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2.
Medicine (Baltimore) ; 99(40): e22642, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019490

RESUMO

RATIONALE: Reactivation of hepatitis B virus (HBV) after treatment with bortezomib-based regimens in HBV-positive patients with multiple myeloma (MM) has been reported in the past few years. Nevertheless, there is evidence of inhibition of HBV replication by bortezomib in transgenic mice. However, there is still no clinical evidence that bortezomib inhibits HBV. PATIENT CONCERNS: A 55-year-old MM patient with a family history of MM, who was also a chronic HBV carrier, achieved HBV clearance after treatment with a bortezomib-based regimen in combination with anti-HBV drugs. DIAGNOSES: The diagnosis was MM with chronic carrier of HBV. INTERVENTIONS: He received bortezomib-based regimen for MM as well as entecavir as a prophylaxis to prevent HBV reactivation. OUTCOMES: This patient achieved HBsAg and HBV-DNA clearance after 2 months and the remission was maintained during the next 2 years. He also achieved complete remission of MM and underwent consolidation therapy with autologous hematopoietic stem cell transplantation. LESSONS: This is the first case of MM with HBV clearance after receiving a bortezomib-based regimen combined with anti-HBV drug. Research on related mechanisms might provide new suggestions and hope for better management of HBV positive patients with MM and for the treatment of HBV patients.


Assuntos
Antineoplásicos/uso terapêutico , Antivirais/uso terapêutico , Bortezomib/uso terapêutico , Guanina/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Protocolos Clínicos , Quimioterapia Combinada , Guanina/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Antígenos de Superfície da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Hepatite B Crônica/complicações , Hepatite B Crônica/prevenção & controle , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Autólogo/métodos , Resultado do Tratamento
3.
PLoS One ; 15(9): e0238839, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915862

RESUMO

In patients who are HIV infected, hepatitis B virus (HBV) infection is an important co-morbidity. However, antiretroviral options for HIV/HBV co-infected children are limited and, at the time of this study, only included lamivudine. These children may remain on this regimen for many years until late adolescence. They are at high risk of developing HBV drug resistance and uncontrolled HBV disease. The aim of this study was to characterize HBV infection in HIV/HBV co-infected children. Known HIV-infected/HBsAg-positive children, previously exposed to lamivudine monotherapy against HBV, and their mothers were recruited at the Katutura Hospital paediatric HIV clinic in Windhoek, Namibia. Dried blood spot and serum samples were collected for HBV characterization and serological testing, respectively. Fifteen children and six mothers participated in the study. Eight of the 15 children (53.3%) tested HBV DNA positive; all eight children were on lamivudine-based ART. Lamivudine-associated resistance variants, together with immune escape mutants in the surface gene, were identified in all eight children. Resistance mutations included rtL80I, rtV173L, rtL180M, rtM204I/V and the overlapping sE164D, sW182*, sI195M and sW196LS variants. HBV strains belonged to genotypes E (6/8, 75%) and D3 (2/8, 25%). Further analysis of the HBV core promoter region revealed mutations associated with reduced expression of HBeAg protein and hepatocarcinogenesis. All six mothers, on HBV-active ART containing tenofovir and lamivudine, tested HBV DNA negative. This study confirms the importance of screening HIV-infected children for HBV and ensuring equity of drug access to effective HBV treatment if co-infected.


Assuntos
Coinfecção/epidemiologia , Farmacorresistência Viral/genética , Infecções por HIV/epidemiologia , Hepatite B/epidemiologia , Mutação , Proteínas do Core Viral/genética , Carga Viral , Adolescente , Adulto , Antirretrovirais/uso terapêutico , Criança , Estudos de Coortes , Coinfecção/genética , Coinfecção/virologia , Estudos Transversais , DNA Viral/análise , Feminino , HIV/efeitos dos fármacos , HIV/isolamento & purificação , Infecções por HIV/complicações , Infecções por HIV/genética , Infecções por HIV/virologia , Hepatite B/complicações , Hepatite B/genética , Hepatite B/virologia , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/isolamento & purificação , Humanos , Masculino , Namíbia/epidemiologia , Adulto Jovem
4.
Arch Virol ; 165(10): 2361-2365, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32743697

RESUMO

In this study, we investigated the seroprevalence of anti-hepatitis D virus (HDV) antibodies in hepatitis B surface antigen (HBsAg)-positive children after 25 years of obligatory vaccination of infants against hepatitis B virus. This cross-sectional study included 120 treatment-naïve HBsAg-positive children, with a male-to-female ratio of 1.8:1 and a mean age of 7.8 ± 3.8 years (range, 1-17 years). Mothers were positive for HBsAg in 96.6% of the cases. HBeAg-positive chronic infection was observed in 60% of the cases, HBeAg-positive chronic hepatitis in 12.5%, and HBeAg-negative chronic infection in 26.7%. Anti-HDV antibodies were not detected in any of the cases. Thus, there is a lack of anti-HDV antibodies in HBsAg-positive children, despite the current burden in adults.


Assuntos
Anticorpos Anti-Hepatite/sangue , Antígenos de Superfície da Hepatite B/sangue , Vacinas contra Hepatite B/administração & dosagem , Vírus da Hepatite B/imunologia , Hepatite B/epidemiologia , Hepatite D Crônica/epidemiologia , Vírus Delta da Hepatite/imunologia , Adolescente , Criança , Pré-Escolar , Coinfecção , Estudos Transversais , Egito/epidemiologia , Feminino , Hepatite B/imunologia , Hepatite B/prevenção & controle , Hepatite B/virologia , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/patogenicidade , Hepatite D Crônica/sangue , Hepatite D Crônica/imunologia , Hepatite D Crônica/virologia , Vírus Delta da Hepatite/patogenicidade , Humanos , Lactente , Masculino , Estudos Soroepidemiológicos
5.
PLoS One ; 15(8): e0237525, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32776972

RESUMO

Hepatitis B is a global epidemic that requires carefully orchestrated vaccination initiatives in geographical regions of medium to high endemicity to reach the World Health Organization's elimination targets by 2030. This study compares two widely-used deterministic hepatitis B models-the Imperial HBV model and the CDA Foundation's PRoGReSs-based on their predicted outcomes in four countries. The impact of scaling up of the timely birth dose of the hepatitis B vaccine is also investigated. The two models predicted largely similar outcomes for the impact of vaccination programmes on the projected numbers of new cases and deaths under high levels of the infant hepatitis B vaccine series. However, scenarios for the scaling up of the infant hepatitis B vaccine series had a larger impact in the PRoGReSs model than in the Imperial model due to the infant vaccine series directly leading to the reduction of perinatal transmission in the PRoGReSs model, but not in the Imperial model. Meanwhile, scaling up of the timely birth dose vaccine had a greater impact on the outcomes of the Imperial hepatitis B model than in the PRoGReSs model due to the greater protection that the birth dose vaccine confers to infants in the Imperial model compared to the PRoGReSs model. These differences underlie the differences in projections made by the models under some circumstances. Both sets of assumptions are consistent with available data and reveal a structural uncertainty that was not apparent in either model in isolation. Those relying on projections from models should consider outputs from both models and this analysis provides further evidence of the benefits of systematic model comparison for enhancing modelling analyses.


Assuntos
Vacinas contra Hepatite B/administração & dosagem , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/prevenção & controle , Programas de Imunização/estatística & dados numéricos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Modelos Estatísticos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Saúde Global , Hepatite B/epidemiologia , Hepatite B/virologia , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Gravidez , Organização Mundial da Saúde , Adulto Jovem
6.
PLoS One ; 15(8): e0237586, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32785260

RESUMO

This study investigated the kinetics of estimated glomerular filtration rate (eGFR) and quantitative hepatitis B surface antigen (qHBsAg) in telbivudine (LdT)-treated chronic hepatitis B (CHB) patients whose treatment was subsequently adjusted with the adding on adefovir or by switching to tenofovir disoproxil fumarate (TDF) as rescue. Of 295 CHB patients initially treated with LdT, 102 of them who subsequently receiving either adding-on adefovir (group A, n = 58) or switching to TDF (group B, n = 44) for more than 24 months were enrolled. Serial eGFR and qHBsAg levels (3 to 6 monthly) in both LdT monotherapy and rescue therapy periods were analyzed retrospectively. Subsequent decline of qHBsAg especially in rescue therapy period were noted (p<0.001 and p = 0.068 in group A and B). However, patients in group B achieved a significant increase of eGFR (p = 0.010) in LdT monotherapy period but had a significant decline of eGFR (p<0.001) in rescue therapy period. In contrast, patients in group A maintained eGFR levels in both periods. Meanwhile, switch to TDF (hazard ratio: 3.036; 95% confidence interval: 1.040-8.861; p = 0.042) was the sole factor related to the decrease of eGFR>20% from baseline. Both rescue therapies achieved subsequent declines of qHBsAg over time but caused different changes in eGFR. LdT-based rescue therapy maintained eGFR but TDF switching therapy descended eGFR. Therefore, it is essential to monitor patient's renal function intensively when switching from LdT to TDF as a rescue strategy.


Assuntos
Antivirais/farmacologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Antígenos de Superfície da Hepatite B/metabolismo , Vírus da Hepatite B/metabolismo , Hepatite B/patologia , Telbivudina/farmacologia , Feminino , Seguimentos , Hepatite B/metabolismo , Hepatite B/virologia , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
7.
Brasília; CONITEC; jun. 2020.
Não convencional em Português | BRISA/RedTESA | ID: biblio-1121768

RESUMO

CONTEXTO: a hepatite B crônica, causada pela infecção decorrente do vírus da hepatite B, tem sido um importante problema de saúde no mundo, afetando cerca de 350 milhões de pessoas mundialmente. Estima-se que mais de 786 mil indivíduos morrem anualmente por conta de suas complicações. O transplante de fígado é considerado padrão-ouro no tratamento da insuficiência hepática e do carcinoma hepatocelular relacionados ao vírus da hepatite B. No entanto, a reativação viral pós-transplante pode ser prejudicial à função do aloenxerto, levando a uma baixa sobrevida e, consequentemente, se configura como grande desafio na prática clínica. A profilaxia da reinfecção pelo vírus da hepatite B pós-transplante hepático é preconizada pelo PCDT, do Ministério da Saúde, por meio da utilização de lamivudina e imunoglobulina humana anti-hepatite B, sendo esta última utilizada na dose de 800 UI ao dia, durante boa parte do tratamento. TECNOLOGIA: imunoglobulina humana anti-hepatite B, na apresentação de 1.000 UI. JUSTIFICATIVA DA DEMANDA: atualmente faz-se a composição de dose por meio de um frasco contendo imunoglobulina humana anti-hepatite B 600 UI ou 500 UI juntamente com frascos de 100 UI. Contudo, devido a questões contratuais com a fabricante, a Coordenação-Geral do Componente Especializado da Assistência Farmacêutica (CGCEAF/DAF/SCTIE/MS) distribuirá a apresentação de 1.000 UI, de forma excepcional. No entanto, atualmente, esta apresentação não consta na Relação Nacional de Medicamentos Essenciais (Rename). Desse modo, apesar da imunoglobulina humana anti-hepatite B já estar incorporada no SUS, foi solicitada a inclusão da apresentação de 1.000 UI do medicamento. DELIBERAÇÃO FINAL: o Plenário da Conitec, em sua 87ª Reunião Ordinária, realizada nos dias 03 e 04 de junho de 2020, deliberou por unanimidade recomendar a incorporação da apresentação de 1.000 UI do medicamento imunoglobulina humana anti-hepatite B no SUS. Assim, foi assinado o registro de deliberação nº 524/2020. DECISÃO: Incorporar a apresentação de 1.000 UI do medicamento imunoglobulina humana anti-hepatite B, no âmbito do Sistema Único de Saúde - SUS, conforme Portaria nº 30, publicada no Diário Oficial da União nº 160, seção 1, página 118, em 20 de agosto de 2020.


Assuntos
Humanos , Imunoglobulinas/uso terapêutico , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Avaliação da Tecnologia Biomédica , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economia
8.
Int J Infect Dis ; 96: 562-566, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32474201

RESUMO

OBJECTIVES: The purpose of this study was to analyze the clinical characteristics of chronic hepatitis B (CHB) cured by antiviral therapy. METHODS: Forty-two patients with CHB were enrolled. All patients had been treated with peginterferon (Peg-IFN) in combination with nucleoside analogue (NA) therapy for variable amounts of time, and all had been successfully cured of the disease. RESULTS: The combined treatment time for all participants was 124.7 ± 58.8 weeks, and the average Peg-IFN treatment time was 102.6 ± 56.1 weeks. At 24 weeks, Hepatitis B surface antigen (HBsAg) and Hepatitis B e antigen (HBeAg) had decreased more than 50% from baseline. Multivariate logistic regression analysis of the week 96 HBsAg-clearing group and the non-HBsAg-clearing group showed a statistically significant difference in baseline HBV DNA levels and week 48 HBsAg levels. Those which baseline HBV DNA was < 2.75 log10 IU/mL, and week 48 HBsAg levels were < 0.88 log10 IU/mL were more likely to achieve rapid HBsAg clearance at 96 weeks. This suggests that low levels of baseline HBV DNA and week 48 HBsAg are a predictor of rapid HBsAg clearance at 96 weeks. CONCLUSIONS: Individualized extension of combination therapy to more than 96 weeks depending on the patient's response and adverse reaction conditions can help achieve a clinical cure. Patients with low baseline HBV DNA and low HBsAg levels at 48 weeks achieve HBsAg clearance more quickly than other populations.


Assuntos
Antivirais/administração & dosagem , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Nucleosídeos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adulto , Quimioterapia Combinada , Feminino , Antígenos de Superfície da Hepatite B/genética , Antígenos de Superfície da Hepatite B/metabolismo , Antígenos E da Hepatite B/genética , Antígenos E da Hepatite B/metabolismo , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Estudos Retrospectivos , Resultado do Tratamento
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.
Zhongguo Zhong Yao Za Zhi ; 45(5): 1076-1081, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32237449

RESUMO

To prepare the herpetolide A nanosuspension lyophilized powder(HPA-NS-LP), in order to investigate its anti-hepatitis B virus(HBV) activity and the dissolution in vitro. Herpetolide A nanosuspension(HPA-NS) was prepared by ultrasonic precipitation method. The formulation and process of HPA-NS were optimized by the single factor experiment. Lyophilized powder(HPA-NS-LP) was prepared by freeze-drying method. Scanning electron microscopy was used to observe morphology of HPA-NS-LP. Paddle method was used to determinate the dissolution of HPT-NS-LP in vitro. The anti-HBV activity of herpetolide A coarse suspension lyophilized powder(HPA-CS-LP) and HPA-NS-LP was evaluated by HepG2.2.15 cell model. The mean particle size of optimized HPA-NS was(173.46±4.36) nm, with a polydispersity index of 0.110±0.012. After redispersion, the mean particle size and the polydispersity index of HPA-NS-LP increased, with changes within a rational range. Scanning electron microscopy showed that HPA-NS-LP was spherical in shape. Cumulative dissolution rate of HPA-NS-LP was more than 90% in 2 hours, which was higher than that of HPA-CS-LP. Both HPA-CS-LP and HPA-NS-LP could effectively inhibit the secretion of HepG2.2.15 cell antigens(HBsAg and HBeAg), and the inhibitory effect of HPA-NS-LP was significantly higher than that of HPA CS-LP(P<0.05). HBV-DNA test showed that high, medium and low-dose HPA-NS-LP(50, 25, 12.5 mg·kg~(-1)) significantly decreased the level of HBV-DNA(P<0.05), and the effect was better than that of the same dose of HPA-CS-LP(P<0.05). The results revealed that HPA-NS-LP exhibited anti-HBV activity in vitro, and its effect was superior to that of HPA-CS-LP.


Assuntos
Cumarínicos/farmacologia , Cucurbitaceae/química , Vírus da Hepatite B/efeitos dos fármacos , Nanopartículas , Compostos Fitoquímicos/farmacologia , Cumarínicos/isolamento & purificação , Células Hep G2 , Humanos , Tamanho da Partícula , Compostos Fitoquímicos/isolamento & purificação , Solubilidade , Suspensões
11.
Zhonghua Gan Zang Bing Za Zhi ; 28(2): 179-182, 2020 Feb 20.
Artigo em Chinês | MEDLINE | ID: mdl-32164074

RESUMO

Small interfering RNA (siRNA) is mainly involved in RNA interference for stopping gene translation by targeting and degrading HBV-transcribed mRNA. Targeting and stability in siRNA can be enhanced via chemical modification, combination use and improved delivery system. Clinical studies have identified JNJ-3989 (ARO-HBV) and ARB-1740 as well-tolerated siRNA drugs, which significantly reduce HBsAg levels. This article expounds the main mechanisms of siRNA in inhibiting HBsAg expression, improving target and stability as well as relevant preclinical and clinical studies.


Assuntos
Vírus da Hepatite B/efeitos dos fármacos , RNA Interferente Pequeno/farmacologia , Replicação Viral/efeitos dos fármacos , DNA Viral/análise , Antígenos de Superfície da Hepatite B/análise , Vírus da Hepatite B/genética , Hepatite B Crônica , Humanos , Interferência de RNA
12.
BMC Biotechnol ; 20(1): 16, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32169063

RESUMO

BACKGROUND: The type I human interferon (IFN) family consists of a group of cytokines with a multiplicity of biological activities, including antiviral, antitumor, and immunomodulatory effects. However, because the half-life of IFN is short, its clinical application is limited. Increasing the yield and biological activity of IFN while extending its half-life is currently the focus of IFN research. RESULTS: Two novel long-acting recombinant human IFN-α2b (rhIFN-α2b) proteins were designed in which the carboxyl-terminal peptide (CTP) of the human chorionic gonadotropin ß su bunit and N-linked glycosylation sequences were linked to rhIFN-α2b. They were designated IFN-1CTPON (fused at the C-terminus of rhIFN-α2b) and IFN-2CTPON (fused at both the C-terminus and N-terminus of rhIFN-α2b). Monoclonal CHO cell strains stably and efficiently expressing the IFNs were successfully selected with methotrexate (MTX), and the highest expression levels were 1468 mg/l and 1196 mg/l for IFN-1CTPON and IFN-2CTPON, respectively. The proteins were purified with affinity chromatography and molecular sieve chromatography. IFN-1CTPON and IFN-2CTPON showed antiviral and antiproliferative activities in vitro. Notably, the half-life of IFN-1CTPON and IFN-2CTPON in vivo were three-fold and two-fold longer than that of commercially available rhIFN-α2b. CONCLUSIONS: CHO cell strains stably expressing long-acting rhIFN-α2b were screened. The purified IFN-CTPON protein has biological activity and an extended half-life, and therefore potential applications.


Assuntos
Antineoplásicos/farmacologia , Antivirais/farmacologia , Gonadotropina Coriônica Humana Subunidade beta/genética , Interferon-alfa/genética , Proteínas Recombinantes de Fusão/farmacologia , Animais , Células CHO , Proliferação de Células/efeitos dos fármacos , Gonadotropina Coriônica Humana Subunidade beta/química , Cromatografia de Afinidade , Cricetulus , Preparações de Ação Retardada , Glicosilação , Meia-Vida , Células HeLa , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Interferon-alfa/metabolismo , Interferon-alfa/farmacologia , Engenharia de Proteínas , Proteínas Recombinantes de Fusão/metabolismo
14.
Sci Rep ; 10(1): 3021, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080249

RESUMO

Chronic hepatitis B virus (HBV) infection is a major public health problem that affects millions of people worldwide. Nucleoside analogue reverse transcriptase (RT) inhibitors, such as entecavir (ETV) and lamivudine (3TC), serve as crucial anti-HBV drugs. However, structural studies of HBV RT have been hampered due to its unexpectedly poor solubility. Here, we show that human immunodeficiency virus type-1 (HIV-1) with HBV-associated amino acid substitutions Y115F/F116Y/Q151M in its RT (HIVY115F/F116Y/Q151M) is highly susceptible to ETV and 3TC. Additionally, we experimentally simulated previously reported ETV/3TC resistance for HBV using HIVY115F/F116Y/Q151M with F160M/M184V (L180M/M204V in HBV RT) substituted. We determined crystal structures for HIV-1 RTY115F/F116Y/Q151M:DNA complexed with 3TC-triphosphate (3TC-TP)/ETV-triphosphate (ETV-TP)/dCTP/dGTP. These structures revealed an atypically tight binding conformation of 3TC-TP, where the Met184 side-chain is pushed away by the oxathiolane of 3TC-TP and exocyclic methylene of ETV-TP. Structural analysis of RTY115F/F116Y/Q151M/F160M/M184V:DNA:3TC-TP also demonstrated that the loosely bound 3TC-TP is misaligned at the active site to prevent a steric clash with the side chain γ-methyl of Val184. These findings shed light on the common structural mechanism of HBV and HIV-1 resistance to 3TC and ETV and should aid in the design of new agents to overcome drug resistance to 3TC and ETV.


Assuntos
Farmacorresistência Viral/efeitos dos fármacos , Guanina/análogos & derivados , HIV-1/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Lamivudina/química , Lamivudina/farmacologia , Nucleosídeos/análogos & derivados , Antivirais/química , Antivirais/farmacologia , Sequência de Bases , Cristalografia por Raios X , DNA Viral/química , Nucleotídeos de Desoxicitosina , Nucleotídeos de Desoxiguanina , Desenho de Fármacos , Guanina/química , Guanina/farmacologia , HIV-1/genética , Mutação/genética , Conformação de Ácido Nucleico , DNA Polimerase Dirigida por RNA/genética , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia
15.
Int J Med Sci ; 17(2): 170-175, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32038100

RESUMO

Background: The aim of this study was to describe biochemical, virological features and Mother-to child-transmission (MTCT) rate in chronic hepatitis B (CHB) women who stopped antiviral therapy before or in the early pregnancy. Methods: This was a single-center, retrospective study. Forty-three CHB women who stopped treatment before or in the early pregnancy and 103 CHB women with tenofovir disoproxil fumarate (TDF) treatment throughout pregnancy were enrolled. The virological and biochemical flares during pregnancy and postpartum period were studied. MTCT rates were also compared. Results: During pregnancy, ALT flares (43.9% vs 1.0%) and viral rebound (31.7% vs 0) were more common in women who stopped treatment (P<0.001). Postpartum ALT flares were less frequent in women with treatment than those stopped treatment (0 vs 6/35, P = 0.001). The birth defect rate in the mothers who stopped treatment did not statistically differ from that of mothers treated throughout pregnancy (4.9 % vs 3.9 %, P = 1.000). There were no significant differences of gestational complications between the two groups, except intrahepatic cholestasis of pregnancy (12.2% vs 0, P = 0.002). The rate of MTCT in mothers who discontinued treatment was higher (2.4% vs 0, P = 0.285), although there was no statistically significant. Conclusion: ALT flares were common in mothers who discontinued antiviral therapy. Thus, these pregnant women should be monitored closely. Cessation of treatment was not recommended although no hepatic failure was observed. Larger studies are needed to evaluate the safety of discontinuation before pregnancy.


Assuntos
Hepatite B Crônica/tratamento farmacológico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Resultado da Gravidez , Tenofovir/efeitos adversos , Adulto , DNA Viral/genética , DNA Viral/isolamento & purificação , Feminino , Antígenos E da Hepatite B , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/complicações , Hepatite B Crônica/transmissão , Hepatite B Crônica/virologia , Humanos , Transmissão Vertical de Doença Infecciosa , Período Pós-Parto/fisiologia , Gravidez , Complicações Infecciosas na Gravidez/patologia , Complicações Infecciosas na Gravidez/virologia , Tenofovir/uso terapêutico , Carga Viral/genética
16.
mBio ; 11(1)2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32071277

RESUMO

The covalently closed circular (CCC) DNA of hepatitis B virus (HBV) functions as the only viral transcriptional template capable of producing all viral RNA species and is essential to initiate and sustain viral replication. CCC DNA is converted from a relaxed circular (RC) DNA, in which neither of the two DNA strands is covalently closed. As RC DNA mimics damaged cellular DNA, the host cell DNA damage repair (DDR) system is thought to be responsible for HBV CCC DNA formation. The potential role of two major cellular DDR pathways, the ataxia telangiectasia mutated (ATM) pathway and the ATM and Rad3-related (ATR) pathway, in HBV CCC DNA formation was thus investigated. Inhibition, or expression knockdown, of ATR and its downstream signaling factor CHK1, but not of ATM, decreased CCC DNA formation during de novo HBV infection, as well as intracellular CCC DNA amplification, when RC DNA from extracellular virions and intracellular nucleocapsids, respectively, is converted to CCC DNA. Furthermore, a novel RC DNA processing product with 5' truncated minus strands was detected when the ATR-CHK1 pathway was inhibited, further indicating that this pathway controls RC DNA processing during its conversion to CCC DNA. These results provide new insights into how host cells recognize and process HBV RC DNA in order to produce CCC DNA and have implications for potential means to block CCC DNA production.IMPORTANCE Hepatitis B virus (HBV) chronically infects hundreds of millions of people and remains a major cause of viral hepatitis, cirrhosis, and liver cancer. HBV persistence is sustained by a viral nuclear episome that directs all viral gene expression needed to support viral replication. The episome is converted from an incomplete DNA precursor in viral particles in an ill-understood process. We report here that the incomplete DNA precursor is recognized by the host cell in a way similar to the sensing of damaged cellular DNA for subsequent repair to form the nuclear episome. Intense efforts are ongoing to develop novel antiviral strategies to eliminate CCC DNA so as to cure chronic HBV infection. Our results here provide novel insights into, and suggest novel ways of perturbing, the process of episome formation. Furthermore, our results inform mechanisms of cellular DNA damage recognition and repair, processes essential for normal cell growth.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Quinase 1 do Ponto de Checagem/metabolismo , DNA Circular/metabolismo , Vírus da Hepatite B/genética , Vírus da Hepatite B/fisiologia , Antivirais/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/efeitos dos fármacos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Linhagem Celular , Quinase 1 do Ponto de Checagem/efeitos dos fármacos , Quinase 1 do Ponto de Checagem/genética , Dano ao DNA , Reparo do DNA , DNA Viral , Regulação Viral da Expressão Gênica , Técnicas de Silenciamento de Genes , Células Hep G2 , Hepatite B , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica , Humanos , Nucleocapsídeo/metabolismo , RNA Interferente Pequeno/genética , Vírion , Replicação Viral/genética
17.
PLoS One ; 15(1): e0227532, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31940324

RESUMO

OBJECTIVES: To assess the potency of anti-viral treatment for hepatitis B virus-associated glomerulonephritis (HBV-GN). Method: We searched for controlled clinical trials on anti-viral therapy for HBV-GN in MEDLINE, Embase, the Cochrane Library, and PubMed from inception to March 11th 2019. Seven trials, including 182 patients met the criteria for evaluating. The primary outcome measures were proteinuria and changes in the estimated glomerular filtration rate, and the secondary outcome measure was hepatitis B e-antigen clearance. A fixed or random effect model was established to analyze the data. Subgroup analyses were performed to explore the effects of clinical trial type, anti-viral drug type, age, and follow-up duration. RESULTS: The total remission rate of proteinuria (OR = 10.48, 95% CI: 4.60-23.89, I2 = 0%), complete remission rate of proteinuria (OR = 11.64, 95% CI: 5.17-26.21, I2 = 23%) and clearance rate of Hepatitis Be Antigen (HBeAg) were significantly higher in the anti-viral treatment group than in the control group (OR = 27.08, 95% CI: 3.71-197.88, I2 = 63%). However, antiviral therapy was not as effective regarding the eGFR (MD = 5.74, 95% CI: -4.24-15.73). In the subgroup analysis, age and drug type had significant impacts on proteinuria remission, and study type and follow-up duration only slightly affected the heterogeneity. CONCLUSION: Antiviral therapy induced remission of proteinuria and increased HBeAg clearance but failed to improve the eGFR. Pediatric patients were more sensitive to antiviral therapy than adults. IFNs seem more effective but are accompanied by more adverse reactions than NAs.


Assuntos
Antivirais/efeitos adversos , Antivirais/farmacologia , Glomerulonefrite/virologia , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/fisiologia , Segurança , Antivirais/uso terapêutico , Glomerulonefrite/tratamento farmacológico , Humanos
18.
Sci Rep ; 10(1): 47, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913341

RESUMO

Nucleos(t)ide analog (NA) therapy has proven effective in treating chronic hepatitis B. However, NAs frequently result in viral relapse after the cessation of therapy. This is because NAs cannot fully eliminate the viral episomal covalently closed circular DNA (cccDNA) in the nucleus. In this study, we identified small molecular compounds that control host factors related to viral replication using in silico screening with simulated annealing based on bioinformatics for protein-ligand flexible docking. Twelve chemical compound candidates for alpha-glucosidase (AG) inhibitors were identified from a library of chemical compounds and used to treat fresh human hepatocytes infected with HBV. They were then monitored for their anti-viral effects. HBV replication was inhibited by one candidate (1-[3-(4-tert-butylcyclohexyl)oxy-2-hydroxypropyl]-2,2,6,6-tetramethylpiperidin-4-ol) in a dose-dependent manner. This compound significantly reduced ccc DNA production, compared to Entecavir (p < 0.05), and had a lower anti-AG effect. Gene expression analysis and structural analysis of this compound showed that its inhibitive effect on HBV was via interaction with Sp1. The nuclear transcription factor Sp1 acts on multiple regions of HBV to suppress HBV replication. Identifying candidates that control nuclear transcription factors facilitate the development of novel therapies. Drugs with a mechanism different from NA are promising for the elimination of HBV.


Assuntos
Antivirais/farmacologia , Desenvolvimento de Medicamentos , Inibidores de Glicosídeo Hidrolases/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Fator de Transcrição Sp1/metabolismo , Replicação Viral/efeitos dos fármacos , Antivirais/química , DNA Circular/genética , DNA Viral/genética , Inibidores de Glicosídeo Hidrolases/química , Hepatite B/virologia , Vírus da Hepatite B/isolamento & purificação , Hepatócitos/efeitos dos fármacos , Hepatócitos/virologia , Ensaios de Triagem em Larga Escala , Humanos , alfa-Glucosidases/química
19.
Biochem Biophys Res Commun ; 523(3): 802-808, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31954513

RESUMO

Chronic hepatitis B virus (HBV) infection is a serious problem due to its extensive worldwide distribution and poor prognosis including cirrhosis and/or hepatocellular carcinoma. The hepatitis B surface antigen(HBsAg) is a vital serum marker in HBV infection and a major obstacle for effective and subsequently virus clearance. However, Current anti-HBV drugs, such as nucleos(t)ide analogs (NA) and PegIFN, do not meet ideal result of sustained HBsAg loss (defined as functional cure). Therefore, there is an urgent need to identify a new compound targeting HBsAg. In this study, nobiletin was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of nobiletin on HBV was determined in HepG2.2.15 and HepG2-NTCP cells. Furthermore, the antiviral capability of nobiletin was also verified in vivo. Unlike entecavir (ETV) therapy, which reduced HBV DNA but do not lead to an effective reduction in HBsAg, nobiletin significantly reduced the level of HBsAg as well as lowered HBV DNA in vivo and in vitro. Meanwhile, combination of nobiletin and ETV led to broad reductions of both HBV DNA and HBsAg level. This study may shed light on the development of a novel class of anti-HBV agents.


Assuntos
Antivirais/farmacologia , Flavonas/farmacologia , Antígenos de Superfície da Hepatite B/metabolismo , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/uso terapêutico , Flavonas/uso terapêutico , Células Hep G2 , Hepatite B/metabolismo , Vírus da Hepatite B/fisiologia , Humanos , Masculino , Camundongos Endogâmicos C57BL
20.
Microbiol Immunol ; 64(5): 345-355, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31981244

RESUMO

Chronic infection with hepatitis B virus (HBV) sometime induces lethal cirrhosis and hepatocellular carcinoma. Although nucleot(s)ide analogs are used as main treatment for HBV infection, the emergence of the drug-resistant viruses has become a problem. To discover novel antivirals with low side effects and low risk of emergence of resistant viruses, screening for anti-HBV compounds was performed with compound libraries of inhibitors targeting G-protein-coupled receptors (GPCRs). HepG2-hNTCP C4 cells infected with HBV were treated with various GPCR inhibitors and harvested at 14 day postinfection for quantification of core protein in the first screening or relaxed circular DNA in the second screening. Finally, we identified a cannabinoid receptor 1 inhibitor, rimonabant, as a candidate showing anti-HBV effect. In HepG2-hNTCP C4 cells, treatment with rimonabant suppressed HBV propagation at the viral RNA transcription step but had no effect on entry or covalently closed circular DNA level. The values of half maximal inhibitory concentration, half maximal effective concentration, and selectivity index of rimonabant in primary human hepatocyte (PHH) are 2.77 µm, 40.4 µm, and 14.6, respectively. Transcriptome analysis of rimonabant-treated primary hepatocytes by RNA sequencing revealed that the transcriptional activity of hepatocyte nuclear factor 4α (HNF4α), which is known to stimulate viral RNA synthesis, was depressed. By treatment of PHH with rimonabant, the expression level of HNF4α protein and the production of the messenger RNAs (mRNAs) of downstream factors promoted by HNF4α were reduced while the amount of HNF4α mRNA was not altered. These results suggest that treatment with rimonabant suppresses HBV propagation through the inhibition of HNF4α activity.


Assuntos
Antivirais/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Fator 4 Nuclear de Hepatócito/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Rimonabanto/farmacologia , Replicação Viral/efeitos dos fármacos , Descoberta de Drogas , Células Hep G2 , Vírus da Hepatite B/fisiologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , RNA Mensageiro/metabolismo , RNA Viral/metabolismo
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