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1.
Biochem Biophys Res Commun ; 555: 147-153, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33813274

RESUMO

Several existing drugs are currently being tested worldwide to treat COVID-19 patients. Recent data indicate that SARS-CoV-2 is rapidly evolving into more transmissible variants. It is therefore highly possible that SARS-CoV-2 can accumulate adaptive mutations modulating drug susceptibility and hampering viral antigenicity. Thus, it is vital to predict potential non-synonymous mutation sites and predict the evolution of protein structural modifications leading to drug tolerance. As two FDA-approved anti-hepatitis C virus (HCV) drugs, boceprevir, and telaprevir, have been shown to effectively inhibit SARS-CoV-2 by targeting the main protease (Mpro), here we used a high-throughput interface-based protein design strategy to identify mutational hotspots and potential signatures of adaptation in these drug binding sites of Mpro. Several mutants exhibited reduced binding affinity to these drugs, out of which hotspot residues having a strong tendency to undergo positive selection were identified. The data further indicated that these anti-HCV drugs have larger footprints in the mutational landscape of Mpro and hence encompass the highest potential for positive selection and adaptation. These findings are crucial in understanding the potential structural modifications in the drug binding sites of Mpro and thus its signatures of adaptation. Furthermore, the data could provide systemic strategies for robust antiviral design and discovery against COVID-19 in the future.


Assuntos
Adaptação Fisiológica/genética , Antivirais/química , Desenho de Fármacos , Farmacorresistência Viral/genética , Mutação , /genética , Sequência de Aminoácidos , Antivirais/farmacologia , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/genética , /antagonistas & inibidores , /metabolismo , Aptidão Genética/genética , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Ligantes , Modelos Moleculares , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Prolina/análogos & derivados , Prolina/química , Prolina/farmacologia , Reprodutibilidade dos Testes , Seleção Genética/genética , Relação Estrutura-Atividade
2.
Molecules ; 26(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652639

RESUMO

Hepatitis C is affecting millions of people around the globe annually, which leads to death in very high numbers. After many years of research, hepatitis C virus (HCV) remains a serious threat to the human population and needs proper management. The in silico approach in the drug discovery process is an efficient method in identifying inhibitors for various diseases. In our study, the interaction between Epigallocatechin-3-gallate, a component of green tea, and envelope glycoprotein E2 of HCV is evaluated. Epigallocatechin-3-gallate is the most promising polyphenol approved through cell culture analysis that can inhibit the entry of HCV. Therefore, various in silico techniques have been employed to find out other potential inhibitors that can behave as EGCG. Thus, the homology modelling of E2 protein was performed. The potential lead molecules were predicted using ligand-based as well as structure-based virtual screening methods. The compounds obtained were then screened through PyRx. The drugs obtained were ranked based on their binding affinities. Furthermore, the docking of the topmost drugs was performed by AutoDock Vina, while its 2D interactions were plotted in LigPlot+. The lead compound mms02387687 (2-[[5-[(4-ethylphenoxy) methyl]-4-prop-2-enyl-1,2,4-triazol-3-yl] sulfanyl]-N-[3(trifluoromethyl) phenyl] acetamide) was ranked on top, and we believe it can serve as a drug against HCV in the future, owing to experimental validation.


Assuntos
Catequina/análogos & derivados , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Proteínas do Envelope Viral/genética , Antivirais/química , Antivirais/farmacologia , Catequina/química , Catequina/farmacologia , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C/virologia , Humanos , Ligantes , Simulação de Acoplamento Molecular , Polifenóis/química , Polifenóis/farmacologia , Chá/química , Proteínas do Envelope Viral/antagonistas & inibidores , Internalização do Vírus/efeitos dos fármacos
3.
Medicine (Baltimore) ; 100(12): e25110, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33761674

RESUMO

ABSTRACT: Oral direct-acting antiviral (DAA) treatment leads to >95% sustained virological response (SVR) and could be clinically useful in regression of liver fibrosis in chronic hepatitis C virus (HCV) infection. We evaluated if ledipasvir/sofosbuvir or sofosbuvir + ribavirin is associated with regression of fibrosis in HCV patients who achieved SVR.In this prospective cohort study performed at 3 sites in Japan, patients with genotype 1 and genotype 2 were given standard treatment of ledipasvir 90 mg/sofosbuvir 400 mg and sofosbuvir 400 mg + 200-1000 mg/day ribavirin, respectively, for 12 weeks. Liver fibrosis was assessed using Mac-2-binding protein glycosylation isomer (M2BPGi) and other fibrosis markers (platelet count, Fib-4 index, liver stiffness measurement [LSM]) in patients who achieved SVR.A total of 98.1% of (n = 101/103) patients in genotype 1 cohort and 100% (n = 16/16) in the genotype 2 cohort achieved SVR12. Based on per-protocol analysis, M2BPGi levels showed a significant decrease (-2.2  cut-off index [COI], P < .0001) at week 48 after treatment initiation. Forty-three patients showed a significant decrease in Fib-4 index (-1.2, P < .0001), and 44 patients showed improvement in LSM (-5.9 kPa, P < .0001).Achievement of SVR after antiviral therapy was associated with fibrosis regression. M2BPGi correlated well with LSM at week 48 after treatment initiation, supporting the sustainable benefit of HCV therapy.


Assuntos
Benzimidazóis/administração & dosagem , Fluorenos/administração & dosagem , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Ribavirina/administração & dosagem , Sofosbuvir/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Feminino , Hepatite C Crônica/complicações , Humanos , Fígado/efeitos dos fármacos , Fígado/virologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resposta Viral Sustentada , Resultado do Tratamento
4.
PLoS One ; 16(2): e0245962, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33524017

RESUMO

Effective SARS-CoV-2 antiviral drugs are desperately needed. The SARS-CoV-2 main protease (Mpro) appears as an attractive target for drug development. We show that the existing pharmacopeia contains many drugs with potential for therapeutic repurposing as selective and potent inhibitors of SARS-CoV-2 Mpro. We screened a collection of ~6,070 drugs with a previous history of use in humans for compounds that inhibit the activity of Mpro in vitro and found ~50 compounds with activity against Mpro. Subsequent dose validation studies demonstrated 8 dose responsive hits with an IC50 ≤ 50 µM. Hits from our screen are enriched with hepatitis C NS3/4A protease targeting drugs including boceprevir, ciluprevir. narlaprevir, and telaprevir. This work suggests previous large-scale commercial drug development initiatives targeting hepatitis C NS3/4A viral protease should be revisited because some previous lead compounds may be more potent against SARS-CoV-2 Mpro than boceprevir and suitable for rapid repurposing.


Assuntos
Antivirais/farmacologia , Antivirais/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Inibidores de Proteases/farmacologia , /efeitos dos fármacos , Bioensaio , Fluorescência , Ensaios de Triagem em Larga Escala , Humanos , Reprodutibilidade dos Testes
5.
Artigo em Inglês | MEDLINE | ID: mdl-33533809

RESUMO

The efficacy of direct-acting antivirals (DAAs) in the treatment of chronic hepatitis C (CHC) in liver transplant recipients is poorly understood, and several factors, including immunosuppression, drug interactions, elevated viraemia, and intolerance to ribavirin (RBV), can reduce cure rates. We conducted a real-life study on liver transplant recipients with CHC treated with a combination of sofosbuvir (SOF) and daclatasvir (DCV) or simeprevir (SIM), with or without RBV, followed-up for 12 to 24 weeks. The treatment effectiveness was assessed by determining the sustained virological response (SVR) rates at 12 or 24 weeks after the treatment cessation. Eighty-four patients were evaluated, with a mean age of 63.4 ± 7.4 years, HCV genotype 1 being the most prevalent (63.1%). Nineteen patients (22.7%) had mild fibrosis (METAVIR < F2) and 41 (48.8%) significant fibrosis (METAVIR ≥ F2). The average time between liver transplantation and the start of treatment was 4 years (2.1-6.6 years). The SOF + DCV regimen was used in 58 patients (69%). RBV in combination with DAAs was used in seven patients (8.3%). SVR was achieved in 82 patients (97.6%), and few relevant adverse events could be attributed to DAA therapy, including a patient who stopped treatment due to a headache. There was a significant reduction in ALT, AST, GGT and FA levels, or the APRI index after 4 weeks of treatment, which remained until 12/24 weeks post-treatment. DAA treatment of CHC in liver-transplanted patients achieved a high SVR rate and resulted in the normalization of serum levels of liver enzymes.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Transplante de Fígado/efeitos adversos , Ribavirina/uso terapêutico , Idoso , Antivirais/efeitos adversos , Brasil , DNA Viral/genética , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Humanos , Cirrose Hepática/cirurgia , Masculino , Pessoa de Meia-Idade , Ribavirina/efeitos adversos , Transplantados , Resultado do Tratamento
6.
Arch Virol ; 166(4): 1071-1081, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33533976

RESUMO

Elimination of hepatitis C virus (HCV) may fail, leading to a non-response outcome because of inappropriate testing for viral RNA in peripheral blood mononuclear cells (PBMCs). Sequelae of HCV genotype 4 therapy with sofosbuvir and daclatasvir ± ribavirin were assessed in our study at the 12th week after end of treatment (EOT) by screening for viral genomic RNA in serum and PBMCs with correlation to hepatic parenchymal changes. We recruited 102 out of 2165 patients who had received sofosbuvir/daclatasvir, either alone (n = 1573) or together with ribavirin (n = 592). Subjects were classified into three groups based on testing by single-step reverse transcription PCR: group I, HCV negative in both serum and PBMCs (n = 25); group II, HCV positive in PBMCs only (n = 52); and group III, HCV positive in both serum and PBMCs (n = 25). Groups I and II (n = 77) were selected out of 2102 (every 27th subject), while group III (n = 25) were selected from every second or third serologic relapse (n = 63). The pre-sampling population (n = 2165) showed sustained virologic response (SVR) in 33.21%; serologic relapse in 2.91%; HCV RNA only in PBMCs (66.79%) compared to serologic relapses and potential cure (P < 0.0001); higher serologic (38 out of 63, P = 0.03210) and cellular (36 out of 52, P = 0.0002) relapses in dual therapy than in triple therapy. The post-sampling population (n = 102) showed more HCV relapses in dual (50 out of 60) than in triple (27 out of 42) therapy (P = 0.0351); increased HCV antisense RNA strand in relapses compared to positive-sense strands alone (P < 0.001); and significant SVR events in undetectable (15 out of 31) compared to early (10 out of 55, P = 0.0058) and cirrhotic liver tissue changes (0 out of 16, P = 0.0006). In summary, HCV treatment with sofosbuvir/daclatasvir is followed by higher rates of serologic and intracellular viral RNA relapse than treatment with sofosbuvir/daclatasvir plus ribavirin. Cellular and serum viral RNA relapses are accompanied by HCV-induced hepatic pathology. An increased SVR with no detectable liver tissue changes was observed after triple therapy due to elimination of HCV RNA from PBMCs.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , RNA Viral/efeitos dos fármacos , Ribavirina/uso terapêutico , Adulto , Carbamatos/uso terapêutico , Quimioterapia Combinada , Feminino , Hepacivirus/genética , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Imidazóis/uso terapêutico , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Tecido Parenquimatoso/efeitos dos fármacos , Tecido Parenquimatoso/patologia , Pirrolidinas/uso terapêutico , RNA Viral/análise , Prevenção Secundária , Sofosbuvir/uso terapêutico , Resultado do Tratamento , Valina/análogos & derivados , Valina/uso terapêutico
7.
Eur J Med Chem ; 213: 113135, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33454548

RESUMO

Many successful anti-viral and anti-cancer drugs are nucleoside analogs, which disrupt RNA and/or DNA synthesis. Here, we present liver-specific prodrugs of the chemotherapy drug gemcitabine (2',2'-difluorodeoxycytidine) for the treatment of hepatitis C virus (HCV) infection and hepatocellular carcinoma. The prodrugs were synthesized by introducing aromatic functional moieties to the cytosine 4-NH2 group of gemcitabine via amide bonds. The chemical modification was designed to i) enable passive diffusion across cellular membrane, ii) protect the prodrugs from inactivating deamination by cellular enzymes, and iii) allow release of active gemcitabine after amide hydrolysis by high levels of carboxylesterases in the liver. We found that many of our prodrugs exhibited similar toxicity as gemcitabine toward liver- and kidney-derived cancer cell lines but were 24- to 620-fold less cytotoxic than gemcitabine in breast- and pancreas-derived cancer cells, respectively. The prodrugs also inhibited an HCV replicon with IC50 values ranging from 10 nM-1.7 µM. Moreover, many of the prodrugs had therapeutic index values of >10,000 and have synergetic effects when combined with other Food and Drug Administration-approved anti-HCV small molecule drugs. These characteristics support the development of gemcitabine prodrugs as liver-specific therapeutics.


Assuntos
Antineoplásicos/farmacologia , Antivirais/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Desoxicitidina/análogos & derivados , Hepatite C/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Pró-Fármacos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antivirais/síntese química , Antivirais/química , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/síntese química , Desoxicitidina/química , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Hepacivirus/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/patologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
8.
Nat Immunol ; 22(2): 229-239, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33398179

RESUMO

In chronic hepatitis C virus (HCV) infection, exhausted HCV-specific CD8+ T cells comprise memory-like and terminally exhausted subsets. However, little is known about the molecular profile and fate of these two subsets after the elimination of chronic antigen stimulation by direct-acting antiviral (DAA) therapy. Here, we report a progenitor-progeny relationship between memory-like and terminally exhausted HCV-specific CD8+ T cells via an intermediate subset. Single-cell transcriptomics implicated that memory-like cells are maintained and terminally exhausted cells are lost after DAA-mediated cure, resulting in a memory polarization of the overall HCV-specific CD8+ T cell response. However, an exhausted core signature of memory-like CD8+ T cells was still detectable, including, to a smaller extent, in HCV-specific CD8+ T cells targeting variant epitopes. These results identify a molecular signature of T cell exhaustion that is maintained as a chronic scar in HCV-specific CD8+ T cells even after the cessation of chronic antigen stimulation.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Memória Imunológica/genética , Transcriptoma , Antígenos Virais/imunologia , Antivirais/uso terapêutico , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Hepatite C Crônica/virologia , Interações Hospedeiro-Patógeno , Humanos , Fenótipo , Indução de Remissão , Análise de Célula Única , Resultado do Tratamento
9.
Lancet Gastroenterol Hepatol ; 6(3): 169-184, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33515496

RESUMO

BACKGROUND: Treatment for infection with hepatitis C virus (HCV) during pregnancy has not yet been approved; however, interventions specifically targeting women, especially those of childbearing age (15-49 years), could prevent vertical transmission and community spread. To assess the impact of such interventions, improved prevalence estimates in this group are needed. We aimed to estimate the global prevalence of viraemic HCV in 2019 among women of childbearing age. METHODS: In this modelling study, we used previously developed models for 110 countries inputted with country-specific demographic and HCV epidemiology data. We did a literature review, searching PubMed, Embase, and grey literature for studies published between Jan 1, 2000, and June 30, 2018, reporting HCV antibody or viraemic prevalence in women of childbearing age. Studies from the literature review and studies in models were compared by use of a data quality scoring system and models were updated, as appropriate, when a better study was identified. We used these HCV disease burden models to calculate the 2019 prevalence of viraemic HCV in women of childbearing age. In countries without a model, prevalence was extrapolated by Global Burden of Disease (GBD) region. FINDINGS: An estimated 14 860 000 (95% uncertainty interval [UI] 9 667 000-18 282 000) women aged 15-49 years had HCV infection worldwide in 2019, corresponding to a viraemic prevalence of 0·78% (95% UI 0·62-0·86). Globally, HCV prevalence increased with age, rising from 0·25% (95% UI 0·20-0·27) in women aged 15-19 years to 1·21% (0·97-1·34) in women aged 45-49 years. China (16% of total infections) and Pakistan (15%) had the greatest numbers of viraemic infections, but viraemic prevalence was highest in Mongolia (5·14%, 95% CI 3·46-6·28) and Burundi (4·91%, 3·80-18·75). Of the countries with 500 cases or more, viraemic prevalence was lowest in Chile (0·07%, 95% UI 0·04-0·12). Among the GBD regions, eastern Europe had the highest viraemic prevalence (3·39%, 95% UI 1·88-3·54). By WHO region, the Eastern Mediterranean region had the highest viraemic prevalence (1·75%, 95% UI 1·26- 1·90). INTERPRETATION: Most research on HCV disease burden among women aged 15-49 years focuses on pregnant women. Using modelling, this analysis provides global and national estimates of HCV prevalence in all women of childbearing age. These data can inform preconception test-and-treat strategies to reduce vertical transmission and total disease burden. FUNDING: Gilead Sciences, John C Martin Foundation, private donors.


Assuntos
Hepatite C/tratamento farmacológico , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Complicações Infecciosas na Gravidez/prevenção & controle , Viremia/epidemiologia , Adolescente , Adulto , Feminino , Carga Global da Doença , Hepacivirus/efeitos dos fármacos , Hepacivirus/isolamento & purificação , Hepatite C/complicações , Hepatite C/epidemiologia , Hepatite C/virologia , Humanos , Pessoa de Meia-Idade , Modelos Teóricos , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/virologia , Prevalência , Literatura de Revisão como Assunto , Adulto Jovem
10.
Public Health ; 190: 116-122, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33450632

RESUMO

OBJECTIVES: We develop a patient prioritization scheme for treating patients infected with hepatitis C virus (HCV) and study under which scenarios it outperforms the current practices in Spain and Chile. STUDY DESIGN: We use simulation to evaluate the performance of prioritization rules under two HCV patient cohorts, constructed using secondary data of public records from Chile and Spain, during 2015-2016. METHODS: We use the results of a mathematical model, which determines individual optimal HCV treatment policies as an input for constructing a patient prioritization rule, when limited resources are present. The prioritization is based on marginal analysis on cost increases and health-outcome gains. We construct the Chilean and Spanish case studies and used Monte Carlo simulation to evaluate the performance of our methodology in these two scenarios. RESULTS: The resulting prioritizations for the Chilean and Spanish patients are similar, despite the significant differences of both countries, in terms of epidemiological profiles and cost structures. Furthermore, when resources are scarce compared with the number of patients in need of the new drug, our prioritization significantly outperforms current practices of treating sicker patients first, both in terms of cost and healthcare indicators: for the Chilean case, we have an increase in the quality-adjusted life years (QALYs) of 0.83 with a cost reduction of 8176 euros per patient, with a budget covering 2.5% of the patients in the cohort. This difference slowly decreases when increasing the available resources, converging to the performance indicators obtained when all patients are treated immediately: for the Spanish case, we have a decrease in the QALYs of 0.17 with a cost reduction of 1134 euros per patient, with a budget covering 20% of the patients in the cohort. CONCLUSION: Decision science can provide useful analytical tools for designing efficient public policies that can excel in terms of quantitative health performance indicators.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/isolamento & purificação , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Antivirais/economia , Orçamentos , Chile/epidemiologia , Estudos de Coortes , Análise Custo-Benefício , Feminino , Custos de Cuidados de Saúde , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/economia , Humanos , Programas de Rastreamento/economia , Modelos Teóricos , Método de Monte Carlo , Anos de Vida Ajustados por Qualidade de Vida , Espanha/epidemiologia , Resultado do Tratamento
11.
Minerva Med ; 112(2): 228-237, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33319975

RESUMO

Hepatitis C virus represents an important global health issue with 71 million of infected people in the word. Direct-acting antivirals are quite new molecules that hit specific Hepatitis C virus proteins useful for viral replication and assembly. Notably, Direct-acting antivirals bring to high sustained virological response rates showing also a great safety profile. This treatment revolution had an impact on transplantation world, in fact the number of liver transplants due to Hepatitis C virus-related cirrhosis and hepatocellular carcinoma is quickly decreasing. Even if this therapy has achieved excellent results in terms of morbility and mortality rates' reduction, there are some debated issues to consider. In the present review the main clinical challenges in every-day management of Hepatitis C virus patients treated with Direct-acting antivirals and the debated effects of viral clearance (metabolic, cardiovascular, immunologic and neoplastic) are discussed. The detection of barriers that can preclude the delivery of Hepatitis C virus care, is the most complex challenge for the scientific community. To obtain the Hepatitis C virus global eradication by 2030, as the World Health Organization has set, will be complex and laborious and will need a further multilevel effort.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Carcinoma Hepatocelular/etiologia , Doenças Cardiovasculares/etiologia , Farmacorresistência Viral , Genótipo , Glucose/metabolismo , Hepacivirus/efeitos dos fármacos , Hepacivirus/fisiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Humanos , Evasão da Resposta Imune , Metabolismo dos Lipídeos/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Recidiva Local de Neoplasia , Ativação Viral , Replicação Viral/fisiologia
12.
Lancet HIV ; 8(2): e96-e105, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33357835

RESUMO

BACKGROUND: In the Netherlands, access to direct-acting antivirals (DAAs) against hepatitis C virus (HCV) has been unrestricted for chronic infection since 2015. We evaluated whether the nationwide incidence of HCV infections in individuals with HIV has changed since 2015. METHODS: In this retrospective cohort study, data from the ATHENA cohort of people with HIV aged 18 years or older attending any of the 24 HIV treatment centres in the Netherlands between 2000 and 2019 were assessed. We used parametric proportional hazards models with a piecewise exponential survival function to model HCV primary infection and reinfection incidence per 1000 person-years. FINDINGS: Of the 23 590 individuals without previous HCV infection, 1269 cases of HCV primary infection were documented (incidence 5·2 per 1000 person-years [95% CI 5·0-5·5]). The highest incidence was observed in men who have sex with men (MSM; 7·7 per 1000 person-years [7·3-8·2]) and was lower in people who inject drugs (PWID; 1·7 per 1000 person-years [0·7-4·1]) and other key populations (1·0 per 1000 person-years [0·8-1·2]). In MSM, incidence increased in 2007 to 14·3 per 1000 person-years and fluctuated between 8·7 and 13·0 per 1000 person-years from 2008 to 2015. In 2016, incidence declined to 6·1 cases per 1000 person-years and remained steady between 4·1 and 4·9 per 1000 person-years from 2017 to 2019. Of the 1866 individuals with a previous HCV infection, 274 reinfections were documented (incidence 26·9 per 1000 person-years [95% CI 23·9-30·3]). The highest incidence rate was observed in MSM (38·5 per 1000 person-years [33·9-43·7]) and was lower in PWID (10·9 per 1000 person-years [3·5-33·8]) and other key populations (8·9 per 1000 person-years [6·3-12·5]). In MSM, reinfection incidence fluctuated between 38·0 and 88·9 per 1000 person-years from 2006 to 2015, reaching 55·6 per 1000 person-years in 2015. In 2016, reinfection incidence declined to 41·4 per 1000 person-years, followed by further decreases to 24·4 per 1000 person-years in 2017 and 11·4 per 1000 person-years in 2019. INTERPRETATION: The sharp decline in HCV incidence in MSM with HIV shortly after restrictions on DAAs were lifted suggests a treatment-as-prevention effect. HCV incidence was already low in PWID and other groups before unrestricted access. Ongoing HCV transmission is occurring in MSM, as illustrated by a declining but high rate of reinfection, stressing the need for additional preventive measures. FUNDING: Dutch Ministry of Health, Welfare, and Sport.


Assuntos
Antivirais/uso terapêutico , Infecções por HIV/epidemiologia , HIV-1/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/epidemiologia , Abuso de Substâncias por Via Intravenosa/epidemiologia , Adulto , Coinfecção , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/prevenção & controle , Hepatite C Crônica/virologia , Homossexualidade Masculina , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Estudos Retrospectivos , Abuso de Substâncias por Via Intravenosa/virologia
13.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333737

RESUMO

Protein kinases (PKs) are enzymes that catalyze the transfer of the terminal phosphate group from ATP to a protein acceptor, mainly to serine, threonine, and tyrosine residues. PK catalyzed phosphorylation is critical to the regulation of cellular signaling pathways that affect crucial cell processes, such as growth, differentiation, and metabolism. PKs represent attractive targets for drugs against a wide spectrum of diseases, including viral infections. Two different approaches are being applied in the search for antivirals: compounds directed against viral targets (direct-acting antivirals, DAAs), or against cellular components essential for the viral life cycle (host-directed antivirals, HDAs). One of the main drawbacks of DAAs is the rapid emergence of drug-resistant viruses. In contrast, HDAs present a higher barrier to resistance development. This work reviews the use of chemicals that target cellular PKs as HDAs against virus of the Flaviviridae family (Flavivirus and Hepacivirus), thus being potentially valuable therapeutic targets in the control of these pathogens.


Assuntos
Infecções por Flaviviridae/tratamento farmacológico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Antivirais/farmacologia , Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Caseína Quinase I/antagonistas & inibidores , Caseína Quinase I/metabolismo , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Flaviviridae/efeitos dos fármacos , Flaviviridae/enzimologia , Infecções por Flaviviridae/enzimologia , Hepacivirus/enzimologia , Hepacivirus/metabolismo , Hepatite C Crônica/metabolismo , Humanos , Fosforilação , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo
14.
PLoS Negl Trop Dis ; 14(12): e0008931, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33326423

RESUMO

BACKGROUND: Despite direct-acting antivirals (DAA), aims to "eradicate" viral hepatitis by 2030 remain unlikely. In Nepal, an expert consortium was established to treat HCV through Nepal earthquakes aftermath offering a model for HCV treatment expansion in a resource-poor setting. METHODOLOGY/PRINCIPAL FINDINGS: In 2015, we established a network of hepatologists, laboratory experts, and community-based leaders at 6 Opioid Substitution Treatment (OST) sites from 4 cities in Nepal screening 838 patients for a treatment cohort of 600 individuals with HCV infection and past or current drug use. During phase 1, patients were treated with interferon-based regimens (n = 46). During phase 2, 135 patients with optimal predictors (HIV controlled, without cirrhosis, low baseline HCV viral load) were treated with DAA-based regimens. During phase 3, IFN-free DAA treatment was expanded, regardless of HCV disease severity, HIV viremia or drug use. Sustained virologic response (SVR) was assessed at 12 weeks. Median age was 37 years and 95.5% were males. HCV genotype was 3 (53.2%) or 1a (40.7%) and 32% had cirrhosis; 42.5% were HIV-HCV coinfected. The intention-to-treat (ITT) SVR rates in phase 2 and 3 were 97% and 81%, respectively. The overall per-protocol and ITT SVR rates were 97% and 85%, respectively. By multivariable analysis, treatment at the Kathmandu site was protective and substance use, treatment during phase 3 were associated with failure to achieve SVR. CONCLUSIONS/SIGNIFICANCE: Very high SVR rates may be achieved in a difficult-to-treat, low-income population whatever the patient's profile and disease severity. The excellent treatment outcomes observed in this real-life community study should prompt further HCV treatment initiatives in Nepal.


Assuntos
Antivirais/uso terapêutico , Infecções por HIV/complicações , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Interferons/uso terapêutico , Cirrose Hepática/complicações , Adulto , Coinfecção , Quimioterapia Combinada , Feminino , Hepatite C/complicações , Hepatite C/virologia , Humanos , Cirrose Hepática/virologia , Masculino , Nepal , Resposta Viral Sustentada , Resultado do Tratamento
15.
PLoS One ; 15(10): e0236543, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33006987

RESUMO

OBJECTIVES: Recently, the results of two economic evaluations were published both of which seemingly demonstrate the cost-effectiveness of sofosbuvir-based regimens for the treatment of chronic hepatitis C genotype 1 infection in Germany. Both analyses were sponsored by the manufacturer of sofosbuvir and use a different methodology: Whereas one evaluation is based on a conventional cost-utility analysis, the other rests upon the efficiency-frontier method used by the German Institute for Quality and Efficiency in Health Care (IQWiG). The purpose of this study is to reanalysis the results of both economic evaluations in combination. DESIGN: Reanalysis of published decision modelling results. SETTING: Primary care in Germany. PARTICIPANTS: Patients with chronic hepatitis C genotype 1 infection (treatment-naïve and -experienced, cirrhotic and non-cirrhotic). INTERVENTIONS: Sofosbuvir, other anti-hepatitis C virus drugs, and no treatment. PRIMARY AND SECONDARY OUTCOME MEASURES: Cost per unit of health benefit and cost per quality-adjusted life year. RESULTS: Reanalysis of the results of both economic evaluations in combination reveals an unclear rationale for choosing the selected cost-effectiveness methods as well as a potential publication bias, favoring the product of the manufacturer. Based on the reanalysis, sofosbuvir is not cost-effective in treatment-experienced non-cirrhotic patients, potentially lacks cost-effectiveness in treatment-experienced cirrhotic patients, and is only partially cost-effective in treatment-naïve non-cirrhotic patients. Taken together, these results indicate a lack of cost-effectiveness in three quarters of the German patient population. CONCLUSIONS: Two economic evaluations on sofosbuvir suggest, in combination, that sofosbuvir cannot be considered a cost-effective treatment in three quarters of the German patient population.


Assuntos
Antivirais/economia , Hepacivirus/genética , Hepatite C Crônica/economia , Sofosbuvir/economia , Antivirais/uso terapêutico , Quimioterapia Combinada , Genótipo , Alemanha/epidemiologia , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/epidemiologia , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/economia , Interferon-alfa/uso terapêutico , Anos de Vida Ajustados por Qualidade de Vida , Ribavirina/economia , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico
16.
Sci Rep ; 10(1): 16577, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024223

RESUMO

SARS-CoV-2 is responsible for COVID-19, resulting in the largest pandemic in over a hundred years. After examining the molecular structures and activities of hepatitis C viral inhibitors and comparing hepatitis C virus and coronavirus replication, we previously postulated that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) might inhibit SARS-CoV-2. We subsequently demonstrated that Sofosbuvir triphosphate is incorporated by the relatively low fidelity SARS-CoV and SARS-CoV-2 RNA-dependent RNA polymerases (RdRps), serving as an immediate polymerase reaction terminator, but not by a host-like high fidelity DNA polymerase. Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells; additionally, COVID-19 clinical trials with EPCLUSA and with Sofosbuvir plus Daclatasvir have been initiated in several countries. SARS-CoV-2 has an exonuclease-based proofreader to maintain the viral genome integrity. Any effective antiviral targeting the SARS-CoV-2 RdRp must display a certain level of resistance to this proofreading activity. We report here that Sofosbuvir terminated RNA resists removal by the exonuclease to a substantially higher extent than RNA terminated by Remdesivir, another drug being used as a COVID-19 therapeutic. These results offer a molecular basis supporting the current use of Sofosbuvir in combination with other drugs in COVID-19 clinical trials.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Exonucleases/metabolismo , Pneumonia Viral/tratamento farmacológico , Pró-Fármacos/farmacologia , RNA Viral/efeitos dos fármacos , Sofosbuvir/farmacologia , Monofosfato de Adenosina/química , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/química , Alanina/farmacologia , Alanina/uso terapêutico , Antivirais/química , Antivirais/uso terapêutico , Betacoronavirus/enzimologia , Infecções por Coronavirus/virologia , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Pandemias , Pneumonia Viral/virologia , Pró-Fármacos/uso terapêutico , RNA Viral/química , RNA Viral/metabolismo , /metabolismo , Sofosbuvir/química , Sofosbuvir/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
17.
Molecules ; 25(21)2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33105694

RESUMO

Viral infections and associated diseases are responsible for a substantial number of mortality and public health problems around the world. Each year, infectious diseases kill 3.5 million people worldwide. The current pandemic caused by COVID-19 has become the greatest health hazard to people in their lifetime. There are many antiviral drugs and vaccines available against viruses, but they have many disadvantages, too. There are numerous side effects for conventional drugs, and active mutation also creates drug resistance against various viruses. This has led scientists to search herbs as a source for the discovery of more efficient new antivirals. According to the World Health Organization (WHO), 65% of the world population is in the practice of using plants and herbs as part of treatment modality. Additionally, plants have an advantage in drug discovery based on their long-term use by humans, and a reduced toxicity and abundance of bioactive compounds can be expected as a result. In this review, we have highlighted the important viruses, their drug targets, and their replication cycle. We provide in-depth and insightful information about the most favorable plant extracts and their derived phytochemicals against viral targets. Our major conclusion is that plant extracts and their isolated pure compounds are essential sources for the current viral infections and useful for future challenges.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Herpes Simples/tratamento farmacológico , Influenza Humana/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Antivirais/química , Antivirais/classificação , Antivirais/isolamento & purificação , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Descoberta de Drogas , HIV/efeitos dos fármacos , HIV/patogenicidade , HIV/fisiologia , Infecções por HIV/patologia , Infecções por HIV/virologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/patogenicidade , Hepacivirus/fisiologia , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Herpes Simples/patologia , Herpes Simples/virologia , Humanos , Influenza Humana/patologia , Influenza Humana/virologia , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/patogenicidade , Orthomyxoviridae/fisiologia , Pandemias , Compostos Fitoquímicos/química , Compostos Fitoquímicos/classificação , Compostos Fitoquímicos/isolamento & purificação , Plantas Medicinais , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Simplexvirus/efeitos dos fármacos , Simplexvirus/patogenicidade , Simplexvirus/fisiologia , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
18.
Viruses ; 12(10)2020 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-33080984

RESUMO

Combination therapies have become a standard for the treatment for HIV and hepatitis C virus (HCV) infections. They are advantageous over monotherapies due to better efficacy, reduced toxicity, as well as the ability to prevent the development of resistant viral strains and to treat viral co-infections. Here, we identify new synergistic combinations against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), echovirus 1 (EV1), hepatitis C virus (HCV) and human immunodeficiency virus 1 (HIV-1) in vitro. We observed synergistic activity of nelfinavir with convalescent serum and with purified neutralizing antibody 23G7 against SARS-CoV-2 in human lung epithelial Calu-3 cells. We also demonstrated synergistic activity of nelfinavir with EIDD-2801 or remdesivir in Calu-3 cells. In addition, we showed synergistic activity of vemurafenib with emetine, homoharringtonine, anisomycin, or cycloheximide against EV1 infection in human lung epithelial A549 cells. We also found that combinations of sofosbuvir with brequinar or niclosamide are synergistic against HCV infection in hepatocyte-derived Huh-7.5 cells, and that combinations of monensin with lamivudine or tenofovir are synergistic against HIV-1 infection in human cervical TZM-bl cells. These results indicate that synergy is achieved when a virus-directed antiviral is combined with another virus- or host-directed agent. Finally, we present an online resource that summarizes novel and known antiviral drug combinations and their developmental status.


Assuntos
Antivirais/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Células A549 , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/uso terapêutico , Antineoplásicos/farmacologia , Antivirais/farmacologia , Linhagem Celular , Infecções por Coronavirus/virologia , Bases de Dados de Produtos Farmacêuticos , Combinação de Medicamentos , Descoberta de Drogas , Sinergismo Farmacológico , Enterovirus Humano B/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Humanos , Pandemias , Pneumonia Viral/virologia
19.
Arch Virol ; 165(12): 2759-2766, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32885325

RESUMO

Oxidative stress (OS) and insulin resistance (IR) induced by hepatitis C virus (HCV) infection, are involved in the development of chronic hepatitis C (CHC) complications and progression to hepatocellular carcinoma. The aim of this study was to investigate the effect of pegylated interferon alpha (IFNα) + ribavirin (PegIFNα+RVB) or sofosbuvir + NS5A inhibitor (SOF+InNS5A) on IR and the components of OS. HCV was genotyped in 20 CHC patients grouped by treatment with either PegIFNα+RVB (n = 10) or SOF+InNS5A (n = 10). The treatment's effect on OS-induced damage to lipids (HNE-HDL), proteins (advanced glycation end products [AGEs]), and DNA (8-OHdG) as well as the concentrations of proinflammatory cytokines (IL-2, TNFα, IFNγ), ALT, AST, GSH and platelets was determined. Superoxide dismutase (SOD) and catalase activity as well as IR, determined by the HOMA1-IR index, was evaluated. The HCV genotypes (GT) found were GT1b (45%), GT1a (30%), GT2b (20%), and GT2a (5%). Viral RNA became undetectable by week 12 with SOF+InNS5A in 100% of the cases and with PegIFNα+RVB in 70% of the cases. After viral RNA became undetectable, regardless of treatment and GT, a significant increase in the platelet concentration and SOD activity was observed, whereas ALT, insulin, and IR decreased (p < 0.05). However, only for the SOF+InNS5A treated group was there an increase in oxidative damage to lipids (p < 0.017) and proteins (p < 0.05). None of the other parameters demonstrated any differences. These data confirm that OS persisted after treatment with either SOF+InNS5A or PegIFNα+RVB. IR could be considered a response biomarker to treatment with direct-acting antivirals.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Resistência à Insulina , Estresse Oxidativo/efeitos dos fármacos , RNA Viral/isolamento & purificação , Adulto , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Resposta Viral Sustentada , Resultado do Tratamento , Proteínas não Estruturais Virais/antagonistas & inibidores
20.
Z Gastroenterol ; 58(9): 841-846, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32947629

RESUMO

Despite the high effectiveness of direct-acting antivirals for the treatment of hepatitis C, a small proportion of patients do not respond to approved regimens. The combination regimen of SOF/VEL/VOX was recently approved for patients with failure to prior NS5A-based treatment. In this German real-world cohort including patients with cirrhosis (27.3 %) and previous decompensation events, 12 weeks of SOF/VEL/VOX resulted in high virologic response rates irrespective of disease severity and prior DAA regimen. Adverse events were mostly mild or moderate and comparable to those seen in the approval studies.


Assuntos
Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Macrocíclicos/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Quimioterapia Combinada , Genótipo , Hepacivirus/isolamento & purificação , Humanos , Sistema de Registros , Resposta Viral Sustentada , Resultado do Tratamento
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