RESUMO
The infection of Hepatitis B virus (HBV) can result in severe consequences, including chronic hepatitis, liver fibrosis, cirrhosis, and even liver cancer. Effective antiviral treatment has the potential to slow down the progression of the disease. HBV serum biomarkers play a crucial role in the dynamic management of chronic hepatitis B (CHB) patients. However, the conventional hepatitis B virus markers, such as hepatitis B serologic testing and HBV DNA, are insufficient to meet the clinical requirements. This review provided a comprehensive overview of the current research on the quantification of HBsAg and anti-HBc, HBV RNA and HBV core-associated antigen, which summarized the crucial role these markers play in the administration of antiviral medications, predicting the efficacy of treatment and anticipating the likelihood of virologic rebound following drug cessation, as well as assessing disease progression in CHB patients.
Assuntos
Hepatite B Crônica , Hepatite B , Humanos , Vírus da Hepatite B/genética , Relevância Clínica , Hepatite B Crônica/tratamento farmacológico , Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , Biomarcadores , Cirrose Hepática/tratamento farmacológico , Antivirais/uso terapêutico , Antígenos de Superfície da Hepatite B/uso terapêutico , DNA Viral/uso terapêutico , Antígenos E da Hepatite B/uso terapêutico , Hepatite B/tratamento farmacológicoRESUMO
BACKGROUND AND AIMS: Liver transplantation (LT) is the primary curative option for cirrhotic patients with early-stage hepatocellular carcinoma (HCC). However, tumor recurrence occurs in 15-20% of cases with unfavorable prognosis. We have developed a library of T cell receptors (TCRs) specific for different hepatitis B virus (HBV) antigens, restricted by different molecules of human leucocyte antigen (HLA)-class I, to redirect T cells against HBV antigens (Banu in Sci Rep 4:4166, 2014). We further demonstrated that these transiently functional T cells specific for HBV obtained through messenger RNA (mRNA) electroporation can eliminate HCC cells expressing HBV antigens in vitro and in vivo (Kah in J Clin Invest 127:3177-3188, 2017). A phase I clinical trial for patients with HCC recurrence post-liver transplant was conducted to assess the safety, tolerability, and anti-tumor efficacy of transiently functional HBV-TCR T cells. Here, we report the clinical findings with regard to the safety and anti-tumor efficacy of mRNA electroporated HBV-specific TCR-T cells. (ClinicalTrials.gov identifier: NCT02719782). PATIENTS AND METHODS: A total of six patients with HBV-positive recurrent HCC post-liver transplant and HLA-matched to TCR targeting hepatitis B surface antigen (HBsAg) or hepatitis B core antigen (HBcAg) (HLA-A*02:01/HBsAg, HLA-A*11:01/HBcAg, HLA-B*58:01/HBsAg or HLA-C*08:01/HBsAg) were enrolled in this study. The primary objective was to assess the safety of short-lived mRNA electroporated HBV-TCR T cells based on the incidence and severity of the adverse event (AE) graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0. The secondary objective was to determine the effectiveness of HBV-TCR T cells as per RECIST 1.1 criteria. Patients were followed up for survival for 2 years post-end of treatment. RESULTS: The median age of the six patients was 35.5 years (range: 28-47). The median number of HBV-TCR T cell infusions administered was 6.5 (range: 4-12). The treatment-related AE included grade 1 pyrexia. This study reported no cytokine release syndrome nor neurotoxicity. One patient remained alive and five were deceased at the time of the data cutoff (30 April 2020). CONCLUSION: This study has demonstrated that multiple infusions of mRNA electroporated HBV-specific TCR T cells were well-tolerated in patients with HBV-positive recurrent HCC post-liver transplant.
Assuntos
Carcinoma Hepatocelular , Hepatite B , Neoplasias Hepáticas , Transplante de Fígado , Humanos , Adulto , Pessoa de Meia-Idade , Vírus da Hepatite B/genética , Antígenos de Superfície da Hepatite B , Neoplasias Hepáticas/patologia , Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , RNA Mensageiro , Recidiva Local de Neoplasia/terapia , Recidiva Local de Neoplasia/complicações , Receptores de Antígenos de Linfócitos T/genética , Hepatite B/complicaçõesRESUMO
INTRODUCTION: Expanding the heart donor pool to include patients with hepatitis B virus (HBV) could help ameliorate the organ shortage in heart transplantation. We performed a systematic review and meta-analysis to evaluate the management and recipient outcomes of D+/R- and D-/R+ heart transplants. METHODS: An electronic search was performed to identify all relevant studies published on heart transplants involving HBV+ donors and/or HBV+ recipients. A comparison was performed between two groups where heart transplants were performed a) D+/R- (n = 98) versus b) D-/R+ (n = 65). RESULTS: Overall, 13 studies were selected, comprising 163 patients. Mean patient age was 55 y (95% CI: 39, 78) and 79% (69, 86) were male. Active post-transplant HBV infection requiring antiviral treatment occurred in 11% (1, 69) of D+/R- recipients and 33% (9, 71) of D-/R+ recipients. Post-transplant antiviral therapy was given to 80% (6, 100) of D+/R- recipients compared to 72% (42, 90) of D-/R+ recipients (P = 0.84). Hepatitis-related mortality was observed in no D+/R- recipients and 7% (2, 27) of D-/R+ recipients. Survival 1-y post-transplant was comparable between both groups at 83% (83, 92) and 81% (61, 92) for D+/R- and D-/R+ transplants, respectively. CONCLUSIONS: Our review found that HBV D+/R- heart transplantation was associated with fewer active hepatitis infections and lower hepatitis-related mortality than D-/R+ transplantation, with comparable survival at 1 y. Additional studies utilizing HBV nucleic acid testing (NAT) to compare outcomes with HBsAg+ and anti-HBc+ donors are crucial to reach more definitive conclusions about the risk of donor-derived infections in this context.
Assuntos
Transplante de Coração , Hepatite B , Humanos , Masculino , Feminino , Hepatite B/epidemiologia , Hepatite B/tratamento farmacológico , Vírus da Hepatite B , Transplante de Coração/efeitos adversos , Antivirais/uso terapêutico , Anticorpos Anti-Hepatite B/uso terapêutico , Doadores de Tecidos , Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , Estudos RetrospectivosRESUMO
BACKGROUND: Studies have shown acute flares of chronic hepatitis B (CHB) might be related to immunologic changes that occur during pregnancy. However, the indicators for predicting acute flares of CHB among pregnant women still need further study. We aimed to distinguish the relevance between serum levels of HBcrAg and acute flares of CHB in pregnant women in the immune-tolerant phase of chronic HBV infection after short-course antiviral therapy. METHODS: A total of 172 chronic HBV-infected pregnant women who were judged to be in the immune-tolerant phase were recruited in our research. All patients received short-course antiviral therapy with TDF. The biochemical, serological, and virological parameters were measured using standard laboratory procedures. The serum levels of HBcrAg were tested by ELISA. RESULTS: Fifty-two (30.2%) out of 172 patients had acute flares of CHB. At postpartum week 12 (TDF cessation), serum HBcrAg (OR, 4.52; 95% CI, 2.58-7.92) and HBsAg (OR, 2.52; 95% CI, 1.13-5.65) were associated with acute flares of CHB. The serum HBcrAg levels were beneficial for confirmation of patients with acute flares of CHB, with an area under the ROC curve of 0.84 (95% CI, 0.78-0.91). CONCLUSIONS: For pregnant women with chronic HBV infection in the immune-tolerant phase, serum HBcrAg and HBsAg levels at postpartum week 12 were associated with acute flares of CHB after short-course antiviral therapy with TDF. The serum HBcrAg level can correctly identify acute flares of CHB and may be a predictor of the need for continuing antiviral therapy after 12 weeks postpartum.
Assuntos
Antígenos do Núcleo do Vírus da Hepatite B , Hepatite B Crônica , Humanos , Feminino , Gravidez , Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , Vírus da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Antígenos de Superfície da Hepatite B/uso terapêutico , Gestantes , Antígenos E da Hepatite B/uso terapêutico , Antivirais/uso terapêutico , DNA Viral/análise , BiomarcadoresRESUMO
BACKGROUND/PURPOSE(S): Since ALT flares after therapy withdrawal are associated with adverse outcomes, risk stratification is of major importance. We aimed to study whether off-treatment flares are related with virological outcomes, and if serum levels of novel biomarkers at end-of-treatment (EOT) can predict flares. METHODS: Chronic hepatitis B patients who participated in three global randomised trials of peginterferon-based therapy were studied (99-01, PARC, ARES). HBV RNA, HBsAg and HBcrAg were quantified at EOT. Associations between EOT biomarker levels and flares were assessed as continuous data and after categorisation. Flares were defined as ALT ≥5xULN during six months after therapy cessation. RESULTS: We included 344 patients; 230 HBeAg-positive and 114 HBeAg-negative. Patients were predominantly Caucasian (77.0%) and had genotype A/B/C/D in 23.3/7.3/13.4/52.3%. Flares were observed in 122 patients (35.5%). Flares were associated with lower rates of sustained response (3.5% vs 26.8% among patients with and without a flare; p < 0.001). Higher HBsAg (OR 1.586, 95%CI 1.231-2.043), HBV RNA (OR 1.695, 95%CI 1.371-2.094) and HBcrAg (OR 1.518, 95%CI 1.324-1.740) levels were associated with higher risk of flares (p < 0.001). Combinations of biomarkers further improved risk stratification, especially HBsAg + HBV RNA. Findings were consistent in multivariate analysis adjusted for potential predictors including HBeAg-status and EOT-response (HBV DNA <200 IU/mL). CONCLUSION: Off-treatment ALT flares were not associated with favourable virological outcomes. Higher EOT serum HBsAg, HBcrAg and HBV RNA were associated with a higher risk of flares after therapy withdrawal. These findings can be used to guide decision-making regarding therapy discontinuation and off-treatment follow-up. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00114361, NCT00146705, NCT00877760.
Assuntos
Hepatite B Crônica , Humanos , Antivirais/uso terapêutico , Biomarcadores , DNA Viral , Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , Antígenos E da Hepatite B/uso terapêutico , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , RNARESUMO
The infection of Hepatitis B virus (HBV) can result in severe consequences, including chronic hepatitis, liver fibrosis, cirrhosis, and even liver cancer. Effective antiviral treatment has the potential to slow down the progression of the disease. HBV serum biomarkers play a crucial role in the dynamic management of chronic hepatitis B (CHB) patients. However, the conventional hepatitis B virus markers, such as hepatitis B serologic testing and HBV DNA, are insufficient to meet the clinical requirements. This review provided a comprehensive overview of the current research on the quantification of HBsAg and anti-HBc, HBV RNA and HBV core-associated antigen, which summarized the crucial role these markers play in the administration of antiviral medications, predicting the efficacy of treatment and anticipating the likelihood of virologic rebound following drug cessation, as well as assessing disease progression in CHB patients.
Assuntos
Humanos , Vírus da Hepatite B/genética , Relevância Clínica , Hepatite B Crônica/tratamento farmacológico , Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , Biomarcadores , Cirrose Hepática/tratamento farmacológico , Antivirais/uso terapêutico , Antígenos de Superfície da Hepatite B/uso terapêutico , DNA Viral/uso terapêutico , Antígenos E da Hepatite B/uso terapêutico , Hepatite B/tratamento farmacológicoRESUMO
Chronic hepatitis B (CHB) infection remains a serious public health problem worldwide; however, the relationship between cholesterol levels and CHB remains unclear. We isolated peripheral blood mononuclear cells from healthy blood donors and CHB patients to analyze free cholesterol levels, lipid raft formation, and cholesterol metabolism-related pathways. Hepatitis B virus (HBV)-carrier mice were generated and used to confirm changes in cholesterol metabolism and cell-surface lipid raft formation in dendritic cells (DCs) in the context of CHB. Additionally, HBV-carrier mice were immunized with a recombinant HBV vaccine (rHBVvac) combined with lipophilic statins and evaluated for vaccine efficacy against HBV. Serum samples were analyzed for HBsAg, anti-HBs, and alanine aminotransferase levels, and liver samples were evaluated for HBV DNA and RNA and HBcAg. CHB reduced free cholesterol levels and suppressed lipid raft formation on DCs in patients with CHB and HBV-carrier mice, whereas administration of lipophilic statins promoted free cholesterol accumulation and restored lipid rafts on DCs accompanied by an enhanced antigen-presentation ability in vitro and in vivo. Cholesterol accumulation on DCs improved the rHBVvac-mediated elimination of serum HBV DNA and intrahepatic HBV DNA, HBV RNA, and HBcAg and promoted the rHBVvac-mediated generation and polyfunctionality of HBV-specific CD11ahi CD8αlo cells, induction of the development of memory responses against HBV reinfection, and seroconversion from HBsAg to anti-HBs. The results demonstrated the important role of cholesterol levels in DC dysfunction during CHB, suggesting that strategies to increase cholesterol accumulation on DCs might enhance therapeutic vaccine efficacy against HBV and support development toward clinical CHB treatment.
Assuntos
Hepatite B Crônica , Hepatite B , Inibidores de Hidroximetilglutaril-CoA Redutases , Vacinas , Camundongos , Animais , Antígenos de Superfície da Hepatite B , Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , DNA Viral , Leucócitos Mononucleares , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Vírus da Hepatite B , Anticorpos Anti-Hepatite B , Células Dendríticas , Colesterol/uso terapêutico , RNARESUMO
Background and aim: Chronic hepatitis B (CHB) can be divided into immune tolerance (IT), immune clearance (IC), hepatitis B e antigen (HBeAg)-negative inactive/quiescent carrier (ENQ), and HBeAg-negative hepatitis (ENH) phases. The conventional biomarkers used to distinguish these phases have limitations. We examined the clinical significance of hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg) as novel biomarkers. Methods: One hundred eighty-nine patients without treatment currently were categorized by CHB phase (IT = 46, IC = 45, ENQ = 49, ENH = 49). The associations of HBV RNA and HBcrAg with HBV DNA and alanine transaminase (ALT) were analyzed. The decision tree model was used to distinguish the four phases in the natural course of CHB. Results: The concentrations of HBV RNA and HBcrAg were highest in the IT and IC phases (P < 0.01). Serum HBV RNA was similar to HBcrAg in treatment-naïve patients. HBV RNA and HBcrAg correlated with HBV DNA in the HBeAg+ and HBeAg- status (HBV RNA: e+ r = 0.51, e- r = 0.62; HBcrAg: e+ r = 0.51, e- r = 0.71), but their association with HBV DNA differed among phases. The accuracy, sensitivity, and specificity of HBcrAg with ALT in distinguishing the CHB phases were 95.65%, 95.83%, and 95.55%, respectively. Conclusion: Serum HBV RNA and HBcrAg may be useful to monitor CHB progression.
Assuntos
Hepatite B Crônica , Hepatite B , Humanos , Antígenos E da Hepatite B/uso terapêutico , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , DNA Viral/uso terapêutico , Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , Biomarcadores , RNA/uso terapêuticoRESUMO
Standard treatment of hepatitis delta virus (HDV) infection remains pegylated-interferon alfa (peg-IFNα) in most centers, which is not only associated with rather low efficacy but several adverse events. Hepatitis B core-related antigen (HBcrAg) is linked to intrahepatic covalently closed circular DNA levels and has previously been suggested as response predictor in IFN-based treatment of hepatitis B virus (HBV) mono-infection. This study aimed to investigate the value of HBcrAg in the management of patients with HBV/HDV co-infection undergoing peg-IFNα treatment. The Hep-Net-International-Delta-Hepatitis-Intervention Trial-2 study included 120 patients co-infected with HBV/HDV. Patients were treated for 96 weeks with peg-IFNα and either tenofovir or placebo. Ninety-nine patients with HDV-RNA results 24 weeks after end of treatment (FU24) were included in this analysis, of whom 32 patients (32.3%) had undetectable HDV RNA at FU24. HBcrAg was measured at baseline, week 12, 24, 48, 96, and FU24. HBcrAg levels showed no significant correlation with HDV RNA but were significantly linked to treatment outcome. HBcrAg levels < 4.5 log IU/mL at baseline, week 24, and week 48 had high negative predictive value (NPV) for achieving undetectable HDV RNA at FU24 (81.8%, 87.1% and 95.0%, respectively). Similarly, HBcrAg levels at week 96 were significantly higher in patients with viral relapse until FU24 (3.0 vs. 3.63 log IU/mL; P = 0.0089). Baseline, week 24, and week 48 HBcrAg levels were also associated with the likelihood of achieving HBsAg level < 100 IU/mL at FU24 (HBcrAg < 3.0 log IU/mL: NPV 91.7%, 90.4% and 92.3%, respectively). Test statistics improved when combining HBcrAg with additional viral and clinical parameters. Conclusion: HBcrAg is linked to treatment response to peg-IFNα in patients with HBV/HDV co-infection and could be a promising marker to determine treatment futility.
Assuntos
Coinfecção , Hepatite B Crônica , Antivirais/efeitos adversos , Coinfecção/tratamento farmacológico , DNA Viral/análise , Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Vírus Delta da Hepatite/genética , Humanos , Interferon-alfa/efeitos adversos , RNA/uso terapêuticoRESUMO
Hepatitis B core-related antigen (HBcrAg) is a composite measure of the serum levels of hepatitis B e antigen, hepatitis B core antigen, and a 22-kDa precore protein. It has been shown to reflect the level and transcriptional activity of covalently closed circular DNA in the liver. Longitudinal cohort studies have improved our understanding of the role of this novel viral marker in the natural history of chronic hepatitis B. HBcrAg kinetics reflect the response to peginterferon, and its role in defining guidelines for stopping peginterferon therapy has been evaluated. HBcrAg is a marker of intrahepatic viral activity, which may influence the risk of hepatocellular carcinoma. In this article, we review the virology and role of HBcrAg in defining phases of chronic hepatitis B. Furthermore, the function of HBcrAg in predicting treatment outcomes and its role in monitoring response to novel antiviral agents will be discussed.
Assuntos
Hepatite B Crônica , Neoplasias Hepáticas , Antivirais/uso terapêutico , Biomarcadores , DNA Viral , Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Estudos LongitudinaisRESUMO
BACKGROUND: Viral quasispecies dynamics between pre- and post-nucleos(t)ide analog (NA) therapy remains unclear. AIM: This study aimed to investigate the HBV quasispecies evolution and its relationship with durability of off-therapy responses in HBeAg-negative chronic hepatitis B (CHB) patients who stopped NA therapy. METHODS: Fifty-four HBeAg-negative CHB patients who stopped NAs, including 19 virological controllers (VC) who maintained serum HBV DNA < 2000 IU/mL beyond 1-year off-therapy, and 35 virological relapsers (VR) experiencing virological relapse within 1-year off-therapy were recruited. Viral quasispecies was analyzed by deep sequencing. Hepatitis B core-related antigen (HBcrAg) and HBsAg were also measured. RESULTS: VC had significantly higher baseline viral quasispecies diversity of the precore/core gene, measured by nucleotide diversity, than VR. Low baseline viral nucleotide diversity (< 0.01) and high HBcrAg (⧠2.0 KU/mL), but not HBsAg, at end of treatment (EOT) were significantly associated with higher risk of 1-year virological relapse (hazard ratio [HR] 6.09 and 3.31, respectively). Combination of low baseline viral nucleotide diversity and high HBcrAg at EOT could identify patients at high risk (HR 15.82). Further analysis of the evolution of HBV whole genome showed that HBV nucleotide diversity negatively correlated with serum HBV DNA levels. Notably, the viral quasispecies diversity between pre- and post-NA treatment remained relatively unchanged. CONCLUSION: Higher baseline HBV quasispecies diversity associates with more durable off-therapy viral suppression in HBeAg-negative CHB patients. Combination of baseline viral nucleotide diversity and HBcrAg at EOT can identify patients at high risk for virological relapse after stopping NAs.
Assuntos
Hepatite B Crônica , Antivirais/uso terapêutico , DNA Viral , Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , Antígenos de Superfície da Hepatite B , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Quase-EspéciesRESUMO
BACKGROUND/PURPOSE: The study investigated the role of hepatitis B core-related antigen (HBcrAg) in hepatitis B virus (HBV) relapse after stopping tenofovir disoproxil fumarate (TDF) in HBeAg-negative patients. METHODS: A total of 185 HBeAg-negative patients without cirrhosis who had stopped TDF treatment for at least 6 months were recruited. All patients fulfilled the stopping criteria proposed by the Asian Pacific Association for the Study of the Liver 2012. RESULTS: The 3-year cumulative incidences of virological relapse, clinical relapse, and hepatitis B surface antigen (HBsAg) loss were 72, 60.1 and 14.5%, respectively. End-of-treatment (EOT) HBsAg level was an independent predictor of virological relapse (hazard ratio (HR): 2.263; 95% confidence interval (CI): 1.779-2.887), clinical relapse (HR 1.773; 95% CI 1.367-2.298), and HBsAg loss (HR 0.179; 95% CI 0.096-0.335). Among patients who had HBsAg < 100 and ≥ 100 IU/mL, the 3-year virological relapse rates were 37.4% and 85.3% (p < 0.001), clinical relapse rates were 30.3 and 71.7% (p < 0.001), and HBsAg loss rates were 40.6 and 2.6% (p < 0.001), respectively. Among the 53 patients with EOT HBsAg level < 100 IU/mL, the 3-year virological relapse rates in patients with baseline HBcrAg levels < 4.7 and ≥ 4.7 log10 U/mL were 20.3 and 60.4% (p = 0.003), and the clinical relapse rates were 10.3 and 59.5% (p < 0.001) respectively. Additionally, the 3-year HBsAg loss rates in patients with baseline HBcrAg ≤ 3 and > 3 log10 U/mL were 42.9 and 7.9% (p < 0.001). CONCLUSIONS: The combination of EOT HBsAg and baseline HBcrAg levels could further reduce the risk of HBV relapse after stopping TDF therapy in HBeAg-negative patients.
Assuntos
Hepatite B Crônica , Antivirais/uso terapêutico , DNA Viral , Guanina/uso terapêutico , Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , Antígenos de Superfície da Hepatite B , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Recidiva , Tenofovir/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Hepatitis B core-related antigen (HBcrAg) is a promising disease-monitoring marker for chronic hepatitis B (CHB). We investigated correlations between HBcrAg with antiviral efficacy and virological and histological variables. METHODS: One hundred and forty-five CHB patients from the mainland of China between August 2013 and September 2016 who underwent liver biopsy received entecavir therapy and had paired liver biopsy at 78 weeks. We analyzed correlations between HBcrAg and virological and histological variables in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. We also explored the predictors of HBeAg loss after 78 weeks of antiviral therapy. Pearson correlation analysis and logistic forward stepwise regression were the main statistic methods. RESULTS: HBeAg-positive patients (nâ=â93) had higher baseline HBcrAg (median 7.4 vs. 5.3 log10 U/mL Pâ<â0.001) and greater HBcrAg declines (median 1.6 vs. 0.9 log10 U/mL Pâ=â0.007) than HBeAg-negative patients after 78 weeks of therapy. At baseline, HBcrAg correlated with hepatitis B virus (HBV) DNA in both HBeAg-positive (râ=â0.641, Pâ<â0.001) and -negative patients (râ=â0.616, Pâ<â0.001), with hepatitis B surface antigen (HBsAg) in HBeAg-positive patients (râ=â0.495, Pâ<â0.001), but not with anti-hepatitis B virus core antibody (anti-HBc). Weak correlations existed between HBcrAg, histology activity index (HAI; râ=â0.232, Pâ=â0.025), and Ishak fibrosis score (râ=â-0.292, Pâ=â0.005) in HBeAg-positive patients. At 78 weeks, significant correlations existed only between HBcrAg and anti-HBc in HBeAg-positive (râ=â-0.263, Pâ=â0.014) and HBeAg-negative patients (râ=â-0.291, Pâ=â0.045). Decreased HBcrAg significantly correlated with reduced HBV DNA (râ=â0.366, Pâ=â0.001; râ=â0.626, Pâ<â0.001) and HBsAg (râ=â0.526, Pâ=â0.001; râ=â0.289, Pâ=â0.044) in HBeAg-positive and -negative patients, respectively, and with reduced HAI in HBeAg-positive patients (râ=â0.329, Pâ=â0.001). Patients with HBeAg loss (nâ=â29) showed a larger reduction in HBcrAg than those without (median 2.3 vs. 1.3 log10 U/mL, Pâ=â0.001). In multivariate analysis, decreased HBcrAg was an independent predictor of HBeAg loss (Pâ=â0.005). CONCLUSIONS: HBcrAg reflects viral replication and protein production. Decreased HBcrAg could predict HBeAg loss after antiviral therapy. TRIAL REGISTRATION: Clinical Trials.gov: NCT01962155; https://www.clinicaltrials.gov/ct2/show/NCT01962155?term=NCT01962155&draw=2&rank=1.
Assuntos
Antígenos do Núcleo do Vírus da Hepatite B , Hepatite B Crônica , Antivirais/uso terapêutico , Biomarcadores , China , DNA Viral , Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , Antígenos de Superfície da Hepatite B , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Replicação ViralRESUMO
BACKGROUND@#Hepatitis B core-related antigen (HBcrAg) is a promising disease-monitoring marker for chronic hepatitis B (CHB). We investigated correlations between HBcrAg with antiviral efficacy and virological and histological variables.@*METHODS@#One hundred and forty-five CHB patients from the mainland of China between August 2013 and September 2016 who underwent liver biopsy received entecavir therapy and had paired liver biopsy at 78 weeks. We analyzed correlations between HBcrAg and virological and histological variables in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. We also explored the predictors of HBeAg loss after 78 weeks of antiviral therapy. Pearson correlation analysis and logistic forward stepwise regression were the main statistic methods.@*RESULTS@#HBeAg-positive patients (n = 93) had higher baseline HBcrAg (median 7.4 vs. 5.3 log10 U/mL P < 0.001) and greater HBcrAg declines (median 1.6 vs. 0.9 log10 U/mL P = 0.007) than HBeAg-negative patients after 78 weeks of therapy. At baseline, HBcrAg correlated with hepatitis B virus (HBV) DNA in both HBeAg-positive (r = 0.641, P < 0.001) and -negative patients (r = 0.616, P < 0.001), with hepatitis B surface antigen (HBsAg) in HBeAg-positive patients (r = 0.495, P < 0.001), but not with anti-hepatitis B virus core antibody (anti-HBc). Weak correlations existed between HBcrAg, histology activity index (HAI; r = 0.232, P = 0.025), and Ishak fibrosis score (r = -0.292, P = 0.005) in HBeAg-positive patients. At 78 weeks, significant correlations existed only between HBcrAg and anti-HBc in HBeAg-positive (r = -0.263, P = 0.014) and HBeAg-negative patients (r = -0.291, P = 0.045). Decreased HBcrAg significantly correlated with reduced HBV DNA (r = 0.366, P = 0.001; r = 0.626, P < 0.001) and HBsAg (r = 0.526, P = 0.001; r = 0.289, P = 0.044) in HBeAg-positive and -negative patients, respectively, and with reduced HAI in HBeAg-positive patients (r = 0.329, P = 0.001). Patients with HBeAg loss (n = 29) showed a larger reduction in HBcrAg than those without (median 2.3 vs. 1.3 log10 U/mL, P = 0.001). In multivariate analysis, decreased HBcrAg was an independent predictor of HBeAg loss (P = 0.005).@*CONCLUSIONS@#HBcrAg reflects viral replication and protein production. Decreased HBcrAg could predict HBeAg loss after antiviral therapy.@*TRIAL REGISTRATION@#Clinical Trials.gov: NCT01962155; https://www.clinicaltrials.gov/ct2/show/NCT01962155?term=NCT01962155&draw=2&rank=1.
Assuntos
Humanos , Antivirais/uso terapêutico , Biomarcadores , China , DNA Viral , Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , Antígenos de Superfície da Hepatite B , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Replicação ViralRESUMO
CONTEXT: Current drugs for chronic hepatitis B therapy have a poor efficacy in terms of post-treatment sustained viral suppression and generate important side effects during and after therapy. Therapeutic vaccination with HBV antigens is an attractive alternative to test. OBJECTIVE: Evaluating the efficacy of a therapeutic vaccine candidate (designated NASVAC) containing both hepatitis B surface antigen (HBsAg) and core antigen (HBcAg) versus pegylated interferon (Peg-IFN) in naïve chronic hepatitis B patients. DESIGN, SETTING, PARTICIPANTS: An open phase III, randomised and treatment controlled clinical trial was conducted in a total of 160 CHB patients, allocated into two groups of 80 patients each to receive NASVAC or Peg-IFN. The vaccine formulation comprised 100 µg of each HBsAg and HBcAg, and was administered in 2 cycles of 5 doses. The control group received 48 subcutaneous injections of Peg-IFN alfa 2b, 180 µg per dose, every week, for 48 consecutive weeks. MAIN OUTCOME MEASURE: The primary outcome measure was in relation with the proportion of patients showing reduction of the viral load under the limit of detection (250 copies/mL) after 24 weeks of treatment completion. RESULTS: Sustained control of HBV DNA was significantly more common in NASVAC group (p<0.05) at 24 weeks of follow up. NASVAC-induced increases of alanine aminotransferases (ALT) were detected in 85% patients after 5 nasal vaccinations, although seen in only 30% of patients receiving Peg-IFN. At the end of treatment (EOT) antiviral effect was comparable in both NASVAC and Peg-IFN groups. Clearance of Hepatitis B e antigen (HBeAg) was also more frequent in NASVAC group compared to Peg-IFN recipients. A lower progression to cirrhosis was found in NASVAC group compared to Peg-IFN group. CONCLUSION: Nasvac induced a superior reduction of the viral load under the limit of detection compared to Peg-IFN treatment. It is a safe and efficacious finite alternative of antiviral treatment for CHB patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT 01374308.
Assuntos
Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , Antígenos de Superfície da Hepatite B/uso terapêutico , Hepatite B Crônica/terapia , Adolescente , Adulto , Antivirais/uso terapêutico , Quimioterapia Combinada , Feminino , Vacinas contra Hepatite B/uso terapêutico , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/virologia , Humanos , Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Interferons/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Vacinas/uso terapêutico , Carga ViralRESUMO
Chronic hepatitis B virus (HBV) infection is characterized by functionally impaired type 1 T-helper cell (Thl) immunity and poor HBVspecific Tcell responses. Ubiquitin (Ub), a highly conserved small regulatory protein, commonly serves as a signal for target proteins that are recognized and degraded in proteasomes. The rapid degradation of Ubmediated antigens results in efficient stimulation of cellmediated immune responses. Thus, the UbHBV core antigen (HBcAg)cytoplasmic transduction peptide (CTP) fusion protein was designed for specific delivery of a foreign modified antigen to the cytoplasm of antigenpresenting cells. HBV transgenic mice were used to determine whether UbHBcAgCTP would restore HBVspecific immune responses and antiviral immunity in these animals. The results demonstrated that synthesized UbHBcAgCTP not only significantly increased the levels of interleukin2 and interferon (IFN)γ compared with those in the HBcAgCTP, IFNα, UbHBcAg, HBcAg and phosphatebuffered saline groups, but additionally induced the highest IFNγ+ CD8+ Tcell numbers and HBVspecific cytotoxic T lymphocyte (CTL) responses, indicating a strong immune response. In addition, enhancement of specific CTL activity provoked by the fusion protein reduced hepatitis B surface antigen (HBsAg) and HBV DNA serum levels and diminished the expression of HBsAg and HBcAg in liver tissue of HBV transgenic mice, suggesting that there was a therapeutic effect. In conclusion, the present study provided evidence that UbHBcAgCTP activated the Th1dependent immunity, triggered functional T cell responses and subsequently inhibited viral replication in HBV transgenic mice. These observations suggested that the fusion protein may represent an innovative and promising candidate for active immunotherapy during chronic and persistent HBV.
Assuntos
Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/terapia , Linfócitos T Citotóxicos/imunologia , Ubiquitina/uso terapêutico , Vacinas Virais/uso terapêutico , Animais , Antígenos do Núcleo do Vírus da Hepatite B/genética , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/sangue , Hepatite B Crônica/patologia , Imunidade Celular , Interferon gama/imunologia , Interleucina-2/imunologia , Fígado/imunologia , Fígado/patologia , Fígado/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Peptídeos/genética , Peptídeos/imunologia , Peptídeos/uso terapêutico , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/uso terapêutico , Linfócitos T Citotóxicos/virologia , Ubiquitina/genética , Ubiquitina/imunologia , Vacinação , Vacinas Virais/genética , Vacinas Virais/imunologiaRESUMO
A major problem in chronic hepatitis B virus (HBV) infection is that treatment with specific antivirals is life-long since they rarely induce a sustained response. An attractive option is therefore to combine antiviral therapy with some type of immune stimulator, such as a therapeutic vaccine. Several lines of evidence suggest that a key target for the cellular immune response is the HBV core antigen (HBcAg). However, it may also be of advantage to simultaneously improve the neutralizing antibody response to the surface (S) region of HBV. We therefore generated chimeric HBcAg particles expressing preS1 residues 1-42 at the tip of the spike region. We could show that this chimeric HBcAg-preS1 protein primed both HBcAg-specific T cells and antibodies to preS1. This strongly suggests that this may be a viable approach to develop an effective bi-functional therapeutic vaccine as an add-on for the treatment of chronic HBV infections.
Assuntos
Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , Antígenos de Superfície da Hepatite B/uso terapêutico , Vírus da Hepatite B/imunologia , Hepatite B Crônica/tratamento farmacológico , Linfócitos T/imunologia , Vacinação/métodos , Animais , Anticorpos Neutralizantes , Feminino , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Imunidade Celular/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/uso terapêuticoRESUMO
The hepatitis C virus (HCV)-specific T cell response in patients with chronic HCV is dysfunctional. In this study, we aimed at restoring immunological function through therapeutic vaccination in a transgenic mouse model with impaired HCV-specific T cell responses due to a persistent presence of hepatic HCV nonstructural (NS)3/4A Ags. The HCV-specific T cells have an actively maintained dysfunction reflected in reduced frequency, impaired cytokine production, and impaired effector function in vivo, which can be partially restored by blocking regulatory T cells or programmed cell death ligand 1. We hypothesized that the impairment could be corrected by including sequences that created a normal priming environment by recruiting "healthy" heterologous T cells and by activating innate signaling. Endogenously expressed hepatitis B core Ag (HBcAg) can recruit heterologous T cells and activate TLR (TLR7) signaling. Hence, by combining HCV NS3/4A with different forms of HBcAg we found that heterologous sequences somewhat improved activation and expansion of NS3/4A-specific T cells in a wild-type host. Importantly, the signals provided by HBcAg effectively restored the activation of HCV-specific T cells in a tolerant NS3/4A-transgenic mouse model. The adjuvant effect could also be transferred to the priming of dysfunctional HLA-A2-restricted NS3-specific T cells in vivo. Thus, recruiting healthy heterologous T cells to the site of priming may also help restore HCV-specific responses present in a chronically infected host.
Assuntos
Hepatite C Crônica/imunologia , Linfócitos T/imunologia , Vacinação/métodos , Vacinas contra Hepatite Viral/imunologia , Proteínas não Estruturais Virais/imunologia , Animais , Animais Geneticamente Modificados , Antígenos Virais/imunologia , Antígenos Virais/uso terapêutico , Western Blotting , Linhagem Celular Tumoral , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Hepacivirus/imunologia , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , Hepatite C Crônica/terapia , Humanos , Imunoprecipitação , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
The epidermal growth factor receptor variant III (EGFRvIII) is the most common variation of EGFR. Because it shows a high frequency in several different types of tumor and has not been detected in normal tissues, it is an ideal target for tumor specific therapy. In this study, we prepared EGFRvIII-HBcAg fusion protein. After immunization with fusion protein, HBcAg or PBS, the titers of antibody in BALB/c mice immunized with fusion protein reached 2.75 x 10(5). Western blot analysis demonstrated that the fusion protein had specific antigenicity against anti-EGFRvIII antibody. Further observation showed fusion protein induced a high frequency of IFN-gamma-secreting lymphocytes. CD4+T cells rather than CD8+T cells were associated with the production of IFN-gamma. Using Renca-vIII(+) cell as specific stimulator, we observed remarkable cytotoxic activity in splenocytes from mice immunized with fusion protein. Mice were challenged with Renca-vIII(+) cells after five times immunization. In fusion protein group, three of ten mice failed to develop tumor and all survived at the end of the research. The weight of tumors in fusion protein were obviously lighter than that in other two groups (t = 4.73, P = 0.044; t = 6.89, P = 0.040). These findings demonstrated that EGFRvIII-HBcAg fusion protein triggered protective responses against tumor expressing EGFRvIII.
Assuntos
Vacinas Anticâncer/imunologia , Receptores ErbB/imunologia , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Neoplasias Experimentais/terapia , Proteínas Recombinantes de Fusão/imunologia , Animais , Western Blotting , Linfócitos T CD4-Positivos/imunologia , Eletroforese em Gel de Poliacrilamida , Ensaio de Imunoadsorção Enzimática , Receptores ErbB/uso terapêutico , Antígenos do Núcleo do Vírus da Hepatite B/uso terapêutico , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/imunologia , Proteínas Recombinantes de Fusão/uso terapêuticoRESUMO
AIM: To test the feasibility of delivering a plasmid encoding IL-15 as a DNA vaccine adjuvant for improving the immune responses induced by hepatitis B virus core gene DNA vaccine. METHODS: We used RT-PCR based strategies to develop IL-15 expression constructs. We first confirmed that the gene could be expressed in Escherichia coli due to the poor expression of IL-15. Then the bioactivity of IL-15 plasmid expression product was identified by CTLL-2 proliferation assay. One hundred micrograms of DNA from each of the IL-15 eukaryotic expressed plasmid and the recombinant plasmid harboring DNA encoding the 144 amino acids of the N-terminus of HBV core gene (abbreviated pHBc144) was used to co-immunize C57 BL/6 mice. The titer of anti-HBcIgG was detected by ELISA and the antigen-specific CD8(+) T cells (CD8(+)IFN-gamma(+) T cells) were detected by intracellular cytokine staining at different time points. RESULTS: After co-immunization by pIL-15 and pHBc144 DNA vaccine the antigen-specific CD8(+) cells of mice increased gradually, the first peak of immune response appeared 14 d later, then the number of antigen-specific CD8(+) Ts cells decreased gradually and maintained at a steady level in 3 mo. After boosting, the number of antigen-specific CD8(+) T cells reached the second peak 10 d later with a double of the 1st peak, then the number of antigen-specific CD8(+) T cells decreased slowly. IL-15 as a gene adjuvant had no significant effect on humoral immune responses induced by hepatitis B virus core gene DNA vaccine, but increased the memory antigen-specific CD8(+) T cells induced by hepatitis B virus core gene DNA vaccine. CONCLUSION: DNA vaccine constructed by HBc Ag 1-144 amino acid induces effective cell immunity, and cytokine plasmid-delivered IL-15 enhances the longevity of CD8(+) T cells.