Prevalence of resistance-associated substitutions and retreatment of patients failing a glecaprevir/pibrentasvir regimen.

OBJECTIVES: To investigate resistance-associated substitutions (RASs) as well as retreatment efficacies in a large cohort of European patients with failure of glecaprevir/pibrentasvir. METHODS: Patients were identified from three European Resistance Reference centres in Spain, Italy and Germany. Sequencing of NS3, NS5A and NS5B was conducted and substitutions associated with resistance to direct antiviral agents were analysed. Clinical and virological parameters were documented retrospectively and retreatment efficacies were evaluated. RESULTS: We evaluated 90 glecaprevir/pibrentasvir failures [3a (n = 36), 1a (n = 23), 2a/2c (n = 20), 1b (n = 10) and 4d (n = 1)]. Ten patients were cirrhotic, two had previous exposure to PEG-interferon and seven were coinfected with HIV; 80 had been treated for 8 weeks. Overall, 31 patients (34.4%) failed glecaprevir/pibrentasvir without any NS3 or NS5A RASs, 62.4% (53/85) showed RASs in NS5A, 15.6% (13/83) in NS3 and 10% (9/90) in both NS5A and NS3. Infection with HCV genotypes 1a and 3a was associated with a higher prevalence of NS5A RASs. Patients harbouring two (n = 34) or more (n = 8) RASs in NS5A were frequent. Retreatment was initiated in 56 patients, almost all (n = 52) with sofosbuvir/velpatasvir/voxilaprevir. The overall sustained virological response rate was 97.8% in patients with end-of-follow-up data available. CONCLUSIONS: One-third of patients failed glecaprevir/pibrentasvir without resistance. RASs in NS5A were more prevalent than in NS3 and were frequently observed as dual and triple combination patterns, with a high impact on NS5A inhibitor activity, particularly in genotypes 1a and 3a. Retreatment of glecaprevir/pibrentasvir failures with sofosbuvir/velpatasvir/voxilaprevir achieved viral suppression across all genotypes.

High efficacy of resistance-guided retreatment of HCV patients failing NS5A inhibitors in the real world.

BACKGROUND & AIMS: Most hepatitis C virus (HCV)-infected patients failing NS5A inhibitors develop resistance-associated substitutions (RASs). Here we report the use of resistance-guided retreatment of patients who failed prior NS5A inhibitor-containing regimens in the GEHEP-004 cohort. This is the largest direct-acting antiviral (DAA)-resistance cohort study conducted in Spain. We aim to provide indications on how to use resistance information in settings where sofosbuvir/velpatasvir/voxilaprevir may not be available. METHODS: GEHEP-004 is a prospective multicenter cohort enrolling HCV-infected patients treated with interferon (IFN)-free DAA regimens. Prior to retreatment, population-based sequencing of HCV NS3, NS5A and NS5B genes was performed. After receiving a comprehensive resistance interpretation report, the retreatment regimen was chosen and the sustained virological response (SVR) at 12 weeks after treatment completion (SVR12) was recorded. RESULTS: A total of 342 patients experiencing virological failure after treatment with sofosbuvir/ledipasvir±ribavirin (54%), sofosbuvir/daclatasvir±ribavirin (23%), or paritaprevir-ritonavir/ombitasvir±dasabuvir±ribavirin (20%) were studied. After a resistance report, 186 patients were retreated. An SVR12 was achieved for 88.1% of the patients who failed after sofosbuvir/ledipasvir±ribavirin, 83.3% of the patients who failed after sofosbuvir/daclatasvir±ribavirin, 93.7% of the patients who failed after paritaprevir-ritonavir+ombitasvir±dasabuvir±ribavirin. CONCLUSIONS: In our study, we show how resistance-guided retreatment in conjunction with an interpreted report allows patients to achieve SVR rates close to 90%. We hypothesize that SVR rates may even be improved if resistance data are discussed between experienced virologists and treating clinicians. We believe that our data may be relevant for countries where the access to new DAA combination regimens is limited. LAY SUMMARY: Hepatitis C infection can be cured with currently available antiviral agents. Only a small proportion of patients experience treatment failure, however, in absolute numbers, a high number of patients may require retreatment. Highly effective combinations of antivirals are also available for retreatment. However, these antivirals might not be available in resource-limited settings. Herein, we show how, by analyzing the cause of resistance, retreatment efficacy with old drugs can get very close to the efficacy of new drug combinations.

Insulin resistance and the metabolic syndrome are related to the severity of steatosis in the pediatric population with obesity

Background: To determine the factors associated with an increased risk for severe steatosis (SS) and establish the Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) as a screening tool. Methods: A cross-sectional study was performed in obese children to assess the relationship between the metabolic syndrome (MetS) and glucose metabolism alterations (GMA) and the risk for severe steatosis. Results: A total of 94 children (51 males) aged from six to 14 years were included. Thirteen children (14.8%) had severe steatosis (SS). The anthropometric variables associated with SS included body mass index (BMI) (SS 34.1 vs non-SS 29.7, p = 0.005), waist circumference (cm) (100 vs 92.5, p = 0.015) and hip circumference (cm) (108 vs 100, p = 0.018). The blood parameters included alanine aminotransferase (ALT) (UI/dl) (27 vs 21, p = 0.002), gamma-glutamil transpeptidase (GGT) (UI/dl) (16 vs 15, p = 0.017), fasting glycemia (mg/dl) (96 vs 88, p = 0.006), fasting insulin (UI/dl) (25 vs 15.3, p < 0.001) and HOMA-IR score (7.1 vs 3.7, p < 0.001). Eighteen children with MetS were found to be at an increased risk for severe steatosis (odds ratio [OR] 11.36, p <0.001). After receiver operating characteristic (ROC) curve analysis, the best area under the curve (AUC) was obtained for HOMA-R of 0.862. The HOMA-R 4.9 cut-off value had a 100% sensitivity (CI 95%: 96.2-100) and 67.9% specificity (CI 95%: 57.1-78.7) for severe steatosis. Conclusions: The presence of MetS and glucose metabolism alterations are risk factors for severe steatosis. The 4.9 cut-off value for HOMA-IR may be a risk factor for severe steatosis in obese children (AU)

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Insulin resistance and the metabolic syndrome are related to the severity of steatosis in the pediatric population with obesity.

BACKGROUND: To determine the factors associated with an increased risk for severe steatosis (SS) and establish the Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) as a screening tool. METHODS: A cross-sectional study was performed in obese children to assess the relationship between the metabolic syndrome (MetS) and glucose metabolism alterations (GMA) and the risk for severe steatosis. RESULTS: A total of 94 children (51 males) aged from six to 14 years were included. Thirteen children (14.8%) had severe steatosis (SS). The anthropometric variables associated with SS included body mass index (BMI) (SS 34.1 vs non-SS 29.7, p = 0.005), waist circumference (cm) (100 vs 92.5, p = 0.015) and hip circumference (cm) (108 vs 100, p = 0.018). The blood parameters included alanine aminotransferase (ALT) (UI/dl) (27 vs 21, p = 0.002), gamma-glutamil transpeptidase (GGT) (UI/dl) (16 vs 15, p = 0.017), fasting glycemia (mg/dl) (96 vs 88, p = 0.006), fasting insulin (UI/dl) (25 vs 15.3, p < 0.001) and HOMA-IR score (7.1 vs 3.7, p < 0.001). Eighteen children with MetS were found to be at an increased risk for severe steatosis (odds ratio [OR] 11.36, p < 0.001). After receiver operating characteristic (ROC) curve analysis, the best area under the curve (AUC) was obtained for HOMA-R of 0.862. The HOMA-R 4.9 cut-off value had a 100% sensitivity (CI 95%: 96.2-100) and 67.9% specificity (CI 95%: 57.1-78.7) for severe steatosis. CONCLUSIONS: The presence of MetS and glucose metabolism alterations are risk factors for severe steatosis. The 4.9 cut-off value for HOMA-IR may be a risk factor for severe steatosis in obese children.

Caso de pancreatitis aguda tóxica por infusiones de cola de caballo / Case of drug-induced acute pancreatitis produced by horsetail infusions

Introducción: las causas más frecuentes de pancreatitis aguda son las litiasis biliares, el consumo de alcohol, el tabaquismo o los tumores. Hay un porcentaje de ellas que quedan sin causa establecida, catalogándose de pancreatitis idiopática. Caso clínico: presentamos el caso de una mujer de 56 años con antecedente de suprarrenalectomía bilateral de las glándulas suprarrenales en tratamiento hormonal sustitutivo con corticoides, que presenta episodios de pancreatitis aguda leve de repetición con estudio etiológico (analítico y pruebas de imagen) sin hallazgos. Se sospecha el origen tóxico, por lo que se retiran los corticoides y se modifica el tratamiento antihipertensivo, pero la clínica persiste. Posteriormente se detecta el consumo habitual de infusiones de cola de caballo. Tras su suspensión la paciente se queda asintomática y no vuelve a presentar nuevos episodios. Discusión: la pancreatitis aguda tóxica es una causa rara de pancreatitis que con cierta frecuencia queda sin diagnosticar por la dificultad de establecer una relación entre el agente tóxico y la pancreatitis. Los fármacos relacionados con las pancreatitis agudas son múltiples, mientras que la información disponible es escasa con los productos de herboristería. Se suelen presentar como episodios leves y recurrentes, sin objetivar la causa en el estudio tanto analítico como por pruebas complementarias (ecografía de abdomen, tomografía computarizada [TC] de abdomen, colangiopancreatografía por resonancia magnética [RMN] y ecoendoscopia). Es importante detectar el origen de estas pancreatitis para evitar su recurrencia (AU)

Introduction: The most frequent causes of acute pancreatitis are biliary stones, alcohol consumption, smoking and tumors. Some of them do not have any established cause, and they are catalogued as idiopathic pancreatitis. Case report: We report the case of a 56-year-old woman with a history of bilateral adrenalectomy on hormone replacement therapy with corticosteroids, who has recurrent episodes of mild acute pancreatitis with an etiologic study (laboratory and imaging tests) without significant findings. A drug-induced etiology was suspected, so corticosteroids were removed and antihypertensive treatment was modified, but the clinical manifestations persisted. Later regular consumption of horsetail infusions was detected, and after their suspension the patient became asymptomatic and has not presented new episodes. Discussion: The drug-induced acute pancreatitis is a strange cause of pancreatitis that is frequently underdiagnosed because of the difficulty to establish a relationship between the drugs and the pancreatitis. Lots of drugs have been related with acute pancreatitis, while the information available for herbal products is limited. They usually present like mild and recurrent episodes, without significant findings in both laboratory and imaging tests (abdominal ultrasound, abdominal computed tomography [CT], cholangiography and endoscopic ultrasound). It is important to detect the origin of this type of pancreatitis to prevent recurrence (AU)

Case of drug-induced acute pancreatitis produced by horsetail infusions.

INTRODUCTION: The most frequent causes of acute pancreatitis are biliary stones, alcohol consumption, smoking and tumors. Some of them do not have any established cause, and they are catalogued as idiopathic pancreatitis. CASE REPORT: We report the case of a 56-year-old woman with a history of bilateral adrenalectomy on hormone replacement therapy with corticosteroids, who has recurrent episodes of mild acute pancreatitis with an etiologic study (laboratory and imaging tests) without significant findings. A drug-induced etiology was suspected, so corticosteroids were removed and antihypertensive treatment was modified, but the clinical manifestations persisted. Later regular consumption of horsetail infusions was detected, and after their suspension the patient became asymptomatic and has not presented new episodes. DISCUSSION: The drug-induced acute pancreatitis is a strange cause of pancreatitis that is frequently underdiagnosed because of the difficulty to establish a relationship between the drugs and the pancreatitis. Lots of drugs have been related with acute pancreatitis, while the information available for herbal products is limited. They usually present like mild and recurrent episodes, without significant findings in both laboratory and imaging tests (abdominal ultrasound, abdominal computed tomography [CT], cholangiography and endoscopic ultrasound). It is important to detect the origin of this type of pancreatitis to prevent recurrence.

Metástasis pancreática única de carcinoma renal / Solitary pancreatic metastasis from renal carcinoma

Presentamos el caso de un varón de 60 años, con antecedentes de nefrectomía radical izquierda por carcinoma renal, en grado nuclear II de Fuhrman, 8 años atrás. Por traumatismo abdominal cerrado se solicitó una TC abdominal en la que se observó una lesión sólida, hipervascular en la cabeza pancreática de 4cm de diámetro. Con la sospecha diagnóstica de metástasis pancreática de carcinoma renal se realizó duodenopancreatectomía cefálica con preservación pilórica. El estudio anatomopatológico confirmó la presunción diagnóstica. A los 23 meses de seguimiento el paciente está libre de enfermedad (AU)

We present the case of a 60-year-old man with a history of left radical nephrectomy due to Fuhrman nuclear grade II renal carcinoma 8 years previously. Abdominal computed tomography was performed due to a closed abdominal injury, revealing a solid, 4-cm hypervascular mass in the head of the pancreas. The suspected diagnosis was pancreatic metastasis from renal carcinoma. Cephalic duodenopancreatectomy was performed. The diagnosis was confirmed by histopathological analysis. At 23 months of follow-up, the patient remains disease free (AU)