RESUMEN
Evolutionary changes in the hepatitis B virus (HBV) genome could reflect its adaptation to host-induced selective pressure. Leveraging paired human exome and ultra-deep HBV genome-sequencing data from 567 affected individuals with chronic hepatitis B, we comprehensively searched for the signatures of this evolutionary process by conducting "genome-to-genome" association tests between all human genetic variants and viral mutations. We identified significant associations between an East Asian-specific missense variant in the gene encoding the HBV entry receptor NTCP (rs2296651, NTCP S267F) and mutations within the receptor-binding region of HBV preS1. Through in silico modeling and in vitro preS1-NTCP binding assays, we observed that the associated HBV mutations are in proximity to the NTCP variant when bound and together partially increase binding affinity to NTCP S267F. Furthermore, we identified significant associations between HLA-A variation and viral mutations in HLA-A-restricted T cell epitopes. We used in silico binding prediction tools to evaluate the impact of the associated HBV mutations on HLA presentation and observed that mutations that result in weaker binding affinities to their cognate HLA alleles were enriched. Overall, our results suggest the emergence of HBV escape mutations that might alter the interaction between HBV PreS1 and its cellular receptor NTCP during viral entry into hepatocytes and confirm the role of HLA class I restriction in inducing HBV epitope variations.
Asunto(s)
Virus de la Hepatitis B , Mutación , Transportadores de Anión Orgánico Sodio-Dependiente , Simportadores , Humanos , Virus de la Hepatitis B/genética , Transportadores de Anión Orgánico Sodio-Dependiente/genética , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Simportadores/genética , Simportadores/metabolismo , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Hepatitis B Crónica/virología , Hepatitis B Crónica/genética , Genoma Viral , Antígenos de Superficie de la Hepatitis B/genética , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Genómica/métodos , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismoRESUMEN
BACKGROUND: Chronic hepatitis B (CHB) is endemic to Asia and is a leading cause of liver-related morbidity. The prevalence of concomitant CHB and hepatic steatosis (HS) is increasing in Asia. Non-invasive tests (NITs) including FIB-4, NFS and APRI assess fibrosis in populations with a single aetiology, but not in subjects with concomitant CHB and HS. AIM: To explore the accuracy of NITs in predicting advanced fibrosis in patients with concomitant CHB and HS. METHODOLOGY: This multicentre study of CHB patients who underwent liver biopsy explored clinical characteristics of these subjects, stratified by presence of HS. Fibrosis scores from NITs were compared against histological fibrosis stage in CHB subjects with and without HS. RESULTS: 2262 subjects were enrolled, 74.5% were males, and the mean age was 39.5 years ±11.8 SD. 984 (44.4%) had HS, 824 (36.4%) had advanced fibrosis. In the CHB group, the AUROC for advanced fibrosis were 0.65 (95% CI 0.62-0.69) for FIB-4 and 0.63 (95% CI 0.60-0.66) for APRI. The specificities were 0.94 for FIB-4 greater than 3.25 and 0.81 for APRI greater than 1.5. In the CHBHS group, the AUROC for advanced fibrosis were 0.67 (95% CI 0.63-0.71) for FIB-4, 0.60 (95% CI 0.56-0.64) for APRI and 0.65 (95% CI 0.61-0.69) for NFS. The specificities were 0.95 for FIB-4 greater than 3.25, 0.88 for APRI greater than 1.5 and 0.99 for NFS greater than 0.675. CONCLUSION: The performance of NITs to exclude advanced fibrosis did not differ greatly regardless of HS. FIB-4 and NFS have the best negative predictive values of 0.80 and 0.78, respectively, to exclude advanced fibrosis in CHBHS subjects.
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Hígado Graso , Hepatitis B Crónica , Masculino , Humanos , Adulto , Femenino , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/epidemiología , Cirrosis Hepática/complicaciones , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/diagnóstico , Hepatitis B Crónica/patología , Hígado Graso/diagnóstico , Hígado Graso/epidemiología , Hígado Graso/complicaciones , Valor Predictivo de las Pruebas , Biopsia , Aspartato Aminotransferasas , Índice de Severidad de la Enfermedad , Biomarcadores , Curva ROCRESUMEN
BACKGROUND: Serum hepatitis B surface antigen (HBsAg) levels correlate with the duration of chronic hepatitis B virus (HBV) infection and may predict the extent of hepatic fibrosis. METHODS: We analyzed data from the SONIC-B database, which contains data from 8 global randomized trials and 2 large hepatology centers. Relationship between HBsAg levels and presence of significant fibrosis (Ishak 3-4) or cirrhosis (Ishak 5-6) were explored, and clinically relevant cutoffs were identified to rule out cirrhosis. RESULTS: The dataset included 2779 patients: 1866 hepatitis B e antigen (HBeAg)-positive; 322 with cirrhosis. Among HBeAg-positive patients, lower HBsAg levels were associated with higher rates of significant fibrosis (odds ratio [OR], 0.419; P < .001) and cirrhosis (OR, 0.435; P < .001). No relationship was observed among HBeAg-negative patients. Among HBeAg-positive patients, genotype-specific HBsAg cutoffs had excellent negative predictive values (>97%) and low misclassification rates (≤7.1%) and may therefore have utility in ruling out cirrhosis. Diagnostic performance of the HBsAg cutoffs was comparable among patients in whom cirrhosis could not be ruled out with fibrosis 4 (FIB-4). CONCLUSIONS: Hepatitis B virus genotype-specific HBsAg cutoffs may have utility in ruling out presence of cirrhosis in HBeAg-positive patients with genotypes B, C, and D and can be an adjunct to FIB-4 to reduce the need for further testing.
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Antígenos e de la Hepatitis B , Hepatitis B Crónica , Humanos , Hepatitis B Crónica/complicaciones , Antígenos de Superficie de la Hepatitis B , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/complicaciones , Virus de la Hepatitis B/genética , ADN ViralRESUMEN
BACKGROUND AND AIMS: The uptake of antiviral treatment for patients with chronic hepatitis B (CHB) has been suboptimal. We aimed to determine the secular trend of treatment uptake in the territory-wide CHB cohort in Hong Kong from 2000 to 2017 and the factors for no treatment despite fulfilling treatment criteria. METHODS: Chronic hepatitis B patients under public clinics and hospitals were identified through electronic medical records. The treatment indications were defined according to the Asian-Pacific guidelines published at the time of patients' first appearance in four periods: 2000-2004, 2005-2009, 2010-2013, and 2014-2017. RESULTS: There were 135 395 CHB patients were included; 1493/12472 (12.0%), 7416/43426 (17.1%), 10 129/46559 (21.8%), 8051/32 938 (24.4%) patients fulfilled treatment criteria in the four periods, respectively. The treatment uptake rate increased with time: 35.1%, 43.4%, 60.2%, and 68.6% respectively. High fibrosis indices (APRI, FIB-4, and Forns indices) appeared to be the main factors for treatment indication in non-cirrhotic patients, with over 90% fulfilling treatment criteria due to high fibrosis indices alone. Of those fulfilling treatment criteria by high fibrosis indices, less than 60% of patients (25.2%, 36.1%, 46.0%, and 58.9%, respectively) had antiviral treatment initiated. Normal platelet count (odds ratio 0.42, P < 0.001) was the independent factor associated with not initiating antiviral treatment in patients fulfilling treatment criteria. CONCLUSIONS: Treatment uptake rates have been increasing over time. Normal platelet count, which reflects less advanced liver disease, precludes patients from receiving antiviral treatment even if treatment indication is fulfilled. Hence, the importance to identify non-cirrhotic patients with significant liver fibrosis should be emphasized.
Asunto(s)
Antivirales , Hepatitis B Crónica , Aceptación de la Atención de Salud , Antivirales/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Hong Kong , Humanos , Aceptación de la Atención de Salud/estadística & datos numéricosRESUMEN
Achieving hepatitis B e antigen (HBeAg) seroconversion is a satisfactory endpoint during antiviral treatment for chronic hepatitis B (CHB). This study aimed to develop and validate a novel scoring system to predict HBeAg seroconversion during entecavir (ETV) treatment. A total of 526 patients with HBeAg-positive CHB treated with ETV for at least 1 year were randomly assigned to the training and validation cohorts. Baseline parameters including hepatitis B virus DNA, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), and alanine aminotransferase level were quantified. Patients who achieved HBeAg seroconversion were compared with those without HBeAg seroconversion. A prediction model was established to predict HBeAg seroconversion during ETV treatment. After a median follow up of 2.67 years, 93 (36.0%) and 87 (32.5%) patients in the training and validation cohorts developed HBeAg seroconversion. A prediction score composed of age, HBsAg and HBcAb quantification was derived. Areas under receiver operating characteristic curve at 5 years of this prediction score were 0.70 and 0.72 in the training and validation cohorts. By using the dual cutoff values of 0.28 and 0.58, the model was endowed with high sensitivity and specificity to exclude or identify patients developing HBeAg seroconversion (90.3% sensitivity and 90.2% specificity in the training cohort as well as 92.8% sensitivity and 84.4% specificity in the validation cohort, respectively). A novel prediction score that uses baseline clinical variables was developed and validated. The score accurately estimates the probabilities of developing HBeAg seroconversion at 5-years ETV therapy in patients with CHB.
Asunto(s)
Antivirales/uso terapéutico , Guanina/análogos & derivados , Anticuerpos contra la Hepatitis B/sangre , Antígenos e de la Hepatitis B/sangre , Hepatitis B Crónica/tratamiento farmacológico , Seroconversión , Adulto , Femenino , Guanina/uso terapéutico , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Curva ROC , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: The rates of hepatitis B surface antigen (HBsAg) seroclearance after stopping nucleos(t)ide analogues (NA) in European (19% in 2 years) and Asian (13% in 6 years) patients with chronic hepatitis B (CHB) vary dramatically. We evaluated the incidence of hepatitis flare and HBsAg seroclearance in hepatitis B e antigen (HBeAg)-negative Chinese CHB patients who had stopped NA. METHODS: This was a territory-wide retrospective study in Hong Kong. We identified HBeAg-negative CHB patients from January 2000 to December 2017 who had stopped NA treatment for more than 3 months. Hepatitis flare was defined as ALT >2×ULN. RESULTS: The 1076 patients were predominantly middle-aged men (mean age 52 years, male 74.8%) when starting NA; they stopped NA after 82 ± 35 months of treatment. At 44.3 ± 24.6 months after stopping NA, 147 (13.6%) patients had hepatitis flare, which led to resumption of NA; whereas 77 (7.2%) patients had flare but did not resume NA. Decompensation occurred in 7/914 (0.8%) patients. A total of 695 (64.6%) patients remained on NA treatment at the last visit. Eleven patients had achieved HBsAg seroclearance (6 of them had hepatitis flare and 1 of these 6 patients achieved HBsAg seroclearance after NA was restarted). Hepatic events developed in 75/695 (10.8%) patients who had NA resumed vs 43/381 (11.3%) patients who did not resume NA (P = .677). CONCLUSIONS: Hepatitis flare and retreatment were common in HBeAg-negative CHB patients who stopped NA treatment; whereas HBsAg seroclearance rarely occurred. Stopping NA to achieve functional cure should not be recommended at this moment.
Asunto(s)
Hepatitis B Crónica , Antivirales/efectos adversos , ADN Viral , Antígenos de Superficie de la Hepatitis B , Antígenos e de la Hepatitis B , Virus de la Hepatitis B/genética , Hepatitis B Crónica/tratamiento farmacológico , Hong Kong/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Brote de los Síntomas , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Liver biopsy is the gold standard for diagnosing non-alcoholic fatty liver disease (NAFLD) but with practical constraints. Phosphorus magnetic resonance spectroscopy ((31)P-MRS) allows in vivo assessment of hepatocellular metabolism and has shown potential for biochemical differentiation in diffuse liver disease. Our aims were to describe spectroscopic signatures in biopsy-proven NAFLD and to determine diagnostic performance of (31)P-MRS for non-alcoholic steatohepatitis (NASH). METHODS: (31)P-MRS was performed in 151 subjects, comprised of healthy controls (n=19) and NAFLD patients with non-NASH (n=37) and NASH (n=95). Signal intensity ratios for phosphomonoesters (PME) including phosphoethanolamine (PE), phosphodiesters (PDE) including glycerophosphocholine (GPC), total nucleotide triphosphate (NTP) including α-NTP, and inorganic phosphate (Pi), expressed relative to total phosphate (TP) or [PME+PDE] and converted to percentage, were obtained. RESULTS: Compared to controls, both NAFLD groups had increased PDE/TP (p<0.001) and decreased Pi/TP (p=0.011). Non-NASH patients showed decreased PE/[PME+PDE] (p=0.048), increased GPC/[PME+PDE] (p<0.001), and normal NTP/TP and α-NTP/TP. Whereas, NASH patients had normal PE/[PME+PDE] and GPC/[PME+PDE], but decreased NTP/TP (p=0.004) and α-NTP/TP (p<0.001). The latter was significantly different between non-NASH and NASH (p=0.047) and selected as discriminating parameter, with area under the receiver-operating characteristics curve of 0.71 (95% confidence interval, 0.62-0.79). An α-NTP/TP cutoff of 16.36% gave 91% sensitivity and cutoff of 10.57% gave 91% specificity for NASH. CONCLUSIONS: (31)P-MRS shows distinct biochemical changes in different NAFLD states, and has fair diagnostic accuracy for NASH.
Asunto(s)
Espectroscopía de Resonancia Magnética/métodos , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Fósforo/metabolismo , Adulto , Estudios de Casos y Controles , Etanolaminas/metabolismo , Femenino , Glicerilfosforilcolina/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/patología , Nucleótidos/metabolismo , Fosfatos/metabolismoRESUMEN
UNLABELLED: On-treatment levels of hepatitis B surface antigen (HBsAg) may predict response to peginterferon (PEG-IFN) therapy in chronic hepatitis B (CHB), but previously proposed prediction rules have shown limited external validity. We analyzed 803 HBeAg-positive patients treated with PEG-IFN in three global studies with available HBsAg measurements. A stopping-rule based on absence of a decline from baseline was compared to a prediction-rule that uses HBsAg levels of <1,500 IU/mL and >20,000 IU/mL to identify patients with high and low probabilities of response. Patients with an HBsAg level <1,500 IU/mL at week 12 achieved response (HBeAg loss with HBV DNA <2,000 IU/mL at 6 months posttreatment) in 45%. At week 12, patients without a decline in HBsAg achieved a response in 14%, compared to only 6% of patients with HBsAg >20,000 IU/mL, but performance varied across HBV genotype. In patients treated with PEG-IFN monotherapy (n = 465), response rates were low in patients with genotypes A or D if there was no decline of HBsAg by week 12 (negative predictive value [NPV]: 97%-100%), and in patients with genotypes B or C if HBsAg at week 12 was >20,000 IU/mL (NPV: 92%-98%). At week 24, nearly all patients with HBsAg >20,000 IU/mL failed to achieve a response, irrespective of HBV genotype (NPV for response and HBsAg loss 99% and 100%). CONCLUSION: HBsAg is a strong predictor of response to PEG-IFN in HBeAg-positive CHB. HBV genotype-specific stopping-rules may be considered at week 12, but treatment discontinuation is indicated in all patients with HBsAg >20,000 IU/mL at week 24, irrespective of HBV genotype.
Asunto(s)
Antivirales/uso terapéutico , Antígenos de Superficie de la Hepatitis B/sangre , Antígenos e de la Hepatitis B/sangre , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/inmunología , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Adulto , Biomarcadores/sangre , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/sangre , Humanos , Masculino , Valor Predictivo de las Pruebas , Proteínas Recombinantes/uso terapéutico , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: We aim to describe the liver immune microenvironment by analyzing liver biopsies from patients with chronic HBV infection (CHB). Host immune cell signatures and their corresponding localization were characterized by analyzing the intrahepatic transcriptome in combination with a custom multiplex immunofluorescence panel. METHOD: Matching FFPE and fresh frozen liver biopsies were collected from immune active patients within the open-label phase IV study GS-US-174-0149. RNA-Seq was conducted on 53 CHB liver biopsies from 46 patients. Twenty-eight of the 53 samples had matched FFPE biopsies and were stained with a 12-plex panel including cell segmentation, immune and viral biomarkers. Corresponding serum samples were screened using the MSD Human V-plex Screen Service to identify peripheral correlates for the immune microenvironment. RESULTS: Using unsupervised clustering of the transcriptome, we reveal two unique liver immune signatures classified as immune high and immune low based on the quantification of the liver infiltrate gene signatures. Multiplex immunofluorescence analysis demonstrated large periportal lymphoid aggregates in immune high samples consisting of CD4 and CD8 T cells, B cells and macrophages. Differentiation of the high and low immune microenvironments was independent of HBeAg status and peripheral viral antigen levels. In addition, longitudinal analysis indicates that treatment and normalization of ALT correlates with a decrease in liver immune infiltrate and inflammation. Finally, we screened a panel of peripheral biomarkers and identified ICAM-1 and CXCL10 as biomarkers that strongly correlate with these unique immune microenvironments. CONCLUSION: These data provide a description of immune phenotypes in patients with CHB and show that immune responses are downregulated in the liver following nucleotide analogue treatment. This may have important implications for both the safety and efficacy of immune modulator programs aimed at HBV cure. LAY SUMMARY: Liver biopsies from patients with chronic hepatitis B were submitted to RNA-Seq and multiplex immunofluorescence and identified two different liver immune microenvironments: immune high and immune low. Immune high patients showed elevated immune pathways, including interferon signaling pathways, and increase presence of immune cells. Longitudinal analysis of biopsies from treatment experienced patients showed that treatment correlates with a marked decrease in inflammation and these findings may have important implications for both safety and efficacy of immune modulator programs for HBV cure.
RESUMEN
BACKGROUND AND AIM: Liver stiffness measurement (LSM) with transient elastography is a non-invasive and reliable test for liver fibrosis. However a small proportion of patients may have unreliable LSM or LSM failure. The aim of the present study was to investigate the factors associated with unreliable LSM or LSM failure in Chinese patients. METHODS: We prospectively recruited liver patients for LSM. Unreliable LSM was defined as < 10 valid shots, an interquartile range (IQR)/LSM > 30%, or a success rate < 60%. LSM failure was defined as zero valid shots. RESULTS: Among 3205 patients with LSM, 371 (11.6%) and 88 (2.7%) had unreliable LSM and LSM failure, respectively. The rates started to increase when body mass index (BMI) ≥ 28.0 kg/m(2) . Comparing patients with BMI ≥ 28.0-29.9 kg/m(2) versus those with BMI ≥ 30.0 kg/m², the rates of unreliable LSM (16.4% vs 18.9%; P = 0.62) and LSM failure (11.8% vs 17.8%; P = 0.16) were similar. BMI ≥ 28.0 kg/m² was the most important factor associated with unreliable LSM (odds ratio [OR] = 2.9, 95% confidence interval [CI] = 2.1-3.9, P < 0.0001) and LSM failure (OR = 10.1, 95% CI = 6.4-14.2, P < 0.0001). Central obesity, defined as waist circumference > 80 cm in women and > 90 cm in men, was another independent risk factor of unreliable LSM (OR = 1.3, 95% CI = 1.0-1.6, P = 0.04) and LSM failure (OR = 5.8, 95% CI = 2.9-11.5, P < 0.0001). CONCLUSION: BMI ≥ 28.0 kg/m² and central obesity were the independent risk factors of unreliable LSM and LSM failure in Chinese, and these rates were significantly higher in patients with extreme BMI.
Asunto(s)
Pueblo Asiatico , Diagnóstico por Imagen de Elasticidad , Cirrosis Hepática/diagnóstico por imagen , Adulto , Índice de Masa Corporal , Distribución de Chi-Cuadrado , China , Estudios Transversales , Femenino , Humanos , Cirrosis Hepática/etnología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Obesidad Abdominal/etnología , Oportunidad Relativa , Valor Predictivo de las Pruebas , Estudios Prospectivos , Reproducibilidad de los Resultados , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Circunferencia de la Cintura/etnologíaRESUMEN
The combination of pegylated-interferon (PEG-IFN)/ribavirin is currently the standard of care antiviral treatment for chronic hepatitis C (CHC), but optimal results require an individual approach. Key issues are to deliver doses that confer optimal antiviral efficacy against hepatitis C virus (HCV) for a time sufficient to minimise relapse. Viral monitoring during therapy guides the subsequent treatment course, particularly HCV RNA results at 4 weeks (rapid viral response [RVR]) and 12 weeks (complete early viral response [cEVR]). There is strong evidence that for most patients with genotypes 2 or 3 HCV infection, RVR allows truncation of treatment to 16 weeks, provided ribavirin dose is weight-based. However, those patients with cirrhosis, insulin resistance/diabetes or older than 50 years need 6-12 months treatment. For "difficult-to-treat" CHC (genotypes 1 and 4), RVR is infrequent (approximately 15% in European studies), but allows treatment to be truncated from 48 to 24 weeks. Without RVR, there is some evidence that longer treatment (72 weeks) improves sustained viral response (SVR). However, "induction dosing" first 12 weeks of PEG-IFN clearly does not improve SVR. To prevent dose reductions and complete therapy, it is critical to detect and treat depression and other disabling side-effects, including judicious use of growth factors for severe anemia or neutropenia and possibly, thrombocytopenia. Another potentially important aspect may be attempts to counter central obesity and insulin resistance, which confer suboptimal antiviral response with any HCV genotype. Treatment partnerships with specialist nurses, psychological therapists and other healthcare workers are also essential for optimal individual management of patients with CHC.
Asunto(s)
Antivirales/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Medicina de Precisión , Antivirales/efectos adversos , Esquema de Medicación , Monitoreo de Drogas , Quimioterapia Combinada , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/diagnóstico , Humanos , Interferones/administración & dosificación , Grupo de Atención al Paciente , ARN Viral/sangre , Ribavirina/administración & dosificación , Factores de Tiempo , Resultado del Tratamiento , Carga ViralRESUMEN
BACKGROUND: Guidelines recommend liver biopsy to rule out significant inflammatory activity in chronic hepatitis B (CHB) patients with elevated hepatitis B virus (HBV) DNA but without other indications for treatment. AIM: To study rates and determinants of clinically significant liver inflammation. METHODS: We selected patients with HBV DNA > 2000 IU/mL from the SONIC-B database. The presence of significant inflammation (METAVIR ≥ A2 or HAI ≥ 9) was assessed by liver biopsy and correlated with alanine aminotransferase (ALT) levels (according to AASLD upper limits of normal [ULN]) and stratified by the presence of significant liver fibrosis (Ishak ≥ 3 or METAVIR ≥ F2). RESULTS: The cohort included 2991 patients; 1672 were HBeAg-positive. ALT was < ULN in 270 (9%), 1-2 times ULN in 852 (29%) and > 2 times ULN in 1869 (63%). Significant fibrosis was found in 1419 (47%) and significant inflammatory activity in 630 (21%). Significant inflammatory activity was found in 34% of patients with liver fibrosis, compared to 9.5% of those without (P < 0.001). Among patients without fibrosis, significant inflammatory activity was detected in 3.6% of those with normal ALT, 5.0% of those with ALT 1-2 times ULN and in 13% of those with ALT > 2 times ULN (P < 0.001). ALT < 2 times ULN had a negative predictive value of 95% for ruling out significant inflammatory activity among patients without liver fibrosis. CONCLUSIONS: Among patients without significant fibrosis, an ALT level < 2 times ULN is associated with < 5% probability of significant inflammatory activity. If fibrosis can be ruled out using non-invasive methods, liver biopsy solely to assess inflammatory activity should be discouraged.
Asunto(s)
Alanina Transaminasa/sangre , Hepatitis B Crónica/complicaciones , Hepatitis/diagnóstico , Hepatitis/etiología , Adulto , Biopsia , Estudios de Cohortes , Femenino , Hepatitis/sangre , Hepatitis/epidemiología , Hepatitis B Crónica/sangre , Hepatitis B Crónica/diagnóstico , Hepatitis B Crónica/epidemiología , Humanos , Inflamación/sangre , Inflamación/diagnóstico , Inflamación/epidemiología , Inflamación/etiología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/epidemiología , Masculino , Persona de Mediana Edad , Probabilidad , Pronóstico , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND AND AIMS: The proposed cut-off values for the degree of fibrosis as assessed by liver stiffness measurement (LSM) might not be applicable in severe acute exacerbation of chronic hepatitis B (CHB). We aimed to assess the effect of necroinflammatory activity on LSM in this condition. METHODS: We prospectively recruited consecutive patients with severe acute exacerbation of CHB (alanine aminotransferase or ALT > 10x upper limit of normal). The relationship of ALT levels and LSM were serially assessed and liver biopsy was carried out after ALT normalization. RESULTS: Eleven patients (10 male, median age 43 years) were followed up for 25 weeks; nine patients received antiviral therapy. Overall, LSM was positively correlated with ALT levels (r = 0.67, P < 0.001). At initial presentation, the median serum ALT and LSM was 1136 (581-2210) IU/L and 26.3 (11.1-33.3) kPa. A progressive reduction in LSM was observed during subsequent visits in parallel with the reduction of ALT levels. At the last visit, the median ALT was 27 (11-52) IU/L and LSM was 7.7 (4.7-10.8) kPa. Among the five patients who had liver biopsy carried out at week 25, four patients had F2 fibrosis (LSM 5.7-8.1 kPa) and one patient had F3 fibrosis (LSM 8.6 kPa). CONCLUSIONS: LSM using transient elastography with the current proposed cut-off values might misdiagnose liver cirrhosis in patients suffering from severe acute exacerbation of CHB. LSM should be assessed after normalization of ALT levels in order to accurately assess the degree of fibrosis.
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Diagnóstico por Imagen de Elasticidad/métodos , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/diagnóstico por imagen , Cirrosis Hepática/diagnóstico por imagen , Adulto , Distribución de Chi-Cuadrado , Femenino , Hepatitis B Crónica/fisiopatología , Humanos , Cirrosis Hepática/fisiopatología , Pruebas de Función Hepática , Masculino , Estudios ProspectivosRESUMEN
BACKGROUND: Ruling out the presence of cirrhosis is important for the management of chronic hepatitis B. We aimed to study and optimise the performance of two non-invasive indices for ruling out cirrhosis: the aspartate aminotransferase-platelet ratio index (APRI) and fibrosis score based on four factors (FIB-4). METHODS: We applied established cutoffs to rule in (APRI >2·00; FIB-4 >3·25) or rule out (APRI <1·00; FIB-4 <1·45) cirrhosis to data from eight global randomised trials that required baseline biopsy, and identified new cutoffs aiming for a sensitivity for detection of cirrhosis greater than 90% and a negative predictive value (NPV) of greater than 95% in the same dataset. We externally validated the new cutoffs using data from all consecutive biopsied patients from two tertiary referral hospitals in the Netherlands and Canada. FINDINGS: In the derivation dataset (n=2926; of whom 1750 were Asian); 340 (12%) individuals had cirrhosis. The validation cohort consisted of 1034 individuals (of whom 575 were Asian), with 155 (15%) individuals with cirrhosis. Application of conventional cutoffs for FIB-4 in the derivation dataset yielded unclassifiable results in 686 (23%) individuals, and 139 (41%) of the 340 patients with cirrhosis were misclassified as having no cirrhosis. Similarly, conventional cutoffs for APRI in the derivation dataset yielded unclassifiable results in 706 (24%) individuals, and 153 (45%) were misclassified as having no cirrhosis. An APRI of 0·45 or less had sensitivity of 91·5%, an NPV of 95·4%, and misclassified 29 (9%) of 340 individuals with cirrhosis in the derivation dataset, but performance was reduced in the validation set (22 [14%] of 155 individuals with cirrhosis misclassified). A FIB-4 score of 0·70 had a sensitivity of 90·9%, an NPV of 96·6%, and misclassified 31 (9%) of individuals with cirrhosis in the derivation dataset. In the validation cohort, the same score gave a sensitivity of 94·2%, an NPV of 97·3%, and misclassified nine (6%) of the individuals with cirrhosis. Subgroup analysis indicated that the new FIB-4 cutoff performed acceptably in all subgroups except for individuals aged 30 years or younger. INTERPRETATION: Conventional cutoffs for APRI and FIB-4 should not be used to guide management of patients with chronic hepatitis B due to high rates of misclassification. A newly identified and externally validated cutoff for FIB-4 (≤0·70) can be used to exclude cirrhosis in patients over 30 years of age. FUNDING: Foundation for Liver and Gastrointestinal Research, Rotterdam, Netherlands.
Asunto(s)
Aspartato Aminotransferasas/metabolismo , Plaquetas/fisiología , Hepatitis B Crónica/patología , Cirrosis Hepática/patología , Adulto , Biomarcadores , Biopsia , Femenino , Hepatitis B Crónica/enzimología , Humanos , Cirrosis Hepática/enzimología , Masculino , Estudios Multicéntricos como Asunto , Curva ROC , Ensayos Clínicos Controlados Aleatorios como Asunto , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Although nucleot(s)ide analogues can effectively suppress hepatitis B virus (HBV) replication, many patients experience relapse of hepatitis after cessation of treatment. We aimed to investigate the efficacy of pegylated interferon alpha2a (PEG-IFN-alpha2a) in these difficult-to-treat patients. METHODS: Chronic hepatitis B patients who have received antiviral drugs for > or =12 months and stopped for > or =6 months were treated by 48-week PEG-IFN-alpha2a. Virological response was defined as HBV DNA <10,000 copies/ml and hepatitis B e antigen (HBeAg) seroconversion (for HBeAg-positive patients). RESULTS: A total of 40 patients, 29 HBeAg-positive and 11 HBeAg-negative, with median log10 HBV DNA 7.3 copies/ml and alanine aminotransferase 110 IU/ml were studied. The last antiviral treatment was given for 92 +/- 61 weeks and stopped for 176 +/- 88 weeks. At the end of treatment, 22 (12 HBeAg-positive and 10 HBeAg-negative; 55%) patients had virological response and 16 (7 HBeAg-positive and 9 HBeAg-negative; 40%) patients had undetectable HBV DNA (<100 copies/ml). At 24 weeks post-treatment, 14 (8 HBeAg-positive and 6 HBeAg-negative; 35%) patients had virological response and 9 (5 HBeAg-positive and 4 HBeAg-negative; 23%) patients had undetectable HBV DNA. Two (5%) patients had lost hepatitis B surface antigen. HBV DNA levels at week 24 best predicted sustained virological response (area under curve 0.76, 95% confidence interval 0.60-0.92, P=0.007). At HBV DNA cutoffs of 3 logs and 5 logs at week 24, the sensitivity/specificity for sustained virological response were 50%/85% and 86%/62%, respectively. CONCLUSIONS: PEG-IFN-alpha2a was effective in the treatment of chronic hepatitis B patients who have failed previous antiviral treatment.
Asunto(s)
Antivirales , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa , Polietilenglicoles , Adulto , Antivirales/administración & dosificación , Antivirales/uso terapéutico , ADN Viral/sangre , Femenino , Antígenos de Superficie de la Hepatitis B/sangre , Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B/inmunología , Virus de la Hepatitis B/aislamiento & purificación , Hepatitis B Crónica/virología , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/uso terapéutico , Masculino , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
BACKGROUND AND AIM: Symptoms and complications of primary biliary cirrhosis (PBC) have been shown to impair patients' health-related quality of life (HRQOL) in the West. We aimed to measure the HRQOL and to determine the factors associated with worse HRQOL among the Chinese PBC patients in Hong Kong. METHODS: Chinese patients with biopsy-proven PBC were compared with an age- and gender-matched control group of patients suffering from uncomplicated hypertension (HT) and chronic hepatitis B (CHB). Their HRQOL was assessed by a Chinese (Hong Kong) version of the 36-item short-form health survey (SF-36). The psychological aspect of patients was assessed by the Hospital Anxiety and Depression Scale (HADS). RESULTS: Forty-four PBC patients aged 60 +/- 11 years were identified. PBC patients had more profound impairment in their HRQOL, as evidenced by their significantly lower Physical Component Summary (PCS) scores (39 +/- 11 vs 45 +/- 9 and 45 +/- 11, P = 0.009 and 0.01) and slightly lower Mental Component Summary (MCS) score (47 +/- 12 vs 51 +/- 10 and 48 +/- 11, P = 0.051 and 0.80) as compared with the HT and CHB control groups, respectively. High HADS-depression score was independently associated with lower PCS scores. More severe fatigue and higher HADS-anxiety and HADS-depression scores were independently associated with lower MCS scores. CONCLUSION: Chinese PBC patients have significant impairment of the HRQOL. The anxiety and depression status of patients had important contribution to the HRQOL.
Asunto(s)
Cirrosis Hepática Biliar/complicaciones , Cirrosis Hepática Biliar/diagnóstico , Calidad de Vida , China , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
BACKGROUND AND AIM: As liver fibrosis is the result of persistent necroinflammation in the liver, pro-inflammatory cytokines secreted in response to cell injury have a central role in the pathogenesis of liver fibrosis. We aimed to investigate the association of cytokine gene polymorphism and liver fibrosis among Chinese patients with chronic hepatitis B. METHODS: Polymorphisms at interleukin-10 (IL-10-627, -1117), interleukin-1-beta (IL-1beta-511, -31, -3964), interleukin-1 receptor antagonist (IL-1RN), and tumor necrosis factor-alpha (TNF-alpha-308, -238) among Chinese chronic hepatitis B patients were determined. Severe liver fibrosis was defined as Ishak fibrosis score = 4 (of 6). RESULTS: Fifty-nine of 273 (22%) patients had severe fibrosis. The distribution of genotypes for IL-10-627 was CC (11%), CA (41%), and AA (48%). The CC genotype at IL-10-627 was protective against severe fibrosis (odds ratio (OR) 0.11; 95% CI 0.014-0.82; P = 0.032). After adjusted for baseline variables, the adjusted OR of CC genotypes at IL-10-627 for severe fibrosis was 0.063 (95% CI 0.06-0.64; P = 0.063). Other gene polymorphisms at IL-1beta, IL-1RN, TNF-alpha, and IL-10 had no significant association with severe fibrosis. Weak linkage disequilibrium was observed between IL-10-627 and IL-10-1117 with linkage disequilibrium coefficient of 0.12 (P < 0.001). The distribution of haplotypes of IL-10-1117 and IL-10-627 was A-A (69%), A-C (26%), and G-C (5%). High and intermediate IL-10 production (A-C and G-C) haplotypes were protective against severe fibrosis (OR 0.62; 95% CI 0.39-0.99; P = 0.046). CONCLUSIONS: High production genotype and haplotypes of IL-10 were associated with less severe liver fibrosis in chronic hepatitis B in Chinese.
Asunto(s)
Hepatitis B Crónica/complicaciones , Proteína Antagonista del Receptor de Interleucina 1/genética , Interleucina-10/genética , Interleucina-1beta/genética , Cirrosis Hepática/complicaciones , Cirrosis Hepática/genética , Polimorfismo Genético , Factor de Necrosis Tumoral alfa/genética , Adulto , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: A 2-year roadmap study was conducted to evaluate the efficacy and safety of tenofovir intensification at Week 24 in patients with chronic hepatitis B (CHB) receiving telbivudine. SCOPE: A prospective multicenter study was conducted in treatment-naive patients with hepatitis B e antigen (HBeAg)-positive CHB. All patients received telbivudine (600 mg/day) until Week 24. Thereafter, patients with detectable hepatitis B virus (HBV) DNA (≥300 copies/mL) were administered tenofovir (300 mg/day) plus telbivudine, and patients with undetectable HBV DNA continued telbivudine monotherapy until Week 104. The primary endpoint was the proportion of patients with undetectable HBV DNA (<300 copies/mL) at Weeks 52 and 104. FINDINGS: A total of 105 patients were enrolled in the trial, of which 100 were eligible for efficacy analysis. Undetectable HBV DNA levels were observed at Week 24 in 55 patients who continued on with telbivudine monotherapy. The remaining 45 patients with detectable HBV DNA received tenofovir add-on therapy. With monotherapy, 100% (55/55) and 94.5% (52/55) of patients achieved HBV DNA <300 copies/mL at Weeks 52 and 104, respectively; the corresponding values for patients with add-on therapy were 84.4% (38/45) and 93.3% (42/45). Overall, undetectable HBV DNA (<300 copies/mL) was found in 93% (93/100) and 94% (94/100) of patients at Weeks 52 and 104, respectively. HBeAg seroconversion rate was 44.4% (44/99) at Week 104 for the overall patient population. One patient in the monotherapy group and six in the intensification group demonstrated HBsAg clearance at Week 104. HBsAg seroconversion was observed in four patients at Week 104, all belonged to the tenofovir intensification group. Eight patients sustained HBsAg loss during a posttreatment follow-up period of 16 weeks. Alanine aminotransferase (ALT) normalization was constant in the telbivudine monotherapy group, whereas a progressive improvement was observed in the tenofovir intensification group. Two patients in the monotherapy and none in the intensification group experienced viral breakthrough by Week 104. There were no reports of myopathy in either group. The mean changes in estimated glomerular filtration rate (eGFR), estimated using the Modification of Diet in Renal Disease (MDRD) formula, from baseline to Week 104 were +6.145 mL/min/1.73 m(2) (p=0.0230) and +7.954 mL/min/1.73 m(2) (p=0.0154) in the telbivudine monotherapy and tenofovir intensification groups, respectively. The incidence of serious AEs was four in the telbivudine monotherapy and two in the tenofovir intensification group. The main limitation of this study was limited sample size, which made the power of the observation low, and the absence of a comparative subgroup to assess the progression of patients with detectable HBV DNA without treatment intensification. CONCLUSIONS: Data from this 2-year roadmap study confirmed that telbivudine with add-on tenofovir was effective and well tolerated in patients with CHB. Telbivudine was associated with an improvement in eGFR from baseline in both the groups.
RESUMEN
BACKGROUND: Kinetics of serum hepatitis B surface antigen (HBsAg) level in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients presented with severe reactivation and received oral antiviral therapy is unknown. We aimed to investigate the kinetics of HBsAg level among these patients. METHODS: HBeAg-negative patients on antiviral therapy with follow-up for 2 years were studied. Those presented with severe reactivation (alanine aminotransferase [ALT] ≥5 times of normal) were compared to those with mild hepatitis. Serum HBsAg level was measured by Elecsys HBsAg II Quant assay (Roche) at baseline and 6-monthly. RESULTS: A total of 192 (74 severe reactivation) patients were studied. Eighty-one (42%), 74 (39%) and 37 (19%) patients were on lamivudine, entecavir and telbivudine, respectively. Forty-four (23%) patients had early HBsAg decline, that is, ≥0.5 log10 reduction, at month 6. Patients with severe reactivation had higher serum baseline ALT (1,415 ±897 versus 73 ±39 IU/l), HBV DNA (6.4 ±1.6 versus 5.2 ±1.2 log10 IU/ml) and HBsAg (3.3 ±1.0 versus 2.9 ±0.6 log10 IU/ml), as well as an earlier HBsAg decline (50% versus 6%; all P<0.001) than those without. The HBsAg change of patients with severe reactivation was higher at months 0-6 (-0.58 ±-1.26 versus -0.01 ±-0.26 log10 IU/ml; P<0.001) but then became comparable from months 6-24 (-0.19 ±-0.60 versus -0.13 ±-0.19 log10 IU/ml; P=0.85), compared to those presented with mild hepatitis. CONCLUSIONS: Patients who presented with severe reactivation of HBeAg-negative hepatitis were more likely to develop early HBsAg decline during antiviral therapy. It may indicate a transient strong immune clearance with rapid initial reduction in serum HBsAg, which cannot be sustained due to a faster clearance of serum HBsAg.
Asunto(s)
Antivirales/uso terapéutico , Antígenos de Superficie de la Hepatitis B/sangre , Antígenos e de la Hepatitis B/sangre , Hepatitis B Crónica/tratamiento farmacológico , Adulto , Anciano , Alanina Transaminasa/sangre , ADN Viral/sangre , Femenino , Guanina/análogos & derivados , Guanina/uso terapéutico , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/sangre , Hepatitis B Crónica/inmunología , Humanos , Lamivudine/uso terapéutico , Masculino , Persona de Mediana Edad , Inhibidores de la Síntesis del Ácido Nucleico/uso terapéutico , Recurrencia , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Telbivudina , Timidina/análogos & derivados , Timidina/uso terapéutico , Carga Viral , Adulto JovenRESUMEN
BACKGROUND: The timing of antiviral therapy cessation in hepatitis B e antigen (HBeAg)-negative patients is controversial. Here, we aimed to investigate the role of HBV DNA and hepatitis B surface antigen (HBsAg) monitoring to predict off-treatment sustained response. METHODS: A total of 53 HBeAg-negative chronic hepatitis B patients who received lamivudine for 34 ±23 (range 12-76) months and had lamivudine stopped for 47 ±35 months were studied. Primary outcome was sustained response, defined as HBV DNA≤200 IU/ml, at 12 months post-treatment (SR-12). RESULTS: A total of 9 (17%) patients achieved SR-12. HBV DNA at baseline, month 6 and end of treatment had no association with SR-12. HBsAg levels tended to decrease more significantly during treatment among SR-12 responders. At the end of treatment, both HBsAg ≤2 log IU/ml and reduction by >1 log from baseline had sensitivity, specificity, positive and negative predictive values for SR-12 of 78%, 96%, 78% and 96%, respectively. All 5 patients with HBsAg≤2 log IU/ml and reduction >1 log at the end of treatment achieved SR-12 and all 40 patients with HBsAg>2 log IU/ml and reduction ≤1 log did not have SR-12. The cumulative probability of sustained response and HBsAg clearance at 5 years among patients with HBsAg≤2 log IU/ml were 88% and 72%, respectively, that among patients with HBsAg reduction >1 log were 74% and 61%, respectively. CONCLUSIONS: Monitoring of HBsAg level can guide the timing of stopping lamivudine in HBeAg-negative chronic hepatitis B.