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1.
Expert Rev Clin Pharmacol ; 13(1): 7-14, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31786966

RESUMO

Introduction: The introduction of direct-acting antiviral therapy has generated tremendous interest in transplanting organs from HCV-infected donors, an option which has the potential to lower waiting times for solid organ transplantation (including kidneys). Safe, effective and pangenotypic direct-acting antiviral agents are currently available.Areas covered: We have identified studies from PubMed, EMBASE, and the Cochrane database to review risks and benefits on solid organ transplantation from HCV-exposed donors in uninfected recipients.Expert opinion: The transmission of HCV with transplantation from anti-HCV positive kidneys without viremia is extremely uncommon whereas recent evidence (five clinical studies, n = 94 patients) shows the absence of HCV infection in HCV-naïve recipients who received kidneys from HCV RNA-positive donors and underwent early DAAs. The evidence regarding non-kidney solid organ transplantation from HCV-infected donors is more limited. One report showed the occurrence of dialysis-dependent kidney failure due to glomerulonephritis induced by acute HCV after liver transplant from a NAT-positive donor into an HCV-naïve recipient. Transplantation of kidneys and other solid organs from HCV-viremic donors into uninfected recipients has the potential to become the standard of care resulting in lower waitlist mortality. Further studies are needed urgently to establish clinical practice guidelines on this topic.


Assuntos
Antivirais/administração & dosagem , Hepatite C/tratamento farmacológico , Doadores de Tecidos , Hepatite C/prevenção & controle , Hepatite C/transmissão , Humanos , Transplante de Órgãos/métodos , Listas de Espera
2.
Georgian Med News ; (295): 105-109, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31804209

RESUMO

Georgia is among the countries with a very high prevalence of hepatitis C virus (HCV) infection. The recent availability of highly effective, direct-acting antivirals (DAAs) capable of curing >90% of persons treated has made HCV elimination a possibility. All adult citizens infected with HCV are eligible to receive free DAAs through the Georgia National HCV Elimination Program (Program). From April 2015 to December 2018, 54,087 persons were enrolled in the Program throughout the country. However, more than 20,000 individuals are aware of their HCV antibody positive status but did not have HCV RNA testing, a necessary step to determine treatment needs. We hypothesized that a reason for hesitance to enroll in the Program may be a low level of trust of the Program. A cross-sectional study was conducted in Tbilisi, the capital of Georgia. Reproductive aged women were randomly selected from three maternity care centers during prenatal care. The self-administered questionnaire included questions on socio-demographic information, knowledge about HCV infection and trust in the Program. A total of 2185 women of reproductive age were enrolled in the study. The mean age was 28.5 (age range: 17-46) years. The majority of the study participants (76.4%) had a university degree. The vast majority of study participants (>95%) were married and 95.1% were Georgian ethnicity. Almost 90% of the participants were aware of their HCV infection status. Most women (85.3%) had heard of HCV elimination program in Georgia; 74.6% stated that they trust the Program. However, almost 10% of surveyed women stated they would refuse to get enrolled in the Program if their anti-HCV test result is positive. Trust in the Program was higher among women aged >25 years (80.7%) compared to younger women (68.4%) (p<0.0001). Level of education was also associated with trust to the program: more women with higher education level reported that they trust the Program (78.7%) compared to women with lower education level (68.5%) (p<0.0001). Trust in the Georgia National HCV Elimination Program is not sufficiently high among women of reproductive age in Georgia. Effective educational campaigns are needed to improve trust to the Program for this targeted group.


Assuntos
Antivirais , Hepatite C , Adolescente , Adulto , Antivirais/uso terapêutico , Estudos Transversais , Feminino , República da Geórgia , Hepacivirus , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Humanos , Pessoa de Meia-Idade , Adulto Jovem
4.
Ann. hepatol ; 18(6): 849-854, Nov.-Dec. 2019. ilus, tab
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IIERPROD, Sec. Est. Saúde SP | ID: biblio-1025379

RESUMO

INTRODUCTION AND OBJECTIVES: Direct antiviral agents (DAAs) including sofosbuvir (SOF), daclatasvir (DCV), simeprevir (SIM) and ombitasvir, paritaprevir and dasabuvir were introduced 2015 in Brazil for treatment of hepatitis C virus (HCV) infection. The aims of this study were to assess effectiveness and safety of HCV treatment with DAA in real-life world in a highly admixed population from Brazil. MATERIALS AND METHODS: All Brazilian reference centers for HCV treatment were invited to take part in a web-based registry, prospectively conducted by the Brazilian Society of Hepatology, to assess outcomes of HCV treatment in Brazil with DAAs. Data to be collected included demographics, disease severity and comorbidities, genotype (GT), viral load, DAA regimens, treatment side effects and sustained virological response (SVR). RESULTS: 3939 patients (60% males, mean age 58±10 years) throughout the country were evaluated. Most had advanced fibrosis or cirrhosis, GT1 and were treated with SOF/DCV or SOF/SIM. Overall SVR rates were higher than 95%. Subjects with decompensated cirrhosis, GT2 and GT3 have lower SVR rates of 85%, 90% and 91%, respectively. Cirrhosis and decompensated cirrhosis in GT1 and male sex and decompensated cirrhosis in GT3 were significantly associated with no SVR. Adverse events (AD) and serious AD occurred in 18% and 5% of those subjects, respectively, but less than 1% of patients required treatment discontinuation. CONCLUSION: SOF-based DAA regimens are effective and safe in the heterogeneous highly admixed Brazilian population and could remain an option for HCV treatment at least in low-income countries


Assuntos
Humanos , Masculino , Feminino , Hepatite C/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade
5.
Wiad Lek ; 72(11 cz 2): 2218-2221, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31860840

RESUMO

Chronic infection with hepatitis virus C affects more than 70 million individuals worldwide. Hepatitis C infection is the leading cause of end-stage liver disease, hepatocellular carcinoma, and multiple extrahepatic manifestations associated with immune system disorders and chronic inflammation. In the era of interferon-free anti-HCV regimens, clinical care for patients with HCV-related liver disease and extrahepatic complications has advanced significantly because of improvements in therapy and prevention. The antiviral capacity of a new generation of direct-acting agents provide high rates of sustained virological response, and it is expected to improve clinical outcomes in these patient populations. The article aims to review published data on the treatment strategy of hepatitis C, including the EASL (European Association for the Study of the Liver) recommendations.


Assuntos
Hepatite C , Antivirais , Hepacivirus , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Humanos , Interferon-alfa
6.
BMC Infect Dis ; 19(1): 875, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640596

RESUMO

BACKGROUND: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease globally. Direct acting antivirals (DAAs) have proven effective in curing HCV. However, the current standard of care (SOC) in Botswana remains PEGylated interferon-α (IFN-α) with ribavirin. Several mutations have been reported to confer resistance to interferon-based treatments. Therefore, there is a need to determine HCV genotypes in Botswana, as these data will guide new treatment guidelines and understanding of HCV epidemiology in Botswana. METHODS: This was a retrospective cross-sectional pilot study utilizing plasma obtained from 55 participants from Princess Marina Hospital in Gaborone, Botswana. The partial core region of HCV was amplified, and genotypes were determined using phylogenetic analysis. RESULTS: Four genotype 5a and two genotype 4v sequences were identified. Two significant mutations - K10Q and R70Q - were observed in genotype 5a sequences and have been associated with increased risk of hepatocellular carcinoma (HCC), while R70Q confers resistance to interferon-based treatments. CONCLUSION: Genotypes 5a and 4v are circulating in Botswana. The presence of mutations in genotype 5 suggests that some patients may not respond to IFN-based regimens. The information obtained in this study, in addition to the World health organization (WHO) recommendations, can be utilized by policy makers to implement DAAs as the new SOC for HCV treatment in Botswana.


Assuntos
Hepacivirus/genética , Hepatite C/virologia , Mutação , Filogenia , Adulto , Antivirais/uso terapêutico , Botsuana , Carcinoma Hepatocelular/virologia , Estudos Transversais , Farmacorresistência Viral , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/isolamento & purificação , Hepatite C/tratamento farmacológico , Humanos , Interferon-alfa/uso terapêutico , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Retrospectivos , Ribavirina/uso terapêutico
7.
BMC Public Health ; 19(1): 1335, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640625

RESUMO

BACKGROUND: Australia is committed to eliminating the hepatitis C virus (HCV) by 2030. Despite regulations in Australia that enable the prescription of subsidised direct acting antiviral (DAA) by primary health care providers, the number of providers who treat patients for HCV remains low and this limits the prospect of HCV elimination. The Prince Charles Hospital, Brisbane, Australia, implemented an innovative program called Cure-It aimed at engaging primary care providers in community-based HCV treatment. This paper aims to describe initial experiences and short-term patient outcomes of this program. METHODS: A formative evaluation was conducted using program data for the period March 2016 to April 2018. Descriptive statistics were used to report the number of engaged primary care providers, patients' baseline characteristics, treatment plans, and treatment outcomes. RESULTS: Thirty primary care providers from different settings were engaged in HCV treatment. Among 331 patients eligible for community-based treatment, 315 (95.2%) commenced treatment, the completion rate was 92.4 and 66.5% achieved sustained virological response at 12 weeks (SVR12). The SVR12 had not been documented for 26.8% of patients. Among patients whose SVR12 was documented, 98.2% achieved SVR12. Only 1.3% of patients experienced treatment failure. CONCLUSION: A flexible tertiary-led model can improve primary care providers and patients' engagement with provision of HCV treatment. Tertiary centres need to play their role to improve the accessibility of HCV treatment through providing training and on-going support for primary care providers while enabling those providers to become more confident in providing treatment independently.


Assuntos
Antivirais/uso terapêutico , Difusão de Inovações , Hepatite C/tratamento farmacológico , Médicos de Atenção Primária/psicologia , Atenção Terciária à Saúde/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
8.
BMC Health Serv Res ; 19(1): 765, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660966

RESUMO

BACKGROUND: Direct Acting Antiviral (DAAs) drugs have a much lower burden of treatment and monitoring requirements than regimens containing interferon and ribavirin, and a much higher efficacy in treating hepatitis C (HCV). These characteristics mean that initiating treatment and obtaining a virological cure (Sustained Viral response, SVR) on completion of treatment, in non-specialist environments should be feasible. We investigated the English-language literature evaluating community and primary care-based pathways using DAAs to treat HCV infection. METHODS: Databases (Cinahl; Embase; Medline; PsycINFO; PubMed) were searched for studies of treatment with DAAs in non-specialist settings to achieve SVR. Relevant studies were identified including those containing a comparison between a community and specialist services where available. A narrative synthesis and linked meta-analysis were performed on suitable studies with a strength of evidence assessment (GRADE). RESULTS: Seventeen studies fulfilled the inclusion criteria: five from Australia; two from Canada; two from UK and eight from USA. Seven studies demonstrated use of DAAs in primary care environments; four studies evaluated integrated systems linking specialists with primary care providers; three studies evaluated services in locations providing care to people who inject drugs; two studies evaluated delivery in pharmacies; and one evaluated delivery through telemedicine. Sixteen studies recorded treatment uptake. Patient numbers varied from around 60 participants with pathway studies to several thousand in two large database studies. Most studies recruited less than 500 patients. Five studies reported reduced SVR rates from an intention-to-treat analysis perspective because of loss to follow-up before the final confirmatory SVR test. GRADE assessments were made for uptake of HCV treatment (medium); completion of HCV treatment (low) and achievement of SVR at 12 weeks (medium). CONCLUSION: Services sited in community settings are feasible and can deliver increased uptake of treatment. Such clinics are able to demonstrate similar SVR rates to published studies and real-world clinics in secondary care. Stronger study designs are needed to confirm the precision of effect size seen in current studies. Prospero: CRD42017069873.


Assuntos
Antivirais/uso terapêutico , Serviços de Saúde Comunitária/estatística & dados numéricos , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Programas de Rastreamento/estatística & dados numéricos , Atenção Primária à Saúde/estatística & dados numéricos , Pesquisa sobre Serviços de Saúde , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
New Microbiol ; 42(4): 189-196, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31609453

RESUMO

Safety, efficacy, and predictor factors of sustained-virological-response after 24 weeks of new direct-acting antivirals were evaluated in hepatitis C virus patients with different stages of hepatic disease. 260 patients, median age 60 years, of whom 48.1% cirrhotics, 17.7% liver transplant recipients, and 45.7% naïve were treated with Sofosbuvir+Ribavirine, Sofosbuvir+Simeprevir±Ribavirine, Sofosbuvir+Daclatasvir± Ribavirine, Sofosbuvir+Ledispavir±Ribavirine, Ombitasvir/Paritaprevir/Ritonavir+Ribavirine and Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir±Ribavirine. Therapy outcomes, hematochemical parameters, viral replication, genotype, and resistance-associated-mutations were analyzed retrospectively. Sustained virological response was 90.4% in the whole population, 83.2% in cirrhotics, 85% in patients with previous virological failure, 93.6% in patients >60 years, and 95.6% in liver transplant recipients. SVR24 for each drug regimen was 75% Sofosbuvir+Ribavirine, 80.4% Sofosbuvir+Simeprevir±Ribavirine, 94.3% Sofosbuvir+Daclatasvir±Ribavirine, 98.7% Sofosbuvir+Ledispavir±Ribavirine, 100% Ombitasvir/ Paritaprevir/Ritonavir+Ribavirine and Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir±Ribavirine. The highest sustained virological response rates were obtained with genotype-1b (95.9%). Twenty-five patients, mostly cirrhotics or suffering from severe liver complications, manifested relapse (84%), breakthrough (12%), or non-response (4%). Mild side effects were observed in 41.1% of patients. Model-for-End-Liver- Disease score <10 and alanine aminotransferase ≤20 U/L at week 8 of therapy proved positive predictors of sustained virological response. Direct-acting antiviral therapy is efficacious and safe even in patients with advanced liver disease and/ or previous virological failure; Model-for-End-Liver-Disease <10 and alanine aminotransferase reduction during therapy were found to be reliable predicting markers of sustained-virological-response.


Assuntos
Antivirais , Hepatite C , Antivirais/administração & dosagem , Antivirais/normas , Biomarcadores Farmacológicos/análise , Quimioterapia Combinada , Genótipo , Hepacivirus , Hepatite C/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Humanos , Compostos Macrocíclicos/administração & dosagem , Pessoa de Meia-Idade , Estudos Retrospectivos , Ribavirina/administração & dosagem , Ritonavir/administração & dosagem , Simeprevir/administração & dosagem , Sofosbuvir/administração & dosagem , Sulfonamidas/administração & dosagem , Resultado do Tratamento , Uracila/administração & dosagem , Uracila/análogos & derivados
11.
Acta Gastroenterol Belg ; 82(3): 379-387, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31566325

RESUMO

BACKGROUND AND STUDY AIMS: Hepatitis C virus (HCV) infection often causes asymptomatic disease and patients are frequently diagnosed at an advanced stage. Oral direct acting antivirals (DAAs) are successful in treating HCV with high sustained virologic response (SVR) and excellent tolerability. The aim of this study is to evaluate cost-effectiveness of a broad screening strategy proposing screening to all undiagnosed members of a population (comprehensive HCV screening), in the general adult population, emergency department (ED) attendees, men who have sex with men (MSM) and people who inject drugs (PWID). PATIENTS AND METHODS: We populated a theoretical model with Belgian data. A decision tree model simulating HCV screening and diagnosis was combined with a Markov state transition model simulating treatment. There was one screening round per year during five years. In the ED population only one screening round was considered. RESULTS: The model calculated that more HCV patients could be detected and treated with comprehensive screening compared to the current situation. Incremental cost per incremental quality adjusted life years (QALY) gained was lower than 10.000€/QALY for one and for five screening rounds in the general population (5.139 and 5.200 respectively), in ED attendees (one screening round 5.967), in MSMs (4.292 and 4.302 respectively) and in PWIDs (3.504 and 3.524 respectively). CONCLUSION: A broad screening strategy combined with treatment is likely to be a cost-effective strategy to detect and treat HCV infected patients and diminish the HCV burden in Belgium.


Assuntos
Testes Diagnósticos de Rotina/economia , Hepacivirus/isolamento & purificação , Hepatite C/diagnóstico , Hepatite C/economia , Programas de Rastreamento/economia , Vigilância da População/métodos , Adulto , Antivirais/uso terapêutico , Bélgica/epidemiologia , Análise Custo-Benefício , Hepatite C/tratamento farmacológico , Humanos , Masculino , Programas de Rastreamento/métodos , Minorias Sexuais e de Gênero
12.
BMC Infect Dis ; 19(1): 809, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31521121

RESUMO

BACKGROUND: With one in every 20 Pakistanis already infected, Pakistan has the second largest number of hepatitis C virus (HCV) infections globally. The aim of this study was to present a quantitative and analytical characterization of the HCV epidemic in Pakistan. METHODS: A standardized database of HCV antibody incidence and prevalence and HCV genotypes in all subpopulations was systematically assembled. Random-effects meta-analyses and random-effects meta-regressions were performed. Shannon Diversity Index was calculated to determine genotype diversity. RESULTS: The database included two incidence, 309 prevalence, and 48 genotype measures. Pooled mean HCV prevalence ranged between 7.0% (95% confidence interval (CI): 5.8-8.3%) in Sindh and 0.9% (95% CI: 0.1-2.4%) in Federally Administered Tribal Areas (F.A.T.A). Estimated number of chronically-infected persons ranged between 4.2 million in Punjab and 0.03 million in F.A.T.A. HCV prevalence was stable over time [adjusted odds ratio (AOR) of 1.0 (95% CI: 1.0-1.0)]. Population classification was the strongest predictor of HCV prevalence, explaining 51.8% of prevalence variation. Relative to the general population, HCV prevalence was higher in people who inject drugs [AOR of 23.8 (95% CI: 13.0-43.6)], populations with liver-related conditions [AOR of 22.3 (95% CI: 15.7-31.6)], and high-risk clinical populations [AOR of 7.8 (95% CI: 4.8-12.7)]. Low genotype diversity was observed (Shannon diversity index of 0.67 out of 1.95; 34.5%). There were only minor differences in genotype diversity by province, with genotype 3 being most common in all provinces. CONCLUSION: Pakistan's HCV epidemic shows homogeneity across the provinces, and over time. HCV prevalence is strikingly persistent at high level, with no evidence for a decline over the last three decades. Scale up of HCV treatment and prevention is urgently needed.


Assuntos
Epidemias/estatística & dados numéricos , Hepacivirus/genética , Hepatite C/epidemiologia , Antivirais/uso terapêutico , Variação Genética , Genótipo , Hepatite C/tratamento farmacológico , Anticorpos Anti-Hepatite C/análise , Humanos , Incidência , Análise Multivariada , Razão de Chances , Paquistão/epidemiologia , Prevalência , Fatores de Risco , Testes Sorológicos
13.
Eur J Med Chem ; 183: 111723, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31557613

RESUMO

A set of ortho-, meta- and para-substituted cinnamic hydroxamic acids (CHAs) was synthesized. In each series of structural isomers, a phenyl substituent was linked to an aromatic ring of the parent cinnamic acid via a linker of one to four atoms in length. Using a cell test system with the full-length replicon of hepatitis C virus (HCV), we established a relationship between the suppression of HCV replicon propagation and the inhibition of class I/IIb histone deacetylases (HDACs). Anti-HCV activity correlated with the inhibition of HDAC8 in the case of ortho-CHAs, while in the case of meta-CHAs it correlated with the inhibition of HDAC1/2/3 and HDAC6. The antiviral activity of para-CHAs was many times stronger than that of meta-CHAs with about the same efficiency of HDAC1/2/3/6 inhibition, which indicated the existence of an additional cell target that does not belong to the studied group of HDACs.


Assuntos
Antivirais/química , Antivirais/farmacologia , Cinamatos/química , Cinamatos/farmacologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/fisiologia , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Humanos , Isomerismo , Replicação Viral/efeitos dos fármacos
14.
BMC Infect Dis ; 19(1): 703, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395019

RESUMO

BACKGROUND: Hepatitis C virus (HCV) is a major public health problem in correctional settings. HCV treatment is often not possible in U.S. jails due to short lengths of stay. Linkage to care is crucial in these settings, but competing priorities complicate community healthcare engagement and retention after incarceration. METHODS: We conducted a single arm clinical trial of a combined transitional care coordination (TCC) and patient navigation intervention and assessed the linkage rate and factors associated with linkage to HCV care after incarceration. RESULTS: During the intervention, 84 participants returned to the community after their index incarceration. Most participants were male and Hispanic, with a history of mental illness and a mean age of 45 years. Of those who returned to the community, 26 (31%) linked to HCV care within a median of 20.5 days; 17 (20%) initiated HCV treatment, 15 (18%) completed treatment, 9 (11%) had a follow-up lab drawn to confirm sustained virologic response (SVR), and 7 (8%) had a documented SVR. Among those with follow-up labs the known SVR rate was (7/9) 78%. Expressing a preference to be linked to the participant's existing health system, being on methadone prior to incarceration, and feeling that family or a loved one were concerned about the participant's wellbeing were associated with linkage to HCV care. Reporting drinking alcohol to intoxication prior to incarceration was negatively associated with linkage to HCV care. CONCLUSION: We demonstrate that an integrated strategy with combined TCC and patient navigation may be effective in achieving timely linkage to HCV care. Additional multicomponent interventions aimed at treatment of substance use disorders and increasing social support could lead to further improvement. TRIAL REGISTRATION: Clinicaltrials.gov NCT04036760 July 30th, 2019 (retrospectively registered).


Assuntos
Continuidade da Assistência ao Paciente , Hepatite C/tratamento farmacológico , Prisioneiros/estatística & dados numéricos , Adulto , Serviços de Saúde Comunitária , Feminino , Hepatite C/virologia , Hispano-Americanos , Humanos , Masculino , Metadona/uso terapêutico , Pessoa de Meia-Idade , New York , Navegação de Pacientes , Prisões , Estudos Prospectivos , Transtornos Relacionados ao Uso de Substâncias/terapia , Resposta Viral Sustentada
15.
Nat Commun ; 10(1): 3468, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371704

RESUMO

Targeted protein degradation is a promising drug development paradigm. Here we leverage this strategy to develop a new class of small molecule antivirals that induce proteasomal degradation of viral proteins. Telaprevir, a reversible-covalent inhibitor that binds to the hepatitis C virus (HCV) protease active site is conjugated to ligands that recruit the CRL4CRBN ligase complex, yielding compounds that can both inhibit and induce the degradation of the HCV NS3/4A protease. An optimized degrader, DGY-08-097, potently inhibits HCV in a cellular infection model, and we demonstrate that protein degradation contributes to its antiviral activity. Finally, we show that this new class of antiviral agents can overcome viral variants that confer resistance to traditional enzymatic inhibitors such as telaprevir. Overall, our work provides proof-of-concept that targeted protein degradation may provide a new paradigm for the development of antivirals with superior resistance profiles.


Assuntos
Antivirais/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antivirais/química , Linhagem Celular Tumoral , Desenho de Drogas , Farmacorresistência Viral/genética , Técnicas de Silenciamento de Genes , Células HEK293 , Hepacivirus/efeitos dos fármacos , Hepacivirus/metabolismo , Hepatite C/tratamento farmacológico , Hepatite C/genética , Hepatite C/virologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ligantes , Modelos Moleculares , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Estudo de Prova de Conceito , Inibidores de Proteases/química , Proteólise/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo , Proteínas não Estruturais Virais/metabolismo
17.
Am J Health Syst Pharm ; 76(17): 1273-1280, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31418789

RESUMO

PURPOSE: We previously reported an interaction with warfarin anticoagulation when initiating treatment with direct-acting antiviral agents for hepatitis C infection. A decreased warfarin sensitivity led to subtherapeutic anticoagulation. To study this interaction further, we expanded our research to include patients treated with the combination of elbasvir and grazoprevir concurrent with warfarin anticoagulation and investigated changes in warfarin sensitivity during and after treatment. METHODS: Using electronic health records of the Veterans Health Administration, patients starting treatment with elbasvir-grazoprevir for hepatitis C infection concurrent with warfarin anticoagulation were identified. Inclusion required stable warfarin anticoagulation prior to 12 weeks of treatment with elbasvir-grazoprevir. A warfarin sensitivity index (WSI) was calculated at the start of treatment, after 12 weeks after treatment, and at the end of treatment. The primary endpoint was the difference in WSI from pre- to end-treatment. The secondary endpoint was the WSI difference from before treatment to Changes in International Normalized Ratio, warfarin doses, and time in therapeutic range were measured. RESULTS: In the final sample of 43 patients, the mean WSI decreased during treatment from 0.53 to 0.40, or 25.2%. After treatment, the mean WSI rose to 0.51. Although the mean weekly warfarin dose increased from 40.3 to 44.6 mg during treatment, the mean International Normalized Ratio decreased from 2.40 to 1.96, recovering to 2.59 after treatment. The time spent in therapeutic range decreased from 74.1% before treatment to 39.8% during treatment and back to 64.9% 12 weeks posttreatment. CONCLUSION: When elbasvir-grazoprevir was added to stable warfarin anticoagulation, warfarin sensitivity decreased significantly during treatment and returned to baseline after treatment.


Assuntos
Antivirais/administração & dosagem , Benzofuranos/administração & dosagem , Hepatite C/tratamento farmacológico , Imidazóis/administração & dosagem , Quinoxalinas/administração & dosagem , Varfarina/farmacologia , Anticoagulantes/administração & dosagem , Anticoagulantes/farmacologia , Antivirais/farmacologia , Benzofuranos/farmacologia , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Interações de Medicamentos , Humanos , Imidazóis/farmacologia , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Quinoxalinas/farmacologia , Estudos Retrospectivos , Varfarina/administração & dosagem
18.
Asian Pac J Cancer Prev ; 20(8): 2311-2317, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31450900

RESUMO

Background: Even with the fantastic successes of direct-acting antivirals (DAA) in the treatment of Hepatitis C Virus (HCV) infection, natural drug resistance remains a challenging obstacle for their impacts. The data regarding protease inhibitors (PIs) resistance in Iran population are limited. The aim of this study was to investigate the variations in NS3 protease of HCV from non-responder patients. Methods: In this cross-sectional study, 14 HCV infected patients with genotype 1(N=5) and 3(N=9) who have not responded to Interferon-related regime were enrolled from Liver Clinic, Shiraz. The NS3 protease region was amplified by Nested-PCR followed by product gel extraction. Besides, some amplified protease regions were cloned into a cloning vector to improve the sensitivity of mutation detection. Both crude and cloned sequences were then introduced into sequencing. The obtained sequences were compared with the NS3 reference sequences and analyzed by Geno2pheno available software to find possible substitutions. In the end, the phylogenetic tree was constructed. Results: Among variations responsible for PIs resistance, only one out of 14 (7%) sample who was infected with genotype 1a, harbored R117C+N174S double mutation, which causes reduced susceptibility to Telaprevir. Any another resistance mutation was not found among the studied population. The most frequent substitutions were determined as I52M(N=9), S102A(N=9), S166A(8) and V170I(8) for genotype 3a, and F147S/A(4) for genotype 1. However, some uncharacterized substitutions on scored position, including I132L(N=1), I170V(N=3) and N174S(N=2) were also determined among sequences. Phylogenetic analysis demonstrated that the protease region has enough power to correctly classify enrolled samples into relevant clusters on the tree. There were 2, 3 and 9 cases of sub-genotypes 1a, 1b, and 3a, respectively. Conclusion: A low frequency of PIs resistance mutations in our HCV infected population is a hopeful point of starting these drugs in HCV infected patients.


Assuntos
Farmacorresistência Viral/genética , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Mutação , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/genética , Adulto , Idoso , Substituição de Aminoácidos , Antivirais/farmacologia , Estudos Transversais , Feminino , Seguimentos , Hepacivirus/enzimologia , Hepacivirus/genética , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia
19.
BMC Infect Dis ; 19(1): 712, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31438873

RESUMO

BACKGROUND: Almost 1% of Canadians are hepatitis C (HCV)-infected. The liver-specific complications of HCV are established but the extra-hepatic comorbidity, multimorbidity, and its relationship with HCV treatment, is less well known. We describe the morbidity burden for people with HCV and the relationship between multimorbidity and HCV treatment uptake and cure in the pre- and post-direct acting antiviral (DAA) era. METHODS: We linked adults with HCV at The Ottawa Hospital Viral Hepatitis Program as of April 1, 2017 to provincial health administrative data and matched on age and sex to 5 Ottawa-area residents for comparison. We used validated algorithms to identify the prevalence of mental and physical health comorbidities, as well as multimorbidity (2+ comorbidities). We calculated direct age- and sex-standardized rates of comorbidity and comparisons were made by interferon-based and interferon-free, DAA HCV treatments. RESULTS: The mean age of the study population was 54.5 years (SD 11.4), 65% were male. Among those with HCV, 4% were HIV co-infected, 26% had liver cirrhosis, 47% received DAA treatment, and 57% were cured of HCV. After accounting for age and sex differences, the HCV group had greater multimorbidity (prevalence ratio (PR) 1.38, 95% confidence interval (CI) 1.20 to 1.58) and physical-mental health multimorbidity (PR 2.71, 95% CI 2.29-3.20) compared to the general population. Specifically, prevalence ratios for people with HCV were significantly higher for diabetes, renal failure, cancer, asthma, chronic obstructive pulmonary disease, substance use disorder, mood and anxiety disorders and liver failure. HCV treatment and cure were not associated with multimorbidity, but treatment prevalence was significantly lower among middle-aged individuals with substance use disorders despite no differences in prevalence of cure among those treated. CONCLUSION: People with HCV have a higher prevalence of comorbidity and multimorbidity compared to the general population. While HCV treatment was not associated with multimorbidity, people with substance use disorder were less likely to be treated. Our results point to the need for integrated, comprehensive models of care delivery for people with HCV.


Assuntos
Hepatite C/epidemiologia , Adolescente , Adulto , Idoso , Antivirais/uso terapêutico , Canadá/epidemiologia , Coinfecção/epidemiologia , Comorbidade , Feminino , Infecções por HIV/epidemiologia , Hepatite C/tratamento farmacológico , Humanos , Cirrose Hepática/epidemiologia , Masculino , Pessoa de Meia-Idade , Multimorbidade , Prevalência , Estudos Retrospectivos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adulto Jovem
20.
PLoS Pathog ; 15(8): e1007949, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31374104

RESUMO

Host encounters with viruses lead to an innate immune response that must be rapid and broadly targeted but also tightly regulated to avoid the detrimental effects of unregulated interferon expression. Viral stimulation of host negative regulatory mechanisms is an alternate method of suppressing the host innate immune response. We examined three key mediators of the innate immune response: NF-KB, STAT1 and STAT2 during HCV infection in order to investigate the paradoxical induction of an innate immune response by HCV despite a multitude of mechanisms combating the host response. During infection, we find that all three are repressed only in HCV infected cells but not in uninfected bystander cells, both in vivo in chimeric mouse livers and in cultured Huh7.5 cells after IFNα treatment. We show here that HCV and Flaviviruses suppress the innate immune response by upregulation of PDLIM2, independent of the host interferon response. We show PDLIM2 is an E3 ubiquitin ligase that also acts to stimulate nuclear degradation of STAT2. Interferon dependent relocalization of STAT1/2 to the nucleus leads to PDLIM2 ubiquitination of STAT2 but not STAT1 and the proteasome-dependent degradation of STAT2, predominantly within the nucleus. CRISPR/Cas9 knockout of PDLIM2 results in increased levels of STAT2 following IFNα treatment, retention of STAT2 within the nucleus of HCV infected cells after IFNα stimulation, increased interferon response, and increased resistance to infection by several flaviviruses, indicating that PDLIM2 is a global regulator of the interferon response.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Infecções por Flavivirus/imunologia , Flavivirus/imunologia , Hepacivirus/imunologia , Hepatite C/imunologia , Imunidade Inata/imunologia , Proteínas com Domínio LIM/fisiologia , Fator de Transcrição STAT2/metabolismo , Animais , Antivirais/farmacologia , Flavivirus/efeitos dos fármacos , Infecções por Flavivirus/tratamento farmacológico , Infecções por Flavivirus/virologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Imunidade Inata/efeitos dos fármacos , Interferon-alfa/farmacologia , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , NF-kappa B , Fator de Transcrição STAT2/genética , Transdução de Sinais
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