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1.
Medicine (Baltimore) ; 98(51): e18442, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31861015

RESUMO

Genetic variation and genotype of Hepatitis B virus (HBV) are related to the efficiency of interferon alpha (IFN-α)-based antiviral therapy. However, the correlation of variation in interferon-stimulated response element (ISRE) and HBV genotype response to IFN-α therapy remains elusive.Differences of ISRE between genotype B and C HBV were explored using the HBV sequences retrieved from GenBank, and further investigated by ISRE region cloning and sequencing from 60 clinical samples post-IFN-α therapy. Additionally, ISRE mutants were constructed and their relation to responsiveness of IFN-α was evaluated by real-time PCR and Southern blot analysis.ISRE pattern between genotype B and C were found based on both clinical sample sequencing and full-length sequence alignment. The primary difference is the fourth base within the ISRE region, with T and C for genotype B and C, respectively. HBV with genotype C-type ISRE had a higher replicative capability as compared to HBV with genotype B-type ISRE after IFN-α treatment in huh7 cells. CONCLUSION:: Preference of ISRE between genotype B and C HBV are distinct. Single nucleotide difference (C to T) within the HBV ISRE region may link to the efficacy of IFN-α therapy to genotype B and C HBV. Therefore, this study provides a clue for the determination of IFN-α therapy response to HBV treatment.


Assuntos
Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Interferon-alfa/farmacologia , Elementos de Resposta , Adulto , Feminino , Genótipo , Vírus da Hepatite B/genética , Humanos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutação , Adulto Jovem
2.
Nat Rev Gastroenterol Hepatol ; 16(10): 631-641, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31477873

RESUMO

Chronic hepatitis B virus (HBV) infection is a serious problem owing to its worldwide distribution and potential adverse sequelae that include cirrhosis and/or hepatocellular carcinoma. Current antiviral therapies have much improved outcomes, but few patients achieve the ultimate goal of hepatitis B surface antigen (HBsAg) loss (functional cure). As hepatitis B e antigen (HBeAg)-negative chronic HBV infection is the final phase prior to HBsAg loss, the management of patients in this phase together with quantification of HBsAg has attracted increasing clinical and research interest. This Review integrates the findings from research in HBsAg kinetics and discusses how they might inform our understanding and management of HBeAg-negative chronic HBV infection. Studies have shown that HBsAg levels are highly predictive of the presence of inactive HBV infection and that serial changes in HBsAg levels might predict HBsAg loss within 1-3 years. Data also suggest that quantitative HBsAg monitoring is important during hepatitis flare and antiviral therapy, especially in the timing of the decision to stop therapy and to start off-therapy retreatment. These findings have shed new light on the natural course of HBV infection and might lead to optimization of the management of HBeAg-negative chronic HBV infection and contribute to the paradigm shift from indefinite to finite therapy for patients with HBV infection.


Assuntos
Carcinoma Hepatocelular/virologia , Antígenos da Hepatite B/imunologia , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/imunologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/virologia , Antivirais/uso terapêutico , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/prevenção & controle , Progressão da Doença , Antígenos de Superfície da Hepatite B/imunologia , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/imunologia , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/prevenção & controle
3.
Acta Gastroenterol Belg ; 82(2): 279-284, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31314189

RESUMO

BACKGROUND AND AIM: Hepatitis B Virus (HBV) screening before starting immunosuppressive treatment is of vital importance in order to prevent HBV reactivation and its associated clinical consequences. Despite all recommendations by international organizations, screening rates are far below desired. The aim of this study was to assess the efficacy of a computer alert programme 'HBVision' for increasing HBV screening rates. MATERIAL AND METHODS: 'HBVision' identifies patients at risk of HBV reactivation by specific ICD-10 codes and immunosuppressive medication reports and sends sequential alert messages to screen for HBsAg, anti-HBc IgG and consult a specialist if one of them is positive. The demographic variables, treatment protocols, HBV screening and consultation rates of oncology and hematology patients who started immunosuppressive treatments within one year before (control group) and after "HBVision" (study group) were retrospectively compared. RESULTS: HBsAg and anti-HBc IgG screening rates (68.6% and 13.1%, respectively) were significantly higher in the study group (n=602) compared to control group (n=815) (55% and 4.3%, respectively) (p<0.001, for both). Subgroup analysis revealed significant improvements in the screening rates of HBsAg (65.8%) and anti-HBc IgG (5.1%) in oncology patients (p<0.001), anti-HBc IgG (89.1%) in hematology patients (p<0.001). CONCLUSION: The computer alert programme significantly increased HBV screening rates before starting immunosuppressive treatments, however the results were still below ideal. Additional efforts, such as modifying the computer programme according to feedbacks, are probably needed.


Assuntos
Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/sangue , Hepatite B/virologia , Imunossupressores/efeitos adversos , Ativação Viral/efeitos dos fármacos , Hepatite B/induzido quimicamente , Hepatite B/tratamento farmacológico , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Vírus da Hepatite B/isolamento & purificação , Vírus da Hepatite B/patogenicidade , Humanos , Imunossupressores/uso terapêutico , Programas de Rastreamento/métodos , Estudos Retrospectivos , Software
4.
Virol J ; 16(1): 88, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31272463

RESUMO

BACKGROUND: Currently, there is no consensus on the effects and safety of lamivudine therapy for chronic hepatitis B (CHB) in children. METHOD: Both English and Chinese databases were searched comprehensively. An odds ratio (OR) and a standard mean difference (SMD) were used to assess the effects and safety of lamivudine therapy for CHB in children. RESULTS: Thirteen eligible studies were included in our analysis. The rates of Hepatitis B virus (HBV) response, biochemical response, hepatitis B e antigen (HBeAg) loss, HBeAg seroconversion, and hepatitis B surface antigen (HBsAg) loss were significantly higher in the lamivudine (LAM) therapy group than in the control group. The changes in children's weight and height were similar between the two groups. CONCLUSIONS: LAM therapy was efficacious for CHB in children. Additionally, it had no side effect on children's height and weight.


Assuntos
Antivirais/uso terapêutico , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Criança , Farmacorresistência Viral , Humanos , Lamivudina/administração & dosagem , Razão de Chances
5.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(6): 605-609, 2019 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-31238605

RESUMO

In 2016, the WHO proposed the goal for elimination of hepatitis B as public health threat, by 2030. China has the heaviest burden caused by hepatitis B virus (HBV) infection in the world, and serves as the major contributor to the goal of eliminating hepatitis B by 2030, globally. During the past 30 years, great progress has been made towards the implementation on prevention and control programs of HBV infection, in China, that enabling the WHO 2030 target to be fulfilled. However, due to the size of population, the large number of HBV infections and the low coverage of diagnosis and treatment programs, China is still facing the challenge in reaching the 2030 target, on time. This paper elaborates the achievements and gaps regarding the on-going prevention and control programs, including vaccination, prevention of maternal-to-child transmission, blood and injection safety, diagnosis and treatment on HBV infection and putting forward several suggestions on relevant policies for achieving the goal of hepatitis B elimination by 2030, in China.


Assuntos
Antivirais/uso terapêutico , Metas , Vacinas contra Hepatite B/administração & dosagem , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/prevenção & controle , Programas de Imunização , Vacinação/métodos , Criança , China/epidemiologia , Saúde Global , Acesso aos Serviços de Saúde , Hepatite B/epidemiologia , Hepatite B/virologia , Vírus da Hepatite B/isolamento & purificação , Humanos , Programas de Rastreamento , Saúde Pública
6.
Molecules ; 24(11)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151219

RESUMO

A series of oxime Cyclohexyl (E)-4-(hydroxyimino)-4-phenylbutanoates and their ethers were designed, synthesized, and evaluated for anti-hepatitis B virus (HBV) activities with HepG 2.2.15 cell line in vitro. Most of these compounds possessed anti-HBV activities, and among them, compound 4B-2 showed significant inhibiting effects on the secretion of HBsAg (IC50 = 63.85 ± 6.26 µM, SI = 13.41) and HBeAg (IC50 = 49.39 ± 4.17 µM, SI = 17.34) comparing to lamivudine (3TC) in HBsAg (IC50 = 234.2 ± 17.17 µM, SI = 2.2) and HBeAg (IC50 = 249.9 ± 21.51 µM, SI = 2.07). Docking study of these compounds binding to a protein residue (PDB ID: 3OX8) from HLA-A2 that with the immunodominant HBcAg18-27 epitope (HLA-A2.1- restricted CTL epitope) active site was carried out by using molecular operation environment (MOE) software. Docking results showed that behaviors of these compounds binding to the active site in HLA-A protein residue partly coincided with their behaviors in vitro anti-HBV active screening.


Assuntos
Antivirais/química , Antivirais/farmacologia , Técnicas de Química Sintética , Desenho de Drogas , Vírus da Hepatite B/efeitos dos fármacos , Antivirais/síntese química , Sítios de Ligação , Domínio Catalítico , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Oximas/síntese química , Oximas/química , Oximas/farmacologia , Ligação Proteica , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
7.
Eur J Med Chem ; 176: 41-49, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31091479

RESUMO

Hepatitis B virus (HBV) infection is a worldwide public health issue. Search for novel non-nucleoside anti-HBV agents is of great importance. In the present study, a series of quinazolinones derivatives (4a-t and 5a-f) were synthesized and evaluated as novel anti-HBV agents. Among them, compounds 5e and 5f could significantly inhibit HBV DNA replication with IC50 values of 1.54 µM and 0.71 µM, respectively. Interestingly, the selective index values of 5f was higher than that of lead compound K284-1405, suggesting 5f possessed relatively safety profile than K284-1405. Notably, 5e and 5f exhibited remarkably anti-HBV activities against lamivudine and entecavir resistant HBV strain with IC50 values of 1.90 and 0.84 µM, confirming their effectiveness against resistant HBV strain. In addition, molecular docking studies indicated that compounds 5e and 5f could well fit into the dimer-dimer interface of HBV core protein dominated by hydrophobic interactions. Notably, their binding modes were different from the lead compound K284-1405, which may be attributed to the additional substituent groups in the quinazolinone scaffold. Taken together, 5e and 5f possessed novel chemical structure and potent anti-HBV activity against both drug sensitive and resistant HBV strains, thus warranting further research as potential non-nucleoside anti-HBV candidates.


Assuntos
Antivirais/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Quinazolinonas/farmacologia , Antivirais/síntese química , Antivirais/química , Antivirais/toxicidade , Sítios de Ligação , Replicação do DNA/efeitos dos fármacos , Células Hep G2 , Antígenos do Núcleo do Vírus da Hepatite B/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Quinazolinonas/toxicidade , Relação Estrutura-Atividade
8.
Nat Commun ; 10(1): 2184, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097716

RESUMO

Chronic hepatitis B virus (HBV) infection can cause cirrhosis and hepatocellular carcinoma and is therefore a serious public health problem. Infected patients are currently treated with nucleoside/nucleotide analogs and interferon α, but this approach is not curative. Here, we screen 978 FDA-approved compounds for their ability to inhibit HBV replication in HBV-expressing HepG2.2.15 cells. We find that ciclopirox, a synthetic antifungal agent, strongly inhibits HBV replication in cells and in mice by blocking HBV capsid assembly. The crystal structure of the HBV core protein and ciclopirox complex reveals a unique binding mode at dimer-dimer interfaces. Ciclopirox synergizes with nucleoside/nucleotide analogs to prevent HBV replication in cells and in a humanized liver mouse model. Therefore, orally-administered ciclopirox may provide a novel opportunity to combat chronic HBV infection by blocking HBV capsid assembly.


Assuntos
Antivirais/farmacologia , Ciclopirox/farmacologia , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/tratamento farmacológico , Montagem de Vírus/efeitos dos fármacos , Animais , Antivirais/uso terapêutico , Capsídeo/efeitos dos fármacos , Capsídeo/metabolismo , Ciclopirox/química , Ciclopirox/uso terapêutico , Cristalografia por Raios X , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Células Hep G2 , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Hepatócitos/transplante , Hepatócitos/virologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , RNA Viral/metabolismo , Quimeras de Transplante , Resultado do Tratamento , Proteínas do Core Viral/química , Proteínas do Core Viral/metabolismo , Replicação Viral/efeitos dos fármacos
9.
Virol J ; 16(1): 61, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064399

RESUMO

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.


Assuntos
Antivirais/uso terapêutico , DNA Viral/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Feminino , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Organofosfonatos/uso terapêutico , Curva ROC , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Soroconversão , Adulto Jovem
10.
Mikrobiyol Bul ; 53(2): 156-169, 2019 Apr.
Artigo em Turco | MEDLINE | ID: mdl-31130120

RESUMO

HBV is a DNA virus and the causative agent of hepatitis B infection. Hepatitis B is a contagious disease and is still a major health problem all over the world. When the infection become chronic, it may cause serious diseases such as fibrosis, cirrhosis and/or hepatocellular carcinoma. Interferon/pegylated interferon by intravenous route and nucleoside/nucleotide (NA) analogues such as lamivudine, adefovir, entecavir, telbivudine and tenofovir given by oral route are used in the treatment. Antivirals given by oral route are mostly preferred in the treatment. However, because of the replication strategy and biological properties of HBV, mutations that cause antiviral resistance against these drugs can occur at different rates, although they can vary from drug to drug over time. It is possible that drug resistant virus may transmit from patient to healthy individuals. Therefore, there is a possibility of infection with drug-resistant HBV before treatment. Antiviral resistance mutations are divided into four categories; i) Nucleos(t)ide analog resistance (NAr)-related mutations, ii) primary drug resistance mutations, iii) secondary/compensatory mutations, iv) putative antiviral resistance mutations and pre-treatment variations. Recent studies have focused particularly on putative mutations and pre-treatment variations. The aim of this study was to better understanding of the antiviral resistance profiles of chronic hepatitis B (CHB) patients treated and untreated with NA, and help to prevent unnecessary drug use, minimize the side effects and economic damages. A total of 124 patients who have received nucleoside analog (NA) drug treatments (n= 72) and patients without NA treatment (n= 52) were included in the study. Viral DNA was isolated from the plasma samples of the patients. A DNA fragment, which is 551 bp, was amplified and sequenced including the binding side of all nucleoside analogs containing the B, C and D domains located in the reverse transcriptase region in the HBV genome. Different types of mutations were detected in 13 (18.05%) of 72 treated patients and in 18 (34.61%) of 52 untreated patients (p< 0.05). Primary drug resistance mutations such as rtI169T, rtA181T/V, rtT184A/C/F/G/I/L/M/S, rtA194T, rtS202C/G/I, rtM204I/V/S, rtN236T, rt M250I/L/V and rtV173L were not detected in any of the patient samples. However, potential drug resistance mutations such as rtR164R, rtG165D/A, rtG172Q, rtS176N, rtF178V, rtA181G, rtS185N/G/C, rtV207M, rtQ215H/S, rtL231V, rtI233K, rtN238S, rtV253T, rtC256G/S and rtI266R/V were detected in untreated patient samples in B, C, D and D domains of reverse transcriptase region. Our results have suggested that the detection of pretreatment variations could be helpful for choosing the correct antiviral drug for the better treatment management.


Assuntos
Farmacorresistência Viral , Vírus da Hepatite B , Hepatite B Crônica , Antivirais/farmacologia , Farmacorresistência Viral/genética , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Humanos , Mutação , Inibidores da Transcriptase Reversa/farmacologia
11.
Artigo em Inglês | MEDLINE | ID: mdl-30929566

RESUMO

Dengue (DENV) viral infection is a global public health problem that infrequently develops life threatening diseases such as dengue hemorrhagic fever (DFS) and dengue shock syndrome (DSS). Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic human corona virus with 38% fatality rate of infected patients. A series of 4-arylhydrazono-5-trifluoromethyl-pyrazolones, their ribofuranosyl, and 5'-deoxyribofuranosyl nucleosides were synthesized, geometry optimized using Density functional theory (DFT), and evaluated for their antiviral activity. 2-Nitrophenylhydrazonopyra-zolone derivative 5 showed significant activity against MERS-CoV (EC50 = 4.6 µM). The nucleoside analog 8 showed moderate activity against DENV-2 (EC50 = 10 µM), while the activity was abolished with the corresponding 5'-deoxyribonucleoside analogs. The identified hits in this study set this category of compounds for further future optimizations.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Pirazolonas/química , Vírus da Dengue/efeitos dos fármacos , Desenho de Drogas , Hepacivirus/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Influenzavirus A/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Estrutura Molecular , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
12.
Midwifery ; 74: 116-125, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30953967

RESUMO

OBJECTIVE: HBV mother to child transmission (MTCT) can be prevented by passive and active immunoprophylaxis. In this study, we aim to assess whether vaginal delivery is safe for HBV MTCT after immunoprophylaxis. MATERIAL AND METHODS: PubMed and Web of Science were systematically searched. We compared the MTCT incidence of infants at 6 months or older between vaginal delivery and caesarean section. Serological HBV positive incidences for newborns at birth were also compared. RESULTS: Eighteen studies with 11,446 mother-child pairs were included in the meta-analysis. The average incidence of serological HBV positive for newborns at birth was 7.2% in the cesarean section group, and 16.6% in the vaginal delivery group. The summary odds ratio (OR) was 0.499 (95% CI 0.364-0.684; Z = 4.33, P < 0.00001) between two groups. However, the average incidences of MTCT were 3.3% and 4.1% for the cesarean section group and the vaginal delivery group, respectively. The summary OR compared between two groups was 0.790 (95% CI 0.614 to 1.016; Z = 1.83, P = 0.067). The funnel plot, Begg's Test (z = -0.55, P = 0.583) and Egger's test (t = -0.29, P = 0.777) suggested there was no publication bias among the included studies. Sensitive analyze showed the ORs were 0.764 (95% CI 0.490 to 1.192; Z = 1.19, P = 0.236), and 0.386 (95% CI 0.132 to 1.125; Z = 1.74, P = 0.0081), respectively. CONCLUSION: The vaginal delivery did not increase the HBV MTCT incidence after immunoprophylaxis at 6 months old or more. The existing evidence does not support the conclusion that caesarean section can prevent MTCT in HBsAg-positive mother after immunoprophylaxis. However, this conclusion should be cautious in the HBV mother with high viral load.


Assuntos
Parto Obstétrico/efeitos adversos , Vírus da Hepatite B/efeitos dos fármacos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Profilaxia Pré-Exposição/normas , Adulto , Parto Obstétrico/métodos , Feminino , Vírus da Hepatite B/patogenicidade , Humanos , Incidência , Recém-Nascido , Razão de Chances , Gravidez
13.
Science ; 364(6438): 399-402, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31023926

RESUMO

The maintenance of terminally differentiated cells, especially hepatocytes, in vitro has proven challenging. Here we demonstrated the long-term in vitro maintenance of primary human hepatocytes (PHHs) by modulating cell signaling pathways with a combination of five chemicals (5C). 5C-cultured PHHs showed global gene expression profiles and hepatocyte-specific functions resembling those of freshly isolated counterparts. Furthermore, these cells efficiently recapitulated the entire course of hepatitis B virus (HBV) infection over 4 weeks with the production of infectious viral particles and formation of HBV covalently closed circular DNA. Our study demonstrates that, with a chemical approach, functional maintenance of PHHs supports long-term HBV infection in vitro, providing an efficient platform for investigating HBV cell biology and antiviral drug screening.


Assuntos
Vírus da Hepatite B/crescimento & desenvolvimento , Hepatócitos/fisiologia , Hepatócitos/virologia , Cultura Primária de Células/métodos , Cultura de Vírus/métodos , Antivirais/isolamento & purificação , Antivirais/farmacologia , DNA Circular/biossíntese , DNA Circular/isolamento & purificação , DNA Viral/biossíntese , DNA Viral/isolamento & purificação , Avaliação Pré-Clínica de Medicamentos , Vírus da Hepatite B/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Transcriptoma , Vírion/efeitos dos fármacos , Vírion/crescimento & desenvolvimento
14.
Fitoterapia ; 137: 104151, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30999024

RESUMO

The norbisabolane-type sesquiterpenoids bearing a spiroketal functionality have been found in Phyllanthus spp. and showed anti-HBV activities. As part of an ongoing effort to search for promising anti-HBV sesquiterpenes from Phyllanthus plants, we report four new norbisabolane-type sesquiterpenoids, phyacidusin A (1), phyacidusin B (2), phllanthacidoid A1 (3) and phllanthacidoid N1 (4), from stem of P. acidus collected in Xishuangbanna, Yunnan province, China. The absolute configuration of new compounds was established by coupling constants and ROESY correlations, as well as comparation of NMR data with those of known compounds. The absolute configuration of new compounds 1 and 2 was further confirmed by X-ray diffraction. Compound 2 showed effect to HBsAg with an IC50 value of 11.2 ±â€¯0.01 µM, while compound 3 inhibited HBeAg secretion with an IC50 value of 57.1 ±â€¯0.02 µM. The results enriched the diversity of anti-HBV norbisabolane sesquiterpenes.


Assuntos
Antivirais/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Phyllanthus/química , Sesquiterpenos/farmacologia , Antivirais/isolamento & purificação , China , Células Hep G2 , Humanos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Caules de Planta/química , Sesquiterpenos/isolamento & purificação
15.
Jpn J Clin Oncol ; 49(7): 646-655, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30968933

RESUMO

BACKGROUND AND AIM: The impact of transarterial chemoembolization (TACE) and preventive antiviral therapy on the occurrence of hepatitis B virus (HBV) reactivation and subsequent hepatitis remains controversial. This meta-analysis aimed to evaluate the effect of TACE and preventive antiviral therapy on the risk of HBV reactivation and subsequent hepatitis. Meanwhile, we explored the role of HBeAg status in HBV reactivation after TACE. METHODS: We performed this meta-analysis with 11 included studies to assess the effect of TACE and preventive antiviral therapy on predicting clinical outcomes in HBV-related hepatocellular carcinoma (HCC). The pooled odds ratios (OR) were calculated using a random or fixed effects model. PUBMED, MEDLINE, EMBASE and the Cochrane Central Register of Controlled were searched for the included articles (from 2000 to December 2017). RESULTS: Our results showed that TACE significantly increased the risk of HBV reactivation (OR: 3.70; 95% CI 1.45-9.42; P < 0.01) and subsequent hepatitis (OR: 4.30; 95% CI 2.28-8.13; P < 0.01) in HCC patients. There was no significant difference in HBV reactivation after TACE between HBeAg positive and negative patients (OR: 1.28; 95% CI 0.31-5.34; P = 0.73). Preventive antiviral therapy could statistically reduce the rate of HBV reactivation (OR: 0.08; 95% CI 0.02-0.32; P < 0.01) and hepatitis (OR: 0.22; 95% CI 0.06-0.80; P = 0.02) in those with TACE treatment. CONCLUSIONS: The present study suggested that TACE was associated with a higher possibility of HBV reactivation and subsequent hepatitis. Preventive antiviral therapy is significantly in favor of a protective effect.


Assuntos
Antivirais/farmacologia , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/virologia , Quimioembolização Terapêutica , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/prevenção & controle , Neoplasias Hepáticas/terapia , Ativação Viral/efeitos dos fármacos , Adulto , Idoso , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Viés de Publicação , Fatores de Risco
16.
Cell Mol Biol (Noisy-le-grand) ; 65(2): 75-81, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30860474

RESUMO

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) was positively correlated with serological hepatitis B surface antigen (HBsAg) levels in hepatitis B e antigen (HBeAg) positive chronic hepatitis B (CHB) patients. We evaluated whether Thymopentin (TP5) and interferon (IFN-a) had a synergic effect on HBV cccDNA and the effect of TP5 addition therapy on HBsAg clearance in CHB patients. Real-time PCR experiments were performed to test cccDNA in HepG2.2.15 cells. 45 HBeAg-positive CHB patients had been distributed into two groups randomly. Treatment group: 23 patients were treated with a 24-week TP5 on the basis of the treatment entecavir (ETV) and peginterferon alfa-2a (PegIFN alpha-2a). Control group: 22 patients were treated with ETV and PegIFNa-2a. The study period was 72 weeks. In HepG2.2.15 cells, TP5 5ug/ml and 10ug/ml respectively combined with IFN-a 2ku/ml could potently inhibit cccDNA level at 72 hours (P<0.05). In clinical study, mean HBsAg levels in two groups are not significantly different at different time points (p=0.112). However, changes of mean HBsAg levels in TP5 add-on group at different time points are significantly different (p<0.05). Patients with HBsAg levels <1500IU/ml in control group had higher HBsAg levels compared with patients with HBsAg levels <1500IU/ml in TP5 add-on group (P=0.019). The latter had the most pronounced HBsAg reduction. TP5 and IFN had a synergic effect on inhibiting cccDNA levels in HepG2.2.15 cells; Patients in treatment group showed no extra side effects compared with the control group. 24 weeks TP5 add-on treatment was safe and had a tendency to accelerate the decline of HBsAg when HBV-DNA was undetectable.


Assuntos
Guanina/análogos & derivados , Antígenos E da Hepatite B/metabolismo , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Timopentina/uso terapêutico , Adulto , DNA Viral/genética , Quimioterapia Combinada , Feminino , Guanina/farmacologia , Guanina/uso terapêutico , Células Hep G2 , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/sangue , Humanos , Masculino , Proteínas Recombinantes/uso terapêutico , Timopentina/farmacologia , Resultado do Tratamento
17.
Carbohydr Polym ; 212: 215-221, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30832850

RESUMO

DrzBC and DrzBS (10-23 DNAzyme) could block the expression of HBV e- and s- gene respectively. But the application of 10-23 DNAzyme was limited owing to the lack of appropriate delivery vehicles. Chitosan oligosaccharide-SS-Octadecylamine (CSSO), a redox-responsive nano-sized polymeric carrier, could self-aggregate and bind with DNA by electrostatic interaction at proper mass ratio. Compared with the traditional commercial carrier Lipo2000, CSSO exhibited lower cytotoxicity, efficient cellular uptake by targeting cells, and rapidly DNA released in cytoplasm after escaping from endosomes. Including the same DNA concentration, Lipo2000/(DrzBC or DrzBS) showed maximum inhibitory rate on HBeAg (47.29 ±â€¯1.86%) and HBsAg (33.58 ±â€¯0.72%) secretion after 48 h incubation, and then both decreased. In contrast, HBeAg secretion inhibition by CSSO/DrzBC and HBsAg secretion inhibition by CSSO/DrzBS were up to 73.86 ±â€¯1.77% and 67.80 ±â€¯2.51% at 48 h, and further increased to 83.83 ±â€¯2.34% and 76.79 ±â€¯2.18% at 72 h, respectively. CSSO is a promising redox-responsive polymeric carrier for efficient anti-Hepatitis B Virus gene therapy.


Assuntos
Aminas/administração & dosagem , Quitosana/administração & dosagem , Terapia Genética/métodos , Vírus da Hepatite B/efeitos dos fármacos , Oligossacarídeos/administração & dosagem , Polímeros/administração & dosagem , Aminas/metabolismo , Quitosana/metabolismo , DNA Viral/efeitos dos fármacos , DNA Viral/genética , DNA Viral/metabolismo , Relação Dose-Resposta a Droga , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/metabolismo , Células Hep G2 , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Humanos , Oligossacarídeos/metabolismo , Oxirredução/efeitos dos fármacos , Polímeros/metabolismo
18.
Life Sci ; 223: 1-8, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30862568

RESUMO

AIMS: The aim of this study was to investigate the relationship between anti-HBV treatment and the regulation of HDACs during HBV DNA replication. METHODS: HDAC activities and HBV DNA levels in CHB patients' sera were measured and correlation analysis was made. The changes of HDAC2, HDAC6, AH3 and histone H3 levels in normal control and 4 CHB patient liver tissue samples before and after antiviral treatment were examined. The HDAC inhibitor, TSA, anti-HBV agents, ETV and IFN-α were used to stimulate HepG2.2.15 cells. The levels of HBV DNA, pgRNA in supernatants, and cccDNA in the cells were determined by PCR. The HDAC activity, HDAC6, HDAC2, AH3 and H3 protein levels in cells were tested at days 3, 6, and 9 after treatments. KEY FINDINGS: HDAC activity was positively correlated with HBV DNA in the HBV patients' sera. The levels of HDAC2, HDAC6 and AH3 were notably decreased after antiviral treatment. When compared with antiviral treatment group, the normal liver tissue showed obviously decreased HDAC2, HDAC6 and AH3 protein levels. In vitro study, the level of HBV DNA, the HDAC activity, and the HDAC2, HDAC6 and AH3 protein levels decreased in the ETV, IFN-α and TSA groups compared with the control group. The pgRNA level in supernatants was declined in the IFN-α group and increased in the ETV and TSA groups. cccDNA expression was suppressed by IFN-α. SIGNIFICANCE: The changes of HBV replicative products during antiviral treatment are associated with histone deacetylation. Acetylated histone H3 is involved in the process of hepatitis B virus DNA replication.


Assuntos
Replicação do DNA/efeitos dos fármacos , DNA Viral/genética , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Histona Desacetilases/metabolismo , Histonas/genética , Adulto , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Técnicas de Cultura de Células , Replicação do DNA/genética , Feminino , Células Hep G2 , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/enzimologia , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/genética , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/virologia , Masculino , Pessoa de Meia-Idade , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética
19.
World J Surg Oncol ; 17(1): 45, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30823932

RESUMO

BACKGROUND: The effect of antiviral therapy (AVT) on clinical outcomes in patients with hepatocellular carcinoma (HCC) who are seronegative for hepatitis B virus (HBV), defined as HBV DNA < 100 IU/ml prior to surgical resection, is unknown. The main purpose of this study was to evaluate the possible value of AVT in this cohort of patients. METHODS: From January 2006 to January 2013, 161 HCC patients with positive serum tests for HBV surface antigen (HBsAg) but negative tests for HBV DNA who had undergone hepatectomy were included and analyzed. Propensity score matching (PSM) was used to balance the heterogeneity in baseline characteristics. RESULTS: All patients were divided into the following two groups: the AVT group (n = 73, 45.34%) and the non-AVT group (n = 88, 54.66%). HBV reactivation occurred in 20 patients in the non-AVT group (22.73%) but in only 2 patients in the AVT group (2.74%, p < 0.001). After PSM, the 1-, 2-, and 3-year recurrence-free survival (RFS) rates in the AVT group and the non-AVT group were 78.38%, 72.97%, and 62.16% and 81.08%, 72.97%, and 72.97%, respectively (p = 0.564); the 1-, 2-, and 3-year overall survival (OS) rates were 97.30%, 97.3%, and 91.89% and 94.59%, 94.59%, and 86.49% in the AVT group and non-AVT group, respectively (p = 0.447). CONCLUSIONS: Antiviral therapy can reduce HBV reactivation but is not correlated with a significant increase in postoperative RFS and OS in HCC patients with HBV DNA levels < 100 IU/ml.


Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/terapia , Hepatectomia , Neoplasias Hepáticas/terapia , Ativação Viral/efeitos dos fármacos , Antivirais/farmacologia , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/virologia , DNA Viral/isolamento & purificação , Intervalo Livre de Doença , Feminino , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Humanos , Fígado/patologia , Fígado/cirurgia , Fígado/virologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Prognóstico , Pontuação de Propensão , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
20.
Zhonghua Gan Zang Bing Za Zhi ; 27(2): 85-87, 2019 Feb 20.
Artigo em Chinês | MEDLINE | ID: mdl-30818909

RESUMO

The main transmission route of chronic hepatitis B virus infection is mother-to-child transmission of hepatitis B virus and the main cause of combined immune prophylaxis failure in neonates at the end of pregnancy is high viral load. Moreover, oral administration of nucleos(t)ide analogues (NAs) during the second and third trimesters of pregnancy can significantly reduce or even completely block mother-to-child transmission of HBV. This article focuses on the necessity and feasibility of oral NAs antiviral therapy for HBV carrier pregnant woman with high viral load, and the issues commences at the time of medication and viral load thresholds.


Assuntos
Antivirais/uso terapêutico , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/transmissão , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Antivirais/administração & dosagem , DNA Viral , Feminino , Hepatite B Crônica/prevenção & controle , Humanos , Recém-Nascido , Nucleosídeos/uso terapêutico , Nucleotídeos/uso terapêutico , Gravidez , Complicações Infecciosas na Gravidez/virologia , Carga Viral
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