RESUMO
Patients with serious mental illness have a higher risk of hepatitis C virus (HCV) infection but suboptimal HCV care. The current study aimed to facilitate HCV treatment uptake by implementing an integrated outreach care model. Multidisciplinary outreach screening followed by HCV reflex testing and onsite treatment for schizophrenia patients was accomplished through the coordination of nongovernmental organizations, remote specialists, and local care providers. The objective was microelimination effectiveness, defined as the multiplication of the rates of anti-HCV antibodies screening, accurate HCV RNA diagnosis, treatment allocation, treatment completion, and sustained virological response (SVR12; no detectable HCV RNA throughout 12 weeks in the post-treatment follow-up period). A total of 1478 of the 2300 (64.3%) psychiatric patients received HCV mass screening. Seventy-three (4.9%) individuals were seropositive for anti-HCV antibodies. Of the 73 anti-HCV seropositive patients, all (100%) received HCV reflex testing, and 29 (37.7%) patients had HCV viremia. Eight patients (34.8%) had advanced liver disease, including 3 with liver cirrhosis and 2 with newly diagnosed hepatocellular carcinoma. Twenty-three of the 24 (95.8%) patients who stayed in the healthcare system received and completed 8 weeks of glecaprevir/pibrentasvir treatment and post-treatment follow-up without significant DDIs or adverse events. The SVR12 rate was 100%. The microelimination effectiveness in the current study was 61.6%. Individuals with serious mental illness are underserved and suffer from diagnostic delays. This patient-centered and integrated outreach program facilitated HCV care in this marginalized population.
Assuntos
Hepatite C Crônica , Hepatite C , Transtornos Mentais , Humanos , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Taiwan , Anticorpos Anti-Hepatite C/genética , Anticorpos Anti-Hepatite C/uso terapêutico , Antivirais/uso terapêutico , Genótipo , Ácidos Aminoisobutíricos/uso terapêutico , Ciclopropanos/uso terapêutico , Hepatite C/tratamento farmacológico , Hepacivirus/genética , RNA , Assistência Centrada no Paciente , Transtornos Mentais/complicações , Transtornos Mentais/diagnóstico , Transtornos Mentais/induzido quimicamenteRESUMO
BACKGROUND: Hepatitis C Virus (HCV) is a common cause of chronic liver disease and its ensuing complications. In the last years, there has been a revolution of the treatment for patients with HCV regarding efficacy, simplicity, safety and duration of treatment. The role of the family physician is vital in all steps of care: screening, diagnosis, linkage to treatment, treatment and follow-up. OBJECTIVES: This review aims to summarise the family physician and the important updated recommendations for diagnosis and treatment of patients with chronic HCV. METHODS: The updated recommendations were reviewed and summarised in a short and simple review. RESULTS: Patients with any risk factor for HCV should first be screened for HCV antibodies. In the case of positive antibodies, reflex testing for RNA polymerase chain reaction (PCR) should be done without waiting for genotype. For patients with positive PCR, fibrosis assessment should be conducted using laboratory panels (Fibrosis-4 index (FIB-4) or aspartate aminotransferase to platelet ratio index (APRI)); if advanced fibrosis is suspected, additional non-invasive fibrosis assessment is needed, such as fibrotest or liver elastography. Naïve non-cirrhotic or compensated cirrhosis (Child-Pugh-Score A) could be treated with pangenotypic drugs, Glecaprevir/pibrentasvir (Maviret) for eight weeks, or Sofosbuvir/velpatasvir (Epclusa) for 12 weeks. CONCLUSION: Patients without advanced fibrosis and comorbidities can be treated by the educated family physician. However, patients with comorbidities, cirrhosis or coinfection (HIV, Hepatitis B Virus (HBV)) should be referred to the liver clinic. In case of screening patients with risk factors or likelihood of dormant HCV, health organisations should provide the appropriate resources, logistics, finances and workforce.
Assuntos
Hepatite C Crônica , Hepatite C , Ácidos Aminoisobutíricos/uso terapêutico , Antivirais/uso terapêutico , Ciclopropanos/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Humanos , Lactamas Macrocíclicas/uso terapêutico , Leucina/uso terapêutico , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Cirrose Hepática/tratamento farmacológicoRESUMO
The study evaluated the real-world treatment outcomes of Glecaprevir/pibrentasvir (GLE/PIB) including effectiveness, safety and healthcare resource utilization based on a nation-wide registry in Taiwan. The Taiwan HCV Registry (TACR) is a nation-wide platform organized and supervised by the Taiwan Association for the Study of the Liver. Data were analyzed for patients treated with GLE/PIB, including 3144 patients who had treatment outcome available. The primary endpoint was sustained virological response (SVR12, undetectable HCV RNA throughout 12 weeks of end-of-treatment). The overall SVR12 rate was 98.9% (3110/3144), with 98.8%, 99.4% and 100% in patients receiving 8 weeks, 12 weeks, and 16 weeks of GLE/PIB respectively. The SVR12 rate in the treatment-naïve cirrhotic patients receiving 8 weeks of GLE/PIB was 98.2% (108/110). The most common AEs were fatigue (7.5%), pruritus (6.7%) and dizziness (1.5%). The mean number of outpatient visits during the GLE/PIB was 5.94 visits for patients treated with 8 weeks, significantly different from the patients treated with 12 weeks of GLE/PIB (6.90 visits). The results support the effectiveness and safety of GLE/PIB treatment in real-world clinical practice, and provide further evidence that the shorter, 8-week GLE/PIB regimen is effective and cost-saving.
Assuntos
Ácidos Aminoisobutíricos/uso terapêutico , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Ciclopropanos/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Lactamas Macrocíclicas/uso terapêutico , Leucina/análogos & derivados , Prolina/análogos & derivados , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Combinação de Medicamentos , Feminino , Hepatite C/virologia , Humanos , Leucina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prolina/uso terapêutico , Estudos Prospectivos , Sistema de Registros , Resposta Viral Sustentada , Taiwan , Resultado do TratamentoRESUMO
INTRODUCTION: Pangenotypic, all-oral direct-acting antivirals, such as glecaprevir/pibrentasvir (G/P), are recommended for treatment of hepatitis C virus (HCV) infection. Concerns exist about the impact on efficacy in patients with suboptimal adherence, particularly with shorter treatment durations. These post hoc analyses evaluated adherence (based on pill count) in patients prescribed 8- or 12-week G/P, the impact of nonadherence on sustained virologic response at post-treatment week 12 (SVR12), factors associated with nonadherence, and efficacy in patients interrupting G/P treatment. METHODS: Data were pooled from 10 phase 3 clinical trials of treatment-naive patients with HCV genotype 1-6 without cirrhosis/with compensated cirrhosis (treatment adherence analysis) and 13 phase 3 clinical trials of all patients with HCV (interruption analysis). RESULTS: Among 2,149 patients included, overall mean adherence was 99.4%. Over the treatment duration, adherence decreased (weeks 0-4: 100%; weeks 5-8: 98.3%; and weeks 9-12: 97.1%) and the percentage of patients with ≥80% or ≥90% adherence declined. SVR12 rate in the intention-to-treat (ITT) population was 97.7% (modified ITT SVR12 99.3%) and remained high in nonadherent patients in the modified ITT population (<90%: 94.4%-100%; <80%: 83.3%-100%). Psychiatric disorders were associated with <80% adherence, and shorter treatment duration was associated with ≥80% adherence. Among 2,902 patients in the interruption analysis, 33 (1.1%) had a G/P treatment interruption of ≥1 day, with an SVR12 rate of 93.9% (31/33). No virologic failures occurred. DISCUSSION: These findings support the impact of treatment duration on adherence rates and further reinforce the concept of "treatment forgiveness" with direct-acting antivirals.
Assuntos
Ácidos Aminoisobutíricos/uso terapêutico , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Ciclopropanos/uso terapêutico , Hepatite C/tratamento farmacológico , Lactamas Macrocíclicas/uso terapêutico , Leucina/análogos & derivados , Adesão à Medicação , Prolina/análogos & derivados , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Feminino , Humanos , Leucina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prolina/uso terapêutico , Resposta Viral Sustentada , Resultado do TratamentoRESUMO
Heart diseases are known as the most primary causes of mortality worldwide. Although many therapeutic approaches and medications are proposed for these diseases, the identification of novel therapeutics in fatal heart conditions is promptly demanded. Besides, the interplay between gene expression data and molecular docking provides several novel insights to discover more effective and specific drugs for the treatment of the diseases. This study aimed to discover potent therapeutic drugs in the heart diseases based on the expression profile of heart-specific genes exclusively. Initially, the heart-specific and highly expressed genes were identified by comparing the gene expression profile of different body tissues. Subsequently, the druggable-genes were identified using in silico techniques. The interaction between these druggable genes with more than 1600 FDA approved drugs was then investigated using the molecular docking simulation. By comprehensively analyzing RNA-sequencing data obtained from 949 normal tissue samples, 48 heart-specific genes were identified in both the heart development and function. Notably, of these, 24 heart-specific genes were capable to be considered as druggable genes, among which only MYBPC3, MYLK3, and SCN5A genes entered the molecular docking process due to their functions. Afterward, the pharmacokinetics properties of top 10 ligands with the highest binding affinity for these proteins were studied. Accordingly, methylergonovine, fosaprepitant, pralatrexate, daunorubicin, glecaprevir, digoxin, and venetoclax drugs were competent, in order to interact with the target proteins perfectly. It was shown that these medications can be used as specific drugs for the treatment of heart diseases after fulfilling further experiments in this regard.
Assuntos
Cardiopatias/tratamento farmacológico , Simulação de Acoplamento Molecular , Ácidos Aminoisobutíricos/uso terapêutico , Aminopterina/análogos & derivados , Aminopterina/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Ciclopropanos/uso terapêutico , Daunorrubicina/uso terapêutico , Digoxina/uso terapêutico , Reposicionamento de Medicamentos , Expressão Gênica , Cardiopatias/genética , Humanos , Lactamas Macrocíclicas/uso terapêutico , Leucina/análogos & derivados , Leucina/uso terapêutico , Ligantes , Metilergonovina/uso terapêutico , Morfolinas/uso terapêutico , Prolina/análogos & derivados , Prolina/uso terapêutico , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêuticoRESUMO
Obesity is an issue of great concern to people all over the world. It is accompanied by serious complications, leading to reduced quality of life and higher morbidity and mortality. Over the past few years, there has been an explosion in knowledge about the roles of potential therapeutic agents in obesity management. Among them, amino acid (AA) derivatives, such as taurine, glutathione (GSH), betaine, α-ketoglutarate (AKG), ß-aminoisobutyric acid (BAIBA), and ß-hydroxy-ß-methylbutyrate (HMB), have recently gained popularity due to their beneficial effects on the promotion of weight loss and improvement in the lipid profile. The mechanisms of action of these derivatives mainly include inhibiting adipogenesis, increasing lipolysis, promoting brown/beige adipose tissue (BAT) development, and improving glucose metabolism. Therefore, this review summarizes these AA derivatives and the possible mechanisms responsible for their anti-obesity effects. Based on the current findings, these AA derivatives could be potential therapeutic agents for obesity and its related metabolic diseases.
Assuntos
Aminoácidos/metabolismo , Aminoácidos/farmacologia , Obesidade/tratamento farmacológico , Adipogenia/efeitos dos fármacos , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Marrom/metabolismo , Aminoácidos/uso terapêutico , Ácidos Aminoisobutíricos/uso terapêutico , Animais , Betaína/uso terapêutico , Glucose/metabolismo , Glutationa/uso terapêutico , Humanos , Ácidos Cetoglutáricos/uso terapêutico , Lipólise/efeitos dos fármacos , Obesidade/metabolismo , Taurina/uso terapêutico , Valeratos/uso terapêutico , Redução de PesoRESUMO
BACKGROUND: Second generation direct acting antivirals (DAAs) drastically changed the landscape of chronic HCV (CHCV). Aim of this paper was to assess the effectiveness of DAAs, also looking at the demographic characteristics of subjects enrolled. RESEARCH DESIGN AND METHODS: Ambispective multi-center real-life study conducted among patients with CHCV treated with DAAs in Campania Region (Southern Italy). Patient were enrolled in two cohorts according to time of enrolment. RESULTS: 1,479 patients were enrolled. Patients aged ≥60 years were 74.7% in the historic cohort (953 patients) and 70.2% in the prospective cohort (526 patients. Patients aged ≥ 60 years showed a higher prevalence of genotype 1b (p<0.001) and 2 (p<0.001), while patients aged < 60 years showed a higher prevalence of genotype 1a (p<0.001), 3 (p<0.001) and 4 (p<0.05). SVR12 was 98.5% in both cohorts. SVR12 was similar among patients of the prospective cohort aged < and ≥ 60 years (99.4% vs 98.1%). SVR12 among patients with and without cirrhosis was 96.0% and 98.9%, respectively. CONCLUSIONS: DAAs provide high efficacy also in harder to treat patients. The effectiveness of DAAs is leading to a shift in patients characteristics with a greater prevalence of younger subjects and persons with mild liver disease.
Assuntos
Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Adulto , Distribuição por Idade , Idoso , Amidas/uso terapêutico , Ácidos Aminoisobutíricos/uso terapêutico , Benzimidazóis/uso terapêutico , Benzofuranos/uso terapêutico , Carbamatos/uso terapêutico , Ciclopropanos/uso terapêutico , Feminino , Genótipo , Hepatite C Crônica/complicações , Hepatite C Crônica/epidemiologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Imidazóis/uso terapêutico , Itália/epidemiologia , Lactamas Macrocíclicas/uso terapêutico , Leucina/análogos & derivados , Leucina/uso terapêutico , Cirrose Hepática/epidemiologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Prolina/análogos & derivados , Prolina/uso terapêutico , Estudos Prospectivos , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , Estudos Retrospectivos , Sulfonamidas/uso terapêutico , Resposta Viral SustentadaRESUMO
Duchenne muscular dystrophy is initiated by dystrophin deficiency, but downstream pathophysiological pathways such as membrane instability, NFĸB activation, mitochondrial dysfunction, and induction of TGFß fibrosis pathways are thought to drive the disability. Dystrophin replacement strategies are hopeful for addressing upstream dystrophin deficiency; however, all methods to date use semi-functional dystrophin proteins that are likely to trigger downstream pathways. Thus, combination therapies that can target multiple downstream pathways are important in treating DMD, even for dystrophin-replacement strategies. We sought to define blood pharmacodynamic biomarkers of drug response in the mdx mouse model of Duchenne muscular dystrophy using a series of repurposed drugs. Four-week-old mdx mice were treated for four weeks with four different drugs singly and in combination: vehicle, prednisolone, vamorolone, rituximab, ß-aminoisobutyric acid (BAIBA) (11 treatment groups; n = 6/group). Blood was collected via cardiac puncture at study termination, and proteomic profiling was carried out using SOMAscan aptamer panels (1,310 proteins assayed). Prednisolone was tested alone and in combination with other drugs. It was found to have a good concordance of prednisolone-responsive biomarkers (56 increased by prednisolone, 39 decreased) focused on NFκB and TGFß cascades. Vamorolone shared 45 (80%) of increased biomarkers and 13 (33%) of decreased biomarkers with prednisolone. Comparison of published human corticosteroid-responsive biomarkers to our mdx data showed 14% (3/22) concordance between mouse and human. Rituximab showed fewer drug-associated biomarkers, with the most significant being human IgG. On the other hand, BAIBA treatment (high and low dose) showed a drug-associated increase in 40 serum proteins and decreased 5 serum proteins. Our results suggest that a biomarker approach could be employed for assessing drug combinations in both mouse and human studies.
Assuntos
Distrofia Muscular Animal/tratamento farmacológico , Distrofia Muscular de Duchenne/tratamento farmacológico , Ácidos Aminoisobutíricos/uso terapêutico , Animais , Biomarcadores , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos mdx , Prednisolona/uso terapêutico , Pregnadienodiois/uso terapêutico , Rituximab/uso terapêuticoRESUMO
Shortening therapy duration with direct-acting antiviral agents (DAAs) is desirable to pursue the WHO target of HCV eradication by 2030. We report two cases of HCV-infected women who achieved sustained virologic response after an ultra-short treatment with glecaprevir/pibrentasvir (G/P), discontinued due to cutaneous adverse events, and analyze similar cases reported in the literature. Female gender seems to be a prevailing characteristic in this group of patients. G/P, due to its pangenotypic and strong antiviral activity, may represent a candidate for a shortened DAA regimen in non-cirrhotic treatment-naive subjects.
Assuntos
Ácidos Aminoisobutíricos , Antivirais , Benzimidazóis , Ciclopropanos , Hepatite C Crônica , Lactamas Macrocíclicas , Leucina/análogos & derivados , Prolina/análogos & derivados , Pirrolidinas , Quinoxalinas , Sulfonamidas , Ácidos Aminoisobutíricos/uso terapêutico , Antirretrovirais/uso terapêutico , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Ciclopropanos/uso terapêutico , Combinação de Medicamentos , Feminino , Hepatite C Crônica/tratamento farmacológico , Humanos , Lactamas Macrocíclicas/uso terapêutico , Leucina/uso terapêutico , Prolina/uso terapêutico , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêuticoRESUMO
BACKGROUND: The real-world data of glecaprevir/pibrentasvir (GLE/PIB) therapy for patients with chronic hepatitis C virus (HCV) genotype 2 infection remained limited. We aimed to evaluate the possible predictors of virological failure and side effects of GLE/PIB therapy for chronic genotype 2 HCV-infected patients in a real-world setting. METHODS: A total of 326 compensated HCV genotype 2 patients treated with GLE/PIB 12 weeks for cirrhotic patients (n = 56) and 8 weeks for non-cirrhotic patients (n = 270) were enrolled. RESULTS: The sustained virological response 12 weeks off therapy (SVR12) was 98.1%, 100%, and 97.7% in overall, GLE/PIB 12-week, and 8-week group, respectively. There were 6 (1.8%) patients with early withdrawal, and 14.1% patients had pruritus, the major adverse effect. In multivariate analyses, end-stage renal disease (odds ratio (OR) = 4.056, 95% confidence interval (CI) = 1.477-11.14, p = 0.007) and hypertension (OR = 2.325, 95% CI = 1.171-4.616, p = 0.016) were two significant factors associated with pruritus. There were 6 patients with virologic failure. In patients receiving 8-week GLE/PIB therapy, the SVR12 rate was significant lower in high baseline viral load (≥107 IU/ml) group compared to low viral load group (90.6% v.s 98.7%, p = 0.025). Multivariate analyses showed that HCV RNA≥107 IU/ml was one of the independent factors (OR = 0.134, 95% CI = 0.024-0.748; p = 0.022) associated with SVR12. CONCLUSION: GIE/PIB is an effective, tolerable and safe agent to treat genotype 2 HCV infected patients. However, high viral load (≥107 IU/ml) may predict virologic failure in non-cirrhotic patients receiving 8 weeks GIE/PIB treatment. This result should be further validated in a large cohort in the future.
Assuntos
Ácidos Aminoisobutíricos/uso terapêutico , Benzimidazóis/uso terapêutico , Ciclopropanos/uso terapêutico , Hepatite C Crônica , Lactamas Macrocíclicas/uso terapêutico , Leucina/análogos & derivados , Prolina/análogos & derivados , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Antivirais/efeitos adversos , Benzimidazóis/urina , Genótipo , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Humanos , Leucina/uso terapêutico , Prolina/uso terapêutico , Pirrolidinas , Carga ViralRESUMO
BACKGROUND: Single-center trials and retrospective case series have reported promising outcomes using kidneys from donors with hepatitis C virus (HCV) infection. However, multicenter trials are needed to determine if those findings are generalizable. METHODS: We conducted a prospective trial at seven centers to transplant 30 kidneys from deceased donors with HCV viremia into HCV-uninfected recipients, followed by 8 weeks of once-daily coformulated glecaprevir and pibrentasvir, targeted to start 3 days posttransplant. Key outcomes included sustained virologic response (undetectable HCV RNA 12 weeks after completing treatment with glecaprevir and pibrentasvir), adverse events, and allograft function. RESULTS: We screened 76 patients and enrolled 63 patients, of whom 30 underwent kidney transplantation from an HCV-viremic deceased donor (median kidney donor profile index, 53%) in May 2019 through October 2019. The median time between consent and transplantation of a kidney from an HCV-viremic donor was 6.3 weeks. All 30 recipients achieved a sustained virologic response. One recipient died of complications of sepsis 4 months after achieving a sustained virologic response. No severe adverse events in any patient were deemed likely related to HCV infection or treatment with glecaprevir and pibrentasvir. Three recipients developed acute cellular rejection, which was borderline in one case. Three recipients developed polyomavirus (BK) viremia near or >10,000 copies/ml that resolved after reduction of immunosuppression. All recipients had good allograft function, with a median creatinine of 1.2 mg/dl and median eGFR of 57 ml/min per 1.73 m2 at 6 months. CONCLUSIONS: Our multicenter trial demonstrated safety and efficacy of transplantation of 30 HCV-viremic kidneys into HCV-negative recipients, followed by early initiation of an 8-week regimen of glecaprevir and pibrentasvir.
Assuntos
Ácidos Aminoisobutíricos/uso terapêutico , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Ciclopropanos/uso terapêutico , Hepacivirus , Hepatite C/prevenção & controle , Transplante de Rim , Lactamas Macrocíclicas/uso terapêutico , Leucina/análogos & derivados , Prolina/análogos & derivados , Quinoxalinas/uso terapêutico , RNA Viral/sangue , Sulfonamidas/uso terapêutico , Adulto , Aloenxertos/fisiologia , Aloenxertos/virologia , Ácidos Aminoisobutíricos/efeitos adversos , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Ciclopropanos/efeitos adversos , Combinação de Medicamentos , Feminino , Taxa de Filtração Glomerular , Hepatite C/sangue , Humanos , Rim/fisiologia , Lactamas Macrocíclicas/efeitos adversos , Leucina/efeitos adversos , Leucina/uso terapêutico , Masculino , Prolina/efeitos adversos , Prolina/uso terapêutico , Estudos Prospectivos , Pirrolidinas , Quinoxalinas/efeitos adversos , Sulfonamidas/efeitos adversos , Resposta Viral SustentadaRESUMO
INTRODUCTION: More than 70 million people are estimated to be infected with hepatitis C virus globally. Glecaprevir/pibrentasvir is a widely used treatment and has recently been approved for an 8-week regimen for treatment-naïve patients with compensated cirrhosis in Europe and the USA, who would previously have received glecaprevir/pibrentasvir for 12 weeks. This label update was based on the EXPEDITION-8 study, which included 343 treatment-naïve patients with compensated cirrhosis. However, there is currently a lack of similarly large-scale real-world studies of the 8-week glecaprevir/pibrentasvir regimen in this population. METHODS: This summary of seven separate smaller real-world studies aims to validate the results seen in EXPEDITION-8 and provide an up-to-date real-world reference for clinicians making treatment decisions for patients with compensated cirrhosis (Child-Pugh A) who may benefit from a shorter-duration therapy with glecaprevir/pibrentasvir. The newly emerging real-world effectiveness data on treatment-naïve patients with compensated cirrhosis treated with 8 weeks of glecaprevir/pibrentasvir help to understand where further research is needed to support patients with hepatitis C virus. RESULTS: Across all seven studies, glecaprevir/pibrentasvir showed high effectiveness with an average sustained virologic response rate of 98.1%, similar to that found in a clinical trial setting (99.7%). Only one patient (0.5%) experienced virologic failure and treatment was well tolerated. CONCLUSION: Expanding the number of patients eligible for the shortened treatment duration will potentially increase treatment initiation and completion, particularly in underserved populations, contributing to the elimination of hepatitis C virus.
Assuntos
Ácidos Aminoisobutíricos/uso terapêutico , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Ciclopropanos/uso terapêutico , Combinação de Medicamentos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Lactamas Macrocíclicas/uso terapêutico , Leucina/análogos & derivados , Cirrose Hepática/tratamento farmacológico , Prolina/análogos & derivados , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Variação Genética , Hepacivirus/efeitos dos fármacos , Humanos , Leucina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prolina/uso terapêutico , Resposta Viral Sustentada , Resultado do TratamentoRESUMO
Endurance exercise training has been shown to induce peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression in skeletal muscle. We recently reported that skeletal muscle-specific PGC-1α overexpression suppressed atherosclerosis in apolipoprotein E-knockout (ApoE-/-) mice. ß-Aminoisobutyric acid (BAIBA) is a PGC-1α-dependent myokine secreted from myocytes that affects multiple organs. We have also reported that BAIBA suppresses tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) gene expression in endothelial cells. In the present study, we hypothesized that BAIBA suppresses atherosclerosis progression, and tested that hypothesis with ApoE-/- mice. The mice were administered water containing BAIBA for 14 weeks, and were then sacrificed at 20 weeks of age. Atherosclerotic plaque area, plasma BAIBA concentration, and plasma lipoprotein profiles were assessed. Immunohistochemical analyses of the plaque were performed to assess VCAM-1 and MCP-1 protein expression levels and macrophage infiltration. The results showed that BAIBA administration decreased atherosclerosis plaque area by 30%, concomitant with the elevation of plasma BAIBA levels. On the other hand, plasma lipoprotein profiles were not changed by the administration. Immunohistochemical analyses indicated reductions in VCAM-1, MCP-1, and Mac-2 protein expression levels in the plaque. These results suggest that BAIBA administration suppresses atherosclerosis progression without changing plasma lipoprotein profiles. We propose that the mechanisms of this suppression are reductions in both VCAM-1 and MCP-1 expression as well as macrophage infiltration into the plaque.
Assuntos
Ácidos Aminoisobutíricos/uso terapêutico , Aterosclerose/tratamento farmacológico , Ácidos Aminoisobutíricos/sangue , Ácidos Aminoisobutíricos/farmacocinética , Ácidos Aminoisobutíricos/farmacologia , Animais , Valva Aórtica/efeitos dos fármacos , Valva Aórtica/patologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Quimiocina CCL2/metabolismo , Galectina 3/metabolismo , Lipídeos/sangue , Camundongos Knockout para ApoE , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Over 3 million paediatric patients globally and ~50 000 in the United States are estimated to be infected with HCV. Eradicating HCV in children helps prevent liver fibrosis, cirrhosis and hepatocellular carcinoma; reduces extra-hepatic manifestations of HCV; improves quality of life; and increases survival. The 2019 American Association for the Study of Liver Diseases-Infectious Diseases Society of America (AASLD-IDSA) guidelines now recommend direct-acting antiviral (DAA) treatment with an approved regimen for all children and adolescents with HCV infection aged ≥3 years. We conducted a descriptive review of the new DAA treatments for HCV infection in the paediatric population. Ledipasvir/sofosbuvir (LDV/SOF) and sofosbuvir with ribavirin (SOF/RBV) are now approved for those ≥3 years old under specific clinical scenarios; sofosbuvir/velpatasvir (SOF/VEL) is the only pangenotypic agent approved for those ≥6 years or ≥17 kg, and glecaprevir/pibrentasvir (GLE/PIB) is approved for adolescents ≥12 years old or ≥45 kg. These DAA regimens are well-tolerated and have comparable sustained virologic response rates at 12 weeks post-treatment compared to those reported in adults (close to 100%). The introduction of DAAs has significantly changed the landscape of HCV treatment in adults and children with HCV infection and has increased confidence that the 2030 World Health Organization elimination goal may be attainable. Further studies are warranted to determine the optimal treatment for children with HCV infection, including timing, regimen and duration. Additionally, with the recent paediatric approvals, long-term safety data are needed.
Assuntos
Antivirais , Hepatite C , Pediatria , Adolescente , Adulto , Ácidos Aminoisobutíricos/uso terapêutico , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Criança , Pré-Escolar , Ciclopropanos/uso terapêutico , Erradicação de Doenças , Quimioterapia Combinada , Fluorenos/uso terapêutico , Genótipo , Hepacivirus , Hepatite C/tratamento farmacológico , Hepatite C/prevenção & controle , Humanos , Lactamas Macrocíclicas/uso terapêutico , Leucina/análogos & derivados , Leucina/uso terapêutico , Prolina/análogos & derivados , Prolina/uso terapêutico , Pirrolidinas/uso terapêutico , Qualidade de Vida , Quinoxalinas/uso terapêutico , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Resposta Viral Sustentada , Resultado do Tratamento , Organização Mundial da SaúdeRESUMO
Data on direct-acting antiviral agent (DAA) treatment for mixed genotype hepatitis C virus (HCV) infection are scant. This study examined the effectiveness of glecaprevir/pibrentasvir (GLE/PIB) and ledipasvir/sofosbuvir (LDV/SOF) for mixed HCV genotype infection in a real-world setting in Taiwan. We analysed the data from all patients with mixed HCV genotype infections treated with GLE/PIB or LDV/SOF from 2017 to 2019 in three Chang Gung Memorial Hospitals in Taiwan. The primary treatment outcome was sustained virologic response 12 weeks after treatment cessation (SVR12). Adverse events (AEs) were also evaluated. A total of 5190 HCV patients received DAA treatment during this time period. Among them, 116 patients (2.2%) had mixed infections of any 2 or 3 genotypes of 1a, 1b, 2, 3 and 6. Fifty-four patients received GLE/PIB and 62 received LDV/SOF. SVR12 rates for LDV/SOF vs GLE/PIB therapy were 96.6% (56/58) vs 100% (51/51) by the per-protocol analysis and 90.3% (56/62) vs 94.4% (51/54) by the evaluable population analysis. Two patients with 1b + 6 and 1b + 2 genotype infections in the LDV/SOF group had relapse. Evaluating the GLE/PIB vs LDV/SOF groups for the most common AEs revealed pruritus (16.7% vs 4.8%), abdominal discomfort (5.6% vs 8%) and fatigue (5.6% vs 4.8%). One patient with AE-related treatment discontinuation presented with liver decompensation after 4-week GLE/PIB therapy. DAA-related significant laboratory abnormalities occurred in two patients with >3× elevated bilirubin level in the GLE/PIB group. GLE/PIB and LDV/SOF are well tolerated and achieve high SVR12 rates for patients with mixed HCV genotype infection.
Assuntos
Antivirais , Hepatite C Crônica , Hepatite C , Ácidos Aminoisobutíricos/uso terapêutico , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Ciclopropanos/uso terapêutico , Fluorenos/uso terapêutico , Genótipo , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Humanos , Lactamas Macrocíclicas/uso terapêutico , Leucina/análogos & derivados , Leucina/uso terapêutico , Prolina/análogos & derivados , Prolina/uso terapêutico , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Resposta Viral Sustentada , TaiwanAssuntos
Ácidos Aminoisobutíricos/uso terapêutico , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Ciclopropanos/uso terapêutico , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Lactamas Macrocíclicas/uso terapêutico , Leucina/análogos & derivados , Prolina/análogos & derivados , Quinoxalinas/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Quimioterapia Combinada , Genótipo , Hepacivirus/efeitos dos fármacos , Hepatite C/diagnóstico , Hepatite C/virologia , Humanos , Leucina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prolina/uso terapêutico , Pirrolidinas , Resultado do TratamentoRESUMO
Data are limited regarding the real-world effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) in patients with chronic hepatitis C virus (HCV) infection and severe renal impairment (RI). We aimed to evaluate the performance of GLE/PIB in patients with chronic kidney disease (CKD) stage 4 or 5 in Taiwan. 108 chronic HCV patients with CKD stage 4 (n = 32) or 5 (n = 76) receiving GLE/PIB for 8-12 weeks were retrospectively recruited at 4 academic centres in Taiwan. The effectiveness was determined by sustained virologic response at off-therapy week 12 (SVR12 ) for evaluable (EP) and per-protocol populations (PP). The safety profiles were also assessed. By EP and PP analyses, the SVR12 rate was 99.1% (107 of 108 patients; 95% confidence interval (CI): 94.9%-99.8%) and 100% (107 of 107 patients; 95% CI: 96.5%-100%). The SVR12 rates were 100% (95% CI: 89.3%-100%) and 98.7% (95% CI: 92.9%-99.8%) in patients with CKD stage 4 and 5, respectively. One patient, who declined off-therapy follow-up after permanently discontinuing GLE/PIB at on-treatment week 9 due to scheduled cardiac surgery, had nonvirologic failure. Sixteen (14.8%) patients had serious adverse events (AEs), which were judged not related to GLE/PIB. The three most common AEs were pruritus (19.4%), fatigue (15.7%) and nausea (13.9%). None had ≥3-fold upper limit of normal for total bilirubin and alanine aminotransferase levels. None of the 9 patients with hepatitis B virus (HBV) coinfection developed HBV-associated hepatitis. In conclusion, GLE/PIB for 8-12 weeks is effective and well-tolerated in HCV patients with severe RI.
Assuntos
Ácidos Aminoisobutíricos/uso terapêutico , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Ciclopropanos/uso terapêutico , Hepatite C Crônica , Lactamas Macrocíclicas/uso terapêutico , Leucina/análogos & derivados , Prolina/análogos & derivados , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , Insuficiência Renal Crônica/complicações , Sulfonamidas/uso terapêutico , Genótipo , Hepacivirus , Hepatite C Crônica/tratamento farmacológico , Humanos , Leucina/uso terapêutico , Prolina/uso terapêutico , Estudos Retrospectivos , Resposta Viral Sustentada , TaiwanRESUMO
NS5A-P32 deletion (P32del) is a resistance-associated amino acid change that has recently gained popularity in direct-acting antiviral treatment for chronic hepatitis C. Although not yet detected in naive patients, it appears in 5 to 10% of hepatitis C genotype 1b patients who fail to respond to daclatasvir/asunaprevir and sofosbuvir/ledipasvir treatments. In contrast to signature resistance-associated substitutions, such as substitutions at the NS5A-L31 and NS5A-Y93 positions, it shows complete resistance to all NS5A inhibitors in replicon and cell culture. Studies of humanized liver mice suggest that P32del retains good replication fitness and requires two classes of antivirals, except NS5A inhibitors, to be suppressed effectively. Patients with the P32del virus do not respond to glecaprevir/pibrentasvir but do respond to sofosbuvir/velpatasvir/voxilaprevir, presumably to sofosbuvir + glecaprevir/pibrentasvir, and at least partially to sofosbuvir/velpatasvir + ribavirin. Attention should be given to P32del in patients who experience failure with any NS5A inhibitor, especially those with genotype 1b infection.
Assuntos
Hepatite C Crônica , Hepatite C , Humanos , Animais , Camundongos , Sofosbuvir/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Ácidos Aminoisobutíricos/farmacologia , Ácidos Aminoisobutíricos/uso terapêutico , GenótipoAssuntos
Ácidos Aminoisobutíricos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Benzimidazóis/uso terapêutico , Doença de Crohn/tratamento farmacológico , Ciclopropanos/uso terapêutico , Hepatite C/complicações , Lactamas Macrocíclicas/uso terapêutico , Leucina/análogos & derivados , Porfiria Cutânea Tardia/virologia , Prolina/análogos & derivados , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Doença de Crohn/complicações , Fármacos Gastrointestinais/uso terapêutico , Hepatite C/tratamento farmacológico , Humanos , Leucina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Porfiria Cutânea Tardia/tratamento farmacológico , Prolina/uso terapêutico , PirrolidinasRESUMO
Hyperlipidemia is often associated with obesity and diabetes, and can lead to serious complications like atherosclerosis and fatty liver disease. Coagonist of GLP-1 and glucagon receptors is a therapy under clinical investigation for treatment of obesity and diabetes. In this study, we have characterized the mechanism of hypolipidemic effect of a balanced coagonist using high cholesterol-fed hamsters. Tyloxapol-induced hypertriglyceridemia, lipolysis in adipose tissue, and bile homeostasis were assessed after repeated dose treatment of the coagonist of GLP-1 and glucagon receptors (Aib2 C24 chimera 2, SC). Antagonists of GLP-1, glucagon, and FGF21 receptors were coadministered, and FGF21 sensitivity was determined in liver and adipose tissue. Repeated dose treatment of coagonist reduced cholesterol and increased FGF21 in blood and liver. Coagonist treatment reduced hepatic triglyceride secretion, increased lipolysis and reduced body weight. Antagonism of GLP-1 and glucagon receptors partially blocked the effect of the coagonist on lipid metabolism in circulation and liver, while FGF21 receptor antagonist completely abolished it. Glucagon and GLP-1 receptors antagonists blocked the action of coagonist on cholesterol excretion and bile flow in liver, but FGF21 antagonist was not effective. Treatment with the coagonist increased expression of FGF21, FGF21R and cofactor ßKlotho in liver and adipose. In conclusion, coagonist of GLP-1 and glucagon receptors improved lipid metabolism in liver of dyslipidemic hamsters. This effect is partially mediated by GLP-1 and glucagon receptors, and the improved FGF21 sensitivity could be the mechanism of hypolipidemic action of the coagonist of GLP-1/glucagon receptors.