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1.
J Formos Med Assoc ; 118(1 Pt 1): 7-38, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30527436

RESUMO

The experts of Taiwan Association for the Study of Liver (TASL) have actively participated and led the guidelines on hepatitis B virus (HBV) management by Asian Pacific Association for the Study of Liver (APASL) which is the first international association for the study of liver to publish the statement on HBV management before. However, there are more and more new data on the natural history and treatment of HBV infection in the past decade. These include new application of an old biomarker (quantitative HBsAg), clinical significance of HBV genotype and naturally occurring mutations, the role of non-invasive examination in evaluating severity of hepatic fibrosis, clinical significance of outcome calculators, new drug or new combination strategies towards more effective therapy and organ transplantation including liver and non-liver transplantation. It is time to publish the guidelines on HBV management of Taiwan. Hence, TASL have conducted an expert meeting to review, to discuss and to debate the relevant literatures, followed by draft the manuscript of HBV management guidelines and recommendations. The guidelines include general management, indications for fibrosis assessment, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patient receiving immune suppression or chemotherapy and patients in the setting of liver transplantation and hepatocellular carcinoma, are also included.


Assuntos
Carcinoma Hepatocelular/prevenção & controle , Hepatite B Crônica/tratamento farmacológico , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/prevenção & controle , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Carcinoma Hepatocelular/virologia , Consenso , Gerenciamento Clínico , Progressão da Doença , Feminino , Guanina/análogos & derivados , Guanina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Antígenos de Superfície da Hepatite B/sangue , Vacinas contra Hepatite B/uso terapêutico , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/complicações , Hepatite B Crônica/diagnóstico , Humanos , Programas de Imunização , Interferon-alfa/efeitos adversos , Interferon-alfa/uso terapêutico , Cirrose Hepática/virologia , Neoplasias Hepáticas/virologia , Masculino , Gravidez , Sociedades Médicas , Taiwan , Carga Viral
2.
Liver Int ; 38(11): 1997-2005, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29797410

RESUMO

BACKGROUND & AIMS: This study investigates the long-term incidences and predictors of developing hepatocellular carcinoma (HCC), cirrhotic events and mortality in cirrhotic patients receiving entecavir (ETV) therapy. METHODS: We enrolled 481 nucleos(t)ide analogue-naïve chronic hepatitis B (CHB) patients who had compensated cirrhosis upon entry and had received ETV monotherapy for >12 months. RESULTS: The 8-year cumulative incidences of developing HCC, cirrhotic events and liver-related mortality were 26.5%, 8.62% and 10.03% respectively. Multivariate analysis revealed that diabetic mellitus (DM), higher fibrosis-4 (FIB-4) and alpha-foetoprotein (AFP) levels at 12 months of treatment, and FIB-4 increase from baseline to 12 months were independent factors of HCC. FIB-4 and AFP levels at 12 months of treatment were also independent factors of cirrhotic events and mortality. FIB-4 cut-off values of 3, 3 and 5 as well as AFP cut-offs of 5, 5, and 9 ng/mL at 12 months of treatment were optimal for predicting HCC, cirrhotic events and mortality during therapy respectively. The FIB-4 and AFP levels at 12 months of treatment were assessed for the combined risk of developing clinical outcomes. The 8-year incidences of HCC, cirrhotic events and liver-related mortality in the subgroups with low FIB-4 and AFP levels were only 5.95%, 1.03% and 2.43% respectively. DM was an independent predictor of HCC and mortality. CONCLUSION: The combination of FIB-4 and AFP levels at 12 months of treatment is a useful marker for predicting the development of HCC, cirrhotic events and mortality in compensated cirrhotic patients with CHB who are receiving ETV therapy.


Assuntos
Biomarcadores/sangue , Carcinoma Hepatocelular/epidemiologia , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Cirrose Hepática/mortalidade , Neoplasias Hepáticas/epidemiologia , Adulto , Idoso , Alanina Transaminase/sangue , Antivirais/uso terapêutico , Aspartato Aminotransferases/sangue , Carcinoma Hepatocelular/virologia , China/epidemiologia , Feminino , Guanina/uso terapêutico , Hepatite B Crônica/complicações , Humanos , Incidência , Cirrose Hepática/sangue , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Contagem de Plaquetas , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taiwan/epidemiologia , alfa-Fetoproteínas/metabolismo
3.
J Formos Med Assoc ; 117(7): 588-597, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29456079

RESUMO

BACKGROUND: Efficacy of sequential therapy with nucleos(t)ide analogues and interferons versus monotherapy in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) remains unexplored. We aimed to assess efficacy and safety of sequential therapy with adefovir (ADV) or entecavir (ETV) followed by peginterferon (PEG-IFN) alfa-2a in Taiwanese patients with HBeAg-positive. METHODS: This randomized, placebo-controlled, double-blind trial was conducted at nine sites in Taiwan from April 2010 to October 2013. Patients (N = 280) were randomized 1:1:1 to receive placebo, ETV or ADV alone for four weeks, combined with PEG-IFN alfa-2a for two weeks, then PEG-IFN alfa-2a alone for 46 weeks. The primary efficacy end point was HBeAg seroconversion at 48 weeks post-treatment. RESULTS: No significant differences were observed among groups for HBeAg seroconversion (PEG-IFN alfa-2a+placebo, 36.3%; PEG-IFN alfa-2a+ETV, 29.5%; and PEG-IFN alfa-2a+ADV, 27.4%), HBeAg loss (37.4%, 32.2%, and 28.6%, respectively) or change in hepatitis B surface antigen (HBsAg) levels from baseline (-0.56 IU/mL, -0.60 IU/mL, and -0.41 IU/mL, respectively). However, hepatitis B virus DNA levels were higher with PEG-IFN alfa-2a+placebo than PEG-IFN alfa+ETV at week 64 (p = 0.0412), 76 (p = 0.0311), and 88 (p = 0.0113), and alanine aminotransferase (ALT) normalization rate was higher with PEG-IFN alfa-2a+placebo than PEG-IFN alfa-2a+ADV (p = 0.0283) or PEG-IFN alfa-2a+ETV (p = 0.0369) at week 88. Sub-analysis of results revealed an association between on-treatment HBsAg and ALT levels and efficacy 48 weeks post-treatment. Safety was comparable among treatment groups. CONCLUSION: Pre-therapy with ADV or ETV followed by PEG-IFN alfa-2a is not superior to PEG-IFN alfa-2a monotherapy in Taiwanese patients with HBeAg-positive CHB. CLINICAL TRIAL ID: NCT: 00922207.


Assuntos
Adenina/análogos & derivados , Antivirais/administração & dosagem , Guanina/análogos & derivados , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Organofosfonatos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adenina/administração & dosagem , Adulto , Alanina Transaminase/sangue , DNA Viral/sangue , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Guanina/administração & dosagem , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Taiwan
4.
Oncotarget ; 8(54): 92431-92441, 2017 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-29190928

RESUMO

BACKGROUND: Until now, no risk score could predict hepatocellular carcinoma (HCC) in nucleos(t)ide analog (NA)-treated Asian patients. METHODS: We enrolled 1325 NA-naïve chronic hepatitis B patients with entecavir monotherapy for >12 months, with 883 and 442 patients randomly assigned to the development and validation groups, respectively, in the risk model. RESULTS: The cumulative probabilities of HCC were 2.4%, 4.1%, and 9.9% after 2, 3, and 5 years of treatment, respectively. In the development group, age, platelet counts, and alpha-fetoprotein levels after 12 months of treatment were the independent predictors of HCC. We converted the Cox proportional hazards regression coefficients for these predictors into risk scores and developed the APA-B model, with the total risk scores ranging from 0 to 15. The risk scores accurately categorized patients with low (0-5), medium (6-9), and high (10-15) risks in the validation group (P <0.001). The areas under the receiver operating characteristic curve for predicting HCC risk after 2, 3, and 5 years were 0.877, 0.842, and 0.827, respectively, in the development group and 0.939, 0.892, and 0.862, respectively, in the validation group. CONCLUSION: The proposed HCC risk prediction model exhibited excellent predictive accuracy in NA-naïve Asian patients receiving entecavir therapy.

5.
Medicine (Baltimore) ; 96(46): e8696, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29145306

RESUMO

Some patients with hepatitis C virus (HCV) infections who fail to achieve sustained virological responses (SVRs) after interferon (IFN) therapy do not develop hepatocellular carcinoma (HCC). Risk stratification of these patients may help identify those who would benefit most from treatment with direct-acting antivirals (DAAs).A total of 552 HCV-infected patients with non-SVR status were enrolled. Laboratory data before and after IFN treatment were analyzed to determine the relationship of changes in serum markers with development of HCC during the 7-year study period.HCC developed in 93 patients. The risk factors for HCC were pre-existing liver cirrhosis, low hemoglobin level at baseline, low pretreatment platelet count, high post-treatment alpha-fetoprotein (AFP) level (≥15 ng/mL), and high post-treatment Fibrosis 4 (FIB4) index (>3.25). For patients without pre-existing cirrhosis, those with high post-treatment AFP level and FIB4 index had the highest risk of HCC (1 year: 6.7%; 3 years: 10.9%; 5 years: 29.7%), followed by those with high post-treatment AFP level and low post-treatment FIB4 index (5 years: 25%), and those with low post-treatment AFP level and high post-treatment FIB4 index (1 year: 3.7%; 3 years: 5.2%; 5 years: 10.6%). The risk was even lower for patients with low post-treatment AFP level and FIB4 index (1 year: 0%; 3 years: 0.4%; 5 years: 2.5%). None of the patients with FIB4 indexes consistently below 1.45 developed HCC.The combined use of post-treatment AFP level and FIB4 index was useful for risk stratification of HCV-infected patients with non-SVR status after IFN therapy. These data may help clinicians to identify patients who most urgently need DAA treatment.


Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/etiologia , Hepatite C Crônica/sangue , Hepatite C Crônica/complicações , Interferons/uso terapêutico , Neoplasias Hepáticas/etiologia , Resposta Viral Sustentada , Biomarcadores/sangue , Estudos de Coortes , Feminino , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos
6.
J Formos Med Assoc ; 116(7): 512-521, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27720344

RESUMO

BACKGROUND/PURPOSE: This study aimed to evaluate the outcomes of chronic hepatitis B patients with cirrhosis who received long-term nucleos(t)ide analog therapy. METHODS: A total of 546 consecutive cirrhotic patients treated with entecavir (n = 359), telbivudine (n = 104), or tenofovir (n = 83) for chronic hepatitis B were enrolled. The incidence of hepatocellular carcinoma (HCC) and overall survival were evaluated. RESULTS: During a median follow-up of 39 months, 56 (10.3%) patients developed HCC and 14 (2.6%) patients died. These outcomes were not associated with different antiviral use. Cox proportional hazard analysis showed that old age (≥60 years) [hazard ratio (HR), 1.74; p = 0.046], statin use (HR, 2.42; p = 0.017), low platelet count (<100,000/µL; HR, 2.00; p = 0.039), and variceal bleeding history (HR, 5.12; p < 0.001) were independent factors for HCC development. With regard to survival, Child-Pugh B/C (HR, 3.78; p = 0.039) and low platelet count (<105/µL; HR, 7.82; p = 0.049) were independent factors. The estimated glomerular filtration rate significantly increased in patients receiving telbivudine (p = 0.047), but decreased in those receiving tenofovir (p < 0.001) at Year 2. Tenofovir use (HR, 1.98; p = 0.005) was one of the independent factors associated with the progression of chronic kidney disease stage. CONCLUSION: Long-term nucleos(t)ide analog therapy does not guarantee against the HCC development and mortality in chronic hepatitis B-related cirrhotic patients. Careful HCC surveillance is necessary in patients with old age, statin use, low platelet count, and variceal bleeding history.


Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Cirrose Hepática/complicações , Adulto , Idoso , Carcinoma Hepatocelular/etiologia , Feminino , Guanina/análogos & derivados , Guanina/uso terapêutico , Hepatite B Crônica/complicações , Humanos , Cirrose Hepática/mortalidade , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Insuficiência Renal Crônica/etiologia , Telbivudina , Tenofovir/uso terapêutico , Timidina/análogos & derivados , Timidina/uso terapêutico , Resultado do Tratamento
7.
Sci Rep ; 6: 33816, 2016 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-27665934

RESUMO

It has been demonstrated that microRNA-122 (miR-122) plays key roles in the modulation of hepatitis B virus (HBV) replication. This study examined the role of miR-122 in patients with hepatitis C virus (HCV)-HBV dual infection with active hepatitis C who received pegylated interferon-α and ribavirin dual therapy. We enrolled 121 patients with HCV-HBV dual infection after dual therapy. Stored serum was collected before treatment. RT-PCR was used to analyze miR-122. HBsAg seroclearance was noted in 37 (30.1%) cases during a median follow-up period of 5.4 years. miR-122 was significantly lower in HBsAg seroclearance patients than in non-HBsAg seroclearance patients (P < 0.014). Multivariate analysis showed that miR-122 was an independent factor of HBsAg seroclearance (OR: 0.30, 95% CI: 0.09-0.98, P = 0.046). miR-122 was significantly higher in patients who were qHBsAg > 100 IU/mL versus ≤100 IU/mL (P < 0.001). We concluded that in patients with HBV-HCV dual infection with active hepatitis C, miR-122 was associated with HBsAg seroclearance after therapy and qHBsAg level before therapy, indicating that miR-122 plays key roles in modulating HBV replication.

8.
BMC Gastroenterol ; 16(1): 73, 2016 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-27457659

RESUMO

BACKGROUND: Toll-like receptors (TLRs) are effectors of the innate immune system that are able to recognize hepatitis C virus (HCV) and give rise to an immune response. Failure of interferon (IFN)-α-based treatment is related to host immunity. Therefore, we sought to study the clinical importance of TLRs in HCV genotype 1 patients who received pegylated IFN (PEG-IFN) plus ribavirin (RBV) therapy. METHODS: We enrolled 79 treatment-naïve patients with HCV genotype 1. Patients completed a 24- to 48-week course of response-guided therapy. Peripheral blood monocyte (PBMC) expression of mRNA for TLRs 2, 3, 4, 7, and 9 was quantified by real-time PCR before therapy. TLR mRNA expression is shown as a log ratio relative to GAPDH mRNA (log 2 (-(∆Ct))). RESULTS: Forty-five patients (57.0 %) showed a rapid virological response (RVR). Univariate analysis revealed that TLR 2, 3, 4, 7, and 9 were significantly lower in the RVR group than in the non-RVR group (P = 0.001, 0.014, < 0.001, 0.008, and 0.001, respectively). Multivariate analysis revealed that TLR 4 < -2 log (OR: 7.17, 95 % CI: 1.70-30.34, P = 0.007) was an independent predictor for RVR. In addition, levels of TLR 2, 3, 4, 7, and 9 were positively correlated with HCV viral load (P = 0.009, 0.013, < 0.001, 0.007, and 0.001, respectively). CONCLUSIONS: A low level of TLR 4 mRNA in PMBCs was correlated with RVR, which indicates that TLR4 may play a critical role in HCV recognition and activation of innate immunity. TLR expression levels were correlated with HCV viral load, indicating that TLR activation upon exposure to HCV may subsequently limit HCV replication.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Receptor 4 Toll-Like/sangue , Idoso , Feminino , Expressão Gênica , Genótipo , Hepatite C Crônica/genética , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , RNA Mensageiro/genética , Proteínas Recombinantes/uso terapêutico , Receptor 4 Toll-Like/genética , Carga Viral
9.
Liver Int ; 36(12): 1793-1799, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27254286

RESUMO

BACKGROUND & AIMS: Patients with chronic hepatitis C (CHC) after successful antiviral therapy remain at risk of hepatocellular carcinoma (HCC). This study was to determine whether liver stiffness measurement (LSM) was useful in HCC risk assessment and to develop a risk-score system for clinical use. METHODS: This retrospective study enrolled patients with CHC achieving sustained virological response (SVR) after interferon-based therapy with LSM at/after SVR determination. The demographics, clinical characteristics and HCC development were obtained from medical chart reviews. The diagnosis of HCC was based on recommended criteria. RESULTS: A total of 376 (M/F: 185/191, mean age: 54.1 years) patients, including 278 with pretreatment liver biopsy specimens, with a median follow-up period of 7.6 years were enrolled. Twenty-one patients developed HCC. The 5- and 10-year cumulative HCC incidences were 1.4% and 7.8%, respectively. Multivariate analysis showed advanced fibrosis/cirrhosis, diabetes and LSM were associated with HCC developments with odds ratio (OR) of 12.38, 2.80 and 1.01, respectively. For LSM in HCC prediction, the performance and cut-off were 0.783 and 12 kilopascal (kPa), respectively. For 278 patients with pretreatment biopsy, a risk-score system (score 0-4) combining advanced fibrosis/cirrhosis, diabetes and LSM >12 kPa was developed. With the low-risk group as a reference, patients in intermediate- (OR: 12.57) and high-risk (OR: 197.33) groups carried higher risk of HCC development. CONCLUSIONS: For patients with CHC achieving SVR, liver stiffness value at/after SVR determination was associated with HCC development independently. Patients with pretreatment advanced fibrosis/cirrhosis, diabetes and LSM >12 kPa after SVR were at high risk of HCC development.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Hepatite C Crônica/complicações , Cirrose Hepática/diagnóstico por imagem , Neoplasias Hepáticas/epidemiologia , Fígado/patologia , Resposta Viral Sustentada , Antivirais/uso terapêutico , Técnicas de Imagem por Elasticidade , Feminino , Hepatite C Crônica/tratamento farmacológico , Humanos , Incidência , Estimativa de Kaplan-Meier , Fígado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Curva ROC , Estudos Retrospectivos , Medição de Risco , Taiwan/epidemiologia
10.
Gastroenterology ; 151(3): 472-480.e1, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27269245

RESUMO

BACKGROUND & AIMS: The incidence of hepatocellular carcinoma (HCC) increases with age, but protective antibody responses decrease with time after infants are immunized against hepatitis B virus (HBV). We investigated whether immunization of infants against HBV prevents their developing HCC as adults. We also searched for strategies to maximize the cancer-preventive effects. METHODS: We collected data from 2 Taiwan HCC registry systems on 1509 patients (6-26 years old) diagnosed with HCC from 1983 through 2011. Data on history of HBV immunization and prenatal maternal levels of HBV antigens of all HCC patients born after July 1984 were retrieved from the HBV immunization data bank of the Taiwan Center for Disease Control. We collected data on birth cohort-specific populations (6-26 years old) of Taiwan using the National Household Registry System. Rates of HCC incidence per 10(5) person-years were derived by dividing the number of patients with HCC by the person-years of the general population. Relative risks (RR) for HCC were estimated by Poisson regression analysis in vaccinated vs unvaccinated birth cohorts. We stratified patients by age group to evaluate the association of birth cohorts and HCC risks. RESULTS: Of the 1509 patients with HCC, 1343 were born before, and 166 were born after, the HBV vaccination program began. HCC incidence per 10(5) person-years was 0.92 in the unvaccinated cohort and 0.23 in the vaccinated birth cohorts. The RRs for HCC in patients 6-9 years old, 10-14 years old, 15-19 years old, and 20-26 years old who were vaccinated vs unvaccinated were 0.26 (95% confidence interval [CI], 0.17-0.40), 0.34 (95% CI, 0.25-0.48), 0.37 (95% CI, 0.25-0.51), and 0.42 (95% CI, 0.32-0.56), respectively. The RR for HCC in 6- to 26-year-olds was lower in the later vs the earlier cohorts (born in 1992-2005 vs 1986-1992; P < .001 and 1986-1992 vs 1984-1986; P < .002). Transmission of HBV from highly infectious mothers and incomplete immunization were associated with development of HCC. CONCLUSIONS: Based on an analysis of 1509 patients with HCC in Taiwan, immunization of infants against HBV reduces their risk of developing HCC as children and young adults. Improving HBV vaccination strategies and overcoming risk factors could reduce the incidence of liver cancer.


Assuntos
Carcinoma Hepatocelular/prevenção & controle , Vacinas contra Hepatite B/administração & dosagem , Neoplasias Hepáticas/prevenção & controle , Vacinação/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/virologia , Criança , Feminino , Hepatite B/prevenção & controle , Humanos , Incidência , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/virologia , Masculino , Sistema de Registros , Análise de Regressão , Fatores de Risco , Taiwan/epidemiologia , Tempo , Vacinação/métodos , Adulto Jovem
11.
J Antimicrob Chemother ; 71(7): 1943-7, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27073265

RESUMO

BACKGROUND: Hepatitis C virus (HCV)-infected patients who achieve viral eradication may still develop hepatocellular carcinoma (HCC). Little is known about the impact of dynamic change of serum markers on HCC development. METHODS: We enrolled 1351 HCV-infected patients who achieved sustained virological response (SVR). Laboratory data were collected at least 1 year after IFN-based therapy and to the latest follow-up. Data on α-fetoprotein (AFP) were obtained >6 months prior to HCC development to exclude HCC-related AFP elevation. RESULTS: HCC developed in 49 patients. Risk factors for HCC in SVR patients were old age, liver cirrhosis, higher pre- and post-treatment AFP and high post-treatment AST-to-platelet ratio index (APRI). Patients with pre-AFP ≥15 ng/mL → post-AFP ≥15 ng/mL (at 1 year, 23.1%; 5 years, 42.3%) and pre-AFP <15 ng/mL → post-AFP ≥15 ng/mL (at 1 year, 25%; 5 years, 50%) had the highest risk of HCC development, followed by pre-AFP ≥15 ng/mL → post-AFP <15 ng/mL (at 1 year, 5.2%; 5 years, 7.6%) and pre-AFP <15 ng/mL → post-AFP ng/mL <15 ng/mL (at 1 year, 0.5%; 5 years, 0.9%) (P < 0.001). The pattern was similar for platelets and APRI (P < 0.001). SVR patients with pre-APRI ≥0.7 → post-APRI ≥0.7 had the highest risk of HCC development, followed by comparable risks among the other three groups. CONCLUSIONS: SVR patients with a persistently high AFP level (≥15 ng/mL) and a high APRI (≥0.7) before and after treatment had the highest incidence of HCC development. Patients with a reduction of AFP and APRI to the normal range after treatment had a markedly decreased risk of HCC. The risk was lowest for patients who kept persistently normal AFP and APRI before and after treatment.


Assuntos
Antivirais/uso terapêutico , Aspartato Aminotransferases/sangue , Carcinoma Hepatocelular/diagnóstico , Hepatite C Crônica/complicações , Contagem de Plaquetas , Resposta Viral Sustentada , alfa-Fetoproteínas/análise , Idoso , Carcinoma Hepatocelular/patologia , Estudos de Coortes , Feminino , Hepatite C Crônica/patologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico
12.
Medicine (Baltimore) ; 95(15): e3284, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27082566

RESUMO

Hepatocellular carcinoma (HCC) is the leading cancer death in Taiwan. Chronic viral hepatitis infections have long been considered as the most important risk factors for HCC in Taiwan. The previously published reports were either carried out by individual investigators with small patient numbers or by large endemic studies with limited viral marker data. Through collaboration with 5 medical centers across Taiwan, Taiwan liver cancer network (TLCN) was established in 2005. All participating centers followed a standard protocol to recruit liver cancer patients along with their biosamples and clinical data. In addition, detailed viral marker analysis for hepatitis B virus (HBV) and hepatitis C virus (HCV) were also performed. This study included 3843 HCC patients with available blood samples in TLCN (recruited from November 2005 to April 2011). There were 2153 (56.02%) patients associated with HBV (HBV group); 969 (25.21%) with HCV (HCV group); 310 (8.07%) with both HBV and HCV (HBV+HCV group); and 411 (10.69%) were negative for both HBV and HCV (non-B non-C group). Two hundred two of the 2463 HBV patients (8.20%) were HBsAg(-), but HBV DNA (+). The age, gender, cirrhosis, viral titers, and viral genotypes were all significantly different between the above 4 groups of patients. The median age of the HBV group was the youngest, and the cirrhotic rate was lowest in the non-B non-C group (only 25%). This is the largest detailed viral hepatitis marker study for HCC patients in the English literatures. Our study provided novel data on the interaction of HBV and HCV in the HCC patients and also confirmed that the HCC database of TLCN is highly representative for Taiwan and an important resource for HCC research.


Assuntos
Carcinoma Hepatocelular , Hepacivirus , Vírus da Hepatite B , Hepatite B , Hepatite C , Adulto , Fatores Etários , Idoso , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , DNA Viral/análise , Coleta de Dados , Feminino , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite B/diagnóstico , Hepatite B/epidemiologia , Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/análise , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite C/diagnóstico , Hepatite C/epidemiologia , Hepatite C/imunologia , Humanos , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Taiwan/epidemiologia
13.
PLoS One ; 11(3): e0142378, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26968010

RESUMO

BACKGROUND AND AIMS: Patients with chronic hepatitic C (HCV) infection and normal serum alanine transaminase (ALT) levels were considered to have mild disease. In Taiwan, these patients were not suggested for interferon (IFN) based therapies. The aim of study is to compare therapeutic outcomes between HCV patients with normal and elevated ALT levels. METHODS: We conducted a retrospective study on 3241 HCV patients treated by IFN based therapies. Patients with normal ALT levels were classified as group A (n = 186) while those with elevated ALT levels were group B (n = 3055). RESULTS: At baseline, incidence of diabetes mellitus, low platelet counts and cirrhosis were significantly higher in group B patients. The sustained virologic response (SVR) rate was comparable between the 2 groups (65.3% vs. 65.3%, P = .993). But significantly higher incidence of HCC development after HCV treatment was observed in group B (7.4% vs. 3.2%, P = .032). No significant differences with respect to the outcome of liver decompensation, spontaneous bacterial peritonitis, and mortality were noted between 2 groups. Multivariate analysis showed younger age, female gender, non-HCV genotype 1, lower viral load, higher platelet counts and non-cirrhosis were favorable factors for achieving SVR, rather than ALT levels. Further analysis revealed older age, cirrhosis, lower platelet levels and non- peg-interferon treatment are risk factors of HCC development. CONCLUSIONS: HCV patients with normal ALT levels had similar response to antiviral therapy and low rate of HCC development after therapy. Antiviral therapies begun at early course of HCV infection may be beneficial to prevent disease progression.


Assuntos
Alanina Transaminase/sangue , Antivirais/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Idoso , Antivirais/uso terapêutico , Comorbidade , Feminino , Hepacivirus/genética , Hepatite C Crônica/enzimologia , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Taiwan , Resultado do Tratamento
14.
J Formos Med Assoc ; 115(4): 278-83, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26725771

RESUMO

BACKGROUND/PURPOSE: Recent studies have shown that serum vitamin D deficiency is a negative predictor of response to peginterferon plus ribavirin therapy for Caucasian patients with chronic hepatitis C (CHC). Whether vitamin D receptor (VDR) gene polymorphisms associate with antiviral response in Asian CHC patients remains unclear. METHODS: We recruited 139 Asian patients with CHC genotype-1 who achieved 80/80/80 adherence of response-guided peginterferon plus ribavirin therapy. BsmI rs1544410, ApaI rs7975232, and TaqI rs731236 were genotyped and related to clinical and virological features and to treatment outcome. RESULTS: Patients carrying bAt [CCA] haplotype (p=0.033), ApaI CC genotype (p = 0.033), and TaqI AA genotype (p = 0.037) had a higher HCV load as compared to those with other haplotypes, ApaI CA/AA genotype and TaqI AG genotype, respectively. A sustained virological response (SVR) was achieved in 74 (53%) of the patients. Polymorphisms in VDR gene did not correlate with rapid virological response and SVR achievement. Stepwise logistic regression analysis showed that rs12979860 CC type [odds ratio (OR): 5.56, p=0.007], platelet counts ≥ 15 × 10(10)/L (OR: 4.80, p=0.001), and rapid virological response achievement (OR: 8.36, p<0.001) were independent factors of SVR. CONCLUSION: Despite their associations with high hepatitis C virus load, VDR gene polymorphisms are not related to the response to peginterferon plus ribavirin therapy in Asian CHC patients.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Interferon-alfa/uso terapêutico , Receptores de Calcitriol/genética , Ribavirina/uso terapêutico , Feminino , Genótipo , Haplótipos , Hepacivirus , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Taiwan , Resultado do Tratamento , Carga Viral
15.
J Formos Med Assoc ; 115(6): 440-4, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26786212

RESUMO

BACKGROUND/PURPOSE: While new direct-acting antiviral therapies for hepatitis C virus (HCV) are the standard of care, interferon-α (IFN-α) remains a standard therapy in Taiwan based on its low cost and high response rate to IFN-α-based therapy. IFN-α exerts antiviral activity by inducing the expression of hundreds of genes that establish an antiviral state via Jak kinase (JAK)/signal transducers and activators of transcription (STAT) signaling. We quantified the transcript levels of JAK/STAT signaling genes in peripheral blood mononuclear cells of HCV genotype 1 patients and estimated the correlation between transcript levels and patient responses to IFN-α-based therapy. METHODS: A total of 100 HCV genotype 1 naïve patients were enrolled. All patients received response-guided therapy for 24-48 weeks with pegylated IFN-α and ribavirin. Peripheral blood mononuclear cells were collected before treatment. Twenty patients with sustained virological responses (SVR) and 20 patients without SVR were selected for a JAK/STAT signaling genes transcript analysis using multiplex reverse transcription-polymerase chain reaction. Transcripts that were upregulated or downregulated were further validated in 100 patients. RESULTS: Suppressor of cytokine signaling 1 (SOCS1) expression was upregulated in SVR patients compared with non-SVR patients (relative quantification = 2.14) based on a multiplex reverse transcription-polymerase chain reaction analysis. We further analyzed SOCS1 expression in 100 patients. We found that SOCS1 expression did not differ significantly between SVR and non-SVR patients. CONCLUSION: Peripheral blood SOCS1 expression before treatment was not associated with SVR in HCV genotype 1 patients treated with pegylated IFN-α and ribavirin.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Ribavirina/uso terapêutico , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Adulto , Idoso , Feminino , Hepacivirus/genética , Humanos , Janus Quinases/genética , Leucócitos Mononucleares/metabolismo , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina/genética , Taiwan , Regulação para Cima
16.
J Gastroenterol Hepatol ; 31(7): 1307-14, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26758501

RESUMO

BACKGROUND AND AIMS: This study compared the efficacy and safety of tenofovir disoproxil fumarate (TDF) up to 3 years of innucleos(t)ide analog (NA)-naïve and NA-experienced chronic hepatitis B (CHB) patients. METHODS: Tenofovir disoproxil fumarate-treated NA-naïve and NA-experienced CHB patients were retrospectively analyzed. RESULTS: After 3 years of TDF therapy, 97.7%, 71%, and 45.5% NA-naïve patients achieved a virological response, alanine aminotransferase normalization, and hepatitis B e antigen seroconversion, respectively. Compared with NA-naïve patients, NA-experienced patients without drug resistance and infected with lamivudine/telbivudine-resistant mutants showed similar results. In contrast, patients previously infected with adefovir-resistant mutants and with a suboptimal entecavir response showed significantly lower rates of virological response and hepatitis B e antigen loss/seroconverion than NA-naïve patients. Mean estimated glomerular filtration rate markedly reduced within 12 months of TDF therapy; however, it did not decrease significantly during 12-36 months of treatment. Diabetes mellitus was an independent predictor of a ≥ 0.5 mg/dL increase above baseline in serum creatinine level, and age, hypertension, diabetes mellitus, and baseline creatinine level were independent factors for > 20% decline in estimated glomerular filtration rate from baseline. Liver stiffness measurements improved significantly, but bone mineral density did not change significantly during treatment. Hepatocellular carcinoma incidence was low at 36 months. Age of > 60 years, cirrhosis, a low baseline platelet count and a high α-fetoprotein level at 12 months were significant predictors of hepatocellular carcinoma development. CONCLUSIONS: Tenofovir disoproxil fumarate is effective and safe for NA-naïve and NA-experienced CHB patients and should be used cautiously in patients with comorbidities because of a renal dysfunction risk.


Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Tenofovir/análogos & derivados , Tenofovir/uso terapêutico , Adulto , Carcinoma Hepatocelular/epidemiologia , Comorbidade , Diabetes Mellitus/epidemiologia , Feminino , Taxa de Filtração Glomerular , Humanos , Neoplasias Hepáticas/epidemiologia , Masculino , Pessoa de Meia-Idade , Nucleosídeos , Nucleotídeos , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
17.
Int J Cancer ; 138(3): 714-20, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26264553

RESUMO

Hepatocarcinogenesis is a multistep process that evolves from cirrhosis or dysplastic nodule (DN), and eventually leads to overt hepatocellular carcinoma (HCC). Differentiation between early HCC and DN is an important issue in the clinical setting. This study aims to investigate the potential of circulating microRNA (miRNA) levels in the diagnosis of early HCC. RNA was extracted from sera of 30 chronic hepatitis B patients with pathologically proven DN and 120 age- and sex-matched patients with early HCC. Paired samples were collected from ten patients with DN who developed overt HCC in the follow-up. A panel of ten cancer-associated miRNAs was analyzed by quantitative real-time reverse-transcription polymerase chain reaction. Serum levels of miR-16, miR-122, miR-221, let-7b and miR-15b were significantly lower in patients with DN than in the HCC group. When DN progressed to overt HCC, serum miR-122, miR-let-7b and miR-15b levels increased significantly (p = 0.046, 0.043 and 0.044, respectively). As a single marker, α-fetoprotein (AFP) and miR-122 as well as let-7b had the similar performance for differentiate HCC from DN. As limited to subjects with normal AFP, let-7b resulted in a sensitivity of 84.8% and a specificity of 50% in separating HCC and DN with a cutoff value of 3.5 (p = 0.001). In conclusion, miR-122 and let-7b, which are upregulated in the serum of early-HCC patients, can be useful markers for differentiating early HCC from DN in chronic hepatitis B patients.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/diagnóstico , Hepatite B Crônica/complicações , Neoplasias Hepáticas/diagnóstico , MicroRNAs/sangue , Lesões Pré-Cancerosas/diagnóstico , Idoso , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/genética , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , alfa-Fetoproteínas/análise
18.
Clin Gastroenterol Hepatol ; 13(11): 1984-92.e1, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26073492

RESUMO

BACKGROUND & AIMS: We investigated the rate of relapse of hepatitis B virus (HBV) infection after entecavir therapy for chronic hepatitis B and the association between level of hepatitis B surface antigen (HBsAg) and relapse. METHODS: In a retrospective study, we analyzed data from 252 patients with chronic HBV infection who were treated with entecavir and met the Asian Pacific Association for the Study of the Liver treatment stopping rules (mean time, 164 ± 45 weeks) from January 2007 through June 2011 in Taiwan. Eighty-three were hepatitis B e antigen (HBeAg)-positive, and 169 were HBeAg-negative. Patients had regular post-treatment follow-up examinations for at least 12 months. Virologic relapse was defined on the basis of serum HBV DNA >2000 IU/mL after entecavir therapy. Clinical relapse was defined as a level of alanine aminotransferase > 2-fold the upper limit of normal and HBV DNA > 2000 IU/mL. RESULTS: Two years after therapy ended, 42% of HBeAg-positive patients had a virologic relapse, and 37.6% had a clinical relapse; 3 years after therapy ended, these rates were 64.3% and 51.6% for HBeAg-negative patients, respectively. On the basis of Cox regression analysis, factors independently associated with virologic and clinical relapse included old age, HBV genotype C, and higher baseline levels of HBsAg for HBeAg-positive patients and old age and higher end-of-treatment levels of HBsAg for HBeAg-negative patients. In HBeAg-positive patients, risk of HBV relapse increased with age ≥ 40 years and HBsAg level ≥ 1000 IU/mL at baseline (P < .001). In HBeAg-negative patients, the combination of age (< 55 years) and HBsAg level (< 150 IU/mL) at the end of treatment was associated with a lower rate of virologic relapse (4.5% of HBeAg-negative patients had viral relapse at year 3). The decrease in level of HBsAg from month 12 of treatment until the end of treatment was greater in patients who did lose HBsAg after entecavir therapy compared with those who did not. CONCLUSIONS: The combination of age and level of HBsAg is associated with relapse of HBV infection after treatment with entecavir. HBsAg levels might be used to guide the timing of cessation of entecavir treatment in patients with chronic HBV infection.


Assuntos
Antirretrovirais/uso terapêutico , Guanina/análogos & derivados , Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/patologia , Adulto , Fatores Etários , Alanina Transaminase , DNA Viral/sangue , Feminino , Seguimentos , Guanina/uso terapêutico , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologia , Resultado do Tratamento
19.
Antimicrob Agents Chemother ; 59(6): 3168-73, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25779569

RESUMO

Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are effective antivirals recommended as first-line monotherapies for treatment of chronic hepatitis B (CHB) infection. This study aimed to compare the short-term efficacies of TDF and ETV in the treatment of CHB with severe acute exacerbation. From 2008 to 2013, 189 consecutive treatment-naive CHB patients receiving TDF (n = 41) or ETV (n = 148) for severe acute exacerbation were enrolled. The primary endpoint was overall mortality or receipt of liver transplantation by week 24. The baseline characteristics were comparable between these two groups. By week 24, 8 (19% [95% confidence interval {CI}, 7% to 32%]) patients in the TDF group and 26 (18% [95% CI, 11 to 24%]) patients in the ETV group died (n = 30) or received liver transplantation (n = 4) (P = 0.749). The two groups of patients developed similar rates of liver-related complications and achieved comparable biochemical and virological responses at week 24. Cox regression analysis showed that baseline viral DNA level (P = 0.002), hypertension (P = 0.002), model for end-stage liver disease (MELD) score (P = 0.01), platelet count (P = 0.005), early presence (within 4 weeks) of ascites (P = 0.005), hepatic encephalopathy (P = 0.002), and hepatorenal syndrome (P < 0.001) were independent factors for mortality or liver transplantation. Among the patients who survived by week 24, there was no difference between the two groups in the percentage of patients who had a serum creatinine increase of ≥0.5 mg/dl from baseline (6.7% [95% CI, 0% to 16%] versus 2.0% [95% CI, 0% to 4.8%] in the TDF and ETV groups, respectively; P = 0.231), whereas a significant reduction in the estimated glomerular filtration rate (eGFR) was found in the two groups (P = 0.001 for both). In conclusion, TDF and ETV produce a similar treatment response and clinical outcome in patients with severe acute exacerbation of CHB.


Assuntos
Antivirais/uso terapêutico , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/patologia , Tenofovir/uso terapêutico , Adulto , Creatinina/sangue , Feminino , Guanina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
20.
J Gastroenterol Hepatol ; 30(2): 358-63, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25088668

RESUMO

BACKGROUND AND AIM: Based on up-to-seven criteria and Child-Pugh score, four substages of Barcelona Clinic Liver Cancer (BCLC) intermediate hepatocellular carcinoma (HCC) were proposed. The purpose of this study was to validate and modify this proposal. METHODS: Between January 2002 and February 2011, newly diagnosed intermediate HCC patients underwent transarterial embolization (TAE) were enrolled. Patients were stratified into four (B1-B4) substages and followed up until death or end of 2012. Patients' survivals and discriminatory ability of substaging systems were compared. RESULTS: Five-hundred and eighty patients were enrolled. There were 56.6%, 33.8%, 7.4%, and 2.2% in substage B1, B2, B3, and B4. The 5-year survival rate was 21.4%, 13.9%, 7.4%, and 7.7% with median survival time of 2.4, 1.3, 0.5, and 0.8 years (P < 0.001). In addition to substage B1-B4, α-fetoprotein (AFP) level was an independent factor associated with survival in multivariate analysis. According to AFP < or > 200 ng/mL, B1 was classified into B1a and B1b, and B2 into B2a and B2b. There were no differences in survivals between B1b and B2a (P = 0.174), and B2b and B3 (P = 0.785). Patients were re-classified into modified (m)B1 (B1a), mB2 (B1b + B2a), mB3 (B2b + B3). The modified substages (mB1-mB3) showed a more desirable substaging system. CONCLUSIONS: For BCLC intermediate HCC patients, substages B1-B4 were useful in predicting survival after TAE. However, modified substaging system provided better prognostic prediction.


Assuntos
Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Estadiamento de Neoplasias/métodos , Idoso , Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/classificação , Carcinoma Hepatocelular/mortalidade , Embolização Terapêutica/métodos , Embolização Terapêutica/mortalidade , Feminino , Seguimentos , Previsões , Humanos , Neoplasias Hepáticas/classificação , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , alfa-Fetoproteínas/análise
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