RESUMO
BACKGROUND: Metabolic risk factors may impact the severity and outcome of alcoholic liver disease. The present study evaluated this effect in patients with alcohol-associated acute-on-chronic liver failure (ACLF). METHODOLOGY: One thousand two hundred and sixteen prospectively enrolled patients with ACLF (males 98%, mean age 42.5 ± 9.4 years, mean CTP, MELD and AARC scores of 12 ± 1.4, 29.7 ± 7 and 9.8 ± 2 respectively) from the Asian Pacific Association for the Study of the Liver (APASL) ACLF Research Consortium (AARC) database were analysed retrospectively. Patients with or without metabolic risk factors were compared for severity (CTP, MELD, AARC scores) and day 30 and 90 mortality. Information on overweight/obesity, type 2 diabetes mellitus (T2DM), hypertension and dyslipidaemia were available in 1028 (85%), 1019 (84%), 1017 (84%) and 965 (79%) patients respectively. RESULTS: Overall, 392 (32%) patients died at day 30 and 528 (43%) at day 90. Overweight/obesity, T2DM, hypertension and dyslipidaemia were present in 154 (15%), 142 (14%), 66 (7%) and 141 (15%) patients, respectively, with no risk factors in 809 (67%) patients. Patients with overweight/obesity had higher MELD scores (30.6 ± 7.1 vs 29.2 ± 6.9, P = .007) and those with dyslipidaemia had higher AARC scores (10.4 ± 1.2 vs 9.8 ± 2, P = .014). Overweight/obesity was associated with increased day 30 mortality (HR 1.54, 95% CI 1.06-2.24, P = .023). None of other metabolic risk factors, alone or in combination, had any impact on disease severity or mortality. On multivariate analysis, overweight or obesity was significantly associated with 30-day mortality (aHR 1.91, 95% CI 1.41-2.59, P < .001), independent of age, CTP, MELD and AARC scores. CONCLUSION: Overweight/obesity and dyslipidaemia increase the severity of alcohol-associated ACLF, and the former also increases the short-term mortality in these patients.
Assuntos
Insuficiência Hepática Crônica Agudizada , Diabetes Mellitus Tipo 2 , Insuficiência Hepática Crônica Agudizada/epidemiologia , Insuficiência Hepática Crônica Agudizada/etiologia , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de RiscoRESUMO
UNLABELLED: The role of CD4(+) cytotoxic T cells (CTLs) in hepatocellular carcinoma (HCC) remains obscure. This study characterized CD4(+) CTLs in HCC patients and further elucidated the associations between CD4(+) CTLs and HCC disease progression. In all, 547 HCC patients, 44 chronic hepatitis B (CHB) patients, 86 liver cirrhosis (LC) patients, and 88 healthy individuals were enrolled in the study. CD4(+) CTLs were defined by flow cytometry, immunohistochemistry, and lytic granule exocytosis assays. A multivariate analysis of prognostic factors for overall survival was performed using the Cox proportional hazards model. Circulating and liver-infiltrating CD4(+) CTLs were found to be significantly increased in HCC patients during early stage disease, but decreased in progressive stages of HCC. This loss of CD4(+) CTLs was significantly correlated with high mortality rates and reduced survival time of HCC patients. In addition, the proliferation, degranulation, and production of granzyme A, granzyme B, and perforin of CD4(+) CTLs were inhibited by the increased forkhead/winged helix transcription factor (FoxP3(+) ) regulatory T cells in these HCC patients. Further analysis showed that both circulating and tumor-infiltrating CD4(+) CTLs were independent predictors of disease-free survival and overall survival after the resection of the HCC. CONCLUSION: The progressive deficit in CD4(+) CTLs induced by increased FoxP3(+) regulatory T cells was correlated with poor survival and high recurrence rates in HCC patients. These data suggest that CD4(+) CTLs may represent both a potential prognostic marker and a therapeutic target for the treatment of HCC.
Assuntos
Linfócitos T CD4-Positivos/patologia , Carcinoma Hepatocelular/patologia , Fatores de Transcrição Forkhead/metabolismo , Hepatite B Crônica/patologia , Neoplasias Hepáticas/patologia , Linfócitos T Citotóxicos/patologia , Adulto , Carcinoma Hepatocelular/mortalidade , Progressão da Doença , Intervalo Livre de Doença , Feminino , Granzimas/biossíntese , Hepatite B Crônica/complicações , Humanos , Fígado/patologia , Neoplasias Hepáticas/mortalidade , Linfócitos do Interstício Tumoral/fisiologia , Masculino , Pessoa de Meia-Idade , Perforina , Proteínas Citotóxicas Formadoras de Poros/biossíntese , Prognóstico , Recidiva , Linfócitos T Reguladores/metabolismoRESUMO
Decompensated liver cirrhosis (LC), a life-threatening complication of chronic liver disease, is one of the major indications for liver transplantation. Recently, mesenchymal stem cell (MSC) transfusion has been shown to lead to the regression of liver fibrosis in mice and humans. This study examined the safety and efficacy of umbilical cord-derived MSC (UC-MSC) in patients with decompensated LC. A total of 45 chronic hepatitis B patients with decompensated LC, including 30 patients receiving UC-MSC transfusion, and 15 patients receiving saline as the control, were recruited; clinical parameters were detected during a 1-year follow-up period. No significant side-effects and complications were observed in either group. There was a significant reduction in the volume of ascites in patients treated with UC-MSC transfusion compared with controls (P < 0.05). UC-MSC therapy also significantly improved liver function, as indicated by the increase of serum albumin levels, decrease in total serum bilirubin levels, and decrease in the sodium model for end-stage liver disease scores. UC-MSC transfusion is clinically safe and could improve liver function and reduce ascites in patients with decompensated LC. UC-MSC transfusion, therefore, might present a novel therapeutic approach for patients with decompensated LC.
Assuntos
Ascite/cirurgia , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Hepatite B Crônica/complicações , Cirrose Hepática/cirurgia , Fígado/metabolismo , Transplante de Células-Tronco Mesenquimais , Adulto , Ascite/metabolismo , Ascite/patologia , Ascite/fisiopatologia , Ascite/virologia , Bilirrubina/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Células Cultivadas , China , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Feminino , Hepatite B Crônica/diagnóstico , Humanos , Estimativa de Kaplan-Meier , Fígado/patologia , Fígado/fisiopatologia , Fígado/virologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática/fisiopatologia , Cirrose Hepática/virologia , Testes de Função Hepática , Masculino , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Albumina Sérica/metabolismo , Fatores de Tempo , Resultado do Tratamento , Carga ViralRESUMO
UNLABELLED: Although threshold levels for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) titers have recently been proposed to guide therapy for chronic hepatitis B (CHB), their relationship to circulating hepatitis B virus (HBV) DNA and intrahepatic HBV replicative intermediates, and the significance of emerging viral variants, remains unclear. We therefore tested the hypothesis that HBsAg and HBeAg titers may vary independently of viral replication in vivo. In all, 149 treatment-naïve CHB patients were recruited (HBeAg-positive, n = 71; HBeAg-negative, n = 78). Quantification of HBeAg and HBsAg was performed by enzyme immunoassay. Virological characterization included serum HBV DNA load, HBV genotype, basal core promoter (BCP)/precore (PC) sequence, and, in a subset (n = 44), measurement of intrahepatic covalently closed circular DNA (cccDNA) and total HBV DNA, as well as quantitative immunohistochemical (IHC) staining for HBsAg. In HBeAg-positive CHB, HBsAg was positively correlated with serum HBV DNA and intrahepatic cccDNA and total HBV DNA (r = 0.69, 0.71, 0.76, P < 0.01). HBeAg correlated with serum HBV DNA (r = 0.60, P < 0.0001), although emerging BCP/PC variants reduced HBeAg titer independent of viral replication. In HBeAg-negative CHB, HBsAg correlated poorly with serum HBV DNA (r = 0.28, P = 0.01) and did not correlate with intrahepatic cccDNA nor total HBV DNA. Quantitative IHC for hepatocyte HBsAg confirmed a relationship with viral replication only in HBeAg-positive patients. CONCLUSION: The correlation between quantitative HBsAg titer and serum and intrahepatic markers of HBV replication differs between patients with HBeAg-positive and HBeAg-negative CHB. HBeAg titers may fall independent of viral replication as HBeAg-defective variants emerge prior to HBeAg seroconversion. These findings provide new insights into viral pathogenesis and have practical implications for the use of quantitative serology as a clinical biomarker.
Assuntos
Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/virologia , Carga Viral , Replicação Viral , Adulto , Biomarcadores/sangue , Feminino , Hepatite B Crônica/imunologia , Humanos , Imuno-Histoquímica , Fígado/virologia , Masculino , Pessoa de Meia-IdadeRESUMO
Two patients with idiopathic multitudinous fundic gland polyposis, a hitherto undescribed condition, were reported. They presented incidentally with a multitude of fundic gland polyps, 52 and 147, without a family history of polyposis, and these polyps were not attributable to the chronic use of proton pump inhibitors. All polyps were removed by hot-biopsy polypectomy, and each was individually subjected to pathological examination, which showed no evidence of dysplasia. When confronted with gastric polyps of clinically undetermined origin, endoscopists would, to exclude dysplasia, usually resect all if they are few and sample some and survey the others periodically if they are numerous. The condition reported presents a management dilemma: Because the number of the polyps is such that they are manageable by total polypectomy, should this be carried out, despite the labor intensiveness involved, to exclude dysplasia, and are the polyps a variant of syndromic polyposis and therefore carry a malignant potential and inform the need for periodic surveillance and to investigate the patient's kindred? The frequency of this condition and whether it is truly not associated with dysplasia require further studies.
RESUMO
BACKGROUND & AIMS: Patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B treated with peginterferon alpha-2a with or without lamivudine achieve significantly higher 6-month posttreatment rates of response compared with those treated with lamivudine alone. The durability of Assuntos
Vírus da Hepatite B/efeitos dos fármacos
, Hepatite B Crônica/tratamento farmacológico
, Interferon-alfa/administração & dosagem
, Lamivudina/administração & dosagem
, Polietilenoglicóis/administração & dosagem
, Adulto
, Estudos Transversais
, Relação Dose-Resposta a Droga
, Esquema de Medicação
, Quimioterapia Combinada
, Educação Médica Continuada
, Feminino
, Seguimentos
, Antígenos E da Hepatite B/imunologia
, Hepatite B Crônica/diagnóstico
, Humanos
, Interferon alfa-2
, Testes de Função Hepática
, Modelos Logísticos
, Masculino
, Análise Multivariada
, Valor Preditivo dos Testes
, Probabilidade
, Proteínas Recombinantes
, Medição de Risco
, Índice de Gravidade de Doença
, Fatores de Tempo
, Resultado do Tratamento
RESUMO
BACKGROUND & AIMS: Therapy with pegylated interferon (PEG-IFN)-alfa results in sustained response in a minority of patients with chronic hepatitis B virus (HBV) infection and has considerable side effects. We analyzed data from the 2 largest global trials of hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B to determine which are most likely to respond to PEG-IFN-alfa therapy. METHODS: The study included 542 patients treated with PEG-IFN-alfa-2a (180 microg/wk, 48 wk) and 266 patients treated with PEG-IFN-alfa-2b (100 microg/wk, 52 wk). Eighty-seven patients were excluded, leaving 721 patients for analysis. A sustained response was defined as HBeAg loss and HBV-DNA level less than 2.0 x 10(3) IU/mL 6 months after treatment. Logistic regression analysis was used to identify predictors of sustained response and a multivariable model was constructed. RESULTS: HBV genotype, high levels of alanine aminotransferase (ALT; >or=2 x upper limit of normal), low levels of HBV DNA (<2.0 x 10(8) IU/mL), female sex, older age, and absence of previous IFN therapy predicted a sustained response. Genotype A patients with high ALT and/or low HBV-DNA levels had a high predicted probability (>30%) of a sustained response. The strongest predictors of response were a high level of ALT in genotype B patients and a low level of HBV DNA in genotype C patients. Genotype D patients had a low chance of sustained response, irrespective of ALT or HBV-DNA levels. CONCLUSIONS: The best candidates for a sustained response to PEG-IFN-alfa are genotype A patients with high levels of ALT or low levels of HBV DNA, and genotypes B and C patients who have both high levels of ALT and low HBV DNA. Genotype D patients have a low chance of sustained response.
Assuntos
Antivirais/uso terapêutico , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/imunologia , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adulto , Alanina Transaminase/sangue , Biomarcadores/sangue , DNA Viral/sangue , Feminino , Genótipo , Vírus da Hepatite B/genética , Hepatite B Crônica/diagnóstico , Humanos , Interferon alfa-2 , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Nomogramas , Razão de Chances , Seleção de Pacientes , Valor Preditivo dos Testes , Proteínas Recombinantes , Fatores de Tempo , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
UNLABELLED: We investigated the relationship between hepatitis B virus surface antigen (HBsAg) serum level decline and posttreatment response in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B from a large multinational study of pegylated interferon alfa-2a (peginterferon alfa-2a), with or without lamivudine, versus lamivudine alone. Serum HBsAg was quantified using the Architect assay (Abbott Diagnostics) at pretreatment, end of treatment (week 48), and 6 months after the end of treatment (week 72) in sera from 386 of the 537 patients who participated in the multinational study (peginterferon alfa-2a, 127; peginterferon alfa-2a plus lamivudine, 137; lamivudine monotherapy, 122). Pretreatment HBsAg levels varied according to genotype, with the highest levels present in patients infected with genotypes A (median, 4.11 log(10) IU/mL) and D (median, 3.85 log(10) IU/mL). Significant on-treatment decline in HBsAg was observed during treatment with peginterferon alfa-2a (alone or combined with lamivudine; mean decline at week 48, -0.71 and -0.67 log(10) IU/mL, respectively, P < 0.001), but not during treatment with lamivudine alone (-0.02 log(10) IU/mL). Significantly more patients treated with peginterferon alfa-2a (21%) or peginterferon alfa-2a plus lamivudine (17%) achieved HBsAg levels <100 IU/mL at the end of treatment compared with lamivudine (1%) (both P < 0.001 versus lamivudine). End-of-treatment HBsAg level correlated strongly with HBV DNA suppression to
Assuntos
Antivirais/uso terapêutico , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Lamivudina/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adulto , DNA Viral/sangue , Quimioterapia Combinada , Feminino , Hepatite B Crônica/imunologia , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes , Estudos Retrospectivos , Resultado do TratamentoRESUMO
HBeAg seroconversion, in association with undetectable levels of hepatitis B virus DNA as determined by polymerase chain reaction, is an important goal in the treatment of patients with HBeAg-positive chronic hepatitis B (CHB). Achievement of sustained HBeAg seroconversion at an early age (<40 years) is associated with a reduced incidence of hepatic complications, increased rates of HBsAg loss and seroconversion and improved survival rates, whether the seroconversion is spontaneous or treatment induced. Patients with HBeAg-positive CHB who achieve sustained HBeAg seroconversion and complete 6-12 months of consolidation therapy are eligible for stopping therapy. In randomized clinical studies involving patients with HBeAg-positive CHB, treatment with pegylated interferon (PegIFN)-alpha is associated with higher and more durable HBeAg seroconversion rates than are lamivudine and adefovir. More recently, newer generation oral nucleos(t)ide analogs (NAs) have become available. These include entecavir, telbivudine and tenofovir, and they demonstrate superior antiviral potency and efficacy. This review examines the importance of HBeAg seroconversion as an end point for therapy in the treatment of patients with HBeAg-positive CHB, and examines the rates and durability of HBeAg seroconversion with PegIFN and oral NA therapy. The mechanisms for enhanced HBeAg seroconversion rates with new-generation NAs are also discussed.
Assuntos
Antivirais/uso terapêutico , Antígenos E da Hepatite B/imunologia , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/imunologia , Adenina/análogos & derivados , Adenina/uso terapêutico , Adjuvantes Imunológicos/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Farmacorresistência Viral , Feminino , Seguimentos , Hepatite B Crônica/diagnóstico , Humanos , Lamivudina/uso terapêutico , Masculino , Organofosfonatos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Testes Sorológicos/métodos , Índice de Gravidade de Doença , Tenofovir , Resultado do TratamentoRESUMO
BACKGROUND: Replication of hepatitis B virus (HBV) is the primary driver of disease progression and clinical outcomes in patients with chronic hepatitis B (CHB), but other factors, such as hepatitis B e antigen (HBeAg) status, also influence disease course. The importance of HBeAg seroconversion is underscored by current CHB treatment guidelines that recommend limiting the duration of antiviral therapy in HBeAg-positive patients who achieve seroconversion. AIMS: A 2-day meeting of leading hepatologists with extensive experience managing patients with CHB in the Asia-Pacific region was held with the overall goals of reviewing and evaluating (1) available data on the relationship between HBeAg seroconversion and clinical outcomes for patients with HBeAg-positive CHB, and (2) the ways in which seroconversion should influence patient management. CONCLUSIONS: It was agreed that HBeAg seroconversion is an important serologic end point for patients with CHB and that achieving this goal should be an important consideration in treatment selection. Patients with HBeAg-positive CHB should consider pegylated interferon if they are aged < 40 years (especially women), have lower HBV DNA levels, can afford this treatment, and have a lifestyle that would support adherence to injection therapy. Alternatively, nucleos(t)ide analogs are recommended in patients with alanine aminotransferase levels ≥ 2 × the upper limit of normal, HBV DNA levels < 9 log(10) IU/ml, and compensated CHB. Entecavir, telbivudine, and tenofovir may be used as first-line therapy; they can be administered as a finite therapeutic course in HBeAg-positive patients who seroconvert. Telbivudine and tenofovir should be considered in women of child-bearing potential.
Assuntos
Anticorpos Anti-Hepatite B/sangue , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/crescimento & desenvolvimento , Hepatite B Crônica/imunologia , Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , HumanosRESUMO
BACKGROUND/AIMS: Clevudine is a pyrimidine analogue with potent activity against hepatitis B virus (HBV) replication in vitro. In a previous pivotal phase III clinical study, 24 weeks treatment with clevudine 30 mg has been shown to profoundly suppress HBV replication and normalize serum alanine aminotransferase level. METHODS: In this study, we compare the efficacy and safety of clevudine (30 mg daily) versus lamivudine (100 mg daily) for 48 weeks in treatment-naive chronic hepatitis B e antigen (HBeAg) positive patients. RESULTS: Ninety-two chronic HBeAg positive patients were randomized to receive clevudine 30 mg daily or lamivudine 100 mg daily in a 1:1 ratio. The clevudine group demonstrated greater viral suppression at week 48 when compared with the lamivudine group (median reduction: 4.27 vs. 3.17 log(10) copies/ml at week 48, p<0.0001). At week 48, serum HBV DNA level was below 300 copies/mL in 73% and 40% in the clevudine and lamivudine groups, respectively (p=0.001). HBeAg seroconversion occurred in 18% of patients in the clevudine group versus 12% in the lamivudine group at week 48. Lamivudine-resistant mutations were detected in 11 (24%) patients in the lamivudine group, who showed viral rebound during lamivudine therapy but no resistance was found in the clevudine group during 48-week treatment period. CONCLUSIONS: A 48-week dosing with clevudine 30 mg daily was superior to lamivudine 100 mg daily in suppressing HBV replication, with no emergence of viral breakthrough in patients with HBeAg positive chronic hepatits B.
Assuntos
Antivirais/administração & dosagem , Arabinofuranosiluracila/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Lamivudina/administração & dosagem , Adulto , Alanina Transaminase/sangue , Arabinofuranosiluracila/administração & dosagem , DNA Viral/sangue , Método Duplo-Cego , Esquema de Medicação , Farmacorresistência Viral , Feminino , Genótipo , Antígenos E da Hepatite B/sangue , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND/AIMS: Programmed death-1 (PD-1) upregulation can impair virus-specific CD8 T-cell responses during chronic viral infection. Whether and how PD-1 affects virus-specific memory CD8 T cells in humans with acute viral infection, however, remains largely undefined. METHODS: The association between PD-1 expression and HBV-specific memory CD8 T-cell responses were longitudinally analyzed in eighteen patients with acute hepatitis B virus (HBV) infection, including ten patients with human leucocyte antigen (HLA)-A201 and eight with other HLA-A2 subtypes. RESULTS: At clinical onset, PD-1 was significantly up-regulated and subsequently led to the functional suppression of HBV-specific effector CD8 T cells, as blocking PD-1/PD-L1 interactions in vitro enhanced their proliferation and IFN-gamma production. Following disease resolution, HBV-specific effector CD8 T cells developed into memory T cells. During this period, the dynamic PD-1 decrease was numerically correlated with the reduction of HBV-specific CD8 T-cell frequency, phenotypically with an acquisition of CCR7, CD45RA and CD127 expressions, and functionally with the increase in proliferation and IFN-gamma production of the memory T cells. CONCLUSIONS: PD-1-mediated inhibitory signaling not only attenuates HBV-specific CD8 T-cell effector function during the acute phase of infection but also correlates with the development of HBV-specific memory CD8 T cells following disease resolution.
Assuntos
Antígenos CD/genética , Antígenos CD/imunologia , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Vírus da Hepatite B/imunologia , Hepatite B/imunologia , Doença Aguda , Adulto , Antígenos Virais/genética , Linfócitos T CD8-Positivos/patologia , Proliferação de Células , Epitopos/genética , Feminino , Expressão Gênica , Antígenos HLA-A/genética , Antígeno HLA-A2/genética , Hepatite B/virologia , Vírus da Hepatite B/genética , Humanos , Memória Imunológica , Técnicas In Vitro , Interferon gama/biossíntese , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Receptor de Morte Celular Programada 1 , Adulto JovemRESUMO
Adoptive immune transfer plays an important role in clearance of hepatitis B virus (HBV) in chronic hepatitis B (CHB) patients. However, it is unclear whether cytokine-induced killer (CIK) cells could suppress HBV replication in CHB patients, especially if drug resistance develops. In this study, functional CIK cells were efficiently generated from 21 CHB patients and were transfused in an autologous manner. We found that CIK cells from the CHB patients displayed substantial proliferation and function. Administration of the CIK cells closely correlated with the decrease in the serum HBV load and improvement in liver function in some patients. The virological response rate in patients with baseline serum alanine aminotransferase (ALT) levels of >40 U/L was higher than that in patients with baseline serum ALT levels of < or = 40 U/L. Moreover, patients who had HBeAg loss or showed seroconversion generally had baseline serum ALT levels of >40 U/L. No serious side effects were observed. This protocol represents an alternative immune therapeutic strategy for the disease.
Assuntos
Transferência Adotiva/métodos , Células Matadoras Induzidas por Citocinas/imunologia , Hepatite B Crônica/imunologia , Replicação Viral/imunologia , Adulto , Idoso , Células Matadoras Induzidas por Citocinas/citologia , Células Matadoras Induzidas por Citocinas/transplante , Feminino , Citometria de Fluxo , Vírus da Hepatite B/imunologia , Hepatite B Crônica/terapia , Hepatite B Crônica/virologia , Humanos , Interferon gama/imunologia , Masculino , Pessoa de Meia-Idade , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND & AIMS: Recent studies have shown that programmed death 1 (PD-1) expression can impair virus-specific CD8 T-cell responses during chronic viral infection, including hepatitis B virus (HBV). This study aimed to characterize the PD-1 expression during acute hepatitis B (AHB) and further address whether and how the PD-1-mediated pathway balances antiviral immunity versus immunopathology, possibly contributing to disease progression. METHODS: Peripheral and intrahepatic PD-1 expression was investigated longitudinally in 23 human HLA-A2-positive patients with acute hepatitis B. Four patients with HBV-related acute liver failure, 13 patients with chronic hepatitis B, and 9 healthy individuals were enrolled as controls. Flow cytometric, immunohistochemical, and immunofunctional assays were performed to analyze the impact of PD-1 expression. RESULTS: PD-1 expression was significantly up-regulated on HBV-specific CD8 T cells in the early phase of acute HBV infection, and successful viral clearance correlated with a subsequent decrease in PD-1 expression. Blocking the PD-1-mediated pathway in vitro enhanced HBV-specific CD8 T-cell proliferation and inflammatory cytokine production, while reducing interleukin-10 production and apoptosis, confirming the essential role of PD-1 in tempering the T-cell response during the acute phase of infection. In contrast, delayed PD-1 expression on HBV-specific CD8 T cells was associated with acute liver failure. CONCLUSIONS: PD-1 up-regulation may efficiently mitigate pathogenic CD8 T-cell responses and liver damage, correlating with disease progression of acute HBV infection. This study therefore shows how this negative signaling pathway functions in such early HBV infection, which will be important for better clinical management, prognosis, and new HBV treatments.
Assuntos
Antígenos CD/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Linfócitos T CD8-Positivos/virologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B/imunologia , Falência Hepática/virologia , Fígado/virologia , Doença Aguda , Adulto , Antígenos CD/sangue , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/sangue , Antígeno B7-H1 , Biomarcadores/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Estudos de Casos e Controles , Proliferação de Células , Citocinas/metabolismo , Progressão da Doença , Feminino , Citometria de Fluxo , Antígeno HLA-A2/metabolismo , Hepatite B/complicações , Hepatite B/patologia , Hepatite B/terapia , Hepatite B Crônica/complicações , Hepatite B Crônica/patologia , Hepatite B Crônica/terapia , Humanos , Imuno-Histoquímica , Fígado/imunologia , Fígado/patologia , Falência Hepática/imunologia , Falência Hepática/patologia , Estudos Longitudinais , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1 , Transdução de Sinais/imunologia , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima , Carga ViralRESUMO
No data on antiviral response of HBV genotypes E-H are available so far although these HBV genotypes contribute significantly to the global HBV burden. Of 49 patients with HBV genotypes E-H, 23 received interferon (IFN)-alpha, 12 nucleos(t)ide analogues and 14 patients were untreated. HBV genotype was determined by direct sequencing of the HBV S gene. Sustained virological response in IFN-treated patients was defined as normalization of ALT and decrease of HBV-DNA <4,000 IU/ml 6 months after treatment. Virological response with nucleos(t)ide analogues was assumed in patients with a HBV-DNA <200 IU/ml after 48 weeks of treatment. HBV genotype E was found in 61.2% (n = 30), HBV genotype F in 8.2% (n = 4), HBV genotype H in 10.2% (n = 5) of patients. Among patients with HBV genotype G (20.4%; n = 10) there were four HBV genotype G/A and three HBV genotype G/C co-infections. Patients had Caucasian (43%), African (55%), or Asian (2%) background. End of treatment response was 70% (16/23) and sustained virological response was 35% (8/23) for patients treated with IFN-alpha. Sustained virological response was 36% for HBV genotype E (n = 5/14), 50% for HBV genotype F or H (n = 2/4), and 20% for HBV genotype G (n = 1/5). Virus suppression at week 48 was achieved in 67% of patients treated with nucleos(t)ide analogues. According to the present preliminary data HBV genotypes E, F, and H appear to be sensitive to IFN-alpha. Lower rates of response to IFN-alpha in patients with HBV genotype G might be related to the frequent occurrence of double infection.
Assuntos
Antivirais/uso terapêutico , Vírus da Hepatite B/classificação , Vírus da Hepatite B/genética , Hepatite B/tratamento farmacológico , Adulto , Idoso , Alanina Transaminase , DNA Viral/sangue , Feminino , Genótipo , Hepatite B/virologia , Antígenos de Superfície da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Humanos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/uso terapêutico , Análise de Sequência de DNA , Resultado do Tratamento , Carga ViralRESUMO
UNLABELLED: The aims of this study were to evaluate the usefulness of quantitative hepatitis B e antigen (HBeAg) values for predicting HBeAg seroconversion in patients treated with peginterferon alfa-2a and to assess the dynamic changes in quantitative HBeAg during therapy, compared with conventional measures of serum hepatitis B virus DNA. Data were analyzed from a large, randomized, multinational phase III registration trial involving 271 HBV-infected HBeAg-positive patients who received peginterferon alfa-2a plus oral placebo for 48 weeks. HBeAg levels were measured serially during therapy using a microparticle enzyme immunoassay validated with in-house reference standards obtained from the Paul Ehrlich Institute (PEIU/mL). In patients who achieved HBeAg seroconversion, levels of HBeAg consistently decreased during treatment and remained at their lowest level during the 24 weeks of posttreatment follow-up. After 24 weeks of treatment, 4% of patients with the highest levels of HBeAg (>or=100 PEIU/mL) achieved HBeAg seroconversion, yielding a negative predictive value of 96%, which was greater than that obtained for levels of HBV DNA (86%). Late responders to peginterferon alfa-2a could also be differentiated from nonresponders by continued decrease in HBeAg values, which were not evident by changes in HBV DNA. CONCLUSION: These analyses suggest quantitative HBeAg is a useful adjunctive measurement for predicting HBeAg seroconversion in patients treated with peginterferon when considering both sensitivity and specificity compared with serum HBV DNA.
Assuntos
Antivirais/uso terapêutico , DNA Viral/sangue , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Biomarcadores/sangue , Monitoramento de Medicamentos/métodos , Hepatite B Crônica/sangue , Humanos , Interferon alfa-2 , Lamivudina/uso terapêutico , Valor Preditivo dos Testes , Proteínas Recombinantes , Resultado do TratamentoRESUMO
Worldwide, chronic hepatitis B virus infection is a major cause of end-stage liver disease and hepatocellular carcinoma. While the past two decades have brought major advances in the availability of treatments to help delay or prevent these outcomes, treatment of chronic hepatitis B remains a serious challenge. With the recent availability of potent new nucleot(s)ide such as entecavir, tenofovir and telbuvidine, I still use pegylated interferon (PEG-IFN)-alpha for the treatment of chronic HBeAg-positive patients. This is based on its relatively higher effectiveness in restoring the host immune control on viral replication, resulting in sustained diseases remission in a proportion of patients, a finite course of therapy and the absence of viral resistance. The two major hindrances to its wide application are its lack of effectiveness in a large proportion of patients and its side-effect profile. The former shortcoming can be circumvented to a certain extent with the use of response predictor models. Recently, based on long-term follow-up study, the better durability of sustained response further enhances the confidence in the use of PEG-IFN-alpha in chronic HBeAg-positive patients.
Assuntos
Antivirais/uso terapêutico , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Hepatite B Crônica/sangue , Humanos , Fatores Imunológicos/uso terapêutico , Interferon alfa-2 , Polietilenoglicóis , Proteínas RecombinantesRESUMO
Chronic hepatitis C virus (HCV) infection is common among patients with chronic kidney disease (CKD) and those on hemodialysis due to nosocomial infections and past blood transfusions. While a majority of HCV-infected patients with end-stage renal disease are asymptomatic, some may ultimately experience decompensated liver diseases and hepatocellular carcinoma. Administration of a combination of elbasvir/grazoprevir for 12 weeks leads to high sustained virologic response (SVR) rates in patients with HCV genotypes (GTs) 1a, 1b or 4 and stage 4 or 5 CKD. Furthermore, a combination of glecaprevir/pibrentasvir for 8-16 weeks also results in high SVR rates in patients with all HCV GTs and stage 4 or 5 CKD. However, these regimens are contraindicated in the presence of advanced decompensated cirrhosis. Although sofosbuvir and/or ribavirin are not generally recommended for HCV-infected patients with severe renal impairment, sofosbuvir-based regimens may be appropriate for those with mild renal impairment. To eliminate HCV worldwide, HCV-infected patients with renal impairment should be treated with interferon-free therapies.
Assuntos
Antivirais , Hepatite C Crônica , Falência Renal Crônica , Humanos , Ácidos Aminoisobutíricos , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Benzofuranos/uso terapêutico , Contraindicações de Medicamentos , Ciclopropanos , Combinação de Medicamentos , Genótipo , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Falência Renal Crônica/complicações , Lactamas Macrocíclicas , Leucina/análogos & derivados , Prolina/análogos & derivados , Pirrolidinas , Quinoxalinas/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Resposta Viral SustentadaRESUMO
In the direct-acting antiviral (DAA) era for hepatitis C virus (HCV) infection, sustained virological response (SVR) is very high, but close attention must be paid to the possible occurrence of hepatocellular carcinoma (HCC) and reactivation of hepatitis B virus (HBV) in patients with co-infection who achieved SVR in short term. HCC occurrence was more often observed in patients with previous HCC history. We found occurrence of HCC in 178 (29.6%) of 602 patients with previous HCC history (15.4 months mean follow-up post-DAA initiation) but, in contrast, in only 604 (1.3%) of 45,870 patients without previous HCC history (18.2 months mean follow-up). Thus, in these guidelines, we recommend the following: in patients with previous HCC history, surveillance at 4-month intervals for HCC by ultrasonography (US) and tumor markers should be performed. In patients without previous HCC history, surveillance at 6- to 12-month intervals for HCC including US is recommended until the long-term DAA treatment effects, especially for the resolution of liver fibrosis, are confirmed. This guideline also includes recommendations on how to follow-up patients who have been infected with both HCV and HBV. When HCV was eradicated in these HBsAg-positive patients or patients with previous HBV infection (anti-HBc and/or anti-HBs-positive), it was shown that HBV reactivation or HBV DNA reappearance was observed in 67 (41.4%) of 162 or 12 (0.9%) of 1317, respectively. For these co-infected patients, careful attention should be paid to HBV reactivation for 24 weeks post-treatment.
Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/virologia , Hepatite B/tratamento farmacológico , Hepatite C/tratamento farmacológico , Neoplasias Hepáticas/virologia , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/prevenção & controle , Coinfecção , Hepacivirus , Hepatite B/complicações , Vírus da Hepatite B , Hepatite C/complicações , Humanos , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/prevenção & controle , Resposta Viral Sustentada , Ativação ViralRESUMO
Early detection is a key step for effective intervention of hepatocellular carcinoma (HCC), the lack of sensitive and specific biomarkers is a major reason for the high rate of HCC-related mortality. This report described an integrated strategy by combining SELDI-ProteinChip, sophisticated algorithm analysis, acetonitrile (ACN) pre-treatment and two-dimensional electrophoresis (2DE)-peptide mass fingerprinting (PMF) techniques to identify serological markers for the prediction of HBV-related HCC. Proteomic profiling of three groups of serum specimens from HBV-related HCC (50 cases), HBV infection (45 cases), and normal subjects (30 cases) was conducted by using SELDI-ProteinChip system and the resulting different protein peaks were subjected to stepwise statistical analyses. Three most discriminatory peaks at 5890, 11615, and 11724 Da, respectively, were screened out from the statistical algorithm and a predictive model based on the three peaks was constructed and tested using the newly enrolled serum samples. 2DE was applied to separate and compare the serum samples that were pre-treated by ACN precipitation. The protein spots obviously intensified in HCC sera in the 2DE region of 12 kDa were identified by PMF to be serum SAA, which was validated by SELDI-TOF spectra of HCC sera after immunoprecipitation using anti-SAA antibody and by Western blot experiments. Given the fact that SAA is not a specific biomarker, further attempt is being made to identify the other two most discriminatory peaks to realize the possibility of using the predictive model for HCC surveillance and prediction.