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The purpose of this retrospective study is to compare the efficacy and safety of the centrifugal separation therapeutic plasma exchange (TPE) using citrate anticoagulant (cTPEc) with membrane separation TPE using heparin anticoagulant (mTPEh) in liver failure patients. The patients treated by cTPEc were defined as cTPEc group and those treated by mTPEh were defined as mTPEh group, respectively. Clinical characteristics were compared between the two groups. Survival analyses of two groups and subgroups classified by the model for end-stage liver disease (MELD) score were performed by Kaplan-Meier method and were compared by the log-rank test. In this study, there were 51 patients in cTPEc group and 18 patients in mTPEh group, respectively. The overall 28-day survival rate was 76% (39/51) in cTPEc group and 61% (11/18) in mTPEh group (P > .05). The 90-day survival rate was 69% (35/51) in cTPEc group and 50% (9/18) in mTPEh group (P > .05). MELD score = 30 was the best cut-off value to predict the prognosis of patients with liver failure treated with TPE, in mTPEh group as well as cTPEc group. The median of total calcium/ionized calcium ratio (2.84, range from 2.20 to 3.71) after cTPEc was significantly higher than the ratio (1.97, range from 1.73 to 3.19) before cTPEc (P < .001). However, there was no significant difference between the mean concentrations of total calcium before cTPEc and at 48 h after cTPEc. Our study concludes that there was no statistically significant difference in survival rate and complications between cTPEc and mTPEh groups. The liver failure patients tolerated cTPEc treatment via peripheral vascular access with the prognosis similar to mTPEh. The prognosis in patients with MELD score < 30 was better than in patients with MELD score ≥ 30 in both groups. In this study, the patients with acute liver failure (ALF) and acute on chronic liver failure (ACLF) treated with cTPEc tolerated the TPE frequency of every other day without significant clinical adverse event of hypocalcemia with similar outcomes to the mTPEh treatment. For liver failure patients treated with cTPEc, close clinical observation and monitoring ionized calcium are necessary to ensure the patients' safety.
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Insuficiencia Hepática Crónica Agudizada , Enfermedad Hepática en Estado Terminal , Humanos , Insuficiencia Hepática Crónica Agudizada/terapia , Intercambio Plasmático/métodos , Estudios Retrospectivos , Heparina/uso terapéutico , Calcio , Enfermedad Hepática en Estado Terminal/terapia , Índice de Severidad de la Enfermedad , Anticoagulantes/uso terapéuticoRESUMEN
BACKGROUND: Hepatitis B e antigen (HBeAg) seroconversion represents an endpoint of treatment of chronic hepatitis B virus (HBV) infections. METHODS: We have studied whether levels of serum hepatitis B virus ribonucleic acid (HBV RNA) during pegylated interferon alfa-2a treatment might be helpful for predicting HBeAg seroconversion. 61 HBeAg-positive chronic hepatitis B (CHB) patients treated with pegylated interferon alfa-2a alone or in combination with adefovir (10 mg/day) for 48 weeks were included in this retrospective analysis. Response was defined as HBeAg seroconversion at 24 weeks posttreatment. Receiver operating characteristic analyses were used to identify baseline and on-treatment HBV RNA levels associated with response. RESULTS: Twenty-two of 61 (36.1%) patients achieved a response. Baseline HBV RNA levels were lower in responders than in nonresponders (4.55 ± 1.19 and 5.90 ± 1.13 copies/mL, respectively, P = 0.001). Baseline HBV RNA cut off level (200,000 copies/mL) provided a positive predictive value (PPV) of 56.0% and a negative predictive value (NPV) of 77.8%. HBV RNA level (3000 copies/mL) at week 12 provide a PPV of 75.0% and a NPV of 82.8%. Moreover, HBeAg seroconversion rates at 24 weeks posttreatment were significantly higher in patients with HBV RNA ≤ 200,000 copies/mL at baseline and HBV RNA ≤ 3000 copies/mL at week 12 (92.9%) versus others (12.5%) (All P < 0.05). CONCLUSIONS: In Conclusions, serum HBV RNA levels may serve as a novel tool for prediction of HBeAg seroconversion during therapy with pegylated interferon alfa-2a in HBeAg-positive CHB patients.
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Antivirales/uso terapéutico , ADN Viral/sangre , Antígenos e de la Hepatitis B/sangre , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Adenina/análogos & derivados , Adenina/uso terapéutico , Adulto , Femenino , Virus de la Hepatitis B/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Organofosfonatos/uso terapéutico , Curva ROC , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Seroconversión , Adulto JovenRESUMEN
BACKGROUND: Hepatitis B virus covalently closed circular DNA (HBV cccDNA) is an important biomarker of hepatitis B virus infection. However, the current methods are not specific and sensitive. The present study aimed to develop a specific and sensitive assay method for the quantification of HBV cccDNA. METHODS: Exonuclease I (Exo I) & Exonuclease III (Exo III) and specific primer probes are used in real-time PCR. The virus particles isolated from peripheral blood mononuclear cells were used as negative control and HBV1.3 recombinant plasmid 3.2â¯kb circular DNA fragment was used as positive control. The methods of cccDNA detection were evaluated in cell lines, plasmid, animal model, patient serum and liver biopsies. RESULTS: A linear range of 101-107 copies/assay using specific primers for HBV cccDNA was established. HBV cccDNA were only detected in cell lines, animal model and liver tissue. It cannot be detected in serum samples. Intrahepatic HBV cccDNA level had good correlation with intrahepatic total HBV DNA level (râ¯=â¯0.765, Pâ¯<â¯0.001). CONCLUSIONS: The real-time quantitative PCR is an effective and feasible method for sensitive and specific detection of low copy number of cccDNA. The novel detection method is fast, provides high sensitivity and specificity and can be used in clinical practice.
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ADN Circular/análisis , Exodesoxirribonucleasas , Virus de la Hepatitis B/aislamiento & purificación , Hepatitis B/sangre , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Animales , Línea Celular , Modelos Animales de Enfermedad , Hepatitis B/metabolismo , Virus de la Hepatitis B/genética , Hepatocitos , Humanos , Hígado/metabolismo , Ratones , Plásmidos , Sensibilidad y EspecificidadRESUMEN
Serum Mac-2-binding protein glycosylation isomer (M2BPGi) level was found to be a useful prognostic marker for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients treated with nucleoside/nucleotide analogs (NUCs) therapy, and the aim of our study is to evaluate the clinical implementation of M2BPGi level in the prediction of antiviral responses to pegylated-interferon-α (PEG-IFN-α) treatment in HBeAg-positive CHB patients. Ninety-six CHB patients who received PEG-IFN-α treatment for at least 48 weeks were recruited. The serum M2BPGi, alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), HBeAg, and HBV DNA levels at baseline, weeks 4, 12, and 24 after PEG-IFN-α treatment were determined and their associations with antiviral responses were evaluated and the virological response (VR) rate and serological response (SR) rate after 48 weeks of treatment were 65.6% and 35.4%, respectively. Baseline serum M2BPGi level was significantly different between VR and non-VR (P = 0.002) or SR and non-SR groups (P = 0.012). Multivariate analyses suggested that baseline serum M2BPGi level was independently associated with VR and SR of PEG-IFN-α treatment at week 48. The area under the ROC curve (AUC) of baseline M2BPGi was 0.682 in predicting VR, which was superior to HBsAg (AUC = 0.566) or HBV DNA (AUC = 0.567). The AUC of baseline M2BPGi in predicting SR was 0.655, which was also higher than that of HBsAg (AUC = 0.548) or HBV DNA (AUC = 0.583). These results suggested that baseline serum M2BPGi level was a novel predictor of VR and SR for PEG-IFN-α treatment in HBeAg-positive CHB patients.
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Antígenos de Neoplasias/sangre , Antivirales/administración & dosificación , Biomarcadores/sangre , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa/administración & dosificación , Glicoproteínas de Membrana/sangre , Polietilenglicoles/administración & dosificación , Adulto , Alanina Transaminasa/sangre , ADN Viral/sangre , Femenino , Estudios de Seguimiento , Antígenos de Superficie de la Hepatitis B/sangre , Antígenos e de la Hepatitis B/sangre , Hepatitis B Crónica/diagnóstico , Hepatitis B Crónica/patología , Humanos , Masculino , Pronóstico , Curva ROC , Proteínas Recombinantes/administración & dosificación , Estudios Retrospectivos , Suero/química , Resultado del TratamientoRESUMEN
BACKGROUND: Current treatment options for chronic hepatitis B (CHB) are pegylated interferon alpha and nucleoside analogues (NAs). NAs have relatively fewer side effects than interferon alpha, and generally well tolerated. Previously 12.9% of patients on telbivudine treatment were reported to develop severe elevation of serum creatine phosphokinase (CPK) levels, but related clinical disease, like lactic acidosis (LA) and rhabdomyolysis (RM) were rare. The pathophysiology may be mitochondrial toxicity, for the NAs inhibit not only hepatitis B virus (HBV) polymerase, but also the host mitochondrial DNA polymerase γ. As mitochondria are the main sites of oxidative phosphorylation, there will be an increase of pyruvate reduction to lactic acid and insufficient adenosine triphosphate. The accumulation of lactic acid causes LA, while lack of energy leads to cell dysfunction and mitochondria-associated disease, including RM. All five NAs, except tenofovir, have been reported causing LA and RM. Here we report the first case of CHB patients developing fatal LA and RM during telbivudine and tenofovir treatment. CASE PRESENTATION: The patient is a 51-year-old man who was hospitalized in November 2015. He had taken telbivudine regularly because of CHB. Later, tenofovir was added to antiviral treatment because of HBV resistance. Then he had myalgia, chest tightness and anorexia. The blood lactate was 12.7 mmol/L. The arterial blood gas analysis showed pH 7.25, base excess 21.1 mmol/L. CPK was 991 U/L, myoglobin was 1745 ng/ml and creatine was 83 µmol/L. Abdomen magnetic resonance revealed cirrhosis. Muscle biopsy revealed myogenic lesion with abnormality of mitochondria and fat metabolism. The patient was diagnosed with Hepatitis B envelope Antigen positive CHB, cirrhosis, LA and RM characterized by myalgia and elevated myoglobin. He was given tenofovir alone as antiviral treatment instead. After hemodialysis and 4 weeks` treatment of corticosteroids, his symptoms recovered, and blood lactate gradually returned to a normal range. CONCLUSIONS: This case shows that tenofovir may trigger muscle damage and fatal RM in combination with telbivudine treatment in CHB patients. Thus, patients receiving tenofovir and telbivudine should be closely monitored for muscular abnormalities, blood lactate level and other mitochondrial toxicity associated side effects.
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Acidosis Láctica/inducido químicamente , Antivirales/efectos adversos , Hepatitis B Crónica/tratamiento farmacológico , Rabdomiólisis/inducido químicamente , Tenofovir/efectos adversos , Timidina/análogos & derivados , Antivirales/uso terapéutico , ADN Polimerasa gamma/antagonistas & inhibidores , Quimioterapia Combinada , Humanos , Masculino , Persona de Mediana Edad , Telbivudina , Tenofovir/uso terapéutico , Timidina/efectos adversos , Timidina/uso terapéuticoRESUMEN
AIM: Chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) levels are not free from significant hepatic lesions. Recently, there has been an improved understanding of the clinical significance of quantitative hepatitis B core antibody levels (qAnti-HBc) during CHB management. In this cross-sectional study, we evaluated the utility of qAnti-HBc in identifying significant liver inflammation in CHB patients. METHODS: A total of 469 patients (training set, n = 363; validation set, n = 106) who underwent liver biopsy (LB) were included. The qAnti-HBc levels were quantified and the relationship between histology and serum markers was systematically analyzed. RESULTS: In the training set, qAnti-HBc levels were found to have significant diagnostic value for moderate to severe liver inflammation (≥G2) in all patients (area under the receiver operating characteristic curve [AUROC] = 0.768; 95% confidence interval [CI], 0.721-0.810; P < 0.001) and in patients with normal or near-normal ALT levels (AUROC = 0.767; 95% CI, 0.697-0.828; P < 0.001). Our novel index (AC index) for the identification of ≥G2 inflammation, which combined the qAnti-HBc and ALT levels, significantly improved diagnostic performance (AUROC = 0.813; 95% CI, 0.768-0.852) compared to the use of ALT alone (AUROC = 0.779; 95% CI, 0.732-0.821) in all patients. In the validation set, the AC index showed an improved AUROC of 0.890 (95% CI, 0.814-0.942) and 0.867 (95% CI, 0.749-0.943) in all patients and patients with normal ALT levels, respectively. CONCLUSIONS: The qAnti-HBc level predicts significant liver inflammation well, even in patients with normal or near-normal ALT levels. Compared with the conventional ALT level, the AC index is a more reliable non-invasive biomarker for significant liver inflammation in CHB patients.
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BACKGROUND AND AIMS: We aimed to define gender-specific, optimal alanine aminotransferase (ALT) cut-off values for the prediction of significant liver histological changes (SLHC) in Chinese patients with grey zone (GZ) chronic hepatitis B (CHB) and normal ALT. METHODS: In a retrospective study, we included 1101 consecutive patients with GZ CHB and normal ALT assigned to training or internal validation cohorts. We included an independent cohort of 842 patients for external validation. We performed receiver operating characteristic (ROC) curve, smoothed curve fitting, and threshold effect analyses to determine optimal ALT cut-off values. Area under the curve (AUC) values were calculated to assess their predictive performance. RESULTS: A proportion of 79.3% of patients with GZ CHB and normal ALT (≤40 U/L) had SLHC. ROC curve analysis initially identified optimal ALT cut-off values of 29 U/L (male) and 22 U/L (female). After smoothed curve fitting and threshold effect analyses, new optimal cut-off values were 27 U/L for males and 24 U/L for females. AUCs for these values were 0.836 (male) and 0.833 (female) in the internal validation cohort, and 0.849 (male) and 0.844 (female) in the external validation cohort. The accuracy and discriminative ability of the newly defined ALT cut-off values were greater than those of the current recommendations. CONCLUSION: This study established novel optimal ALT cut-off values for more precise prediction of SLHC among Chinese patients with GZ CHB and normal ALT levels. This may help identify individuals who will benefit from timely antiviral therapy.
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Hepatitis B Crónica , Humanos , Masculino , Femenino , Hepatitis B Crónica/diagnóstico , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/patología , Estudios Retrospectivos , Cirrosis Hepática , Curva ROC , Alanina Transaminasa , Virus de la Hepatitis B , Antígenos e de la Hepatitis BRESUMEN
BACKGROUND & AIMS: Even though various experimental therapeutic approaches for chronic hepatitis B infection have been reported, few of them have been verified by clinical trials. We have developed an antigen-antibody (HBsAg-HBIG) immunogenic complex therapeutic vaccine candidate with alum as adjuvant (YIC), aimed at breaking immune tolerance to HBV by modulating viral antigen processing and presentation. A double-blind, placebo-controlled, phase II B clinical trial of YIC has been reported previously, and herein we present the results of the phase III clinical trial of 450 patients. METHODS: Twelve doses of either YIC or alum alone as placebo were administered randomly to 450 CHB patients and they were followed for 24weeks after the completion of immunization. The primary end point was HBeAg seroconversion, and the secondary end points were decrease in viral load, improvement of liver function, and histology. RESULTS: In contrast to the previous phase II B trial using six doses of YIC and alum as placebo, six more injections of YIC or alum resulted in a decrease of the HBeAg seroconversion rate from 21.8% to 14.0% in the YIC group, but an increase from 9% to 21.9% in the alum group. Decrease in serum HBV DNA and normalization of liver function were similar in both groups (p>0.05). CONCLUSIONS: Overstimulation with YIC did not increase but decreased its efficacy due to immune fatigue in hosts. An appropriate immunization protocol should be explored and is crucial for therapeutic vaccination. Multiple injections of alum alone could have stimulated potent inflammatory and innate immune responses contributing to its therapeutic efficacy, and needs further investigation.
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Antígenos de Superficie de la Hepatitis B/uso terapéutico , Hepatitis B Crónica/terapia , Inmunoglobulinas/uso terapéutico , Vacunas Virales/uso terapéutico , Adyuvantes Inmunológicos/administración & dosificación , Adulto , Compuestos de Alumbre/administración & dosificación , Complejo Antígeno-Anticuerpo/administración & dosificación , Complejo Antígeno-Anticuerpo/uso terapéutico , Citocinas/sangre , Método Doble Ciego , Femenino , Genotipo , Antígenos de Superficie de la Hepatitis B/administración & dosificación , Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B/clasificación , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/patología , Humanos , Inmunoglobulinas/administración & dosificación , Masculino , Vacunas Virales/efectos adversos , Adulto JovenRESUMEN
This study aimed to explore the effects of the 3 nucleos(t)ide analogues (NAs) on lipid levels. We retrospectively included patients treated with NAs at 2 centers and collected their clinical data at their visiting points. Differences in blood lipid levels were analyzed by statistical methods, and factors related to hyperlipidemia were discussed. In these 2 centers, the prevalence rates of hypercholesterolemia were 12/181 (6.6%) for tenofovir alafenamide fumarate (TAF)-, 0/158 (0%) for tenofovir disoproxil fumarate (TDF)-, and 13/182 (7.1%) for entecavir (ETV)-treated individuals (Pâ =â .003). The prevalence rates of hypertriglyceridemia were 30/181 (16.6%) for TAF-, 11/158 (7.0%) for TDF-, and 26/182 (14.3%) for ETV-treated individuals (Pâ =â .025). In TAF (nâ =â 181, 10 [6, 15] months), TDF (nâ =â 158, 18 [7.5, 45] months), and ETV (nâ =â 182, 24 [10, 60] months) groups, total cholesterol (TC) levels were 4.63â ±â 0.91 mmol/L, 3.86â ±â 0.61 mmol/L, and 4.53â ±â 0.87 mmol/L, respectively; triglyceride (TG) levels were 1.27â ±â 0.76 mmol/L, 0.87â ±â 0.51 mmol/L, and 1.14â ±â 0.67 mmol/L, respectively (Pâ <â .001). In multivariate regression analysis, factors associated with hypercholesterolemia were age (adjusted hazard risk [HR]â =â 1.055 [1.018-1.094]; Pâ =â .003) and body mass index (BMI) (adjusted HRâ =â 0.817 [0.669-0.998]; Pâ =â .048). Factors associated with hypertriglyceridemia were TAF group (vs. TDF group) (adjusted HRâ =â 0.405 [0.167-0.980]; Pâ =â .045), age (adjusted HRâ =â 1.028 [1.002-1.055]; Pâ =â .038), and sex (adjusted HRâ =â 0.190 [0.079-0.456]; Pâ <â .001). Among the patients treated with TAF (10 [6, 15] months), TDF (18 [7.5, 45] months), and ETV (24 [10, 60] months), the blood lipid levels in the TDF group were lower than those in the TAF group and ETV group, and the occurrence of hyperlipidemia was associated with age, sex, BMI, and different treatment.
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Hepatitis B Crónica , Hipercolesterolemia , Hipertrigliceridemia , Humanos , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/epidemiología , Antivirales/uso terapéutico , Estudios Transversales , Estudios Retrospectivos , Hipercolesterolemia/tratamiento farmacológico , Resultado del Tratamiento , Tenofovir/uso terapéutico , Adenina , Lípidos , Hipertrigliceridemia/tratamiento farmacológico , Hipertrigliceridemia/epidemiologíaRESUMEN
To study the gene expression profiles in dendritic cells (DCs) from a hepatitis B surface antigen (HBsAg) positive host, transcriptional analysis of bone marrow -derived DCs from a lineage of HBsAg transgenic mice (#59) was compared to DCs from normal mice. Among the immune-related genes, 12 were up-regulated, and 14 were down-regulated in transgenic mice relative to those of normal mice. The up-regulated genes include genes encoding immunoglobulin, histocompatibility 2 (K region), and several complement component genes, while the down-regulated genes include the TAP1 (transporters associated with antigen processing gene-1), interferon induced gene (Ifi203), chemokine (C-X-C) ligands and leukocyte-immunoglobulin-like genes, Lck-interacting transmembrane adaptor genes and histocompatibility 2 (Q region and T region). Since an immunogenic complex containing HBsAg-anti-HBs has been used as a therapeutic vaccine for clinical trial in chronic hepatitis B patients, DCs from #59 were incubated with immunogenic complex compared to those incubated with HBsAg alone. The immune-related six genes up-regulated with immunogenic complex treatment were Fcgr2b, Cxcl2, Fth1, Clec4n, Lilrb4, and Dbh, with Fcgr2b (Fc gamma receptor IIB) being the highest up-regulated gene. Interestingly, levels of Fcgr2b were found up-regulated in patients with chronic hepatitis B undergoing immunogenic complex immunization, which returned to baseline when immunization was discontinued. In conclusion, by transcriptional analysis, immunogenic complex induced up-regulation of Fcgr2b expression both in dendritic cells from an HBsAg transgenic mouse model and peripheral B cells from patients with chronic hepatitis B, which indicates that Fcgr2b is one of the key molecules up-regulated by immunogenic complex.
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Complejo Antígeno-Anticuerpo/inmunología , Células Dendríticas/inmunología , Expresión Génica , Anticuerpos contra la Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/genética , Antígenos de Superficie de la Hepatitis B/inmunología , Receptores de IgG/biosíntesis , Animales , Femenino , Perfilación de la Expresión Génica , Masculino , Ratones , Ratones TransgénicosRESUMEN
BACKGROUND: Acute-on-chronic liver failure (ACLF) is characterized by an excessive systemic inflammatory response and organ failure and has high mortality. Bacterial infections (BIs) worsen the clinical course of ACLF and carry a poor prognosis in ACLF patients. The efficacy of third-generation cephalosporins has been challenged in recent years. The aim of this study was to characterize the difference between ACLF patients with and without BIs and to provide a reference for medical intervention. METHODS: A total of 140 patients with hepatitis B virus-related ACLF (HBV-ACLF) hospitalized at the Department of Infectious Diseases, Huashan Hospital, Fudan University (Shanghai, China) between May 2013 and January 2020 were enrolled. Mann-Whitney U test was used to compare the baseline characteristics of HBV-ACLF patients with and without BIs. Univariate and multivariate analyses were performed to find predictors of BIs. The characteristics of BIs and the role of prophylactic antibiotics were profiled. RESULTS: A total of 97 episodes of BIs occurred in patients during the course of HBV-ACLF. Patients with and without BIs differed in clinical characteristics. The incidence of BIs showed a positive correlation with the ACLF grade (P = 0.003) and the clinical course (P = 0.003). The 90-day transplant-free survival of patients with BIs was lower than those without BIs (P < 0.0001). Patients administered prophylactic antibiotics showed a lower incidence of BIs and had a higher transplant-free survival probability than those who did not (P = 0.046). No statistical differences in antibiotic efficacy between third-generation and other antibiotics were observed (P = 0.108). CONCLUSIONS: BIs affected the clinical course and prognosis of patients with HBV-ACLF. Prophylactic antibiotics were of potential clinical importance in the prevention of BIs and improving the clinical course and prognosis in HBV-ACLF patients. Third-generation cephalosporins were qualified for use in antibiotic prophylaxis.
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Insuficiencia Hepática Crónica Agudizada , Infecciones Bacterianas , Hepatitis B Crónica , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Antibacterianos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/prevención & control , China/epidemiología , Virus de la Hepatitis B , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Pronóstico , Estudios RetrospectivosRESUMEN
AIMS: Patients with chronic hepatitis B virus (HBV) infection under entecavir (ETV) treatment develop resistant mutants with viral rebound. Here, we report an interesting case of spontaneous loss of HBV-DNA and seroconversion following an acute flare after the development of ETV-resistant mutants. This patient received ETV after lamivudine breakthrough. METHODS: Cloning and sequence analysis of the HBV reverse transcriptase (RT) region were performed with seven samples during ETV therapy. In addition, two full-length HBV genomes derived from samples before and after the emergence of ETV resistance were sequenced. RESULTS: ETV resistant mutants appeared at week 228, with virological and biochemical rebound at the same time. Unexpectedly, HBeAg seroconversion occurred 8 weeks later. The viral load decreased and became undetectable from week 252. Analysis of HBV isolates in the patient at week 124 revealed that wild-type HBV was predominant at that time and ETV resistant mutants were not found among 20 clones. Interestingly, a new mutant type with rtL180M+rtT184L was found alongside rtL180M+rtT184L+rtM204V/I at week 228 and appeared to develop independently, according to the sequence analysis. In contrast to the previously identified ETV resistant mutants, it did not carry the rtM204V/I mutations. CONCLUSION: The data presented here indicates that the flare following the emergence of ETV resistant mutants may reflect immune-mediated control of HBV infection, leading to a spontaneous loss of HBV-DNA and seroconversion.
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BACKGROUNDS: The evaluation of liver fibrosis stages is essential for the clinical management of chronic hepatitis B (CHB). AIMS: To develop and validate a novel noninvasive index for moderate to severe fibrosis (≥S2) in CHB patients. METHODS: A total of 401 CHB patients who underwent liver biopsy were divided into the training (nâ¯=â¯300) and validation (nâ¯=â¯101) cohort. Histological severity was scored using a modified Scheuer system. Clinical and laboratory assessments were collected. RESULTS: In the training cohort, PACG, a novel index combining the quantitative hepatitis B core antibody (qAnti-HBc), platelet count (PLT), and albumin globulin ratio (A/G), presented better diagnostic performance (AUROCâ¯=â¯0.814) than that of APRI (0.735, pâ¯=â¯0.007) and FIB-4 (0.749, pâ¯=â¯0.014). In the validation cohort, the AUROC of the PACG, APRI, FIB-4 and Fibroscan were 0.834, 0.806, 0.791 and 0.810, respectively. More importantly, a higher and lower cutoff of PACG for predicting ≥S2 fibrosis or not had a >90% sensitivity and specificity, with a diagnostic accuracy of 85.9%. CONCLUSION: PACG is a promising noninvasive alternative to liver biopsy in CHB patients for the evaluation of moderate to severe fibrosis.
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Globulinas/metabolismo , Anticuerpos contra la Hepatitis B/sangre , Antígenos del Núcleo de la Hepatitis B/inmunología , Hepatitis B Crónica/complicaciones , Cirrosis Hepática/sangre , Cirrosis Hepática/diagnóstico , Albúmina Sérica/metabolismo , Adulto , Factores de Edad , Alanina Transaminasa/sangre , Área Bajo la Curva , Aspartato Aminotransferasas/sangre , Biomarcadores/sangre , Diagnóstico por Imagen de Elasticidad , Femenino , Humanos , Cirrosis Hepática/patología , Cirrosis Hepática/virología , Masculino , Recuento de Plaquetas , Valor Predictivo de las Pruebas , Curva ROC , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
Inexpensive and simple non-invasive indexes for predicting liver inflammation are urgently required, but have been poorly studied in chronic hepatitis B (CHB) patients with alanine transaminase (ALT) ≤2 times the upper limit of normal (ULN). A total of 356 CHB patients with ALT ≤2 ULN who presented at Huashan Hospital (n=181) and the First Hospital of Quanzhou (n=175) were enrolled and randomly divided into an experimental assessment cohort (n=238) and validation cohort (n=118) at a ratio of 2:1. Histological analysis of liver tissue was performed to determine the pathological stage according to the Scheuer scoring system. For the experimental assessment cohort, univariate and multivariate analysis identified aspartate aminotransferase (AST) and albumin (ALB) as independent predictors of liver necroinflammation [liver necroinflammation grade (G)≥2] in patients with ALT ≤2 ULN. Therefore, a novel index, the AST-to-ALB ratio (ATAR), was proposed, which had a better diagnostic performance [area under receiver operating characteristic curve (AUC)=0.721] than that of ALB (AUC=0.632; P=0.039 vs. ATAR) and AST (AUC=0.682; P=0.082 vs. ATAR). In the validation cohort, the AUC of ATAR (0.728) to identify patients with a G≥2 was slightly greater than that of AST (0.660; P=0.149 vs. ATAR) and ALB (0.672; P=0.282 vs. ATAR). Furthermore, a similar diagnostic superiority was also demonstrated in patients with ALT ≤1 ULN. Thus, ATAR may be a promising non-invasive surrogate marker for liver necroinflammation CHB patients with ALT ≤2 ULN and thereby determine whether anti-viral treatment should be initiated.
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BACKGROUND: The coexistence of hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) in patients with chronic hepatitis B virus (HBV) infection has been explained by the presence of viral escape mutants. Yet, no systematic analysis of such patients has been performed. We analyzed both the HBV strains and the nature of anti-HBs in such patients. METHODS: Four hundred eleven patients with chronic HBV infection were tested for the presence of anti-HBs. The sequences of the HBsAg coding region were analyzed. Anti-HBs were purified and examined in commercial assays alone and with 3 different HBsAg subtypes. RESULTS: Twenty patients had positive results for anti-HBs. This serological status remained stable for 12 months (as tested thus far). Amino acid substitutions and/or variations on HBsAg were found in 13 patients, and the HBV isolates from 4 others were wild types. Importantly, no significant difference in the occurrence of amino acid substitutions within the HBsAg was found in HBV isolates from patients with and without anti-HBs. Purified immunoglobulin fractions from serum samples from patients were reactive to HBsAg but had a lower specific activity, compared with those taken from immunized persons. Anti-HBs in patients were directed to the HBsAg subtypes other than the coexisting one. No circulating immune complex could be detected in these patients. CONCLUSION: HBsAg and anti-HBs with an unmatched specificity coexisted in 4.9% of patients. The presence of anti-HBs was not associated with the appearance of specific HBV mutants in patients with chronic infection. Apparently, the presence of anti-HBs in patients with chronic HBV infection did not lead to a selection of HBV escape mutants.
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Especificidad de Anticuerpos , Anticuerpos contra la Hepatitis B/sangre , Antígenos de Superficie de la Hepatitis B/sangre , Antígenos de Superficie de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Adulto , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Femenino , Genotipo , Anticuerpos contra la Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/inmunología , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia MolecularRESUMEN
OBJECTIVE: To study the resistant rate of hepatitis B virus (HBV) to ADV and the dynamic evolution of HBV in lamivudine (Lam)-resistant chronic hepatitis B (CHB) patients. METHODS: Twenty-three Lam-resistant CHB patients were assigned to a 10mg/d ADV monotherapy for 68-116 weeks. The baseline and different time point blood samples after ADV monotherapy were analyzed for ADV-resistant mutations using direct sequencing of PCR products; the evolution of HBV mutations was examined by clonal analysis of serial samples from one patient infected with ADV-associated resistant HBV strains. RESULTS: The cumulative incidence of genotypic ADV resistance at weeks 48 and 96 was 4.3% and 10.5% respectively respectively. The evolution analysis of HBV mutant strains in an ADV-resistant CHB patient showed that the proportion of YMDD mutants gradually decreased with rtA181S mutants increasing over time after ADV monotherapy, and that rtA181S+N236T mutants became the predominant strains during prolonged ADV monotherapy. The addition of Lam to the ongoing ADV treatment had poorer antiviral response in the patient with rtA181S or rtA181S+N236T mutant infection; one clone with multi-drug resistant mutations was selected during Lam and ADV combination therapy. CONCLUSION: Increased risk of adefovir resistance and selection of multi-drug resistant mutations are associated with long-term ADV monotherapy in patients with Lam-resistant chronic hepatitis B.
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Adenina/análogos & derivados , Farmacorresistencia Viral , Evolución Molecular , Virus de la Hepatitis B/genética , Hepatitis B Crónica/virología , Organofosfonatos/uso terapéutico , Adenina/uso terapéutico , Adulto , Antivirales/uso terapéutico , Femenino , Virus de la Hepatitis B/clasificación , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Lamivudine/farmacología , Masculino , Persona de Mediana EdadRESUMEN
An HBsAg-HBIG therapeutic vaccine (Yeast-derived Immune Complexes, YIC) for chronic hepatitis B (CHB) patients has undergone a series of clinical trials. The HBeAg sero-conversion rate of YIC varied from 21.9% to 14% depending on the immunization protocols from 6 to 12 injections. To analyze the immunological mechanisms exerted by 6 injections of YIC, 44 CHB patients were separately immunized with YIC, alum as adjuvant control or normal saline as blank control, with add on of antiviral drug Adefovir in all groups. Kinetic increase in Th1 and Th2 cells CD4+ T cell sub-populations with association in decrease in Treg cells and increase of Tc1 and Tc17 cells in CD8+ T cells were observed in YIC immunized group. No such changes were found in the other groups. By multifunctional analysis of cytokine profiles, significant increase of IL-2 levels was observed, both in CD4+ and CD8+ T cells in the YIC immunized group, accompanied by increase in IFN-gamma and decrease of inhibitory factors (IL-10, TGF-ß and Foxp3) in CD4+ T cells. In the alum immunized group, slight increase of IL-10, TGF-ß and Foxp3 in CD4+ T cells was found after the second injection, but decreased after more injections, suggesting that alum induced early inflammatory responses to a certain extent. Similar patterns of responses of IL-17A and TNF-α in CD8+T cells were shown between YIC and the saline group. Results indicate that add on of Adefovir, did not affect host specific immune responses.
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Adenina/análogos & derivados , Antígenos de Superficie de la Hepatitis B/inmunología , Vacunas contra Hepatitis B/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Organofosfonatos/uso terapéutico , Adenina/efectos adversos , Adenina/inmunología , Adenina/uso terapéutico , Adyuvantes Inmunológicos , Adulto , Complejo Antígeno-Anticuerpo , Terapia Combinada , Femenino , Vacunas contra Hepatitis B/efectos adversos , Vacunas contra Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Humanos , Interleucina-10/inmunología , Interleucina-17/inmunología , Interleucina-2/inmunología , Masculino , Organofosfonatos/efectos adversos , Organofosfonatos/inmunología , Células TH1/inmunología , Células Th2/inmunología , Factor de Crecimiento Transformador beta/biosíntesis , Factor de Crecimiento Transformador beta/inmunología , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/inmunología , Adulto JovenRESUMEN
AIM: To investigate precore/basal core promoter (PC/BCP) mutants throughout hepatitis B virus (HBV) infection and to determine their relationship to hepatitis B early antigen (HBeAg) titers. METHODS: We enrolled 191 patients in various stages of HBV infection at the Huashan Hospital and the Taizhou Municipal Hospital from 2010 to 2012. None of the patients received antiviral therapy. HBV DNA from serum, was quantified by real-time PCR. The HBV genotype was determined by direct sequencing of the S gene. We used the Simpleprobe ultrasensitive quantitative method to detect PC/BCP mutants in each patient. We compared the strain number, percentage, and the changes in PC/BCP mutants in different phases, and analyzed the relationship between PC/BCP mutants and HBeAg by multiple linear regression and logistic regression. RESULTS: Patients with HBV infection (n = 191) were assigned to groups by phase: Immune tolerance (IT) = 55, Immune clearance (IC) = 67, Low-replicative (LR) = 49, and HBeAg-negative hepatitis (ENH) = 20. Of the patients (male, 112; female, 79) enrolled, 122 were HBeAg-positive and 69 were HBeAg-negative. The median age was 33 years (range: 18-78 years). PC and BCP mutation detection rates were 84.82% (162/191) and 96.86% (185/191), respectively. In five HBeAg-negative cases, we detected double mutation G1896A/G1899A. The logarithm value of PC mutant quantities (log10 PC) significantly differed in IT, IC, and LR phases, as well as in the ENH phase (F = 49.350, P < 0.001). The logarithm value of BCP mutant quantities (log10 BCP) also differed during the four phases (F = 25.530, P < 0.001). Log10 PC and log10 BCP values were high in the IT and IC phases, decreased in the LR phase, and increased in the ENH phase, although the absolute value at this point remained lower than that in the IT and IC phases. PC mutant quantity per total viral load (PC%) and BCP mutant quantity per total viral load (BCP%) differed between phases (F = 20.040, P < 0.001; F = 10.830, P < 0.001), with PC% and BCP% gradually increasing in successive phases. HBeAg titers negatively correlated with PC% (Spearman's rho = -0.354, P < 0.001) and BCP% (Spearman's rho = -0.395, P < 0.001). The negative correlation between PC% and HBeAg status was significant (B = -5.281, P = 0.001), but there was no such correlation between BCP% and HBeAg status (B = -0.523, P = 0.552). CONCLUSION: PC/BCP mutants become predominant in a dynamic and continuous process. Log10 PC, log10 BCP, PC% and BCP% might be combined to evaluate disease progression. PC% determines HBeAg status.