Sofosbuvir and risk of estimated glomerular filtration rate decline or end-stage renal disease in patients with renal impairment.

BACKGROUND: Sofosbuvir, a prodrug nucleoside inhibitor of hepatitis C virus, has a predominant circulating metabolite that is renally eliminated. Whether sofosbuvir is associated with chronic kidney disease (CKD) progression is not well understood. METHODS: We performed a retrospective analysis of patients with estimated glomerular filtration rate (eGFR) 30-89 mL/min/1.73 m2 treated with sofosbuvir in 76 Phase 2/3 registrational trials. We evaluated eGFR at each study visit. Separately, we performed a retrospective analysis of an administrative claims database (IQVIA PharMetrics Plus™) to compare the risk of incident end-stage renal disease (ESRD) associated with the use of sofosbuvir or non-sofosbuvir regimens among patients with CKD using propensity score methods. Exposure, CKD status and outcomes were determined using diagnosis and medication claim codes. Cox proportional hazards methods were used to estimate ESRD risk. RESULTS: Among 4642 trial participants with baseline stage 2 CKD (eGFR 60-89 ml/min/1.73 m2 ) and 682 trial participants with stage 3 CKD (eGFR 30-59 ml/min/1.73 m2 ) mean (SD) eGFR improved from baseline to 4 weeks post-treatment (+0.7 [9.3] and +2.6 [8.8] ml/min/1.73 m2 , respectively; p < 0.001 each). In the second analysis, among 2042 patients with CKD receiving sofosbuvir-based regimens compared to 431 receiving non-sofosbuvir-based regimens, after adjusting for baseline covariates and weighting based on treatment propensity scores, there was no significant difference in risk of ESRD (adjusted HR = 0.85, 95% CI: 0.51-1.42). CONCLUSIONS: Clinical trial participants with CKD did not experience worsening eGFR during sofosbuvir-based treatment, and sofosbuvir was not associated with an increased risk of ESRD in patients with CKD in a nationally-representative administrative claims database.

A minimal monitoring approach for the treatment of hepatitis C virus infection (ACTG A5360 [MINMON]): a phase 4, open-label, single-arm trial.

BACKGROUND: Despite widespread availability of direct-acting antivirals including generic formulations, limited progress has been made in the global adoption of hepatitis C virus (HCV) treatment. Barriers to treatment scale-up include availability and access to diagnostic and monitoring tests, health-care infrastructure, and requirement for frequent visits during treatment. METHODS: ACTG A5360 was a phase 4, open-label, single-arm trial across 38 sites in Brazil, South Africa, Thailand, Uganda, and the USA. Key inclusion criteria were age of 18 years or older, evidence of active HCV infection (HCV RNA >1000 IU/mL) and HCV treatment-naive; patients with compensated cirrhosis and HIV/HCV co-infection were included but their enrolment was capped. All participants received a fixed dose combination of oral sofosbuvir (400 mg) and velpatasvir (100 mg) once daily for 12 weeks. The minimal monitoring (MINMON) approach consisted of four components: (1) there was no pre-treatment genotyping; (2) the entire treatment course (84 tablets) was dispensed at entry; (3) there were no scheduled visits or laboratory monitoring; and (4) there were two points of remote contact, at week 4 for adherence and week 22, to schedule outcome assessment at week 24 (-2 weeks to +4 weeks). Participants who missed the week 24 window could return for a visit to assess treatment response any time before week 72. Unplanned visits for any reason were permissible before the week 24 visit. The primary efficacy outcome was sustained virological response (SVR), defined as HCV RNA less than the lower limit of quantification measured at least 22 weeks post-treatment initiation; the primary safety outcome was serious adverse events. The primary efficacy analysis included all participants who initiated treatment, using a missing=failure approach. The primary safety analysis included all participants who initiated treatment and had at least one post-treatment assessment. This trial is registered at ClinicalTrials.gov, NCT03512210. FINDINGS: Between Oct 22, 2018, and July 19, 2019, 400 participants were enrolled across all 38 sites; 399 initiated treatment. At the SVR assessment visit, 355 (89%) of 397 participants reported taking 100% of the trial medication during the 12-week treatment period; two patients did not have any follow-up visits after the entry visit and were excluded from the safety analyses. Overall, 379 of the 399 who initiated treatment had an SVR (95·0%, 95% CI 92·4-96·7). 14 (4%) of 397 participants reported serious adverse events between treatment initiation and week 28; none were treatment related or led to treatment discontinuation or death. 15 (4%) of 399 participants had unplanned visits; none were related to treatment. INTERPRETATION: In this diverse global population of people with HCV, the MINMON approach with sofosbuvir-velpatasvir treatment was safe and achieved SVR comparable to standard monitoring observed in real-world data. Coupled with innovative case finding strategies, this strategy could be crucial to the global HCV elimination agenda. FUNDING: US National Institutes of Health and Gilead Sciences.

Prevalence of insulin resistance in chronic hepatitis C genotype 1 and 3 patients.

BACKGROUND AND RATIONALE: Chronic infection with the hepatitis C virus (HCV) is associated with a higher prevalence of insulin resistance compared to the general population. This finding is associated with hepatic steatosis, increased liver fibrosis and lower rates of sustained virological response to interferon based therapy. The relationship of insulin resistance and HCV genotype is controversial. Our aim was to compare the prevalence of insulin resistance between patients with HCV genotype 1 and 3. The association of insulin resistance, hepatic steatosis and liver fibrosis was also investigated. RESULTS: Forty four consecutive treatment naïve patients with HCV genotypes 1 or 3, without cirrhosis and without risk factors for metabolic syndrome were prospectively included. Insulin resistance was defined as a homeostasis model assessment for insulin resistance (HOMA-IR) above 2.0. Steatosis and fibrosis were assessed histologically. Insulin resistance was found in 27 (61%) patients and significant steatosis in 37 (84%) patients. Comparison between patients with HCV genotype 1 and 3 showed insulin resistance in 15 (65%) vs. 12 (57%), respectively (P = 0.81) and steatosis in 19 (83%) vs. 18 (86%), respectively (P = 0.93). Comparison between patients with and without insulin resistance showed, respectively, a higher prevalence of significant fibrosis (56% vs. 6%; P = 0.0001), and a higher mean degree of steatosis (1.3 ± 0.72 vs. 0.76 ± 0.56; P = 0.01). CONCLUSIONS: Prevalence of insulin resistance was not different between HCV infected patients with genotype 1 vs. 3. Nevertheless, independent of HCV genotype, there was a statistically significant relationship between insulin resistance and a higher amount of liver fibrosis and steatosis.

Pancreatite autoimune: diagnóstico por ecoendoscopia associada à punção aspirativa / Autoimmune pancreatitis: diagnosis by endoscopic ultrasound and fine needle aspiration

As lesões sólidas do pâncreas são constituídas, na maioria dos casos, pelo adenocarcinoma ductal. Contudo parcela considerável de casos apresentam lesões de outra natureza, as quais requerem abordagens cirúrgicas menos extensas ou tratamento clínico conservador com quimio ou corticoterapia. Neste relato, apresentamos o caso de uma paciente de 56 anos com icterícia e uma massa na cabeça do pâncreas mimetizando um quadro neoplásico. O diagnóstico de pancreatite autoimune foi firmado por meio da ecoendoscopia associada à punção aspirativa (AU)

Solid lesions of the pancreas are, in most cases, constituted of the ductal adenocarcinoma, but a considerable portion of cases have lesions of a different nature, which require less extensive surgical approaches or conservative medical treatment with chemotherapy or corticosteroids. In this report, we present the case of a 56-year-old female patient with jaundice and a mass in the head of the pancreas mimicking a neoplasm. The diagnosis of autoimmune pancreatitis was confirmed by endoscopic ultrasound-guided fine needle aspiration (AU)

Effect of HFE gene polymorphism on sustained virological response in patients with chronic hepatitis C and elevated serum ferritin.

CONTEXT: Abnormal serum ferritin levels are found in approximately 20%-30% of the patients with chronic hepatitis C and are associated with a lower response rate to interferon therapy. OBJECTIVE: To determine if the presence of HFE gene mutations had any effect on the sustained virological response rate to interferon based therapy in chronic hepatitis C patients with elevated serum ferritin. METHODS: A total of 44 treatment naÏve patients with histologically demonstrated chronic hepatitis C, all infected with hepatitis C virus genotype non-1 (38 genotype 3; 6 genotype 2) and serum ferritin above 500 ng/mL were treated with interferon (3 MU, 3 times a week) and ribavirin (1.000 mg, daily) for 24 weeks. RESULTS: Sustained virological response was defined as negative qualitative HCV-RNA more than 24 weeks after the end of treatment. Serum HCV-RNA was measured by qualitative in house polymerase chain reaction with a limit of detection of 200 IU/mL. HFE gene mutation was detected using restriction-enzyme digestion with RsaI (C282Y mutation analysis) and BclI (H63D mutation analysis) in 16 (37%) patients, all heterozygous (11 H63D, 2 C282Y and 3 both). Sustained virological response was achieved in 0 of 16 patients with HFE gene mutations and 11 (41%) of 27 patients without HFE gene mutations (P = 0.002; exact Fisher test). CONCLUSION: Heterozigozity for H63D and/or C282Y HFE gene mutation predicts absence of sustained virological response to combination treatment with interferon and ribavirin in patients with chronic hepatitis C, non-1 genotype and serum ferritin levels above 500 ng/mL.

Effect of HFE gene polymorphism on sustained virological response in patients with chronic hepatitis C and elevated serum ferritin / Efeito do polimorfismo do gene HFE sobre a resposta viral sustentada em portadores de hepatite crônica C com ferritina sérica elevada

CONTEXT: Abnormal serum ferritin levels are found in approximately 20%-30% of the patients with chronic hepatitis C and are associated with a lower response rate to interferon therapy. OBJECTIVE: To determine if the presence of HFE gene mutations had any effect on the sustained virological response rate to interferon based therapy in chronic hepatitis C patients with elevated serum ferritin. METHODS: A total of 44 treatment naÏve patients with histologically demonstrated chronic hepatitis C, all infected with hepatitis C virus genotype non-1 (38 genotype 3; 6 genotype 2) and serum ferritin above 500 ng/mL were treated with interferon (3 MU, 3 times a week) and ribavirin (1.000 mg, daily) for 24 weeks. RESULTS: Sustained virological response was defined as negative qualitative HCV-RNA more than 24 weeks after the end of treatment. Serum HCV-RNA was measured by qualitative in house polymerase chain reaction with a limit of detection of 200 IU/mL. HFE gene mutation was detected using restriction-enzyme digestion with RsaI (C282Y mutation analysis) and BclI (H63D mutation analysis) in 16 (37%) patients, all heterozygous (11 H63D, 2 C282Y and 3 both). Sustained virological response was achieved in 0 of 16 patients with HFE gene mutations and 11 (41%) of 27 patients without HFE gene mutations (P = 0.002; exact Fisher test). CONCLUSION: Heterozigozity for H63D and/or C282Y HFE gene mutation predicts absence of sustained virological response to combination treatment with interferon and ribavirin in patients with chronic hepatitis C, non-1 genotype and serum ferritin levels above 500 ng/mL.

CONTEXTO: Níveis séricos anormais de ferritina são encontrados em aproximadamente 20%-30% dos pacientes com hepatite crônica C e estão associadas a uma baixa taxa de resposta à terapia com interferon. OBJETIVO: Avaliar a associação entre a presença de mutações do gene HFE e a taxa de resposta virológica sustentada ao interferon em pacientes portadores de hepatite crônica C com ferritina sérica elevada. MÉTODOS: Um total de 44 pacientes, virgem de tratamento, infectado pelo vírus da hepatite C de genótipos não-1 (38 genótipo 3; 6 genótipo 2) e ferritina sérica acima de 500 ng/mL foi tratado com interferon (3 MU, três vezes por semana) e ribavirina (1000 mg/dia) por 24 semanas. Resposta virológica sustentada foi definida como HCV-RNA indetectável 24 semanas após o fim do tratamento. Foi utilizado técnica de reação em cadeia da polimerase em tempo-real com limite de detecção de 200 UI /mL. RESULTADOS: Mutações do gene HFE foram detectadas por "restriction-enzyme digestion" com RsaI (análise de mutação C282Y) e BclI (análise de mutação H63D) em 16 pacientes (37%), todos heterozigotos (11 H63D, 2 C282Y e 3 ambos). Resposta virológica sustentada foi alcançada em 0 de 16 pacientes com mutações do gene HFE e 11 (41%) dos 27 pacientes sem mutações do gene HFE (P = 0,002; teste exato de Fisher). CONCLUSÃO: A heterozigose para os genes H63D e/ou C282Y HFE está associada à redução significativa da taxa de resposta virológica sustentada ao tratamento com interferon e ribavirina em pacientes com hepatite crônica C, genótipo não-1 e com níveis séricos de ferritina acima de 500 ng/mL.

Effect of sustained virologic response on the incidence of hepatocellular carcinoma in patients with HCV cirrhosis

BACKGROUND AND OBJECTIVES: Evidence suggests that sustained virologic response to interferon treatment decreases incidence of hepatocellular carcinoma in patients with hepatitis C virus cirrhosis. This study was designed to compare the incidence of hepatocellular carcinoma among cirrhotic patients exposed to interferon based treatment with or without achieving a sustained virological response, in order to evaluate the role of interferon itself in the prevention hepatocellular carcinoma. METHODS: A cohort of 85 patients with compensated hepatitis C cirrhosis was followed after treatment with interferon and ribavirin. Sustained virological response was defined as negative polymerase chain reaction assay 24 weeks after the end of treatment. Patients were followed every 6 months with ultrasound and alpha-fetoprotein. Hepatocellular carcinoma was diagnosed by the finding of a focal liver lesion greater than 2 cm with arterial hypervascularization on two imaging techniques and/or by liver biopsy. RESULTS: The mean follow-up time was 32.1 ± 20 months for patients who achieved a sustained virological response and 28.2 ± 18 months among 47 patients (55 percent) without SVR. Hepatocellular carcinoma was diagnosed in 1 (3 percent) vs. 8 (17 percent) responders and non responders respectively (p = 0.02). CONCLUSION: Patients with cirrhosis due to hepatitis C virus who achieved sustained virological response had significantly lower incidence of hepatocellular carcinoma when compared to those without treatment response. Interferon treatment without achieving sustained virological response does not seem to protect against hepatocellular carcinoma.

Effect of sustained virologic response on the incidence of hepatocellular carcinoma in patients with HCV cirrhosis.

BACKGROUND AND OBJECTIVES: Evidence suggests that sustained virologic response to interferon treatment decreases incidence of hepatocellular carcinoma in patients with hepatitis C virus cirrhosis. This study was designed to compare the incidence of hepatocellular carcinoma among cirrhotic patients exposed to interferon based treatment with or without achieving a sustained virological response, in order to evaluate the role of interferon itself in the prevention hepatocellular carcinoma. METHODS: A cohort of 85 patients with compensated hepatitis C cirrhosis was followed after treatment with interferon and ribavirin. Sustained virological response was defined as negative polymerase chain reaction assay 24 weeks after the end of treatment. Patients were followed every 6 months with ultrasound and alpha-fetoprotein. Hepatocellular carcinoma was diagnosed by the finding of a focal liver lesion greater than 2 cm with arterial hypervascularization on two imaging techniques and/or by liver biopsy. RESULTS: The mean follow-up time was 32.1 ± 20 months for patients who achieved a sustained virological response and 28.2 ± 18 months among 47 patients (55%) without SVR. Hepatocellular carcinoma was diagnosed in 1 (3%) vs. 8 (17%) responders and non responders respectively (p = 0.02). CONCLUSION: Patients with cirrhosis due to hepatitis C virus who achieved sustained virological response had significantly lower incidence of hepatocellular carcinoma when compared to those without treatment response. Interferon treatment without achieving sustained virological response does not seem to protect against hepatocellular carcinoma.

Dilatação endoscópica de esôfago sem o auxílio de fluoroscopia: experiência en 1.358 sessões / Endoscopic dilation of esophagus without fluoroscopy: report on 1.358 procedures

Introdução e objetivos: A dilatação esofágica é considerada a terapêutica de escolha para a maioria dos casos de estenose benigna de esôfago; contudo permanece controversa a utilização da fluoroscipia neste procedimento, bem como qua a etiologia de estenose que melhor responde a esse tratamento. Neste estudo, os autores pretendem expor sua experiência coletada prospectivamente, em 1.358 sessões de dilatação endoscópica esofágica (DEE) sem auxílio fluoroscópico, e comparar os resultados deste método em pacientes de diferentes etiologias de estenose e graus de disfagia. Métodos: Entre 1992 e 2000, 241 pacientes foram submetidos à DEE sem auxílio fluoroscópico. O grau de disfagia dessses pacientes foi graduado de 0, sem disfagia a 4, quando não opto a ingerir líquidos em quantidade suficiente. A resposta de tratamento endoscópica era considerada ótima se fosse inserido um dilatador maior ou igual a 45Fr pela estemose e houvesse leve disfagia ou desaparecimento desta ( graus 0 e 1), e ruim mesmo que fosse inserido um dilatador maior ou igual a 45Fr pela estemose e houvesse disfagia (graus 2, 3 e 4). Resultados: obteve-se seguimento médio de 18,1 meses (1-82) em 207 pacientes (131 M, 76 F, idade média de 55,8 anos) que foram submetidos a 1.358 sessões de dilatação (mediana= 4, elastério de 1-75). A etiologia da estenose era pós-operatória em 125 pacientes, péptica em 46, cáustica em 16 e 20 por outras causas. O grau médio de disfagia antes do tratamento foi de 3,4 e 0,8 após a terapêutica (p=0,001). Resposta ótima ao tratamento foi obtida em 82por cento dos pacientes com estenoses pós-operatórias, em85porm cento dos casos de estenose péptica e em 61por cento dos pacientes com estenose cáustica (p= 0,08). Pacientes com estenose cáustica necessitaram de um número significante maior de sesões (mediana = 5,5) em relação aos casos de estenose pós-operatória (mediana =4) e péptica(mediana=3). Resposta ótima foi obtida em 84por cento dos pacientes que apresentavam disfagia a sólidos em em 41por cento dos casos com disfagia a líquidos à apresentação clínica (p= 0,0001)

Resposta sustentada após 1 ano de interferon isolado ou associado a ribavirina em pacientes com cirrose pelo vírus C / Sustained response after one-year treatment with interferon, exclusively or in association with ribavirin in positive hepatitis c virus cirrhotic patients

O trabalho teve por objetivo avaliar a taxa de resposta completa ao final do tratamento e de resposta sustentada em pacientes com cirrose pelo vírus da hepatite C tratados com interferon isolado ou combinado com ribavirina. Um total de 33 pacientes cirróticos ambulatoriais, VHC positivos, sem outras causas identificáveis de doença hepática, compensados e classificados como Child-Pugh A, foram divididos em dois grupos, de forma não randomizada...

Prevalência de diabetes mellitus em pacientes com hepatite C / Prevalence of diabetes mellitus in patients with chronic hepatitis C

O vírus da hepatite C pode cursar com manifestações extra-hepáticas relacionadas a distúrbio imunológico. Este trabalho objetivou verificar a prevalência de Diabetes mellitus em pacientes com hepatite crônica C. Entre novembro de 1992 e dezembro de 1997 foram avaliados prospectivamente 140 pacientes ambulatoriais e consecutivos, com anti-VHC (ELISA-2) e PCR positivos...

Mecanismos de açäo dos interferons: uma revisäo / Pharmacodynamics of interferons: a review

Os autores realizam uma revisäo sobre os principais aspectos farmacodinâmicos e farmacocinéticos dos interferons humanos. Atualmente classificados no grupo das citocinas, estes agentes säo secretados por diversas células do organismo em resposta à infecçäo viral e a diversos outros estímulos, sendo divididos em alfa, beta e gama...

Colangite esclerosante primária associada à anemia hemolítica auto-imune / Primary sclerosing cholangitis associated to autoimmune hemolytic anemia

Colangite esclerosante primária (CEP) é doença de etiologia desconhecida caracterizada por inflamaçao e fibrose envolvendo a árvore biliar intra e/ou extra-hepática, levando à dilataçao e estenose dos ductos biliares. Estudos recentes têm demonstrado importante papel dos falores imunológicos e genético na patogênese desta condiçao. A anemia hemolítica auto-imune (AHA) caraacteriza-se por anticorpos antieritrocitários que parecem surgir como resultado de distúrbio funcional específico do linfócito T supressor. A oportunidade que tivemos de diagnosticar e tratar dois pacientes com CEP associada à AHA motiva o presente estudo. De nosso conhecimento, existem apenas dois relatos prévios desta associaçao publicados na literatura.

Dor abdominal / Abdominal pain

A dor é uma experiênia universal e previne a extensäo do dano tecidual. A dor abdominal em particular é um dos sintomas mais frequentes em gastroenterologia. Existem três tipos de dor abdominal: a dor visceral, a dor parietal e a referida. A avaliaçäo clínica da dor abdominal depende fundamentalmente da correta realizaçäo da anamnese e do exame físico, os quais iräo nortear a necessidade de investigaçäo complementar para firmr o diagnóstico. Neste estudo, os autores realizam uma revisäo dos aspectos anatômicos, fosiológicos e clínicos da dor abdominal, incluindo uma breve descriçäo deste sintoma em algumas das doenças mais comuns na prática gastrenterológica.