RESUMO
BACKGROUND & AIMS: Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are autoimmune liver diseases of unknown etiology. We studied trends in incidences of AIH, PBC, and PSC in a population-based prospective study Canterbury, New Zealand. METHODS: We collected data on patients with AIH (n = 99), PBC (n = 26), or PSC (n = 47) from public hospitals and private practices in Canterbury from 2008 through 2016. Diagnoses were made based on international standardized criteria. We calculated incidence rates for the time periods of 2008-2010, 2011-2013, and 2014-2016 and compared them using 2-tailed mid-P exact tests. RESULTS: Overall incidence rates were 1.93 per 100,000 for AIH (95% CI, 1.58-2.34), 0.51 per 100,000 for PBC (95% CI, 0.33-0.73), and 0.92 per 100,000 for PSC (95% CI, 0.68-1.21). The incidence of AIH was significantly higher during the period of 2014-2016 (2.39 per 100,000; 95% CI, 1.76-3.23) than during the period of 2008-2010 (1.37 per 100,000; 95% CI, 0.91- 2.06) (P < .05). Incidences of PBC and PSC did not change significantly. In 2016, prevalence values were 27.4 per 100,000 for AIH (95% CI, 23.58-32.0), 9.33 per 100,000 for PBC (95% CI, 7.13-12.05), and 13.17 per 100,000 for PSC (95% CI, 10.56-16.42). CONCLUSIONS: In a population-based prospective study, we found that the incidence of AIH was significantly higher in the 2014-2016 period than the 2008-2010 period; incidences of PBC and PSC were unchanged over the same period. Further studies are needed to determine the reasons for changes in incidence of autoimmune liver diseases.
Assuntos
Doenças Autoimunes , Colangite Esclerosante , Hepatite Autoimune , Cirrose Hepática Biliar , Hepatopatias , Hepatite Autoimune/epidemiologia , Humanos , Incidência , Estudos ProspectivosRESUMO
BACKGROUND: Effective treatment for hepatitis C virus (HCV) in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains an unmet medical need. METHODS: We conducted a multicenter, single-group, open-label study involving patients coinfected with HIV-1 and genotype 1 or 4 HCV receiving an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine, or raltegravir. All patients received ledipasvir, an NS5A inhibitor, and sofosbuvir, a nucleotide polymerase inhibitor, as a single fixed-dose combination for 12 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 335 patients enrolled, 34% were black, 55% had been previously treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had a sustained virologic response at 12 weeks after the end of therapy (95% confidence interval [CI], 93 to 98), including rates of 96% (95% CI, 93 to 98) in patients with HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, and 100% (95% CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were similar regardless of previous treatment or the presence of cirrhosis. Of the 13 patients who did not have a sustained virologic response, 10 had a relapse after the end of treatment. No patient had confirmed HIV-1 virologic rebound. The most common adverse events were headache (25%), fatigue (21%), and diarrhea (11%). No patient discontinued treatment because of adverse events. CONCLUSIONS: Ledipasvir and sofosbuvir for 12 weeks provided high rates of sustained virologic response in patients coinfected with HIV-1 and HCV genotype 1 or 4. (Funded by Gilead Sciences; ION-4 ClinicalTrials.gov number, NCT02073656.).
Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Infecções por HIV/complicações , HIV-1 , Hepacivirus , Hepatite C Crônica/tratamento farmacológico , Uridina Monofosfato/análogos & derivados , Antirretrovirais/uso terapêutico , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , Fluorenos/efeitos adversos , Fluorenos/farmacocinética , Genótipo , Infecções por HIV/tratamento farmacológico , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/complicações , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Sofosbuvir , Uridina Monofosfato/efeitos adversos , Uridina Monofosfato/farmacocinética , Uridina Monofosfato/uso terapêutico , Carga ViralRESUMO
BACKGROUND: In phase 2 trials, treatment with the combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir resulted in high rates of sustained virologic response in patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3. METHODS: We conducted two randomized, phase 3, open-label studies involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment, including patients with compensated cirrhosis. In one trial, patients with HCV genotype 2 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir, in a once-daily, fixed-dose combination tablet (134 patients), or sofosbuvir plus weight-based ribavirin (132 patients) for 12 weeks. In a second trial, patients with HCV genotype 3 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir for 12 weeks (277 patients) or sofosbuvir-ribavirin for 24 weeks (275 patients). The primary end point for the two trials was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Among patients with HCV genotype 2, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 99% (95% confidence interval [CI], 96 to 100), which was superior to the rate of 94% (95% CI, 88 to 97) in the sofosbuvir-ribavirin group (P=0.02). Among patients with HCV genotype 3, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 95% (95% CI, 92 to 98), which was superior to the rate of 80% (95% CI, 75 to 85) in the sofosbuvir-ribavirin group (P<0.001). The most common adverse events in the two studies were fatigue, headache, nausea, and insomnia. CONCLUSIONS: Among patients with HCV genotype 2 or 3 with or without previous treatment, including those with compensated cirrhosis, 12 weeks of treatment with sofosbuvir-velpatasvir resulted in rates of sustained virologic response that were superior to those with standard treatment with sofosbuvir-ribavirin. (Funded by Gilead Sciences; ASTRAL-2 ClinicalTrials.gov number, NCT02220998; and ASTRAL-3, NCT02201953.).
Assuntos
Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Sofosbuvir/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/efeitos adversos , Carbamatos/efeitos adversos , Combinação de Medicamentos , Farmacorresistência Viral , Feminino , Genótipo , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Sofosbuvir/efeitos adversos , Resultado do Tratamento , Proteínas não Estruturais Virais/antagonistas & inibidores , Adulto JovemRESUMO
BACKGROUND & AIMS: Patients with chronic hepatitis C virus (HCV) genotype 2 have high rates of response to treatment with sofosbuvir and ribavirin. However, ribavirin is associated with hemolytic events and is poorly tolerated by some patients. We evaluated the effectiveness of sofosbuvir and ledipasvir in treatment-naïve and treatment-experienced patients with HCV genotype 2, comparing 12 versus 8 weeks of treatment. METHODS: This Phase 2, open-label study included 2 cohorts in New Zealand. The first received a fixed-dose combination tablet of ledipasvir-sofosbuvir (90/400 mg) once daily for 12 weeks. If this cohort had a 90% rate of sustained virologic response (SVR) 4 weeks after treatment, a second cohort receiving 8 weeks of ledipasvir-sofosbuvir was to be enrolled. The primary endpoint in both cohorts was the percentage of patients with HCV RNA <15 IU/mL 12 weeks after therapy (SVR12). RESULTS: SVR12 rates were 96% (25/26; 95% CI, 80%-100%) for 12 weeks and 74% (20/27; 95% CI, 54%-89%) for 8 weeks of ledipasvir-sofosbuvir. The single patient receiving 12 weeks of ledipasvir-sofosbuvir who did not reach SVR12 did not complete treatment because of withdrawing consent after receiving 1 dose of study drug. Six of the 7 patients who did not reach SVR12 after 8 weeks of treatment experienced virologic relapse after stopping therapy. The most common adverse events were headache (26% of patients), fatigue (21%), and nausea (17%). No patients discontinued treatment because of an adverse event. CONCLUSIONS: For treatment-naïve and -experienced patients, ledipasvir-sofosbuvir for 12 weeks is highly effective for the treatment of HCV genotype 2 (ClinicalTrials.gov: NCT02202980).
Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Sofosbuvir/uso terapêutico , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Combinação de Medicamentos , Fadiga/induzido quimicamente , Feminino , Fluorenos/administração & dosagem , Fluorenos/efeitos adversos , Genótipo , Cefaleia/induzido quimicamente , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Sofosbuvir/administração & dosagem , Sofosbuvir/efeitos adversos , Resposta Viral SustentadaRESUMO
BACKGROUND & AIMS: Patients with chronic hepatitis C virus (HCV) infection have high rates of sustained virologic response (SVR) after 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor velpatasvir. We assessed the efficacy of 8 weeks of treatment with sofosbuvir and velpatasvir plus the pangenotypic NS3/4A protease inhibitor voxilaprevir (sofosbuvir-velpatasvir-voxilaprevir). METHODS: In 2 phase 3, open-label trials, patients with HCV infection who had not been treated previously with a direct-acting antiviral agent were assigned randomly to groups given sofosbuvir-velpatasvir-voxilaprevir for 8 weeks or sofosbuvir-velpatasvir for 12 weeks. POLARIS-2, which enrolled patients infected with all HCV genotypes with or without cirrhosis, except patients with genotype 3 and cirrhosis, was designed to test the noninferiority of 8 weeks of sofosbuvir-velpatasvir-voxilaprevir to 12 weeks of sofosbuvir-velpatasvir using a noninferiority margin of 5%. POLARIS-3, which enrolled patients infected with HCV genotype 3 who had cirrhosis, compared rates of SVR in both groups with a performance goal of 83%. RESULTS: In POLARIS-2, 95% (95% confidence interval [CI], 93%-97%) of patients had an SVR to 8 weeks of sofosbuvir-velpatasvir-voxilaprevir; this did not meet the criterion to establish noninferiority to 12 weeks of sofosbuvir-velpatasvir, which produced an SVR in 98% of patients (95% CI, 96%-99%; difference in the stratum-adjusted Mantel-Haenszel proportions of -3.2%; 95% CI, -6.0% to -0.4%). The difference in the efficacy was owing primarily to a lower rate of SVR (92%) among patients with HCV genotype 1a infection receiving 8 weeks of sofosbuvir-velpatasvir-voxilaprevir. In POLARIS-3, 96% of patients (95% CI, 91%-99%) achieved an SVR in both treatment groups, which was significantly superior to the performance goal. Overall, the most common adverse events were headache, fatigue, diarrhea, and nausea; diarrhea and nausea were reported more frequently by patients receiving voxilaprevir. In both trials, the proportion of patients who discontinued treatment because of adverse events was low (range, 0%-1%). CONCLUSIONS: In phase 3 trials of patients with HCV infection, we did not establish that sofosbuvir-velpatasvir-voxilaprevir for 8 weeks was noninferior to sofosbuvir-velpatasvir for 12 weeks, but the 2 regimens had similar rates of SVR in patients with HCV genotype 3 and cirrhosis. Mild gastrointestinal adverse events were associated with treatment regimens that included voxilaprevir. ClinicalTrials.gov numbers: POLARIS-2, NCT02607800; and POLARIS-3, NCT02639338.
Assuntos
Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Macrocíclicos/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácidos Aminoisobutíricos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Ciclopropanos , Quimioterapia Combinada , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prolina/análogos & derivados , Quinoxalinas , Sofosbuvir/administração & dosagem , Sofosbuvir/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resposta Viral Sustentada , Adulto JovemRESUMO
The optimal retreatment strategy for patients chronically infected with hepatitis C virus who experience virologic failure after treatment with direct-acting antiviral-based therapies remains unclear. In this multicenter, open-label, phase 2 study, we evaluated the efficacy and safety of a fixed-dose combination of sofosbuvir-velpatasvir (400 mg/100 mg) plus weight-adjusted ribavirin administered for 24 weeks in patients who did not achieve sustained virologic response after prior treatment with direct-acting antiviral regimens that included the nucleotide analogue nonstructural protein 5B inhibitor sofosbuvir plus the nonstructural protein 5A inhibitor velpatasvir with or without the nonstructural protein 3/4A protease inhibitor voxilaprevir. The primary efficacy endpoint was the proportion of patients achieving sustained virologic response at 12 weeks after the cessation of treatment. In total, 63 of 69 (91%; 95% confidence interval, 82%-97%) patients achieved sustained virologic response at 12 weeks, including 36 of 37 (97%; 95% confidence interval, 86%-100%) patients with hepatitis C virus genotype 1 infection, 13 of 14 (93%; 95% confidence interval, 66%-100%) patients with genotype 2 infection, and 14 of 18 (78%; 95% confidence interval, 52%-94%) patients with genotype 3 infection. Most adverse events were of mild or moderate severity. The most frequently reported adverse events were fatigue, nausea, headache, insomnia, and rash. One patient (1%) with genotype 1a infection discontinued all study drugs due to an adverse event (irritability). CONCLUSION: Retreatment of patients who previously failed direct-acting antiviral-based therapies with sofosbuvir-velpatasvir plus ribavirin for 24 weeks was well tolerated and effective, particularly those with hepatitis C virus genotype 1 or 2 infection. (Hepatology 2017;66:1083-1089).
Assuntos
Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Adulto , Idoso , Combinação de Medicamentos , Farmacorresistência Viral/genética , Quimioterapia Combinada , Feminino , Hepacivirus/genética , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND & AIMS: Studies are needed to determine the optimal regimen for patients with chronic hepatitis C virus (HCV) genotype 2, 3, 4, or 6 infections whose prior course of antiviral therapy has failed, and the feasibility of shortening treatment duration. We performed a phase 2 study to determine the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in these patients. METHODS: We performed a multicenter, open-label trial at 32 sites in the United States and 2 sites in New Zealand from March 3, 2015 to April 27, 2015. Our study included 128 treatment-naïve and treatment-experienced patients (1 with HCV genotype 1b; 33 with HCV genotype 2; 74 with HCV genotype 3; 17 with genotype HCV 4; and 3 with HCV genotype 6), with or without compensated cirrhosis. All patients received sofosbuvir-velpatasvir (400 mg/100 mg fixed-dose combination tablet) and GS-9857 (100 mg) once daily for 6-12 weeks. The primary end point was sustained virologic response 12 weeks after treatment (SVR12). RESULTS: After 6 weeks of treatment, SVR12s were achieved by 88% of treatment-naïve patients without cirrhosis (29 of 33; 95% confidence interval, 72%-97%). After 8 weeks of treatment, SVR12s were achieved by 93% of treatment-naïve patients with cirrhosis (28 of 30; 95% CI, 78%-99%). After 12 weeks of treatment, SVR12s were achieved by all treatment-experienced patients without cirrhosis (36 of 36; 95% CI, 90%-100%) and 97% of treatment-experienced patients with cirrhosis (28 of 29; 95% CI, 82%-100%). The most common adverse events were headache, diarrhea, fatigue, and nausea. Three patients (1%) discontinued treatment due to adverse events. CONCLUSIONS: In a phase 2 open-label trial, we found sofosbuvir-velpatasvir plus GS-9857 (8 weeks in treatment-naïve patients or 12 weeks in treatment-experienced patients) to be safe and effective for patients with HCV genotype 2, 3, 4, or 6 infections, with or without compensated cirrhosis. ClinicalTrials.gov ID: NCT02378961.
Assuntos
Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Macrocíclicos/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácidos Aminoisobutíricos , Ciclopropanos , Esquema de Medicação , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Seguimentos , Genótipo , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Pessoa de Meia-Idade , Prolina/análogos & derivados , Quinoxalinas , Serina Proteases , Resultado do Tratamento , Proteínas não Estruturais Virais , Adulto JovemRESUMO
BACKGROUND: Effective treatment options are needed for patients with genotype 1 or 3 hepatitis C virus (HCV) infection in whom previous therapy has failed. OBJECTIVE: To assess the efficacy and safety of sofosbuvir plus velpatasvir, with and without ribavirin, in treatment-experienced patients. DESIGN: Randomized, phase 2, open-label study. (ClinicalTrials.gov: NCT01909804). SETTING: 58 sites in Australia, New Zealand, and the United States. PATIENTS: Treatment-experienced adults with genotype 3 HCV infection without cirrhosis (cohort 1) and with compensated cirrhosis (cohort 2) and patients with genotype 1 HCV infection that was unsuccessfully treated with a protease inhibitor with peginterferon and ribavirin (50% could have compensated cirrhosis) (cohort 3). INTERVENTION: All patients received 12 weeks of treatment that included 400 mg of sofosbuvir once daily. Patients in each cohort were randomly assigned to 25 mg of velpatasvir once daily with or without ribavirin or 100 mg of velpatasvir once daily with or without ribavirin. MEASUREMENTS: Proportion of patients with sustained virologic response at week 12 after treatment (SVR12). RESULTS: In cohort 1, SVR12 rates were 85% with 25 mg of velpatasvir, 96% with 25 mg of velpatasvir plus ribavirin, 100% with 100 mg of velpatasvir, and 100% with 100 mg of velpatasvir plus ribavirin. In cohort 2, SVR12 rates were 58% with 25 mg of velpatasvir, 84% with 25 mg of velpatasvir plus ribavirin, 88% with 100 mg of velpatasvir, and 96% with 100 mg of velpatasvir plus ribavirin. In cohort 3, SVR12 rates were 100% with 25 mg of velpatasvir, 97% with 25 mg of velpatasvir plus ribavirin, 100% with 100 mg of velpatasvir, and 96% with 100 mg of velpatasvir plus ribavirin. The most common adverse events were headache, fatigue, and nausea. LIMITATION: Treatment assignments were not blinded, and no inferential statistics were planned. CONCLUSION: Treatment with 400 mg of sofosbuvir plus 100 mg of velpatasvir for 12 weeks was well-tolerated and highly effective in treatment-experienced patients with genotype 1 or 3 HCV infection. PRIMARY FUNDING SOURCE: Gilead Sciences.
Assuntos
Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Sofosbuvir/uso terapêutico , Adulto , Idoso , Antivirais/efeitos adversos , Carbamatos/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Ribavirina/efeitos adversos , Ribavirina/uso terapêutico , Sofosbuvir/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
UNLABELLED: Autoimmune hepatitis (AIH) can lead to cirrhosis, hepatic failure, and death. We aimed to identify predictors of advanced liver fibrosis at presentation, predictors of incomplete response to initial immunosuppression, and predictors of poor liver-related outcomes in the population-based AIH cohort from Canterbury, New Zealand. Cases diagnosed after 1980 that fulfilled standard diagnostic criteria were included. Cases were censored at death or liver transplantation and had a median follow-up of 9 years. Analyses were performed with Cox proportional hazards regression and logistic binary regression. The times to event outcomes were summarized using Kaplan-Meier curves. A total of 133 AIH patients were included. Predictors for advanced liver fibrosis at diagnosis were age at presentation of ≤20 years or >60 years (P = 0.02), serum albumin <36 g/L (P < 0.01), platelet <150 U/L (P < 0.01), and International Normalized Ratio (INR) >1.2 (P < 0.01). The only independent predictor for incomplete normalization of alanine aminotransferase (ALT) at 6 months was age at presentation ≤20 years. Independent predictors of poor liver-related outcomes were incomplete normalization of ALT at 6 months (P < 0.01), serum albumin <36 g/L (P < 0.01), and age at presentation of ≤20 years or >60 years (P = 0.01). Kaplan-Meier estimates showed that 10-year adverse liver event-free survival was 80% for age at presentation ≤20 years and >60 years, and 93% and 100% for age at presentation between 21-40 years and 41-60 years, respectively. CONCLUSION: Incomplete normalization of ALT at 6 months, low serum albumin concentration at diagnosis, and age at presentation of ≤20 years or >60 years were significant independent predictors of liver-related death or requirement for liver transplantation. Histological cirrhosis at diagnosis was not associated with poor prognosis and did not influence the response to initial immunosuppressive treatment. (HEPATOLOGY 2013;57:2399-2406).
Assuntos
Hepatite Autoimune/complicações , Hepatite Autoimune/mortalidade , Cirrose Hepática/imunologia , Adolescente , Adulto , Alanina Transaminase/sangue , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Hepatite Autoimune/enzimologia , Hepatite Autoimune/terapia , Humanos , Terapia de Imunossupressão , Imunossupressores/uso terapêutico , Lactente , Estimativa de Kaplan-Meier , Cirrose Hepática/mortalidade , Cirrose Hepática/terapia , Transplante de Fígado , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Modelos de Riscos Proporcionais , Adulto JovemRESUMO
Present interferon-based therapy for chronic hepatitis C is limited by both efficacy and tolerability. Telaprevir and boceprevir are the first two direct-acting antiviral drugs (DAAs) that inhibit hepatitis C virus replication to be licensed for use in conjunction with pegylated interferon and ribavirin. Numerous other DAAs are in clinical development, and phases 2 and 3 trials are evaluating interferon-free combination DAA therapy. Interferon-free sustained virologic responses have now been achieved with combinations of asunaprevir and daclatasvir; sofosbuvir and ribavirin; sofosbuvir and daclatasvir; faldaprevir and BI207127; ABT-450, ritonovir and ABT-333; ABT-450, ritonovir and ABT-072; miracitabine, danoprevir and ritonavir; and alisporivir and ribavirin. Some drugs are genotype-specific in their activity, whereas others are pan-genotypic, and differential responses for the genotype 1 subtypes 1a and 1b have emerged with many DAA combinations. Viral breakthrough and resistance are important considerations for future trial design. The prospect of interferon-free combination DAA therapy for hepatitis C virus is now finally becoming a reality.
Assuntos
Antivirais/uso terapêutico , Quimioterapia Combinada , Inibidores Enzimáticos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Ensaios Clínicos como Assunto , Ciclofilinas/antagonistas & inibidores , Farmacorresistência Viral , Quimioterapia Combinada/efeitos adversos , Hepacivirus/genética , Humanos , Interferons/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
BACKGROUND: Present interferon-based standard of care treatment for chronic hepatitis C virus (HCV) infection is limited by both efficacy and tolerability. We assessed the safety, tolerability, and antiviral activity of an all-oral combination treatment with two experimental anti-HCV drugs-RG7128, a nucleoside polymerase inhibitor; and danoprevir, an NS3/4A protease inhibitor-in patients with chronic HCV infection. METHODS: Patients from six centres in New Zealand and Australia who were chronically infected with HCV genotype 1 received up to 13 days oral combination treatment with RG7128 (500 mg or 1000 mg twice daily) and danoprevir (100 mg or 200 mg every 8 h or 600 mg or 900 mg twice daily) or placebo. Eligible patients were sequentially enrolled into one of seven treatment cohorts and were randomly assigned by interactive voice or web response system to either active treatment or placebo. Patients were separately randomly assigned within each cohort with a block size that reflected the number of patients in the cohort and the ratio of treatment to placebo. The random allocation schedule was computer generated. Dose escalation was started in HCV treatment-naive patients; standard of care treatment-experienced patients, including previous null responders, were enrolled in higher-dose danoprevir cohorts. Investigators, personnel at the study centre, and patients were masked to treatment allocation. However, the pharmacist who prepared the doses, personnel involved in pharmacokinetic sample analyses, statisticians who prepared data summaries, and the clinical pharmacologists who reviewed the data before deciding to initiate dosing in the next cohort were not masked to treatment allocation. The primary outcome was change in HCV RNA concentration from baseline to day 14 in patients who received 13 days of combination treatment. All patients who completed treatment with the study drugs were included in the analyses. This study is registered with ClinicalTrials.gov, NCT00801255. FINDINGS: 88 patients were randomly assigned to a study drug treatment regimen (n=74 over seven treatment groups; 73 received at least one dose of study drug) or to placebo (n=14, all of whom received at least one dose). The median change in HCV RNA concentration from baseline to day 14 ranged from -3·7 to -5·2 log(10) IU/mL in the cohorts that received 13 days of combination treatment. At the highest combination doses tested (1000 mg RG7128 and 900 mg danoprevir twice daily), the median change in HCV RNA concentration from baseline to day 14 was -5·1 log(10) IU/mL (IQR -5·6 to -4·7) in treatment-naive patients and -4·9 log(10) IU/mL in previous standard of care null responders (-5·2 to -4·5) compared with an increase of 0·1 log(10) IU/mL in the placebo group. The combination of RG7128 and danoprevir was well tolerated with no treatment-related serious or severe adverse events, no grade 3 or 4 changes in laboratory parameters, and no safety-related treatment discontinuations. INTERPRETATION: This oral combination of a nucleoside analogue polymerase inhibitor and protease inhibitor holds promise as an interferon-free treatment for chronic HCV. FUNDING: Roche Palo Alto.
Assuntos
Antivirais/administração & dosagem , Desoxicitidina/análogos & derivados , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Lactamas/administração & dosagem , Sulfonamidas/administração & dosagem , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Adulto , Antivirais/efeitos adversos , Ciclopropanos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Isoindóis , Lactamas/efeitos adversos , Lactamas Macrocíclicas , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Prolina/análogos & derivados , RNA Viral/sangue , Proteínas Recombinantes , Sulfonamidas/efeitos adversosRESUMO
BACKGROUND AND AIM: Allopurinol potentiates azathioprine and 6-mercaptopurine (6-MP) by increasing 6-thioguanine nucleotide (6-TGN) metabolite concentrations. The outcome might also be improved by adding allopurinol in individuals who preferentially produce 6-methylmercaptopurine nucleotides (6-MMPN), rather than 6-TGN. The aim of the present study was to investigate the effect of allopurinol on concentrations of 6-MMPN and 6-TGN in individuals with a high ratio of these metabolites (>20), which is indicative of a poor thiopurine response. METHODS: Sixteen individuals were identified who were taking azathioprine or 6-MP, and were commenced on allopurinol to improve a high 6-MMPN:TGN ratio. Metabolite concentrations were compared before and after commencing allopurinol, and markers of disease control were compared. RESULTS: The addition of 100-300 mg allopurinol daily and thiopurine dose reduction (17-50% of the original dose) resulted in a reduction of the median (and range) 6-MMPN concentration, from 11,643 (3,365-27,832) to 221 (55-844) pmol/8×10(8) red blood cells (RBC; P=0.0005), increased 6-TGN from 162 (125-300) to 332 (135-923) pmol/8×10(8) RBC (P=0.0005), and reduced the 6-MMPN:6-TGN ratio from 63 (12-199) to 1 (0.1-4.5) (P=0.0005). There was a significant reduction in steroid dose requirements at 12 months (P=0.04) and trends for improvement in other markers of disease control. One patient developed red cell aplasia that resolved upon stopping azathioprine and allopurinol. CONCLUSIONS: In those with a high 6-MMPN:6-TGN ratio (>20), response to thiopurine treatment might be improved by the addition of allopurinol, together with a reduced thiopurine dose and close hematological monitoring.
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Alopurinol/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Azatioprina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mercaptopurina/uso terapêutico , Xantina Oxidase/antagonistas & inibidores , Adulto , Alopurinol/efeitos adversos , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/farmacocinética , Azatioprina/efeitos adversos , Azatioprina/farmacocinética , Biotransformação , Quimioterapia Combinada , Inibidores Enzimáticos/efeitos adversos , Contagem de Eritrócitos , Feminino , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/farmacocinética , Nucleotídeos de Guanina/sangue , Humanos , Doenças Inflamatórias Intestinais/enzimologia , Masculino , Mercaptopurina/efeitos adversos , Mercaptopurina/farmacocinética , Pessoa de Meia-Idade , Nova Zelândia , Aplasia Pura de Série Vermelha/sangue , Aplasia Pura de Série Vermelha/induzido quimicamente , Estudos Retrospectivos , Esteroides/uso terapêutico , Tionucleotídeos/sangue , Fatores de Tempo , Resultado do Tratamento , Xantina Oxidase/metabolismoRESUMO
BACKGROUND AND AIM: The etiology of autoimmune hepatitis (AIH) is unknown, and limited epidemiological data are available. Our aim was to perform a population based epidemiological study of AIH in Canterbury, New Zealand. METHODS: To calculate point prevalence, all adult and pediatric outpatient clinics and hospital discharge summaries were searched to identify all cases of AIH in the Canterbury region. Incident cases were recruited prospectively in 2008. Demographic and clinical data were extracted from case notes. Both the original revised AIH criteria and the simplified criteria were applied and cases were included in the study if they had definite or probable AIH. RESULTS: When the original revised criteria were used, 138 cases (123 definite and 14 probable AIH), were identified. Prospective incidence in 2008 was 2.0/100,000 (95% confidence interval [CI] 0.8-3.3/100,000). Point prevalence on 31 December 2008 was 24.5/100,000 (95% CI 20.1-28.9). Age-standardized (World Health Organization standard population) incidence and prevalence were 1.7 and 18.9 per 100,000, respectively. Gender-specific prevalence confirmed a female predominance, while ethnicity-specific prevalence showed higher prevalence in Caucasians. 72% of cases presented after 40 years of age and the peak age of presentation was in the sixth decade of life. CONCLUSIONS: This is the first and largest population-based epidemiology study of AIH in a geographically defined region using standardized inclusion criteria. The observed incidence and prevalence rates are among the highest reported. The present study confirms that AIH presents predominantly in older women, with a peak in the sixth decade, contrary to the classical description of the disease.
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Hepatite Autoimune/epidemiologia , Vigilância da População , Adulto , Fatores Etários , Intervalos de Confiança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Prevalência , Estudos Retrospectivos , Distribuição por SexoRESUMO
PURPOSE: The etiology of autoimmune hepatitis (AIH) likely involves a complex interaction of genetic and environmental factors. We aim to investigate the associations between exposure to putative environmental factors and AIH and to quantify AIH risk in a first-degree relative. METHODS: We conducted a population-based case-control study. Cases were AIH patients who were alive and resided in Canterbury, New Zealand, between 1 July 2011 and 30 June 2012. Controls were randomly selected from the Electoral Roll and were matched 2:1 to each case by age and gender. Self-reporting questionnaires that cover lifestyle factors, childhood factors and family history were used. RESULTS: 72 AIH cases and 144 controls were included. We found that exposure to antibiotics within 12 months prior to AIH diagnosis (OR 12.98, 95 % CI 2.49-67.67, p < 0.01) was an independent risk factor for the development of AIH. Alcohol consumption (OR 0.43, 95 % CI 0.28-0.68, p < 0.01) and childhood home with wood heating (OR 0.30, 95 % CI 0.14-0.63, p < 0.01) were independently associated with reduced risks of later development of AIH. The crude risk of AIH in first-degree relatives of a patient with AIH was 0.2 % (95 % CI <0.1-2.0). CONCLUSIONS: We found that antibiotics are an independent risk factor for the development of AIH, whereas alcohol consumption and living in a childhood home with wood heating are independent protective factors against the later development of AIH.
RESUMO
The liver plays a key role in the metabolic conversion and elimination of endo- and xenobiotics. Hepatobiliary transport of many of these compounds is mediated by several ATP-binding cassette (ABC) transporters expressed at the canalicular membrane of the hepatocyte. Impaired function of these ABC transporters leads to impaired bile formation or cholestasis and mutations in these genes are associated with a variety of hereditary cholestatic syndromes. At the transcriptional level, these ABC transporters and the metabolizing enzymes involved in processing of their substrates are coordinately regulated by members of the nuclear receptor (NR) family of ligand-modulated transcription factors. In this review we will focus on ABC transporters involved in hepatobiliary excretion and how they are associated with hepatic physiology and disease states. We will also examine how NRs, acting as intracellular sensors for lipophilic molecules, regulate these ABC transporters and maintain metabolic homeostasis.
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Transportadores de Cassetes de Ligação de ATP/fisiologia , Sistema Biliar/fisiologia , Fígado/fisiologia , Animais , Ácidos e Sais Biliares/fisiologia , Sistema Biliar/anatomia & histologia , Colestase Intra-Hepática/fisiopatologia , Humanos , Fígado/anatomia & histologia , Hepatopatias/fisiopatologia , Modelos Biológicos , Receptores Citoplasmáticos e Nucleares/fisiologiaRESUMO
Cholestasis is associated with accumulation of bile acids and lipids, and liver injury. The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic nuclear receptors that coordinate protective hepatic responses to potentially toxic stimuli, including bile acids. We investigated the role of these receptors in the regulation of bile acid and lipid metabolism in a bile duct ligation (BDL) model of cholestasis applied to receptor knockout mice. Hepatic damage from bile acid accumulation was increased in both CAR knockout (CARKO) and PXR knockout mice, but bile acid concentrations were lower in CARKO mice. High-density lipoprotein (HDL) cholesterol was elevated in CARKO mice, and serum total cholesterol increased less in CARKO or PXR knockout mice than WT mice after BDL. Gene expression analysis of the BDL knockout animals demonstrated that, in response to cholestasis, PXR and CAR both repressed and induced the specific hepatic membrane transporters Oatp-c (organic anion transporting polypeptide C) and Oatp2 (Na+-dependent organic anion transporter 2), respectively. Induction of the xenobiotic transporter multidrug resistance protein 1 in cholestasis was independent of either PXR or CAR, in contrast to the known pattern of induction of multidrug resistance protein 1 by xenobiotics. These results demonstrate that CAR and PXR influence cholesterol metabolism and bile acid synthesis, as well as multiple detoxification pathways, and suggest their potential role as therapeutic targets for the treatment of cholestasis and lipid disorders.
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Colestase/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Esteroides/metabolismo , Fatores de Transcrição/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Ductos Biliares/cirurgia , Colestase/patologia , Colesterol/metabolismo , Receptor Constitutivo de Androstano , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Metabolismo dos Lipídeos , Fígado/citologia , Fígado/metabolismo , Fígado/patologia , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Receptor de Pregnano X , Receptores Citoplasmáticos e Nucleares/genética , Receptores de Esteroides/genética , Fatores de Transcrição/genéticaRESUMO
AIMS: The aims of this study were to determine if patients with SSRI-related hyponatraemia were (1) genetically poor metabolizers of CYP2D6, and/or (2) had excessive plasma concentrations of the SSRI antidepressant. METHODS: Plasma DNA from 20 people with hyponatraemia attributable to fluoxetine or paroxetine was analysed for the CYP2D6 alleles *1-*16. Trough plasma concentrations of fluoxetine and norfluoxetine, or paroxetine were assayed in nine people who remained on the antidepressant. RESULTS: Genotype results were compared with those published in a large population study. The poor metabolizer PM/PM genotype was present in one subject only, or 5% of the study population, compared with 7.2% of a general population. The 95% Cl of this result was 0-21%, suggesting that it is most unlikely that hyponatremia is related to the PM/PM genotype. The intermediate IM/PM genotype was present in 5% compared with 19.7% of a general population. All differences were not statistically significant. Antidepressant concentrations of fluoxetine (n = 5, all EM) and paroxetine (n = 1 IM/PM and n = 3 EM) were all within the lower half of the reference range. CONCLUSIONS: These results do not support the hypothesis that SSRI-related hyponatraemia is linked to genetically poor metabolizers, or excessive drug concentrations.