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1.
World J Gastroenterol ; 27(9): 782-793, 2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33727770

RESUMO

Coronavirus disease 2019 (COVID-19) has become a global pandemic and garnered international attention. The causative pathogen of COVID-19 is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel, highly contagious coronavirus. Numerous studies have reported that liver injury is quite common in patients with COVID-19. Hepatitis B has a worldwide distribution as well as in China. At present, hepatitis B virus (HBV) remains a leading cause of cirrhosis, liver failure, and hepatocellular carcinoma. Because both viruses challenge liver physiology, it raises questions as to how coinfection with HBV and SARS-CoV-2 affect disease progression and mortality. Is there an increased risk of COVID-19 in patients with HBV infection? In this review, we summarize the current reports of SARS-CoV-2 and HBV coinfection and elaborate the interaction of the two diseases. The emphasis was placed on evaluating the impact of HBV infection on disease severity and clinical outcomes in patients with COVID-19 and discussing the potential mechanism behind this effect.


Assuntos
/fisiopatologia , Coinfecção/fisiopatologia , Hepatite B Crônica/fisiopatologia , /diagnóstico , /mortalidade , Coinfecção/diagnóstico , Coinfecção/imunologia , Coinfecção/mortalidade , Progressão da Doença , Saúde Global , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/imunologia , Hepatite B Crônica/mortalidade , Humanos , Prognóstico , Índice de Gravidade de Doença
2.
Viruses ; 13(2)2021 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-33573130

RESUMO

Human hepatitis B virus (HBV) can cause chronic, lifelong infection of the liver that may lead to persistent or episodic immune-mediated inflammation against virus-infected hepatocytes. This immune response results in elevated rates of killing of virus-infected hepatocytes, which may extend over many years or decades, lead to fibrosis and cirrhosis, and play a role in the high incidence of hepatocellular carcinoma (HCC) in HBV carriers. Immune-mediated inflammation appears to cause oxidative DNA damage to hepatocytes, which may also play a major role in hepatocarcinogenesis. An additional DNA damaging feature of chronic infections is random integration of HBV DNA into the chromosomal DNA of hepatocytes. While HBV DNA integration does not have a role in virus replication it may alter gene expression of the host cell. Indeed, most HCCs that arise in HBV carriers contain integrated HBV DNA and, in many, the integrant appears to have played a role in hepatocarcinogenesis. Clonal expansion of hepatocytes, which is a natural feature of liver biology, occurs because the hepatocyte population is self-renewing and therefore loses complexity due to random hepatocyte death and replacement by proliferation of surviving hepatocytes. This process may also represent a risk factor for the development of HCC. Interestingly, during chronic HBV infection, hepatocyte clones detected using integrated HBV DNA as lineage-specific markers, emerge that are larger than those expected to occur by random death and proliferation of hepatocytes. The emergence of these larger hepatocyte clones may reflect a survival advantage that could be explained by an ability to avoid the host immune response. While most of these larger hepatocyte clones are probably not preneoplastic, some may have already acquired preneoplastic changes. Thus, chronic inflammation in the HBV-infected liver may be responsible, at least in part, for both initiation of HCC via oxidative DNA damage and promotion of HCC via stimulation of hepatocyte proliferation through immune-mediated killing and compensatory division.


Assuntos
DNA Viral/genética , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/virologia , Hepatócitos/virologia , Animais , Vírus da Hepatite B/genética , Hepatite B Crônica/genética , Hepatite B Crônica/imunologia , Hepatócitos/imunologia , Humanos , Fígado/imunologia , Fígado/virologia , Integração Viral
3.
BMC Infect Dis ; 21(1): 111, 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33485302

RESUMO

BACKGROUND: T cells play an important role in the prognosis of hepatitis B virus (HBV) infection, and are involved in the seroconversion of a patient from HBsAb negative to positive. To compare the T-cell receptor ß-chain variable region (TcRBV) complementarity-determining region 3 (CDR3) in subjects with or without hepatitis B surface antigen (HBsAg) convert to hepatitis B surface antibody (HBsAb), the TcRBV was determined using high throughput sequencing (HTS). METHODS: The clonotype and diversity of CDR3 in peripheral blood mononuclear cells of subjects with resolved acute hepatitis B (AHB, HBsAb+, HBsAg-) (n = 5), chronic hepatitis B (CHB, HBsAb-, HBsAg+) (n = 5), and healthy controls (HC, HBsAb-, HBsAg-) (n = 3) were determined and analyzed using HTS (MiSeq). RESULTS: The overlapping rate of CDR3 clones of any two samples in AHB group was 2.00% (1.74% ~ 2.30%), CHB group was 1.77% (1.43% ~ 2.61%), and HC group was 1.82% (1.62% ~ 2.12%), and there was no significant difference among the three groups by Kruskal-Wallis H test. However, among the top 10 cumulative frequencies of clonotypes, only the frequency of clonotype (TcRBV20-1/BD1/BJ1-2) in AHB group was lower than that of HC group (P < 0.001). Moreover, exclude the 10 top clonotypes, there are 57 markedly different frequency of clones between AHB and CHB groups (18 clones up, 39 clones down), 179 (180-1) different clones between AHB and HC groups, and 134 different clones between CHB and HC groups. With regard to BV and BJ genotypes, there was no significant different frequency among the groups. Furthermore, there was no significant difference in the diversity of TcRBV CDR3 among the three groups (P > 0.05). CONCLUSIONS: Thus, there are 57 TcRBV clonotypes that may be related to HBsAg seroconversion of AHB subjects, but the diversity of TcRBV CDR3 is not significantly related to the HBsAb positive status.


Assuntos
Regiões Determinantes de Complementaridade/genética , Hepatite B/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/imunologia , Adulto , Feminino , Hepatite B/sangue , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/imunologia , Hepatite B Crônica/genética , Hepatite B Crônica/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Soroconversão , Adulto Jovem
4.
Liver Int ; 41(4): 720-730, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33351265

RESUMO

BACKGROUND & AIMS: The outbreak of coronavirus disease 2019 (COVID-19) has been declared a pandemic. Although COVID-19 is caused by infection in the respiratory tract, extrapulmonary manifestations including dysregulation of the immune system and hepatic injury have been observed. Given the high prevalence of hepatitis B virus (HBV) infection in China, we sought to study the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and HBV coinfection in patients. METHODS: Blood samples of 50 SARS-CoV-2 and HBV coinfected patients, 56 SARS-CoV-2 mono-infected patients, 57 HBeAg-negative chronic HBV patient controls and 57 healthy controls admitted to Renmin Hospital of Wuhan University were collected in this study. Complete blood count and serum biochemistry panels including markers indicative of liver functions were performed. Cytokines including IFN-γ, TNF-α, IL-2, IL-4, IL-6 and IL-10 were evaluated. T cell, B cell and NK cell counts were measured using flow cytometry. RESULTS: SARS-CoV-2 and HBV coinfection did not significantly affect the outcome of the COVID-19. However, at the onset of COVID-19, SARS-CoV-2 and HBV coinfected patients showed more severe monocytopenia and thrombocytopenia as well as more disturbed hepatic function in albumin production and lipid metabolism. Most of the disarrangement could be reversed after recovery from COVID-19. CONCLUSIONS: While chronic HBV infection did not predispose COVID-19 patients to more severe outcomes, our data suggest SARS-CoV-2 and HBV coinfection poses a higher extent of dysregulation of host functions at the onset of COVID-19. Thus, caution needs to be taken with the management of SARS-CoV-2 and HBV coinfected patients.


Assuntos
/complicações , Hepatite B Crônica/complicações , Adulto , /imunologia , Coinfecção , Contagem de Eritrócitos , Feminino , Hepatite B Crônica/sangue , Hepatite B Crônica/imunologia , Humanos , Testes de Função Hepática , Masculino , Contagem de Plaquetas , Estudos Retrospectivos , Adulto Jovem
5.
BMC Med Genet ; 21(1): 241, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33334325

RESUMO

BACKGROUND: Hepatitis B is known to cause several forms of liver diseases including chronic hepatitis B (CHB), and hepatocellular carcinoma. Previous genome-wide association study of CHB risk has demonstrated that rs12614 of complement factor B (CFB) was significantly associated with CHB risk. In this study, fine-mapping study of previously reported GWAS single nucleotide polymorphism (SNP; CFB rs12614) was performed to validate genetic effect of rs12614 on CHB susceptibility and identify possible additional causal variants around rs12614 in a Korean population. This association study was conducted in order to identify genetic effects of CFB single nucleotide polymorphisms (SNPs) and to identify additional independent CHB susceptible causal markers within a Korean population. METHODS: A total of 10 CFB genetic polymorphisms were selected and genotyped in 1716 study subjects comprised of 955 CHB patients and 761 population controls. RESULTS: A non-synonymous variant, rs12614 (Arg32Trp) in exon2 of CFB, had significant associations with risk of CHB (odds ratio = 0.43, P = 5.91 × 10- 10). Additional linkage disequilibrium and conditional analysis confirmed that rs12614 had independent genetic effect on CHB susceptibility with previously identified CHB markers. The genetic risk scores (GRSs) were calculated and the CHB patients had higher GRSs than the population controls. Moreover, OR was found to increase significantly with cumulative GRS. CONCLUSIONS: rs12614 showed significant genetic effect on CHB risk within the Korean population. As such rs12614 may be used as a possible causal genetic variant for CHB susceptibility.


Assuntos
Fator B do Complemento/genética , Éxons , Predisposição Genética para Doença , Hepatite B Crônica/genética , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Casos e Controles , Fator B do Complemento/deficiência , Fator B do Complemento/imunologia , Expressão Gênica , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Razão de Chances , República da Coreia , Risco
6.
BMJ ; 370: m2200, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873599

RESUMO

Hepatitis B virus (HBV) infection causes chronic hepatitis and has long term complications. Individuals ever infected with HBV are at risk of viral reactivation under certain circumstances. This review summarizes studies on HBV persistence and reactivation with a focus on the definitions and mechanisms. Emphasis is placed on the interplay between HBV replication and host immunity as this interplay determines the patterns of persistence following viral acquisition. Chronic infections exhibit as overt persistence when a defective immune response fails to control the viral replication. The HBV genome persists despite an immune response in the form of covalently closed circular DNA (cccDNA) and integrated DNA, rendering an occult state of viral persistence in individuals whose infection appears to have been resolved. We have described HBV reactivation that occurs because of changes in the virus or the immune system. This review aims to raise the awareness of HBV reactivation and to understand how HBV persists, and discusses the risks of HBV reactivation in a variety of clinical settings.


Assuntos
Vírus da Hepatite B/imunologia , Hepatite B Crônica/virologia , Replicação Viral/imunologia , Animais , DNA Viral/sangue , Saúde Global , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/imunologia , Humanos , Imunossupressão , Imunossupressores/uso terapêutico , Fatores de Risco
7.
PLoS One ; 15(7): e0234740, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32716949

RESUMO

BACKGROUND: Turkey is an intermediate hepatitis B virus (HBV) endemic country. However, prevalence among Turkish migrants in Belgium is unknown, especially in those born in Belgium with a foreign-born parent, i.e. second-generation migrants (SGM). AIMS: To evaluate the prevalence of HBV infection and associated risk factors in Turkish first-generation migrants (FGM), i.e. foreign-born, and SGM. METHODS: Between September 2017 and May 2019, free outreach testing for hepatitis B surface antigen (HBsAg), hepatitis B core antibodies (anti-HBc), and antibodies against HBsAg was offered to Turkish migrants in Middle-Limburg, Belgium. Face-to-face questionnaire assessed HBV risk factors. HBsAg positive patients were referred and followed up. Turkish SGM were stratified into birth cohort born before and after 1987, since those born after 1987 should be covered by the universal infant vaccination program. RESULTS: A total of 1,081/1,113 (97.1%) Turkish did go for HBV testing. Twenty-six (2.4%) were HBsAg positive; 11/26 were unaware of their status and 10/11 were successfully referred. HBsAg prevalence was 3.0% in FGM and 1.5% in SGM, p = .070. Only one out of seven HBsAg positive SGM was born after 1987. In the multiple generalized estimating equations model, the most important risk factors for anti-HBc positivity were male gender (p = .021), older age (p < .001), FGM (p < .001), low educational level of the mother (p = .003), HBV infected mother (p = .008), HBV infected siblings (p = .002), HBV infected other family member (p = .004), gynaecological examination in Turkey or unsafe male circumcision (p = .032) and dental treatment in Turkey (p = .049). CONCLUSION: Outreach testing was well-accepted and referral to specialist care was generally successful. National HBV screening should be implemented in the Turkish FGM population and might be considered in SGM not covered by primary prevention strategies.


Assuntos
Hepatite B Crônica/diagnóstico , Hepatite B Crônica/epidemiologia , Adolescente , Adulto , Idoso , Bélgica/epidemiologia , Diagnóstico Precoce , Feminino , Hepatite B/diagnóstico , Hepatite B/epidemiologia , Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Humanos , Programas de Imunização , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Migrantes , Turquia/epidemiologia , Vacinação
8.
BMC Infect Dis ; 20(1): 509, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32664850

RESUMO

BACKGROUND: Complete clearance of intracellular viruses depends on effector cells of innate and adaptive immune systems. This study aimed to identify the relationships among antiviral cytokines produced by natural killer (NK) and T cells and clinical-virological characteristics in untreated chronic hepatitis B (CHB) patients. METHODS: We measured antiviral cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) produced by T, NK and natural killer T (NKT) cells, respectively, in a cohort with chronic hepatitis B virus (HBV) infection (CHB). We also correlated these cytokines with clinical-virological characteristics using a linear regression model. RESULTS: levels of IFN-γ+ and TNF-α+ CD4+ and CD8+ T cells were significantly higher in immune active (IA) phase than in other phases. Immune tolerant (IT) patients showed the lowest expression of IFN-γ by NK and NKT cells, and TNF-α by NK cells. IFN-γ+, TNF-α+ and IL-2+ CD4+ and CD8+ T cells frequencies were similar between IA and gray zone (GZ) phases. Principal component analysis based on cytokines confirmed that most IT patients significantly differed from inactive carriers (IC) and IA patients, while GZ patients were widely scattered. Multivariate analysis showed both T and NK cells producing IFN-γ and TNF-α, but not IL-2, had significant association with serum alanine aminotransferase (ALT). Moreover, IFN-γ+ NKT cells were associated with HBV DNA, while IFN-γ+ CD4+ and CD8+ T cells were correlated with age. CONCLUSION: HBV clinical phases are characterized by distinct cytokine signatures, which showed relationship to viral features in these untreated CHB patients.


Assuntos
Imunidade Adaptativa , Citocinas/metabolismo , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Hepatite B Crônica/imunologia , Imunidade Inata , Adulto , Alanina Transaminase/sangue , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Estudos de Coortes , DNA Viral/sangue , Feminino , Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/virologia , Humanos , Células Matadoras Naturais/imunologia , Masculino , Células T Matadoras Naturais/imunologia , Adulto Jovem
9.
Medicine (Baltimore) ; 99(18): e19907, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32358357

RESUMO

There has been no clear consensus on the optimal consolidation periods following HBeAg seroconversion (SC) in HBeAg-positive chronic hepatitis B (CHB) patients. Our study aimed to prospectively compare relapse rates between 12 months' and 18 months' consolidation periods to see whether or not there is beneficial durability of tenofovir disoproxil fumarate (TDF) therapy with longer consolidation periods.We enrolled a total of 137 HBeAg-positive Asian CHB patients treated with TDF monotherapy. Forty-six patients achieved HBeAg SC. Then, they were randomly assigned to consolidation period of either 12 months (group A) or 18 months (group B). After stopping TDF therapy, all patients were followed up for 12 months.Thirteen patients (56.5%) relapsed in group A and 12 patients (52.2%) relapsed in group B after 12 months' follow-up (P = .958). Pretreatment HBsAg level is the only significant predictor for off-therapy recurrence by univariate analysis (P = .024). Baseline HBeAg >1000 S/CO in group B patients were significantly less likely to relapse than those of group A (P = .046). Baseline alanine aminotransferase (ALT) >133 U/L could significantly predict occurrence of HBeAg SC (P = .008; 95% CI: 0.545-0.763; AUC: 0.654).Overall, a prolonged consolidation period has no positive effect on TDF therapy on sustained viral suppression in HBeAg-positive Asian CHB patients. However, a prolonged consolidation period was beneficial to patients with high baseline semi-quantitative HBeAg levels in terms of off-treatment durability. Baseline ALT > 133 U/L could significantly predict the occurrence of HBeAg SC.


Assuntos
Antivirais/administração & dosagem , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Tenofovir/administração & dosagem , Adulto , Alanina Transaminase/sangue , Esquema de Medicação , Feminino , Antígenos E da Hepatite B/sangue , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Soroconversão/efeitos dos fármacos , Resposta Viral Sustentada , Fatores de Tempo
10.
Int J Infect Dis ; 96: 541-547, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32422377

RESUMO

OBJECTIVES: Genes of host immunity play an important role in disease pathogenesis and are determinants of clinical courses of infections, including hepatitis B virus (HBV). Killer-cell immunoglobulin-like receptor (KIR), expressed on the surface of natural killer cells (NK), regulate NK cell cytotoxicity by interacting with human leukocyte antigen (HLA) class I molecules and are candidates for influencing the course of HBV. This study evaluated whether variations in KIR gene content and HLA-C ligands are associated with HBV and with the development of liver cirrhosis and hepatocellular carcinoma. METHODS: A Vietnamese study cohort (HBV n = 511; controls n = 140) was genotyped using multiplex sequence-specific polymerase chain reaction (PCR-SSP) followed by melting curve analysis. RESULTS: The presence of the functional allelic group of KIR2DS4 was associated with an increased risk of chronic HBV (OR = 1.86, pcorr = 0.02), while KIR2DL2+HLA-C1 (OR = 0.62, pcorr = 0.04) and KIR2DL3+HLA-C1 (OR = 0.48, pcorr = 0.04) were associated with a decreased risk. The pair KIR2DL3+HLA-C1 was associated with liver cirrhosis (OR = 0.40, pcorr = 0.01). The presence of five or more activating KIR variants was associated with hepatocellular carcinoma (OR = 0.53, pcorr = 0.04). CONCLUSIONS: KIR gene content variation and combinations KIR-HLA influence the outcome of HBV infection.


Assuntos
Vírus da Hepatite B/fisiologia , Hepatite B Crônica/genética , Receptores KIR2DL2/genética , Receptores KIR2DL3/genética , Receptores KIR/genética , Adulto , Idoso , Alelos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/virologia , Estudos de Coortes , Feminino , Variação Genética , Genótipo , Antígenos HLA-C/genética , Antígenos HLA-C/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Cirrose Hepática/genética , Cirrose Hepática/imunologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Receptores KIR/imunologia , Receptores KIR2DL2/imunologia , Receptores KIR2DL3/imunologia , Vietnã , Adulto Jovem
11.
Int J Infect Dis ; 96: 260-265, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32387446

RESUMO

OBJECTIVES: The outcomes of hepatitis B virus (HBV) infection vary substantially among affected individuals, providing evidence of the role of host genetic background in the susceptibility to HBV persistence and the dynamics of liver injury progression to cirrhosis and hepatocellular carcinoma (HCC). METHODS: Six single-nucleotide polymorphisms within the interleukin 10 gene (IL10) were genotyped by MALDI-TOF mass spectrometry in 857 patients with chronic HBV infection (CHB), 48 patients with resolved HBV infection, and 100 healthy volunteers. Associations of the selected polymorphisms with susceptibility to chronic HBV infection, liver injury progression, and outcomes were investigated. RESULTS: IL10 -819T (rs1800871), -592A (rs1800872), and +504T (rs3024490) alleles were associated with treatment-induced hepatitis B surface antigen (HBsAg) seroclearance. Additionally, IL10 ATAC haplotype increased the chance of HBsAg loss and was significantly more frequent in patients with less liver injury. Moreover rs1800871TT, rs1518110TT, rs1800872AA, and rs3024490TT genotypes were identified as predictors of a lower FIB-4 score (<0.5). CONCLUSIONS: This study indicates that polymorphisms within the promoter region and intronic sequences of IL10 are associated with chronicity of hepatitis B and with HBV-induced liver damage.


Assuntos
Hepatite B Crônica/genética , Interleucina-10/genética , Adulto , Alelos , Progressão da Doença , Feminino , Genótipo , Antígenos de Superfície da Hepatite B/metabolismo , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
12.
Aliment Pharmacol Ther ; 52(1): 196-204, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32452564

RESUMO

BACKGROUND: Anti-viral therapy is not indicated for patients with chronic hepatitis B (CHB) in the immune-tolerant phase. AIMS: To investigate the cumulative incidence of phase change and hepatocellular carcinoma (HCC) and independent predictors for phase change in patients with CHB in immune-tolerant phase. METHODS: In total, 946 patients in immune-tolerant phase, defined as hepatitis B e antigen positivity, HBV-DNA >20 000 IU/mL and alanine aminotransferase (ALT) ≤40 IU/L, between 1989 and 2017 were enrolled from eight institutes. RESULTS: The mean age of study population (429 men and 517 women) was 36.7 years. The mean ALT and HBV-DNA levels were 24.6 IU/L and 8.50 log10 IU/mL, respectively. Of the study population, 476 (50.3%) patients remained in immune-tolerant phase throughout the study period (median: 63.6 months). The cumulative incidence rates of phase change and HCC at 10 years were 70.7% and 1.7%, respectively. Multivariate analyses revealed that HBV-DNA level >107  IU/mL was associated independently with a reduced risk of phase change (hazard ratio [HR] = 0.734, P = 0.008), whereas a high ALT level, above the cut-off recommended in the Korean Association for the Study of the Liver guidelines (34 IU/L for men and 30 IU/L for women), was associated independently with a greater risk of phase change (HR = 1.885, P < 0.001). CONCLUSIONS: The criterion of HBV-DNA level > 107  IU/mL may be useful to define immune-tolerant phase. In addition, an extremely low risk of HCC development was observed in patients with CHB in immune-tolerant phase.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Hepatite B Crônica/epidemiologia , Neoplasias Hepáticas/epidemiologia , Adulto , Alanina Transaminase/sangue , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/virologia , DNA Viral/sangue , Feminino , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Hepatite B Crônica/complicações , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Tolerância Imunológica , Incidência , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
13.
Life Sci ; 252: 117663, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32302624

RESUMO

AIMS: Interleukin-35 (IL-35) is a new member of the interleukin-12 family and is composed of the P35 and EB virus-inducible gene 3 subunits. The aims of this study were to examine the roles of IL-35 in the exhaustion of HBV-specific CTLs, as little as known on the subject. MAIN METHODS: The relative levels of serum HBV markers were detected using automated biochemical techniques. The HBV DNA copies were measured by RT-qPCR. The expression of inhibitory receptors and the cell cytokines on the surface of CTLs were determined by flow cytometry. The pSTAT1-pSTAT4 protein levels expression was determined by flow cytometry, confocal microscopy and Western blot. KEY FINDINGS: Our results showed that IL-35 can activate the Janus kinase 1 (JAK1)/tyrosine kinase 2 (TYK2)/signal transducer and activator of transcription 1 (STAT1)/STAT4 pathway in CTLs in vitro. Interferon-γ and tumor necrosis alpha-α expression increased in CTLs in the presence of a JAK/STAT-pathway blocker. In addition, we evaluated the expression of the exhaustion-associated molecules programmed death-1, cytotoxic T lymphocyte-associated protein-4, and lymphocyte activation gene-3 in CTLs after adding the JAK-STAT inhibitor The results showed that the expression of exhaustion-associated molecules on the CTL surface decreased after blocking the JAK-STAT pathway. IL-35 inhibited the function of HBV-specific CTLs through the JAK1/TYK2/STAT1/STAT4 pathway, and the function of CTLs was recovered after blocking the JAK/STAT pathway. SIGNIFICANCE: These data provide a new experimental basis for immunotherapy for chronic hepatitis B.


Assuntos
Antígenos E da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Interleucinas/imunologia , Linfócitos T Citotóxicos/virologia , Adulto , Citocinas/imunologia , Feminino , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/isolamento & purificação , Humanos , Janus Quinases/metabolismo , Masculino , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/imunologia
14.
Nat Nanotechnol ; 15(5): 406-416, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32123380

RESUMO

Chronic hepatitis B is caused by prolonged infection with the hepatitis B virus (HBV), which can substantially increase the risk of developing liver disease. Despite the development of preventive vaccines against HBV, a therapeutic vaccine inducing an effective antibody response still remains elusive. The preS1 domain of the large HBV surface protein is the major viral attachment site on hepatocytes and thus offers a therapeutic target; however, its poor immunogenicity limits clinical translation. Here, we design a ferritin nanoparticle vaccine that can deliver preS1 to specific myeloid cells, including SIGNR1+ dendritic cells (which activate T follicular helper cells) and lymphatic sinus-associated SIGNR1+ macrophages (which can activate B cells). This nanoparticle vaccine induces a high-level and persistent anti-preS1 response that results in efficient viral clearance and partial serological conversion in a chronic HBV mouse model, offering a promising translatable vaccination strategy for the functional cure of chronic hepatitis B.


Assuntos
Antígenos de Superfície da Hepatite B/uso terapêutico , Vacinas contra Hepatite B/uso terapêutico , Vírus da Hepatite B/imunologia , Hepatite B Crônica/prevenção & controle , Nanopartículas/uso terapêutico , Precursores de Proteínas/uso terapêutico , Animais , Formação de Anticorpos , Feminino , Antígenos de Superfície da Hepatite B/administração & dosagem , Vacinas contra Hepatite B/administração & dosagem , Hepatite B Crônica/imunologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Mieloides/imunologia , Nanopartículas/administração & dosagem , Precursores de Proteínas/administração & dosagem
15.
Mol Immunol ; 120: 179-186, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32169738

RESUMO

BACKGROUND: The NLRP3 inflammasome has been suggested to play a crucial role in host antiviral defense, including against hepatitis B virus (HBV) infection. In the present study, we measured expression of NLRP3 and its related cytokines in patients with different stages of HBV-related acute-on-chronic liver failure (HBV-ACLF), a pattern of end-stage liver disease that occurs frequently in patients with chronic HBV (CHB) infection or HBV-related cirrhosis. METHODS: A total of 75 subjects including 30 HBV-ACLF patients, 30 CHB patients, and 15 healthy controls (HCs) were enrolled. The NLRP3 inflammasome and its components (caspase-1, interleukin (IL)-1ß, and IL-18) were measured in peripheral blood mononuclear cells (PBMCs), macrophages, and liver using flow cytometry, quantitative real-time polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry. The LPS was used to evaluate changes in NLRP3 and its related cytokines in CD14+ monocytes which may reflect immune status. Cytokine expression was measured using RT-PCR. RESULTS: Patients with HBV-ACLF had lower NLRP3 inflammasome expression in peripheral CD14+ monocytes, particularly in the middle-to-late stage, but higher expression in liver macrophages compared to CHB and HCs. Compared with H-LPS or L-LPS alone, L-LPS sequential H-LPS can significantly inhibit the expression of NLRP3 and its related cytokines. CONCLUSION: Differential expression patterns of the NLRP3 inflammasome in the periphery and liver might be related to immune dysfunction and recruitment of monocytes to the injured liver during disease progression. Persistent systemic inflammation is likely a cause of compromised immune status in patients with HBV-ACLF.


Assuntos
Insuficiência Hepática Crônica Agudizada/imunologia , Hepatite B Crônica/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/metabolismo , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Estudos de Casos e Controles , Citocinas/sangue , Citocinas/genética , Citocinas/metabolismo , Feminino , Hepatite B Crônica/complicações , Hepatite B Crônica/metabolismo , Humanos , Inflamassomos/sangue , Inflamassomos/metabolismo , Fígado/imunologia , Fígado/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/sangue , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
16.
Lancet Gastroenterol Hepatol ; 5(4): 406-417, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32057301

RESUMO

Chronic hepatitis B virus (HBV) infection follows a dynamic and variable course. At different stages in the disease, hepatitis flares might occur, which can be challenging to predict and manage. Flares are believed to be primarily immune-mediated and might mark transitions to inactive disease or clearance of infection, but in certain scenarios they might also lead to hepatic decompensation or death. As such, understanding of the clinical significance of flares in different patient populations and different scenarios is important for optimal management. In this Review, we summarise what is known about flares in different stages of chronic HBV infection; describe flares in the context of the natural history of chronic infection; summarise the immunological mechanisms underlying flares, and describe flares in different clinical scenarios. Each section reviews existing knowledge and highlights key unanswered questions that need to be addressed to improve the understanding of flares, hopefully providing insights into their pathogenesis that can be used to improve current clinical management and ideally to further develop new curative therapeutic approaches for HBV infection. We also propose a working definition of an ALT flare to facilitate future research.


Assuntos
Alanina Transaminase/sangue , DNA Viral/sangue , Vírus da Hepatite B/genética , Hepatite B Crônica/imunologia , Hepatite B/imunologia , Antivirais/uso terapêutico , Linfócitos B/imunologia , Quimiocinas/imunologia , Citocinas/imunologia , Feminino , Hepatite B/tratamento farmacológico , Hepatite B/virologia , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Humanos , Células Matadoras Naturais/imunologia , Macrófagos do Fígado/imunologia , Masculino , Células Supressoras Mieloides/imunologia , Nucleosídeos/uso terapêutico , Exacerbação dos Sintomas , Linfócitos T/imunologia
17.
Sci Rep ; 10(1): 1835, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020034

RESUMO

Chronic hepatitis B (CHB) infection functional cure is defined as sustained loss of HBsAg and several therapeutic strategies are in clinical development designed to pharmacologically reduce serum HBsAg, break immune tolerance, and increase functional cure rates. However, little is known about pre-treatment HBsAg levels as an indicator of HBV immune potential. Here, we compared the phenotypes and HBV-specific response of lymphocytes in CHB patients stratified by serum HBsAg levels <500 (HBslo) or >50,000 IU/ml (HBshi) using immunological assays (flow cytometry, ICS, ELISPOT). HBshi patients had significantly higher expression of inhibitory PD-1 on CD4+ T cells, particularly among TEMRA subset, and higher FcRL5 expression on B cells. Upon HBcAg(core) or HBsAg(env)-stimulation, 85% and 60% of HBslo patients had IFNγ+TNFα+ and IFNγ+ IL2+ CD4+ T cell responses respectively, in comparison to 33% and 13% of HBshi patients. Checkpoint blockade with αPD-1 improved HBV-specific CD4+ T cell function only in HBslo patients. HBsAg-specific antibody-secreting cells (ASCs) response was not different between these groups, yet αPD-1 treatment resulted in significantly higher fold change in ASCs among patients with HBsAg <100 IU/ml compared to patients with HBsAg >5,000 IU/ml. Thus, serum HBsAg correlates with inhibitory receptor expression, HBV-specific CD4+ T cell responses, and augmentation by checkpoint blockade.


Assuntos
Linfócitos B/imunologia , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Linfócitos T/imunologia , Biomarcadores/sangue , Citometria de Fluxo , Hepatite B Crônica/sangue , Humanos , Receptor de Morte Celular Programada 1/metabolismo
18.
Int J Mol Sci ; 21(3)2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32023902

RESUMO

The hepatitis B virus (HBV) cannot be removed completely from infected hepatocytes, owing to the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), predicting HCC development in high-risk patients with high viral replicative activity or advanced fibrosis is important. Novel serological biomarkers reflect intrahepatic viral replicative activity or the progression of liver fibrosis, indicating non-invasive alternatives to liver biopsy: (1) Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients, a decrease in HBcrAg is associated with favorable outcomes. HBcrAg can predict HCC occurrence or recurrence. (2) Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. An increase in M2BPGi in CHB patients is related to the progression of liver fibrosis and high potential (risk) of HCC development. Here, we describe the clinical applications of HBcrAg and M2BPGi in CHB patients. Additionally, because new potential therapeutic agents that eliminate intrahepatic cccDNA are being developed, monitoring of HBcrAg or M2BPGi might be suitable for evaluating therapeutic effects and the clinical outcomes. In conclusion, these would be appropriate surrogate markers for predicting disease progression.


Assuntos
Antígenos de Neoplasias/sangue , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/virologia , Antígenos do Núcleo do Vírus da Hepatite B/sangue , Hepatite B Crônica/metabolismo , Neoplasias Hepáticas/virologia , Biomarcadores/sangue , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , DNA Circular/metabolismo , Progressão da Doença , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Regulação para Cima
19.
Gastroenterology ; 158(6): 1762-1775.e9, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32001321

RESUMO

BACKGROUND & AIMS: Hepatitis B virus (HBV) infection persists because the virus-specific immune response is dysfunctional. Therapeutic vaccines might be used to end immune tolerance to the virus in patients with chronic infection, but these have not been effective in patients so far. In patients with chronic HBV infection, high levels of virus antigens might prevent induction of HBV-specific immune responses. We investigated whether knocking down expression levels of HBV antigens in liver might increase the efficacy of HBV vaccines in mice. METHODS: We performed studies with male C57BL/6 mice that persistently replicate HBV (genotype D, serotype ayw)-either from a transgene or after infection with an adeno-associated virus that transferred an overlength HBV genome-and expressed HB surface antigen at levels relevant to patients. Small hairpin or small interfering (si)RNAs against the common 3'-end of all HBV transcripts were used to knock down antigen expression in mouse hepatocytes. siRNAs were chemically stabilized and conjugated to N-acetylgalactosamine to increase liver uptake. Control mice were given either entecavir or non-HBV-specific siRNAs and vaccine components. Eight to 12 weeks later, mice were immunized twice with a mixture of adjuvanted HBV S and core antigen, followed by a modified Vaccinia virus Ankara vector to induce HBV-specific B- and T-cell responses. Serum and liver samples were collected and analyzed for HBV-specific immune responses, liver damage, and viral parameters. RESULTS: In both models of HBV infection, mice that express hepatocyte-specific small hairpin RNAs or that were given subcutaneous injections of siRNAs had reduced levels of HBV antigens, HBV replication, and viremia (1-3 log10 reduction) compared to mice given control RNAs. Vaccination induced production of HBV-neutralizing antibodies and increased numbers and functionality of HBV-specific, CD8+ T cells in mice with low, but not in mice with high, levels of HBV antigen. Mice with initially high titers of HBV and knockdown of HBV antigen expression, but not mice with reduced viremia after administration of entecavir, developed polyfunctional, HBV-specific CD8+ T cells, and HBV was eliminated. CONCLUSIONS: In mice with high levels of HBV replication, knockdown of HBV antigen expression along with a therapeutic vaccination strategy, but not knockdown alone, increased numbers of effector T cells and eliminated the virus. These findings indicate that high titers of virus antigens reduce the efficacy of therapeutic vaccination. Anti-HBV siRNAs and therapeutic vaccines are each being tested in clinical trials-their combination might cure chronic HBV infection.


Assuntos
Antígenos de Superfície da Hepatite B/genética , Vacinas contra Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/terapia , RNA Interferente Pequeno/administração & dosagem , Animais , Linfócitos B/imunologia , Portador Sadio/imunologia , Portador Sadio/virologia , Terapia Combinada/métodos , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Antígenos de Superfície da Hepatite B/imunologia , Vacinas contra Hepatite B/administração & dosagem , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Hepatócitos/virologia , Humanos , Imunização Secundária , Imunogenicidade da Vacina , Masculino , Camundongos , Linfócitos T Citotóxicos/imunologia , Replicação Viral/genética , Replicação Viral/imunologia
20.
Rev. habanera cienc. méd ; 19(1): 48-62, ene.-feb. 2020. tab, graf
Artigo em Espanhol | LILACS, CUMED | ID: biblio-1099145

RESUMO

Introducción: La efectividad del programa nacional de inmunización ha impactado en la reducción de la incidencia del virus de la hepatitis B en Cuba; sin embargo, no es despreciable la cantidad de pacientes infectados crónicos, que por esta causa, se detectan en la práctica asistencial, aunque insuficientes los estudios epidemiológicos que los caracterizan. Objetivo: Describir las principales características clínicas, biomoleculares e inmunológicas de los pacientes con VHB crónica atendidos en el Instituto de Gastroenterología de Cuba. Materiales y métodos: 97 pacientes que tenían al menos un historial de 6 meses de infección crónica con VHB fueron reclutados en la propia institución desde enero 2016 hasta enero 2018. Se realizaron análisis estadísticos descriptivos para las características clínicas, estudios bioquímicos, virológicos, grado de dureza hepática (medido por elastografía transitoria) y terapia antiviral. Resultados: Todos los pacientes completaron el seguimiento; 61,9 por ciento eran varones y la mediana (rango) de edad fue de 46 (18-84) años. La media de tiempo desde el diagnóstico de la infección fue de 11,7 ± 8,9 años. El 61,9 por ciento tenían enfermedad inactiva sin fibrosis hepática o fibrosis ligera. Solamente el 2 por ciento eran negativos para el antígeno de superficie de la hepatitis B con el DNA cuantificable del VHB, el 81,4 por ciento tenían carga viral detectable y el 85,5 por ciento recibieron uno o más tratamientos antivirales, principalmente los análogos del nucleótido/sido. Conclusiones: Los pacientes con la infección crónica del VHB estudiados, en su mayoría se encuentran en fase inactiva de su enfermedad, sin evidencia significativa de daño hepático, con niveles detectables de viremia y han recibido algún tratamiento antiviral(AU)


Introduction: The effectiveness of the national immunization program has impacted on the reduction of the incidence of hepatitis B virus (HBV) infection in Cuba; however, the number of chronically infected patients is not negligible. These patients are diagnosed in the clinical practice, although the epidemiological studies that indicate the presence of the disease are insufficient. Objective: To describe the main clinical, biomolecular and immunological characteristics of patients with chronic hepatitis B virus infection treated at the National Institute of Gastroenterology, Havana, Cuba. Materials and methods: A total of 97 patients who had at least a 6-month history of chronic HBV infection were recruited at the above mentioned institution from January 2016 to January 2018. Descriptive statistical analyzes were performed to identify the clinical characteristics. Biochemical and virological studies, analysis of both liver stiffness values measured by transient elastography and use of antiviral therapy were also carried out. Results: All patients completed the follow-up. It was observed that 61,9 percent of them were male and the median (range) age was 46 (18-84) years. The mean time since the diagnosis of the infection was 11.7 ± 8,9 years. Inactive disease without liver fibrosis or light fibrosis was present in 61,9 percent. Only 2 percent were negative for hepatitis B surface antigen with quantitative analysis of HBV DNA; also, 81,4 percent of patients had detectable viral load and 85,5 percent received one or more antiviral treatments, mainly nucleotide analogues. Conclusions: The patients with chronic HBV infection studied are mostly in the inactive phase of their disease, without significant evidence of liver damage and detectable levels of viremia. All of them have received some antiviral treatment(AU)


Assuntos
Humanos , Masculino , Feminino , Hepatite B Crônica/imunologia , Hepatite B Crônica/epidemiologia
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