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1.
Viruses ; 15(10)2023 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-37896803

RESUMEN

A fixed-dose combination of sofosbuvir/velpatasvir (SOF/VEL) plus weight-based ribavirin (RBV) for 12 weeks is recommended for the treatment of patients with hepatitis C virus (HCV)-associated decompensated cirrhosis. However, large global studies, while confirming the effectiveness of SOF/VEL in a broad range of patients, often exclude these patients. This Phase 2, single-arm, open-label study in adult patients with HCV-associated decompensated cirrhosis in France and the USA aimed to provide further data on the safety and efficacy of SOF/VEL plus RBV for 12 weeks in this population. Patients were treated with a fixed-dose combination of SOF 400 mg/VEL 100 mg plus weight-based RBV once daily for 12 weeks. The inclusion criteria were chronic HCV infection (≥6 months), quantifiable HCV RNA at screening, Child-Turcotte-Pugh class B or C cirrhosis, and liver imaging within 6 months of Day 1 to exclude hepatocellular carcinoma. Among 32 patients who initiated treatment, 78.1% achieved sustained virologic response 12 weeks after the end of treatment (SVR12). Failure to achieve SVR12 was due to non-virologic reasons (investigator discretion, n = 1; death, n = 6). All 25 patients in the per-protocol population achieved SVR12 and all but one achieved sustained virologic response 24 weeks after the end of treatment. Adverse events (AEs) were as expected for a patient population with advanced liver disease. All Grade 3-4 and serious AEs and deaths were deemed unrelated to treatment. In patients with HCV-associated decompensated cirrhosis, SOF/VEL plus RBV achieved high SVR12 rates and was generally well tolerated.


Asunto(s)
Hepatitis C Crónica , Hepatitis C , Adulto , Humanos , Sofosbuvir/efectos adversos , Ribavirina/efectos adversos , Hepacivirus/genética , Antivirales/efectos adversos , Resultado del Tratamiento , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Genotipo , Quimioterapia Combinada
4.
J Hepatol ; 75(4): 865-878, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33992698

RESUMEN

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies. METHODS: We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays. RESULTS: Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-ß proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved. CONCLUSIONS: NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature. LAY SUMMARY: The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) - a potential tumour suppressor - and the presence of a novel mutational signature that characterises NASH-related HCC.


Asunto(s)
Carcinoma Hepatocelular/genética , Biología Molecular/estadística & datos numéricos , Enfermedad del Hígado Graso no Alcohólico/genética , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/etiología , Femenino , Humanos , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/genética , Masculino , Persona de Mediana Edad , Biología Molecular/métodos , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Factores de Riesgo
5.
Transplant Direct ; 4(12): e411, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30584592

RESUMEN

Human herpesvirus-8 (HHV-8) remains best known as an oncogenic virus, but nonneoplastic disease manifestations, such as bone marrow failure or hemophagocytic lymphohistiocytosis (HLH) have gained greater recognition in recent years. In organ transplantation, HHV-8 infection commonly occurs with reactivation of latent virus among recipients from endemic regions of the world or due to transmission from the organ donor. We describe a case of HHV-8-associated HLH in a liver transplant recipient at increased risk for primary infection. Our case highlights the risk of non-donor-derived, posttransplant primary HHV-8 infection, and demonstrates that HLH can be a life-threatening complication of this infection.

6.
J Hepatol ; 69(2): 353-358, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29704513

RESUMEN

BACKGROUND & AIMS: The RESORCE trial showed that regorafenib improves overall survival (OS) in patients with hepatocellular carcinoma progressing during sorafenib treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.50-0.78; p <0.0001). This exploratory analysis describes outcomes of sequential treatment with sorafenib followed by regorafenib. METHODS: In RESORCE, 573 patients were randomized 2:1 to regorafenib 160 mg/day or placebo for 3 weeks on/1 week off. Efficacy and safety were evaluated by last sorafenib dose. The time from the start of sorafenib to death was assessed. Time to progression (TTP) in RESORCE was analyzed by TTP during prior sorafenib treatment. RESULTS: HRs (regorafenib/placebo) for OS by last sorafenib dose were similar (0.67 for 800 mg/day; 0.68 for <800 mg/day). Rates of grade 3, 4, and 5 adverse events with regorafenib by last sorafenib dose (800 mg/day vs. <800 mg/day) were 52%, 11%, and 15% vs. 60%, 10%, and 12%, respectively. Median times (95% CI) from the start of sorafenib to death were 26.0 months (22.6-28.1) for regorafenib and 19.2 months (16.3-22.8) for placebo. Median time from the start of sorafenib to progression on sorafenib was 7.2 months for the regorafenib arm and 7.1 months for the placebo arm. An analysis of TTP in RESORCE in subgroups defined by TTP during prior sorafenib in quartiles (Q) showed HRs (regorafenib/placebo; 95% CI) of 0.66 (0.45-0.96; Q1); 0.26 (0.17-0.40; Q2); 0.40 (0.27-0.60; Q3); and 0.54 (0.36-0.81; Q4). CONCLUSIONS: These exploratory analyses show that regorafenib conferred a clinical benefit regardless of the last sorafenib dose or TTP on prior sorafenib. Rates of adverse events were generally similar regardless of the last sorafenib dose. LAY SUMMARY: This analysis examined characteristics and outcomes of patients with hepatocellular carcinoma who were treated with regorafenib after they had disease progression during sorafenib treatment. Regorafenib provided clinical benefit to patients regardless of the pace of their disease progression during prior sorafenib treatment and regardless of their last sorafenib dose. The sequence of sorafenib followed by regorafenib for hepatocellular carcinoma may extend survival beyond what has been previously reported. ClinicalTrials.gov NCT01774344.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Compuestos de Fenilurea/administración & dosificación , Piridinas/administración & dosificación , Sorafenib/administración & dosificación , Adulto , Anciano , Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Monitoreo de Drogas/métodos , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
7.
Clin Liver Dis ; 22(1): 213-227, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29128058

RESUMEN

The number of transplants caused by nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) has been progressively increasing and this is expected to become the most common indication for liver transplant in the United States. Patients with NASH show many features of the metabolic syndrome and, as a result, are at higher risk for postoperative cardiovascular morbidity and mortality. Despite this, patients with NASH have long-term graft and patient survival rates comparable with other causes of chronic liver disease. Posttransplant metabolic syndrome is a common occurrence that increases the risk of steatosis in the graft liver.


Asunto(s)
Trasplante de Hígado , Enfermedad del Hígado Graso no Alcohólico/cirugía , Obesidad/complicaciones , Enfermedades Cardiovasculares/complicaciones , Complicaciones de la Diabetes/complicaciones , Humanos , Enfermedades Renales/complicaciones , Lipasa/genética , Trasplante de Hígado/efectos adversos , Proteínas de la Membrana/genética , Síndrome Metabólico/etiología , Mutación , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/genética , Complicaciones Posoperatorias/etiología , Periodo Preoperatorio
8.
World J Virol ; 6(4): 59-72, 2017 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-29147645

RESUMEN

AIM: To assess the real-world effectiveness and cost of simeprevir (SMV), and/or sofosbuvir (SOF)-based therapy for chronic hepatitis C virus (HCV) infection. METHODS: The real-world performance of patients treated with SMV/SOF ± ribavirin (RBV), SOF/RBV, and SOF/RBV with pegylated-interferon (PEG) were analyzed in a consecutive series of 508 patients with chronic HCV infection treated at a single academic medical center. Patients with genotypes 1 through 4 were included. Rates of sustained virological response - the absence of a detectable serum HCV RNA 12 wk after the end of treatment [sustained virological response (SVR) 12] - were calculated on an intention-to-treat basis. Costs were calculated from the payer's perspective using Medicare/Medicaid fees and Redbook Wholesale Acquisition Costs. Patient-related factors associated with SVR12 were identified using multivariable logistic regression. RESULTS: SVR12 rates were as follows: 86% (95%CI: 80%-91%) among 178 patients on SMV/SOF ± RBV; 62% (95%CI: 55%-68%) among 234 patients on SOF/RBV; and 78% (95%CI: 68%-86%) among 96 patients on SOF/PEG/RBV. Mean costs-per-SVR12 were $174442 (standard deviation: ± $18588) for SMV/SOF ± RBV; $223003 (± $77946) for SOF/RBV; and $126496 (± $31052) for SOF/PEG/RBV. Among patients on SMV/SOF ± RBV, SVR12 was less likely in patients previously treated with a protease inhibitor [odds ratio (OR): 0.20, 95%CI: 0.06-0.56]. Higher bilirubin (OR: 0.47, 95%CI: 0.30-0.69) reduced the likelihood of SVR12 among patients on SOF/RBV, while FIB-4 score ≥ 3.25 reduced the likelihood of SVR12 (OR: 0.18, 95%CI: 0.05-0.59) among those on SOF/PEG/RBV. CONCLUSION: SVR12 rates for SMV and/or SOF-based regimens in a diverse real-world population are comparable to those in clinical trials. Treatment failure accounts for 27% of costs.

9.
J Hepatol ; 66(6): 1166-1172, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28131794

RESUMEN

BACKGROUND & AIMS: The Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was developed to overcome the limitations of standard RECIST criteria in response assessment of hepatocellular carcinoma (HCC). We aimed to investigate whether objective response by mRECIST accurately predicted overall survival (OS) in patients with advanced HCC treated with systemic targeted therapies and also to preliminarily assess this end-point as a potential surrogate of OS. METHODS: Individual patient data from the BRISK-PS randomized phase III trial comparing brivanib vs. placebo (the first to prospectively incorporate mRECIST) were used to analyze objective response as a predictor of OS in a time-dependent covariate analysis. Patients with available imaging scans during follow-up were included (n=334; 85% of those randomized). Moreover, a correlation of the survival probability in deciles vs. the observed objective response was performed to evaluate its suitability as a surrogate end-point. RESULTS: Objective response was observed in 11.5% and 1.9% of patients treated with brivanib and placebo respectively, and was associated with a better survival (median OS 15.0 vs. 9.4months, p<0.001). In addition, objective response had an independent prognostic value (HR=0.48; 95% confidence interval [CI], 0.26-0.91, p=0.025) along with known prognostic factors. Finally, objective response showed promising results as a surrogate of OS in this trial (R=-0.92; 95% CI, -1 to -0.73, p<0.001). It was an early indicator of the treatment effect (median time to objective response was 1.4months). CONCLUSIONS: Objective response by mRECIST in advanced HCC predicts OS and thus can be considered as a candidate surrogate end-point. Further studies are needed to support this finding. LAY SUMMARY: There is a need to identify surrogate end-points for overall survival in advanced hepatocellular carcinoma. We studied patients from the phase III BRISK trial, comparing brivanib treatment with placebo after sorafenib progression. We demonstrate that objective response is an independent predictor of survival and qualifies as a potential surrogate end-point for overall survival in this patient population. CLINICAL TRIAL NUMBER: NCT00825955.


Asunto(s)
Alanina/análogos & derivados , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Triazinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Alanina/uso terapéutico , Biomarcadores , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Método Doble Ciego , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Pronóstico , Adulto Joven
10.
World J Gastroenterol ; 22(9): 2844-54, 2016 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-26973423

RESUMEN

AIM: To determine the safety profile of new hepatitis C virus (HCV) treatments in liver transplant (LT) recipients with recurrent HCV infection. METHODS: Forty-two patients were identified with recurrent HCV infection that underwent LT at least 12 mo prior to initiating treatment with a Sofosbuvir-based regimen during December 2013-June 2014. Cases were patients who experienced hepatic decompensation and/or serious adverse events (SAE) during or within one month of completing treatment. Controls had no evidence of hepatic decompensation and/or SAE. HIV-infected patients were excluded. Cumulative incidence of decompensation/SAE was calculated using the Kaplan Meier method. Exact logistic regression analysis was used to identify factors associated with the composite outcome. RESULTS: Median age of the 42 patients was 60 years [Interquartile Range (IQR): 56-65 years], 33% (14/42) were female, 21% (9/42) were Hispanic, and 9% (4/42) were Black. The median time from transplant to treatment initiation was 5.4 years (IQR: 2.1-8.8 years). Thirteen patients experienced one or more episodes of hepatic decompensation and/or SAE. Anemia requiring transfusion, the most common event, occurred in 62% (8/13) patients, while 54% (7/13) decompensated. The cumulative incidence of hepatic decompensation/SAE was 31% (95%CI: 16%-41%). Risk factors for decompensation/SAE included lower pre-treatment hemoglobin (OR = 0.61 per g/dL, 95%CI: 0.40-0.88, P < 0.01), estimated glomerular filtration rate (OR = 0.95 per mL/min per 1.73 m(2), 95%CI: 0.90-0.99, P = 0.01), and higher baseline serum total bilirubin (OR = 2.43 per mg/dL, 95%CI: 1.17-8.65, P < 0.01). The sustained virological response rate for the cohort of 42 patients was 45%, while it was 31% for cases. CONCLUSION: Sofosbuvir/ribavirin will continue to be used in the post-transplant population, including those with HCV genotypes 2 and 3. Management of anemia remains an important clinical challenge.


Asunto(s)
Antivirales/efectos adversos , Enfermedad Hepática en Estado Terminal/cirugía , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Fallo Hepático/inducido químicamente , Trasplante de Hígado/efectos adversos , Sofosbuvir/efectos adversos , Adulto , Anciano , Anemia/inducido químicamente , Quimioterapia Combinada , Enfermedad Hepática en Estado Terminal/diagnóstico , Enfermedad Hepática en Estado Terminal/virología , Femenino , Hepacivirus/patogenicidad , Hepatitis C/diagnóstico , Hepatitis C/virología , Humanos , Estimación de Kaplan-Meier , Fallo Hepático/diagnóstico , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Recurrencia , Ribavirina/efectos adversos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Activación Viral/efectos de los fármacos
11.
J Hepatol ; 63(6): 1368-77, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26220754

RESUMEN

BACKGROUND & AIMS: In patients with hepatocellular carcinoma (HCC), liver transplantation (LT) is an excellent therapy if tumor characteristics are within the Milan criteria. We aimed to define genomic features enabling to identify HCC patients beyond Milan criteria who have acceptable transplant outcomes. METHODS: Among 770 consecutive HCC patients transplanted between 1990 and 2013, 132 had tumors exceeding Milan criteria on pathology and were enrolled in the study; 44% of the patients satisfied the 'up-to-7 rule' [7=sum of the size of the largest tumor and the number of tumors]. Explant tumors were assessed for genomic signatures and immunohistochemical markers associated with poor outcome. RESULTS: At a median follow-up of 88months, 64 patients had died and 45 recurred; the 5-year overall survival (OS) and recurrence rates were 57% and 35%, respectively. Cytokeratin 19 (CK19) gene signature was independently associated with recurrence [Hazard ratio (HR)=2.95, p<0.001], along with tumor size (HR=3.37, p=0.023) and presence of satellites (HR=2.98, p=0.001). S2 subclass signature was independently associated with poor OS (HR=3.18, p=0.001), along with tumor size (HR=5.06, p<0.001) and up-to-7 rule (HR=2.50, p=0.002). Using the presence of progenitor cell markers (either CK19 or S2 signatures) patients were classified into poor prognosis (n=58; 5-year recurrence 53%, survival 45%) and good prognosis (n=74; 5-year recurrence 19%, survival 67%) (HR=3.16, p<0.001 for recurrence, and HR=1.72, p=0.04 for OS). CONCLUSIONS: HCC patients transplanted beyond Milan criteria without gene signatures of progenitor markers (CK19 and S2) achieved survival rates similar as those within Milan criteria. Once prospectively validated, these markers may support a limited expansion of LT indications.


Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirugía , Trasplante de Hígado , Adulto , Anciano , Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/mortalidad , Moléculas de Adhesión Celular/metabolismo , Estudios de Cohortes , Molécula de Adhesión Celular Epitelial , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Queratina-19/genética , Queratina-19/metabolismo , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Células Madre Neoplásicas/metabolismo , Pronóstico
12.
World J Gastroenterol ; 21(20): 6236-45, 2015 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-26034358

RESUMEN

AIM: To describe our experience using a low-accelerating-dose regimen (LADR) with pegylated interferon alpha-2a and ribavirin in treatment of hepatitis C virus (HCV) recurrence. METHODS: From 2003, a protocolized LADR strategy was employed to treat liver transplant (LT) recipients with recurrent HCV at our institution. Medical records of 182 adult patients with recurrent HCV treated with LADR between 1/2003 and 1/2011 were reviewed. Histopathology from all post-LT liver biopsies were reviewed in a blinded fashion. Paired recipient and donor IL28B status were assessed. A novel technique was employed to ascertain recipient and donor IL28B (rs12979860) Gt data using DNA extracted from archival FFPE tissue from explanted native livers and donor gallbladders respectively. The primary endpoint was SVR; secondary endpoints examined include (1) patient and graft survival; (2) effect of anti-viral therapy on liver histology (fibrosis and inflammation); (3) incidence of on-treatment development of ACR, CDR, or PCH; (4) association of recipient and donor IL28B genotype with SVR; and (5) incidence of anti-viral therapy-associated adverse events (anemia, leukopenia, thrombocytopenia, depression) and hepatic decompensation. RESULTS: The overall SVR rate was 38% (29% Gt1, 67% Gt2, 86% Gt3 and 58% Gt4). HCV Gt (P < 0.0001), donor age (P = 0.003), cytomegalovirus mismatch (P = 0.001), baseline serum bilirubin (P = 0.002), and baseline viral load (P = 0.04) were independent predictors for SVR. SVR rates were significantly higher in the recipient-CC/donor-non CC pairs (P = 0.007). Neither baseline fibrosis nor change in fibrosis stage after anti-viral therapy were associated with SVR. Fibrosis progressed in 72% of patients despite SVR. Median graft survival was 91 mo. Five-year patient survival was superior in patients who achieved SVR (97% vs 82%, P = 0.001). Pre-treatment ALP ≥ 150 U/L (P = 0.01), total bilirubin ≥ 1.5 mg/dL (P = 0.001) and creatinine ≥ 2 mg/dL (P = 0.001) were independently associated with patient survival. Only 13% of patients achieving SVR died during the follow-up period. Treatment discontinuation and treatment-related mortality occurred in 35% and 2.2% of patients, respectively. EPO, G-CSF and blood transfusion were needed in 89%, 40% and 23% of patients, respectively. Overall hospitalization rate for treatment-related serious adverse events was 21%. Forty-six (25%) of the patients were deceased; among those who died, 25 (54%) were due to liver-related complications, and 4 deaths (9%) occurred while receiving therapy (2 patients experienced hepatic decompensation and 2 sepsis). CONCLUSION: LADR strategy remains relevant in managing post-LT recurrent HCV where access to DAAs is limited. SVR is associated with improved survival, but fibrosis progression still occurs.


Asunto(s)
Antivirales/administración & dosificación , Enfermedad Hepática en Estado Terminal/cirugía , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Interferón-alfa/administración & dosificación , Trasplante de Hígado/efectos adversos , Polietilenglicoles/administración & dosificación , Ribavirina/administración & dosificación , Antivirales/efectos adversos , Biopsia , Progresión de la Enfermedad , Quimioterapia Combinada , Enfermedad Hepática en Estado Terminal/diagnóstico , Enfermedad Hepática en Estado Terminal/virología , Femenino , Genotipo , Supervivencia de Injerto , Hepacivirus/genética , Hepacivirus/crecimiento & desarrollo , Hepatitis C/complicaciones , Hepatitis C/diagnóstico , Hepatitis C/genética , Hepatitis C/mortalidad , Humanos , Interferón-alfa/efectos adversos , Interferones , Interleucinas/genética , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , Ciudad de Nueva York , Polietilenglicoles/efectos adversos , Modelos de Riesgos Proporcionales , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Recurrencia , Estudios Retrospectivos , Ribavirina/efectos adversos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Carga Viral , Activación Viral/efectos de los fármacos
13.
AJR Am J Roentgenol ; 204(3): 654-61, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25714299

RESUMEN

OBJECTIVE. This single-center study evaluated the use of expanded polytetrafluoroethylene (ePTFE)-covered stent-grafts for transjugular intrahepatic portosystemic shunt (TIPS) placement to manage portal hypertension-related refractory ascites. MATERIALS AND METHODS. One hundred patients at a single tertiary care center in a major metropolitan hospital underwent TIPS placement with an ePTFE-covered stent-graft (Viatorr TIPS Endoprosthesis). Patients with portal hypertension-related ascites and preexisting hepatocellular carcinoma or liver transplant were excluded from the analysis. Records were reviewed for demographic characteristics, technical success of the TIPS procedures, and stent follow-up findings. Clinical results were assessed at 90- and 180-day intervals. RESULTS. Immediate technical success of the TIPS procedure was 100%. Of the 61 patients with documented follow-up, 55 (90.2%) had a partial or complete ascites response to TIPS creation. Of these 55 patients, nine experienced severe encephalopathy. Six of 61 patients (9.8%) did not experience a significant ascites response. Overall survival was 78.7% at 365-day follow-up. The 365-day survival was 84.2% for patients with a model for end-stage liver disease (MELD) score of less than 15, 67.0% for those with a score of 15-18, and 53.8% for those with a score of greater than 18 (p = 0.01). For patients with a MELD score of less than 18, the 365-day survival was 88.0% for those with an albumin value of 3 mg/dL or greater and 72.8% for those with an albumin value of less than 3 mg/dL (p = 0.04). CONCLUSION. TIPS placement using an ePTFE-covered stent-graft is an efficacious therapy for refractory ascites. Patients with preserved liver function-characterized by a MELD score of less than 15 or a MELD score of less than 18 and an albumin value of 3 mg/dL or greater-experience the greatest survival benefit.


Asunto(s)
Ascitis/cirugía , Politetrafluoroetileno , Derivación Portosistémica Intrahepática Transyugular/instrumentación , Stents , Adulto , Anciano , Ascitis/etiología , Ascitis/mortalidad , Femenino , Humanos , Hipertensión Portal/complicaciones , Masculino , Persona de Mediana Edad , Diseño de Prótesis , Estudios Retrospectivos , Tasa de Supervivencia , Factores de Tiempo , Adulto Joven
14.
Hepatol Res ; 44(12): 1248-52, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24107139

RESUMEN

Most studies have shown that lamivudine (LAM) prophylaxis is sufficient to prevent hepatitis B virus (HBV) transmission in recipients of hepatitis B core antibody positive (HBcAb(+) ) allografts. However, de novo hepatitis B (DNHB) is known to occur in this patient population. Herein, we report a case series of four liver transplant recipients who developed DNHB after receiving HBcAb(+) allografts due to acquisition of LAM resistance mutations, suggesting that LAM prophylaxis may be suboptimal. A retrospective chart review was performed of all adult liver transplants performed at Mount Sinai from 2001 to 2010. A total of 79 patients received HBcAb(+) allografts for non-hepatitis B-related liver disease. Of these 79 recipients, four patients developed DNHB and were found to have documented LAM resistance. With the increasing use of HBcAb(+) donor livers, we suspect that there will also be a growing number of cases of DNHB due to acquisition of LAM resistance. We suggest that other agents, such as entecavir or tenofovir, be considered for use as prophylaxis in this patient population to decrease this risk.

15.
J Clin Oncol ; 31(28): 3509-16, 2013 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-23980090

RESUMEN

PURPOSE: Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib. PATIENTS AND METHODS: In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800 mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety. RESULTS: Median OS was 9.4 months for brivanib and 8.2 months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P = .3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P = .1044). Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P < .001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%). CONCLUSION: In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.


Asunto(s)
Alanina/análogos & derivados , Carcinoma Hepatocelular/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Terapia Recuperativa , Triazinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Alanina/uso terapéutico , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Niacinamida/efectos adversos , Pronóstico , Sorafenib , Tasa de Supervivencia , Adulto Joven
16.
Clin Res Hepatol Gastroenterol ; 37(4): 322-7, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23876350

RESUMEN

Focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) are benign hepatocellular tumors that develop most frequently in females and in non-cirrhotic livers. HCA are prone to bleed and to transform into hepatocellular carcinoma (HCC). Four major subgroups of HCA have been thus far identified: HNF1α mutated HCA, inflammatory HCA (IHCA), ß-catenin mutated HCA (b-HCA and b-IHCA), based on mutations in specific oncogenes and tumor suppressors. B-HCA and b-IHCA are strongly associated with HCC transformation. Benign hepatocellular tumors can be classified using immunohistochemistry (LFABP, CRP, GS, b-catenin). Analysis of HCA phenotypes has led to the identification of patients at risk of HCC transformation and therefore improved the indications provided by invasive and non-invasive diagnostic techniques, such as biopsies and MRI. These recent advances have broadened the clinical scope of HCA in various conditions, such as their presence in males, in obese patients, in patients suffering from liver vascular disorders, genetic diseases. However, specific immunohistochemistry has shown limitations particularly for the identification of b-HCA, thereby, outlining the importance of molecular studies to improve the diagnosis/prognosis of HCA. If evaluation of prognosis and treatment has benefited from these advances, much more needs to be done to obtain guidelines for good clinical practice.


Asunto(s)
Adenoma de Células Hepáticas/clasificación , Adenoma de Células Hepáticas/patología , Humanos
18.
Int J Hepatol ; 2013: 604860, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23509632

RESUMEN

Hepatocellular adenoma (HCA) is a benign neoplasm arising from hepatocytes. There is evidence that the inflammatory subtype may be associated with obesity and alcohol use and that men with metabolic syndrome may be at risk for malignant transformation of HCA. We sought to explore the combined experience of US centers as reported in the literature to document the epidemiologic shift in risk factors for HCA formation in the United States, namely, a shift from oral contraceptive pills (OCPs) to an emerging role of obesity as a contributing factor. Methods. Publications reporting HCA in the United States were identified through a PubMed search and a review of the literature. We excluded publications prior to 1970, single case reports, and publications for which there was no data available regarding patient characteristics including OCP use and the number of adenomas. Conclusion. Whereas earlier reports of HCA in the United States described cases exclusively in women exposed to OCPs, there is a trend towards an increase in HCAs reported in men, HCAs in the absence of OCP use, and increased reporting of multiple HCAs. This may be a result of newer OCP formulations and increasing prevalence of obesity.

19.
J Hepatol ; 58(5): 890-7, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23333446

RESUMEN

BACKGROUND & AIMS: Many foreign-born persons in the US are at high risk of chronic hepatitis B (HBV) and C (HCV) infections, yet are not aware of their infection, and lack healthcare coverage or linkage to care. METHODS: A unique partnership, the Hepatitis Outreach Network, combines the expertise and resources of the Mount Sinai School of Medicine, the NYC Department of Health and Mental Hygiene, and community-based organizations, to provide education, screening and link to care in communities with high prevalence of chronic viral hepatitis. Comprehensive HBV and HCV screening identifies infected patients, who then receive further evaluation from either local or Mount Sinai physicians, combined with patient-navigators who organize follow-up visits. RESULTS: Of 1603 persons screened, 76 had HBV and 75 had HCV. Importantly, screening for HCV based on traditional risk factors would have missed 67% of those who tested positive. Of the 76 persons with HCV infection, 49 (64%) received a medical evaluation (26 with local providers and 23 at Mount Sinai). Of the 49 HCV-infected persons evaluated, treatment was recommended in 11 and begun in 8 (73%). Of the 76 persons with HBV infection, 43 (57%) received a medical evaluation (31 with local providers and 12 at Mount Sinai). Of the 43 HBV-infected persons evaluated, treatment was recommended and begun in 5 (100%). CONCLUSIONS: Hepatitis Outreach Network has successfully established novel proof of concept for identifying HBV and HCV infections in foreign-born persons through use of several unique elements that effectively link them to care.


Asunto(s)
Emigrantes e Inmigrantes , Personal de Salud , Hepatitis B Crónica/diagnóstico , Hepatitis C Crónica/diagnóstico , Tamizaje Masivo/métodos , Adulto , Femenino , Educación en Salud , Hepatitis B Crónica/epidemiología , Hepatitis C Crónica/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Navegación de Pacientes , Prevalencia , Factores de Riesgo , Estados Unidos/epidemiología
20.
Semin Liver Dis ; 32(3): 262-6, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22932975

RESUMEN

A 40-year-old man with human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) infection was referred for evaluation of abnormal liver enzyme activities. The patient was maintained on antiretroviral therapy for HIV as well as medication to suppress HBV and had previously undergone treatment for HCV with durable sustained virologic response. The patient was clinically well without any symptoms or evidence of liver decompensation. Laboratory findings were notable for aminotransferase activities in the 200 to 225 U/L range that had been persistent for several months. An extensive workup for the etiology of the aminotransferase elevation ensued. Imaging studies showed no evidence of biliary obstruction. Serology revealed negative autoantibodies, negative serum HCV-RNA, and low level HBV-DNA by polymerase chain reaction. Further testing revealed positive hepatitis delta virus (HDV) antibody and positive HDV RNA in the serum. A percutaneous liver biopsy was performed to further elucidate the cause of the elevated aminotransferase activities. Based on histology, serology, and clinical presentation, a diagnosis of chronic HDV infection was made. HDV infection should be considered in patients with known chronic viral hepatitis B with low viral load, who present with worsening liver function or elevation in aminotransferase activities.


Asunto(s)
Hepatitis D Crónica/diagnóstico , Virus de la Hepatitis Delta/aislamiento & purificación , Adulto , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Coinfección/sangre , Coinfección/virología , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Hepatitis B/sangre , Hepatitis B/tratamiento farmacológico , Hepatitis C/sangre , Hepatitis C/tratamiento farmacológico , Hepatitis D Crónica/sangre , Hepatitis D Crónica/patología , Virus de la Hepatitis Delta/genética , Virus de la Hepatitis Delta/inmunología , Antígenos de Hepatitis delta/sangre , Humanos , Hígado/enzimología , Masculino , ARN Viral/sangre
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