daclatasvir with peginterferon-alfa-2a/ribavirin (pegIFN alfa-2a/RBV) in treatment-naive black/African American (AA), Latino, and white non-Latino patients with chronic HCV genotype 1 infection. MATERIAL AND METHODS: In this single-arm, open-label study, 246 patients received daclatasvir plus pegIFN alfa-2a and weight-based RBV. Patients with an extended rapid virologic response (eRVR; undetectable HCV-RNA at treatment weeks 4 and 12) received 24 weeks of treatment; those without eRVR received an additional 24 weeks of treatment with pegIFN alfa-2a/RBV. The primary endpoint was sustained virologic response at post-treatment week 12 (SVR12; HCV-RNA < 25 IU/mL) compared with the cohort historical rate. RESULTS: Most patients were IL28B non-CC (84.4% black/AA; 77.6% Latino) genotype 1a-infected (72.7%; 81.3%), with HCV-RNA ≥ 800,000 IU/mL (81.3%; 64.5%). SVR12 rates were 50.8% (65/128; 95% confidence interval [CI], 42.1-59.4) for black/AA and 58.9% (63/107; 95% CI, 49.6-68.2) for Latino patients. The majority (55.5%; 58.9%) received 24 weeks treatment; rapid reductions (> 4-log10) in HCV-RNA levels were observed. Only 60.9% (78/128) of black/AA and 63.6% (68/107) of Latino patients completed treatment. On-treatment serious adverse events (SAEs) occurred in 21 patients. Discontinuations due to adverse events (AEs) occurred in 9 black/AA and 6 Latino patients. CONCLUSION: SVR12 rates for black/AA (50.8%) and Latino (58.9%) cohorts treated with daclatasvir plus pegIFN alfa-2a/RBV and the lower bound of the 95% CIs were higher than the estimated historical control (black/AA, 26% SVR; Latino, 36% SVR) treated with pegIFN alfa-2a/RBV. These data support daclatasvir use in all-oral direct-acting antiviral combinations.
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Antivirais/uso terapêutico , Negro ou Afro-Americano , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Hispânico ou Latino , Imidazóis/uso terapêutico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Administração Oral , Adulto , Idoso , Antivirais/efeitos adversos , Biomarcadores/sangue , Carbamatos , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/etnologia , Hepatite C Crônica/virologia , Humanos , Imidazóis/efeitos adversos , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Porto Rico , Pirrolidinas , RNA Viral/sangue , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Ribavirina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologia , Valina/análogos & derivados , Carga Viral , Adulto JovemRESUMO
BACKGROUND & AIMS: Chronic hepatitis B virus (HBV) infection is an important cause of cirrhosis and hepatocellular carcinoma worldwide; populations that migrate to the United States and Canada might be affected disproportionately. The Hepatitis B Research Network (HBRN) is a cooperative network of investigators from the United States and Canada, created to facilitate clinical, therapeutic, and translational research in adults and children with hepatitis B. We describe the structure of the network and baseline characteristics of adults with hepatitis B enrolled in the network. METHODS: The HBRN collected data on the clinical characteristics of 1625 adults with chronic HBV infection who are not receiving antiviral therapy from 21 clinical centers in North America. RESULTS: Half of the subjects in the HBRN are men, and the median age is 42 years; 72% are Asian, 15% are black, and 11% are white; with 82% born outside of North America. The most common HBV genotype was B (39%); 74% of subjects were negative for the hepatitis B e antigen. The median serum level of HBV DNA when the study began was 3.6 log10 IU/mL; 68% of male subjects and 67% of female subjects had alanine aminotransferase levels higher than the normal range. CONCLUSIONS: The HBRN cohort is used to address important clinical and therapeutic questions for North Americans infected with chronic HBV and to guide health policies on HBV prevention and management in North America.
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Emigrantes e Imigrantes , Vírus da Hepatite B/classificação , Vírus da Hepatite B/genética , Hepatite B Crônica/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá , Feminino , Genótipo , Vírus da Hepatite B/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos , Adulto JovemRESUMO
The pathophysiology of hepatic encephalopathy (HE) is complex, with hyperammonemia playing a central role in its development. Traditional therapies for HE have targeted ammonia and include medications such as lactulose and rifaximin. Although these agents are considered standard of care, nontraditional treatments seek to affect other factors in the pathogenesis of HE. Finally, procedural therapies include albumin dialysis, shunt closure, and the ultimate cure for HE, which is liver transplant. The treatments discussed provide alternative options for patients who have failed standard of care. However, more high-quality studies are needed to routinely recommend many of these agents.
Assuntos
Encefalopatia Hepática , Rifamicinas , Humanos , Encefalopatia Hepática/terapia , Encefalopatia Hepática/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Rifamicinas/uso terapêutico , Rifaximina/uso terapêutico , Lactulose/uso terapêuticoRESUMO
Background & Aims: The investigational first-generation core inhibitor vebicorvir (VBR) demonstrated safety and antiviral activity over 24 weeks in two phase IIa studies in patients with chronic HBV infection. In this long-term extension study, patients received open-label VBR with nucleos(t)ide reverse transcriptase inhibitors (NrtIs). Methods: Patients in this study (NCT03780543) previously received VBR + NrtI or placebo + NrtI in parent studies 201 (NCT03576066) or 202 (NCT03577171). After receiving VBR + NrtI for ≥52 weeks, stopping criteria (based on the treatment history and hepatitis B e antigen status in the parent studies) were applied, and patients either discontinued both VBR + NrtI, discontinued VBR only, or continued both VBR + NrtI. The primary efficacy endpoint was the proportion of patients with HBV DNA <20 IU/ml at 24 weeks off treatment. Results: Ninety-two patients entered the extension study and received VBR + NrtI. Long-term VBR + NrtI treatment led to continued suppression of HBV nucleic acids and, to a lesser extent, HBV antigens. Forty-three patients met criteria to discontinue VBR + NrtI, with no patients achieving the primary endpoint; the majority of virologic rebound occurred ≥4 weeks off treatment. Treatment was generally well tolerated, with few discontinuations due to adverse events (AEs). There were no deaths. Most AEs and laboratory abnormalities were related to elevations in alanine aminotransferase and occurred during the off-treatment or NrtI-restart phases. No drug-drug interactions between VBR + NrtI and no cases of treatment-emergent resistance among patients who adhered to treatment were observed. Conclusions: Long-term VBR + NrtI was safe and resulted in continued reductions in HBV nucleic acids following completion of the 24-week parent studies. Following treatment discontinuation, virologic relapse was observed in all patients. This first-generation core inhibitor administered with NrtI for at least 52 weeks was not sufficient for HBV cure. Clinical trial number: NCT03780543. Impact and implications: Approved treatments for chronic hepatitis B virus infection (cHBV) suppress viral replication, but viral rebound is almost always observed after treatment discontinuation, highlighting an unmet need for improved therapies with finite treatment duration producing greater therapeutic responses that can be sustained off treatment. First-generation core inhibitors, such as vebicorvir, have mechanisms of action orthogonal to standard-of-care therapies that deeply suppress HBV viral replication during treatment; however, to date, durable virologic responses have not been observed after treatment discontinuation. The results reported here will help researchers with the design and interpretation of future studies investigating core inhibitors as possible components of finite treatment regimens for patients with cHBV. It is possible that next-generation core inhibitors with enhanced potency may produce deeper and more durable antiviral activity than first-generation agents, including vebicorvir.
RESUMO
Patients with acute liver failure (ALF) can be listed status I for liver transplantation (LT) whereas patients with cirrhosis must follow the MELD scoring system. Liver imaging can mistakenly diagnose submassive hepatic necrosis in ALF as cirrhosis. The purpose of our study was to assess the accuracy of ultrasound (US) and computed tomography (CT) in distinguishing cirrhosis from ALF. All patients listed for ALF and transplanted during the study period were included. Controls were age- and gender-matched cirrhotic patients who underwent LT during the same period. Abdominal US or CT scans obtained on all patients were independently reviewed by three blinded abdominal radiologists. Explants from all patients were reviewed by two blinded pathologists, and histological diagnosis was correlated with radiological diagnosis. Forty-one patients with ALF and 42 patients with cirrhosis were analyzed. Univariate and multivariate analyses both revealed overall accuracy of 85% for ultrasound and 93% for CT. US and CT scans both provide high levels of accuracy in terms of discriminating ALF from cirrhosis but measures taken to determine whether a patient has ALF vs. cirrhosis needs to approach 100% accuracy. Thus, imaging studies alone should not definitively diagnosis one etiology of liver failure over the other.
Assuntos
Abdome/patologia , Erros de Diagnóstico , Cirrose Hepática/diagnóstico , Hepatopatias/diagnóstico , Falência Hepática Aguda/diagnóstico , Tomografia Computadorizada por Raios X , Ultrassonografia Doppler em Cores , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Necrose , Prognóstico , Índice de Gravidade de DoençaAssuntos
Ascite/diagnóstico por imagem , Ascite/etiologia , Tamponamento Cardíaco/diagnóstico por imagem , Ecocardiografia , Derrame Pericárdico/diagnóstico por imagem , Pericardite Constritiva/diagnóstico por imagem , Tamponamento Cardíaco/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Derrame Pericárdico/complicações , Pericardite Constritiva/complicaçõesRESUMO
INTRODUCTION: Hepatitis delta virus (HDV) causes acute and chronic liver disease that requires the co-infection of the Hepatitis B virus and can lead to significant morbidity and mortality. Bulevirtide is a recently introduced entry inhibitor drug that acts on the sodium taurocholate cotransporting peptide, thereby preventing viral entry to target cells in chronic HDV infection. The mainstay of chronic HDV therapy prior to bulevirtide was interferon alpha, which has an undesirable side effect profile. AREAS COVERED: We review bulevirtide data from recent clinical trials in Europe and the United States. Challenges to development and implementation of bulevirtide are discussed. Additionally, we review ongoing trials of emerging drugs for HDV, such as pegylated interferon lambda and lonafarnib. EXPERT OPINION: Bulevirtide represents a major shift in treatment for chronic HDV, for which there is significant unmet need. Trials that compared bulevirtide in combination with interferon alpha vs interferon alpha monotherapy demonstrated significant increase in virologic response. Overall, treatment with different doses of bulevirtide were comparable. Bulevirtide was generally well tolerated, and no serious adverse events occurred. Understanding the true prevalence of HDV, as well as continued studies of emerging drugs will prove valuable to the larger goal of eradication of Hepatitis D.