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1.
Medicine (Baltimore) ; 99(6): e18948, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32028404

RESUMO

The effectiveness of direct-acting antivirals (DAAs) against hepatitis C virus (HCV) infection is ascertained. However, some authors raised the issue of an increased incidence of de novo hepatocellular carcinoma (HCC) in patients treated with DAAs. Aim of the study was to evaluate the rate of HCC occurrence in a real-life cohort of patients who received anti-HCV treatment with DAAs.A prospective multicentre study was conducted. All adult patients with HCV infection who received treatment between March 2015 and December 2017 in 4 hospital of Campania region (South Italy) with at least 6 months of follow-up were enrolled.A total of 323 patients were included in the study. Most patients had HCV genotype 1b (61.8%). The overall SVR12 rate was 95.5%. Median time of observation was 10 months. The incidence rate of HCC was 0.2 per 100 person-months (crude incidence rate 3.4%, 95 confidence interval: 1.5%-5.3%). The median time for HCC occurrence was 11 months. HCC occurrence rate was significantly higher among patients who did not achieve SVR12 compared with patients who did (28.6% vs 2.8%, P < 0.05). No patient with F0-F3 fibrosis developed HCC. Among patients with cirrhosis, at the multivariate time-to-event analysis, no covariates were independently associated with the risk of HCC occurrence.Treatment with DAAs did not increase the risk of HCC occurrence. Patients who achieved SVR12 had a lower rate of HCC occurrence. Further studies are needed to estimate the incidence and the risk for HCC in the long-term follow-up among patients undergoing treatment with DAAs.


Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/epidemiologia , Hepatite C Crônica/tratamento farmacológico , Neoplasias Hepáticas/epidemiologia , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/prevenção & controle , Estudos de Coortes , Feminino , Humanos , Incidência , Itália/epidemiologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/prevenção & controle , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Sobrevida
2.
Expert Opin Pharmacother ; 21(3): 261-273, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31914336

RESUMO

Introduction: Hepatitis C virus (HCV) is estimated to infect approximately 70 million people worldwide. If left untreated, chronic infection can progress to cirrhosis, liver failure or hepatocellular carcinoma. The advent of new direct-acting antivirals (DAA) has revolutionized patients' chances of treatment and viral elimination. Currently, several DAA options are available on the market.Areas covered: This review focuses on the pharmacokinetics, efficacy, tolerability and safety profile of DCV-TRIO, a twice-daily fixed-dose combination of daclatasvir, asunaprevir and beclabuvir approved in Japan for the treatment of genotype 1 HCV infection.Expert opinion: The DCV-TRIO combination achieved good response rates in genotype 1 patients (SVR12 ≥ 95% in naïve subtype 1b), independently from IL28B genotype, cirrhotic status and prior interferon exposure. On the other hand, unsatisfying response rates were reported in DAA-experienced patients and the risk of RAS selection should not be underestimated. Moreover, DCV-TRIO lacks differentiation from its earlier-launched DAA rivals, presents an inconvenient twice-daily dosing schedule and is not recommended in patients with advanced liver and kidney disease. All these drawbacks considerably limit its effective commercial potential. However, it can be a therapeutic option against HCV in tailored approaches according to the needs of different markets across the world.Abbreviations AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ASV: asunaprevir; AUC: area under the curve; BCRP: Breast Cancer Resistance Protein; BCV: boceprevir; BID: bis in die; CI: confidence intervals; CLcr: creatinine clearance; DAA: direct acting antivirals; DCV: daclatasvir; EC50: Half maximal effective concentration; GT: genotype; HCV: Hepatitis C virus; IFN: Interferon; NHL: non-Hodgkin lymphoma; OATP: Organic anion transporting polypeptides; OR: odds ratio; P-gp: P-glycoprotein; PK: pharmacokinetics; QD: quo die; RAS: resistance-associated substitutions; SVR: sustained virological response; USD: Unites States dollar.


Assuntos
Benzazepinas/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Imidazóis/administração & dosagem , Indóis/administração & dosagem , Isoquinolinas/administração & dosagem , Sulfonamidas/administração & dosagem , Antivirais/uso terapêutico , Combinação de Medicamentos , Genótipo , Hepacivirus/efeitos dos fármacos , Humanos , Cirrose Hepática/prevenção & controle , Resposta Viral Sustentada , Comprimidos , Resultado do Tratamento
3.
Arq Gastroenterol ; 56(4): 394-398, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31800735

RESUMO

BACKGROUND: In recent years the management of hepatitis C virus infection and the possibility of its eradication have been researched due to the importance that they represent in the health of the world population. Obtaining data that help to cope with this pathology improves the quality of life of those affected by it. The present study evaluated the effectiveness of direct-acting antiviral therapies provided by the Brazilian Ministry of Health in accordance to the Clinical Protocol and Therapeutic Guidelines of 2015. OBJECTIVE: To evaluate the epidemiological profile of patients with chronic hepatitis C and the rate of sustained virologic response using direct-acting antivirals of all individuals that attended the referral service for the treatment of chronic hepatitis C at the Hospital of the Federal University of Rio Grande. METHODS: This was an observational, retrospective/prospective study with all patients with chronic hepatitis C who had their treatments available from December 2015 to August 2017 according to the criteria of the Clinical Protocol and Therapeutic Guidelines of 2015. In the first phase, the clinical and demographic variables of all individuals enrolled in a treatment for hepatitis C were selected and collected from the Reference Service database. In the second phase, treatment data were collected. The outcome variable, sustained virologic response, was defined as an undetectable viral load on the blood test three months after the end of treatment. The descriptive and bivariate analyzes were performed with Pearson's chi-square and Fisher's Exact test, adopting a P value ≤0.05 in the SPSS 20 software. RESULTS: Of the 252 participants in the study, 228 (90.5%) had a sustained virologic response, 55.2% were male with an average age of 58.6 years (SD±9.1). Genotype 1 was the most prevalent, observed in 54.4% of the participants, and 87.4% of the patients had moderate/advanced hepatic fibrosis. After the statistical analysis, it was observed that the individuals with genotype 3 and moderate/advanced hepatic fibrosis had lower sustained virologic response rate (P=0.05 and P=0.04, respectively). CONCLUSION: It was observed that the use of direct-acting antivirals, in comparison to previous therapeutic regimens, increases the sustained virologic response, reaching all patients with mild fibrosis. This study provides information that helps in the hepatitis C treatment by showing that prescribing early treatment for patients without hepatic fibrosis and/or genotype 3 virus could increase therapeutic effectiveness.


Assuntos
Antivirais/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Resposta Viral Sustentada , Idoso , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Estudos Retrospectivos , Resultado do Tratamento , Carga Viral
4.
Vnitr Lek ; 65(9): 553-563, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31635466

RESUMO

The treatment of chronic hepatitis C is currently based exclusively on the use of drugs from the direct-acting anti-viral class. They are substances that inhibit one of the 3 most important enzymes of the virus replication cycle. Anti-viral drugs are divided according to the target structure into 3 basic classes, further division is mainly based on the chemical structure of individual antivirals. A common feature of all the regimens is high efficiency and safety. Pangenotypic efficacy regimens are those that utilize a combination of 2 or 3 antiviral agents of different classes, and are effective for all HCV genotypes. Currently there are 3 such regimens available. Pangenotypic regimens probably represent the latest stage of development of treatment for chronic hepatitis C. The review discusses in detail the efficiency of different pangenotypic regimens in individual subgroups of patients with HCV infection. Atten-tion is primarily paid to the data bases for their use.


Assuntos
Antivirais , Hepacivirus , Hepatite C Crônica , Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Humanos
5.
BMC Infect Dis ; 19(1): 882, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640579

RESUMO

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) requires lengthy use of second-line drugs, burdened by many side effects. Hepatitis C virus (HCV) chronic infection increases risk of drug-induced liver injury (DILI) in these patients. Data on MDR-TB patients with concurrent HCV chronic infection treated at the same time with second-line antitubercular drugs and new direct-acting antivirals (DAAs) are lacking. We evaluate if treating at the same time HCV infection and pulmonary MDR-TB is feasible and effective. CASES PRESENTATION: In this study, we described two cases of patients with pulmonary MDR-TB and concurrent HCV chronic infection cured with DAAs at a Tertiary Infectious Diseases Hospital in Italy. During antitubercular treatment, both patients experienced a DILI before treating HCV infection. After DAAs liver enzymes normalized and HCV RNA was undetectable. Then antitubercular regimen was started according to the institutional protocol, drawn up following WHO MDR-TB guidelines. It was completed without further liver side effects and patients were declared cured from both HCV infection and MDR-TB. CONCLUSIONS: We suggest to consider treatment of chronic hepatitis C with DAAs as a useful intervention for reintroduction of second-line antitubercular agents in those patients who developed DILI, reducing the risk of treatment interruption when re-exposed to these drugs.


Assuntos
Antituberculosos/uso terapêutico , Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Idoso , Antituberculosos/efeitos adversos , Antivirais/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Feminino , Hepacivirus/genética , Humanos , Itália , Masculino , RNA Viral/sangue , Retratamento , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/virologia , Tuberculose Pulmonar/virologia
6.
Transplant Proc ; 51(9): 2958-2961, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31629537

RESUMO

Taking charge of a liver transplanted (LT) patient implies not only to follow up the transplanted organ (eg, immunosuppression and cancer risk) but also to deal with the prevailing patient's active problems. The recurrence of hepatitis C on the graft has historically been one of the main active problems to be addressed, leading to 30% to 40% mortality per se in these patients and has involved many resources in the hepatological centers responsible for the follow-up. We verified how much the availability of the new drugs with direct-acting antiviral agents (DAAs) against hepatitis C virus (HCV) has impacted the mortality within the assisted population, changing its characteristics and addressing new clinical issues in the LT-patients. We performed a retrospective comparison between 230 LT patients followed up during pre-DAA era (group 1, with 88 HCV RNA-positive) and 244 patients observed from 2014 onward when DAAs became available (group 2, with 79 HCV RNA-positive). Fifty-two antiviral therapies were performed in group 1 with 18 sustained virologic response (SVR) (35%) and 53 treatments, of which 37 were retreatments, in group 2 with 51 SVR (96%), P = .0001. Deaths for HCV-related causes were 19 of 33 (57%) in group 1 and 7 of 24 (24%) in group 2, P = .01. The Kaplan-Meier showed a dramatic reduction in excess mortality in HCV-LT patients after the availability of DAAs. These results suggest that HCV is no longer the main active problem of follow-up in liver transplants, therefore the resources can be relocated to take care of other clinical aspects.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Transplante de Fígado , Resposta Viral Sustentada , Feminino , Seguimentos , Hepacivirus , Hepatite C Crônica/mortalidade , Humanos , Transplante de Fígado/mortalidade , Masculino , Estudos Retrospectivos
7.
West Afr J Med ; 36(3): 280-282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31622492

RESUMO

The advent of direct-acting anti-virals revolutionized the treatment and prognosis of patients infected with hepatitis C. The interest of this presentation is to draw attention to the issue of therapeutic management posed by the hepatitis C virus in a kidney graft in Côte d'Ivoire, a resource-limited country where all the direct-acting anti-virals are not yet available. We report the case of a kidney transplant of 52 years old, chronic carrier of viral hepatitis C who presented after his kidney transplant in decompensated active cirrhosis. A treatment based on Sofosbuvir 400 mg/Ledipasvir 90 mg in this patient with genotype 2 for 12 weeks was initiated. Sustained virologic response 12 weeks and 24 weeks off therapy was observed. This is the first documented case of successful treatment of a genotype 2 viral C infection based on Sofosbuvir/Ledipasvir in a black African cirrhotic kidney transplant patient undergoing immunosuppressive therapy.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepacivirus/isolamento & purificação , Hepatite C Crônica/tratamento farmacológico , Transplante de Rim , Sofosbuvir/uso terapêutico , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Quimioterapia Combinada , Fluorenos/efeitos adversos , Genótipo , Hepacivirus/genética , Hepatite C Crônica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Sofosbuvir/efeitos adversos , Resultado do Tratamento
8.
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
9.
Medicine (Baltimore) ; 98(39): e17343, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574875

RESUMO

RATIONALE: Glecaprevir/pibrentasvir, a pan-genotypic and ribavirin-free direct acting antiviral agent regimen, has shown significant efficacy and very few serious complications. However, as the drug metabolizes in the liver, it is not recommended in patients with decompensated liver cirrhosis. Herein, we report the case of a patient with compensated liver cirrhosis who developed severe jaundice after glecaprevir/pibrentasvir medication. PATIENT CONCERNS: A 77-year-old man diagnosed with chronic hepatitis C-related compensated liver cirrhosis visited hospital due to severe jaundice after 12 weeks of glecaprevir/pibrentasvir medication. DIAGNOSES: On the laboratory work-up, the total/direct bilirubin level was markedly elevated to 21.56/11.68 from 1.81 mg/dL; the alanine aminotransferase and aspartate aminotransferase levels were within the normal range. We checked the plasma drug concentration level of glecaprevir, and 18,500 ng/mL was detected, which was more than 15 times higher than the drug concentration level verified in normal healthy adults. INTERVENTIONS: Glecaprevir/pibrentasvir was abruptly stopped and after 6 days, the drug concentration level decreased to 35 ng/mL and the serum total/direct bilirubin decreased to 7.49/4.06 mg/dL. OUTCOMES: Three months after drug cessation, the serum total bilirubin level normalized to 1.21 mg/dL and HCV RNA was not detected. LESSONS: We report what is likely the first known case of severe jaundice after medication with glecaprevir/pibrentasvir in a patient with compensated liver cirrhosis. Clinicians should bear potential hyperbilirubinemia in mind when treating chronic hepatitis C with this regimen and should monitor the patient closely during follow-up laboratory exams, especially in elderly cirrhotic patients.


Assuntos
Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Hepatite C Crônica/tratamento farmacológico , Hiperbilirrubinemia/induzido quimicamente , Cirrose Hepática/induzido quimicamente , Pirrolidinas/efeitos adversos , Quinoxalinas/efeitos adversos , Sulfonamidas/efeitos adversos , Idoso , Doença Hepática Induzida por Substâncias e Drogas/virologia , Combinação de Medicamentos , Humanos , Hiperbilirrubinemia/virologia , Fígado/efeitos dos fármacos , Fígado/virologia , Cirrose Hepática/virologia , Masculino
10.
Orv Hetil ; 160(40): 1591-1602, 2019 Oct.
Artigo em Húngaro | MEDLINE | ID: mdl-31565976

RESUMO

Introduction: Liver cirrhosis (20-25%), hepatocellular carcinoma (1.5-3%), insulin resistance (30-40%) and type 2 diabetes (25-30%) are common complications in patients with chronic hepatitis C virus (HCV) infection; however, data are missing from Hungary. Aim: To determine the prevalence of diabetes and insulin resistance in Hungarian HCV patients; to evaluate treatment-induced metabolic changes in relation to diabetes/insulin resistance and virological response and to perform a sustained follow-up for hepatocellular carcinoma detection. Method: We enrolled 150 Hungarian HCV genotype 1 patients (mean age: 48.55 ± 8.55 years, male/female ratio: 45/55%) from 2007-2012. We analysed their baseline, week 12, and end of therapeutic follow-up (24 weeks after interferon-based therapy completion) laboratory data. We performed a 5-year follow-up (2012-2017). Results: The prevalence of insulin sensitivity, insulin resistance and diabetes was 37.4%, 35.3% and 27.3%, respectively. Insulin resistant and diabetic patients showed a decrease in fasting glucose from baseline to end of follow-up (5.47 ± 0.66 vs. 5.08 ± 0.60, p<0.001; 7.90 ± 2.67 vs. 7.04 ± 2.75, p = 0.006), as did both the sustained responder and non-responder groups. Treatment efficacy rate was poor in diabetic vs. insulin sensitive and insulin resistant groups (17% vs. 46% and 40%); insulin sensitivity was not a predictor of virological response. Three participants with diabetes were diagnosed with hepatocellular carcinoma during follow-up by regular ultrasound examinations. Conclusion: Hungarian HCV patients showed high prevalence of diabetes and insulin resistance, though antiviral therapy caused favourable changes in their carbohydrate metabolism. Antiviral therapy was less effective in diabetic patients. Follow-up ultrasound examinations are required for hepatocellular carcinoma in HCV patients, especially those with diabetes. Orv Hetil. 2019; 160(40): 1591-1602.


Assuntos
Antivirais/uso terapêutico , Glicemia/metabolismo , Carcinoma Hepatocelular/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/terapia , Resistência à Insulina , Neoplasias Hepáticas/complicações , Adulto , Idoso , Complicações do Diabetes/terapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Hungria/epidemiologia , Cirrose Hepática/complicações , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência
11.
Biochemistry (Mosc) ; 84(8): 941-953, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31522676

RESUMO

Transforming growth factor beta (TGF-ß) acts as a tumor-suppressing cytokine in healthy tissues and non-malignant tumors. Yet, in malignancy, TGF-ß can exert the opposite effects that can promote proliferation of cancer cells. C-Kit plays a prominent role in stem cell activation and liver regeneration after injury. However, little is known about the cross-talk between TGF-ß and C-Kit and its role in the progression of hepatocellular carcinoma (HCC). Here, we studied the effect of increasing doses of TGF-ß1 on CD44+CD90+ liver stem cells (LSCs) and C-Kit gene expression in malignant and adjacent non-malignant liver tissues excised from 32 HCC patients. The percentage of LSCs in malignant tumors was two times higher compared to their counterparts from the non-malignant tissues. When treated with increasing doses of TGF-ß1, proliferation of both malignant and non-malignant LSCs was progressively suppressed, but low TGF-ß1 dose failed to suppress the growth of malignant LSCs. Moreover, C-Kit exons 9 and 11 were expressed in malignant LSCs, but not in their non-malignant counterparts. Analysis of C-Kit detected mutations in exon 9 (but not in exon 11) in some malignant liver cells resulting in the changes in the amino acid sequence and dysregulation of protein structure and function. Interestingly, in malignant liver cells, mutations in exon 9 were associated with high-viremia hepatitis C virus (HCV), and expression of this exon was not suppressed by the TGF-ß1 treatment at all doses. To our knowledge, this is the first report that mutations in the C-Kit gene in HCC patients are associated with high- viremia HCV. Our study emphasizes the need for investigation of the TGF-ß1 level and C-Kit mutations in patients with chronic HCV for HCC prevention and better therapy management.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Hepacivirus , Hepatite C Crônica/genética , Hepatite C Crônica/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteínas Proto-Oncogênicas c-kit/genética , Fator de Crescimento Transformador beta1/farmacologia , Idoso , Carcinoma Hepatocelular/etiologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Farmacorresistência Viral Múltipla , Éxons/genética , Feminino , Expressão Gênica , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Receptores de Hialuronatos/metabolismo , Fígado/patologia , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Células-Tronco Neoplásicas/metabolismo , Antígenos Thy-1/metabolismo , Viremia
12.
J Immunol Res ; 2019: 5878960, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31485460

RESUMO

Chemokine (C-X-C motif) ligand (CXCL)10 and other CXCR3 chemokines are involved in the pathogenesis of acute and "chronic hepatitis C virus (HCV) infection" (CHC). Here, we review the scientific literature about HCV and CXCL10. The combination of circulating CXCL10 and single nucleotide polymorphisms (SNPs) in IL-28B can identify patients with acute HCV infection most likely to undergo spontaneous HCV clearance and those in need of early antiviral therapy. In CHC, the HCV and intrahepatic interferon- (IFN-) γ drive a raised CXCL10 expression by sinusoidal endothelium and hepatocytes, thereby inducing the recruitment of CXCR3-expressing T cells into the liver; thus, CXCL10 plays an important role in the development of necroinflammation and fibrosis. Increased CXCL10 was significantly associated with the presence of active vasculitis in HCV-associated cryoglobulinemia, or with autoimmune thyroiditis in CHC. Pretreatment CXCL10 levels are predictive of early virological response and sustained virological response (SVR) to IFN-α and ribavirin and may be useful in the evaluation of candidates for therapy. The occurrence of SNPs adjacent to IL-28B (rs12979860, rs12980275, and rs8099917), and CXCL10 below 150 pg/mL, independently predicted the first phase viral decline and rapid virological response, which in turn independently predicted SVR. Directly acting antiviral agents-mediated clearance of HCV is associated with the loss of intrahepatic immune activation by IFN-α, associated by decreased levels of CXCL10. In conclusion, CXCL10 is an important marker of HCV clearance and successful therapy in CHC patients. Whether CXCL10 is a novel therapeutic target in CHC will be evaluated.


Assuntos
Quimiocina CXCL10/sangue , Hepatite C Crônica/imunologia , Doença Aguda , Antivirais/uso terapêutico , Quimiocina CXCL10/genética , Hepatite C/imunologia , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Humanos , Imunomodulação , Interferon-alfa/uso terapêutico , Interferon gama/uso terapêutico , Interferons/genética , Fígado/patologia , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptores CXCR3/imunologia , Ribavirina/uso terapêutico
13.
Gastroenterology ; 157(6): 1506-1517.e1, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31401140

RESUMO

BACKGROUND & AIMS: Treatment options are limited for patients with hepatitis C (HCV) infection with treatment failure after sofosbuvir plus an NS5A inhibitor. There are some data for the efficacy of glecaprevir/pibrentasvir (G/P) in these patients. We performed a randomized trial of the safety and efficacy of 12 and 16 weeks of G/P, with or without ribavirin, in patients with HCV genotype 1 infection with treatment failure after sofosbuvir and an NS5A inhibitor. METHODS: We performed a phase 3b, open-label study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor. Patients without cirrhosis were randomly assigned to groups that received G/P for 12 weeks (n = 78, group A) or 16 weeks (n = 49, group B). Patients with compensated cirrhosis were randomly assigned to groups that received G/P and ribavirin for 12 weeks (n = 21, group C) or G/P for 16 weeks (n = 29, group D). The primary end point was a sustained virologic response 12 weeks after treatment. Samples collected at baseline and at time of treatment failure were sequenced for resistance-associated substitutions in NS3 and NS5A. RESULTS: Of the 177 patients in the 4 groups, 81% were men, 79% had HCV genotype 1a infection, and 44% were black. Proportions of patients with sustained virologic response 12 weeks after treatment in groups A, B, C, and D were 90%, 94%, 86%, and 97%, respectively. The treatment failed in 13 (7.3%) patients with HCV genotype 1a infection, 6 (7.9%) in group A, 3 (6.1%) in group B, 3 (6.1%) in group C (6.1%), and 1 (3.4%) in group D. Most patients had baseline resistance-associated substitutions in NS5A. Treatment-emergent resistance-associated substitutions in NS3 and NS5A were observed in 9 and 10 patients with treatment failure, respectively. G/P was well tolerated. Ribavirin increased adverse events but did not increase efficacy. CONCLUSIONS: In a randomized study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor, 16 weeks treatment with G/P produced sustained virologic response 12 weeks after treatment in >90% of patients, including those with compensated cirrhosis. ClinicalTrials.gov, Number: NCT03092375.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/farmacologia , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Combinação de Medicamentos , Farmacorresistência Viral Múltipla/genética , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , Quinoxalinas/farmacologia , Quinoxalinas/uso terapêutico , Ribavirina/farmacologia , Ribavirina/uso terapêutico , Sofosbuvir/farmacologia , Sofosbuvir/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Resposta Viral Sustentada , Falha de Tratamento , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/genética
14.
Acta Med Indones ; 51(2): 128-136, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31383827

RESUMO

BACKGROUND: HIV infection in HCV-infected patients accelerates disease progression and reduces the success rate of Peg-IFN/RBV treatment. HCV mutation in NS5A-ISDR/PKR-BD region improved the outcome in HCV monoinfection treated with Peg-IFN/RBV. SNP-IL28B polymorphism is predicted to have an effect on HCV quasispecies evolution. However, the role of NS5A mutation and SNP IL-28B in HIV-HCV coinfection is still unclear. The aim of the study is to determine the role of HCV NS5A-ISDR/PKR-BD mutation and SNP IL-28 polymorphism on the successfulness of Peg-IFN/RBV therapy in HCV-HIV coinfection. METHODS: prospective cohort was performed in this study. Plasma sample were obtained from 30 and 8 patients with HCV-HIV coinfection and HCV monoinfection, respectively. PCR nucleotide sequencing was performed after RNA virus extraction and cDNA synthesis. Protein secondary structure and prediction of mutation function were analyzed using PredictProtein (PP) program. RESULTS: sixteen HCV-HIV coinfected patients and none from eight HCV patients achieved sustained virological response (SVR). ≥1 non-neutral mutation was found in 24/30 HCV-HIV coinfection and more frequent in SVR group (14 patients). ≥1 non-neutral mutation were found statistically significant for overall SVR achievement (p<0.05) in all patients regardless of coinfection or monoinfection status. Of the 27 HCV-HIV coinfected patients with CC-gene, 21 subjects had non-neutral mutation. The structure which was expected as NS5A binding site structure was different from consensus (wild type) in SVR group, while the structure was similar to consensus in non-SVR group. CONCLUSION: having ≥1 non-neutral mutation was associated with SVR achievement in Peg-IFN/RBV therapy, regardless of monoinfection and coinfection status.


Assuntos
Infecções por HIV/complicações , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Interferons/genética , Proteínas não Estruturais Virais/genética , Adulto , Antivirais/uso terapêutico , Coinfecção/tratamento farmacológico , Coinfecção/virologia , Quimioterapia Combinada , Feminino , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutação , Polietilenoglicóis , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Ribavirina/uso terapêutico , Resposta Viral Sustentada
15.
Pan Afr Med J ; 33: 26, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31384341

RESUMO

Introduction: approximately eighty million people around the world are living with hepatitis C, and 700,000 people die every year, due to hepatitis C related complications. In Seychelles, a total of 777 cases of hepatitis C were reported from 2002 to 2016, but up to mid of 2016, the cases were not being treated. Treatment with Harvoni, a combination of sofosbuvir and ledipasvir (SOF/LDV), is now being offered on the condition that the patient does not, or has stopped, injecting drugs. This paper is the first to establish the cost effectiveness of treating all cases of hepatitis C in Seychelles with Harvoni, as compared to no treatment. Methods: data extracted from literature was used to populate an economic model to calculate cost-effectiveness from Seychelles' government perspective. The model structure was also informed by the systematic review and an accompanying grading of economic models using the Consolidated Health Economic Evaluation Reporting Standard (CHEERS) checklist. A Markov model was developed, employing a lifetime horizon and costs and benefits were analysed from a payer's perspective and combined into incremental cost effectiveness ratios (ICERs). Results: the direct-acting antiviral (DAA), Harvoni, was found to be cost-saving in Seychelles hepatitis C virus (HCV) cohort, as compared to no treatment, with an ICER of € 753.65/QALY. The treatment was also cost-saving when stratified by gender, with the ICER of male and female being € 783.74/QALY and € 635.20/QALY, respectively. Moreover, the results obtained from acceptability curves showed that treating patients with Harvoni is the most cost-effective option, even for low thresholds. Conclusion: treating hepatitis C cases in Seychelles is cost-saving. It is worth developing a treatment programme to include all cases of hepatitis C, regardless of status of drug injection.


Assuntos
Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Fluorenos/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Uridina Monofosfato/análogos & derivados , Antivirais/economia , Benzimidazóis/economia , Análise Custo-Benefício , Feminino , Fluorenos/economia , Hepatite C Crônica/economia , Humanos , Masculino , Cadeias de Markov , Anos de Vida Ajustados por Qualidade de Vida , Fatores Sexuais , Seicheles , Abuso de Substâncias por Via Intravenosa/epidemiologia , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/economia
16.
Diabetes Metab Syndr ; 13(4): 2641-2646, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31405688

RESUMO

BACKGROUND AND OBJECTIVES: sustained virologic response (SVR) can be achieved in high percentage of HCV patients with the availability of direct acting antiviral agents DAAs. However, the effect of DAAs on insulin resistance and T2DM has yet to be clearly documented in spite of higher prevalence of T2DM in chronic HCV patients. This study tested the hypothesis that eradication of HCV is associated with either complete recovery or improvement of the symptoms of IR and T2DM. PATIENTS AND METHODS: In our study 240 Chronic HCV patients candidate to centers of NCCVH with Coordination to departments of internal medicine and clinical pathology, Zagzig University for treatment with DAAs. Measurement of HbA1c, FPG and fasting insulin hormone and calculation of HOMA-IR before and 3 months after DDAs therapy is done. Statistical analysis was done for these data. RESULTS: After SVR; HbA1c decreased from 7.6 ±â€¯0.69 to 6.7 ±â€¯0.78 in diabetic group and from 5.8 ±â€¯0.5 to 5.1 ±â€¯0.3 in non-diabetic group, with decreased in the percentage of uncontrolled T2DM patients from 22.4% to 5.2% after treatment. HOMA-IR decreased in diabetic group from 4.9 ±â€¯0.7 to 3.7 ±â€¯0.75 and in non-diabetic group from 3.1 ±â€¯0.56 to 2.3 ±â€¯0.4 with complete improvement of IR to ≤2.5 in 20.7% of diabetic patients. 20% of diabetic patient needed to decrease oral hypoglycemic dose and 13.3% of them needed to decrease insulin dose. CONCLUSIONS: This study shows that eradication of HCV by DAAs will result in a parallel decrease in IR and improve clinical outcomes in patients with established T2DM.


Assuntos
Antivirais/uso terapêutico , Diabetes Mellitus Tipo 2/prevenção & controle , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Resistência à Insulina , Adolescente , Adulto , Idoso , Biomarcadores/análise , Glicemia/análise , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/virologia , Egito/epidemiologia , Feminino , Seguimentos , Hemoglobina A Glicada/análise , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Adulto Jovem
17.
Expert Rev Gastroenterol Hepatol ; 13(9): 839-848, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31392907

RESUMO

Introduction: Over 70 million people are infected with hepatitis C virus (HCV), increasing the risk of cirrhosis and hepatocellular carcinoma. Areas covered: Since the approval of the first interferon-free direct-acting antiviral (DAA) therapy in 2011, a number of DAAs have been approved, and HCV is now considered curable. Until recently, however, there were no clear guidelines on how to re-treat patients who fail DAA therapy. Current protease inhibitors (PIs) are generally unaffected by earlier resistance-associated variants (RAVs), but many NS5A inhibitors continue to have overlapping resistance profiles, and NS5A RAVs can persist even in the absence of DAAs. Expert opinion: Fortunately, RAVs affecting NS5B polymerase inhibitors are rare, making sofosbuvir a safe choice as the backbone of re-treatment therapies. Recent re-treatment guidelines that take into account genotype, fibrosis, treatment history, and RAV suggest that >90% of patients with prior treatment failures can be successfully re-treated with sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir or glecaprevir/pibrentasvir.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Antivirais/efeitos adversos , Humanos , Falha de Tratamento
18.
BMJ Case Rep ; 12(7)2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31352386

RESUMO

In the USA, mortality associated with hepatocellular carcinoma (HCC) continues to rise. Globally, HCC is the third most common cause of cancer-related death. In early stages of HCC, hepatic resection or liver transplantation are the preferred treatment options with a high probability of recurrence-free postoperative course. However, ineffective screening of chronic liver diseases in high-risk populations, poor linkage to care and suboptimal HCC surveillance has led to increasing rates of late-stage HCC at clinical presentation or diagnosis amenable only to palliative and experimental treatment options. Our case is a 66-year-old man with chronic hepatitis C virus infection complicated by cirrhosis and inoperable HCC which was non-responsive to selective intrahepatic trans-arterial chemoembolisation by interventional radiology. Therefore, he was treated with nivolumab immunotherapy and demonstrated normalisation of previously elevated alpha-fetoprotein levels suggestive of at least a partial response to immunotherapy. No adverse events related to nivolumab immunotherapy were encountered.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Imunoterapia , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , alfa-Fetoproteínas/efeitos dos fármacos , Idoso , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Hepatite C Crônica/imunologia , Hepatite C Crônica/patologia , Humanos , Fatores Imunológicos/uso terapêutico , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Masculino , Nivolumabe/uso terapêutico , Prognóstico , Resultado do Tratamento , alfa-Fetoproteínas/metabolismo
19.
J Formos Med Assoc ; 118(8): 1187-1192, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31279502

RESUMO

BACKGROUND: Glecaprevir/pibrentasvir (GLE/PIB) is a pangenotypic direct-acting antiviral agent for the treatment of chronic hepatitis C virus (HCV) infection. Real-world data of GLE/PIB in Asian patients other than Japanese are limited. We thus investigated the effectiveness and safety profile of GLE/PIB in Taiwanese patients with chronic hepatitis C (CHC). METHODS: CHC patients who received 8, 12, or 16 weeks of GLE/PIB between August and October of 2018 were consecutively enrolled. The treatment duration was determined according to drug label. The hepatic fibrosis was staged according to liver histology, transient elastography, fibrosis index based on 4 factors (FIB-4), or findings of ultrasonography/endoscopy. The primary endpoint was sustained virological response at week 12 off therapy (SVR12). The safety profiles were also assessed. RESULTS: A total of 110 CHC patients with 51% of males were enrolled. The median age was 70 years. A majority (82%) of patients were infected with HCV genotype 2. Forty-six (42%) and 64 (58%) patients had advanced hepatic fibrosis and compensated cirrhosis, respectively. Forty-five (41%) non-cirrhotic patients were treated for 8 weeks. The overall SVR12 rates were 100%, regardless of baseline clinical characteristics. The common adverse events (AEs) were pruritus (12%), anorexia (6%), and fatigue (5%). Nine (8%) serious AEs unrelated to GLE/PIB occurred. Three (2%) patients had Grade 3 elevation of total bilirubin level. None had premature treatment termination, hepatic decompensation, or death. CONCLUSION: Interferon-free GLE/PIB regimen is highly effective and safe for Asian chronic hepatitis C patients with advanced hepatic fibrosis or compensated cirrhosis.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/virologia , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Quimioterapia Combinada , Feminino , Hepacivirus/efeitos dos fármacos , Humanos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Quinoxalinas/efeitos adversos , Estudos Retrospectivos , Sulfonamidas/efeitos adversos , Resposta Viral Sustentada , Taiwan
20.
Medicine (Baltimore) ; 98(26): e16254, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261592

RESUMO

The aim of this study was to obtain real-world, US, observational data on the effect of baseline resistance-associated substitutions (RASs) on achieving sustained virologic response (SVR) in hepatitis C (HCV) patients treated with direct-acting antiviral (DAA) regimens; the need for long-term follow-up in post-SVR patients.It is uncertain if the presence of RASs limits efficacy to DAAs. Once SVR is achieved, society guidelines recommend long-term surveillance for hepatocellular carcinoma in certain patients. Real-world data are limited on these topics.Adult patients treated with DAAs at community hepatitis clinics between January 2015 and April 2017 were included in this study. Baseline resistance testing was performed before treatment. Per guidelines, post-SVR long-term monitoring was required in patients with F3 to F4 fibrosis before treatment or with elevated ALT levels (>19 U/L females; >30 U/L males).A total of 875 chronic, mostly GT1a (60%) HCV patients were treated with an approved DAA regimen. Average baseline AST and ALT were 75 and 67 U/L, respectively, and 47% had F3 to F4 fibrosis at baseline. SVR was achieved in 863 (98.6%) patients despite a high presence of baseline RASs (61%). Long-term monitoring was required post-SVR in 539 patients (62%).In a real-life, US cohort of HCV-infected patients, nearly all patients achieved SVR with available DAA regimens regardless of baseline RASs. Approximately two-thirds of these patients required long-term follow-up, despite viral eradication.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Farmacorresistência Viral , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vigilância da População , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
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