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Resumen La incorporacion de los antivirales de accion directa al tratamiento de la hepatitis C cronica permite simplificar el diagnostico y seguimiento del paciente, optimizando los recursos asistenciales (consultas y pruebas) dedicados al abordaje de la enfermedad. El objetivo fue estimar el impacto economico derivado de esta simplificacion. La optimizacion de recursos asistenciales se estimo, mediante el metodo Delphi, a partir de un panel de 36 expertos clinicos espanoles, y de las guias de practica clinica. Los costes unitarios (€ en 2017) de los recursos sanitarios considerados se obtuvieron de fuentes espanolas. La simplificacion del proceso, asi como la coordinacion entre el medico especialista, enfermeria y el servicio de farmacia, generarian unos ahorros por paciente de 591,17 €. Asimismo, se estima que la duracion media de las consultas seria inferior con regimenes diarios de 1 solo comprimido que con regimenes de mas de 1 comprimido al dia. Informacion sobre el suplemento: este articulo forma parte del suplemento titulado “El valor de la simplicidad en el tratamiento de la hepatitis C”, que ha sido patrocinado por Gilead. © 2019 Elsevier Espana, S.L.U. Todos los derechos reservados.

Background and objective The emergence of highly tolerable, effective, and shorter duration direct-acting antivirals (DAAs) regimens offers the opportunity to simplify hepatitis C virus management but medical costs are unknown. Thus, we aimed to determine the direct medical costs associated with a combo-simplified strategy (one-step diagnosis and low monitoring) to manage HCV infection within an 8-week glecaprevir/pibrentasvir (GLE/PIB) regimen in clinical practice in Spain. Patients and methods Healthcare resources and clinical data were collected retrospectively from medical charts of 101 eligible patients at 11 hospitals. Participants were adult, treatment naive subjects with HCV infection without cirrhosis in whom a combo-simplified strategy with GLE/PIB for 8 weeks were programmed between Apr-2018 and Nov-2018. Results The GLE/PIB effectiveness was 100% (CI95%: 96.2–100%) in the mITT population and 94.1% (CI95%: 87.5–97.8%) in the ITT population. Three subjects discontinued the combo-simplified strategy prematurely, none of them due to safety reasons. Five subjects reported 8 adverse events, all of mild-moderate intensity. Combo-simplified strategy mean direct costs were 754.35 ± 103.60€ compared to 1689.42€ and 2007.89€ of a theoretical 12-week treatment with 4 or 5 monitoring visits, respectively; and 1370.95€ and 1689.42€ of a theoretical 8-week with 3 or 4 monitoring visits, respectively. Only 4.9% of the subjects used unexpected health care resources. Conclusions 8-week treatment with GLE/PIB combined with a combo simplified strategy in real-life offers substantial cost savings without affecting the effectiveness and safety compared to traditional approaches.

TThe incorporation of direct-acting antiviral agents to the treatment of chronic hepatitis C infection has simplified diagnosis and follow-up, allowing optimisation of health resources (consultations and tests) dedicated to the management of the disease. The aim of this study was to estimate the economic impact of this simplification. Health resource optimisation was estimated through the Delphi method, based on a panel of 36 experts, consisting of Spanish clinicians, and on clinical practice guidelines. The unit costs (€ in 2017) of the health resources included were obtained from Spanish sources. Simplification of the process, as well as liaison between the medical specialist, nurses and the pharmacy service, would generate savings of €591.17 per patient. Likewise, the mean length of consultations would be shorter with regimens of only 1 tablet daily compared with regimens of more than 1 tablet daily. Supplement information: This article is part of a supplement entitled "The value of simplicity in hepatitis C treatment", which is sponsored by Gilead. © 2019 Elsevier España, S.L.U. All rights reserved.

Resumen Introduccion GIDEON es un estudio internacional prospectivo, no intervencionista, que evaluo la seguridad de sorafenib en pacientes con carcinoma hepatocelular (CHC) no resecable en la practica clinica diaria, incluidos pacientes Child-Pugh B. Objetivos Analisis de datos recogidos en Espana sobre seguridad y efectividad de sorafenib y los patrones de tratamiento. Metodos Se recogieron los datos demograficos y de la enfermedad, la dosis inicial usada, los acontecimientos adversos emergentes del tratamiento (AA) y las modificaciones de dosis a lo largo del seguimiento. Se valoraron la supervivencia global y el tiempo hasta la progresion de la enfermedad. La eficacia y la seguridad se analizaron en funcion de la clasificacion Child-Pugh y la dosis inicial. Resultados Se incluyo a 143 pacientes de 19 hospitales espanoles. El 24,5% eran pacientes Child-Pugh B. El 90,9% de los pacientes recibio una dosis inicial de 400 mg/12 h. En pacientes Child-Pugh A se modifico mas frecuentemente la dosis y la duracion del tratamiento fue mas larga. La incidencia de AA y de aquellos relacionados con el farmaco fue similar en los pacientes Child-Pugh A y B, aunque los AA graves fueron mas frecuentes en los pacientes Child-Pugh B. Los mas frecuentes fueron diarrea, fatiga y eritrodisestesia palmo-plantar. La mediana de supervivencia global fue de 384 dias, y superior en pacientes Child-Pugh A (593 vs. 211 dias en Child-Pugh B); la mediana hasta la progresion de la enfermedad fue de 177 dias, similar en ambos subgrupos. Conclusion El perfil de seguridad de sorafenib en pacientes espanoles con CHC no resecable es independiente de la funcion hepatica. El estado Child-Pugh no parece influir en el enfoque de dosificacion de sorafenib ni en el tiempo hasta la progresion, pero si parece ser un fuerte predictor de la supervivencia.

Chronic hepatitis C virus infection is usually asymptomatic. The severity of the hepatic lesion in these patients at diagnosis varies and, from the histopathologic point of view, most have mild disease. A series of factors have been described that correlate with the progression of fibrosis in patients with mild fibrosis: age at diagnosis, the duration of the infection, male sex, HIV coinfection, transaminase levels during follow-up, alcohol consumption, metabolic factors such as diabetes and overweight, necroinflammatory activity in the initial biopsy, and the degree of steatosis. In patients with genotype 1 hepatitis C infection, the standard treatment has been pegylated interferon and ribavirin. However, response rates are markedly increased by concomitant use of first-generation protease inhibitors, boceprevir or telaprevir. In patients with moderate fibrosis, these drugs are well tolerated, in addition to being effective. Currently, dual therapy should be reserved for patients with good baseline predictive factors of response and/or contraindications for treatment with telaprevir or boceprevir. In patients with genotypes other than genotype 1, the standard treatment continues to be the combination of pegylated interferon and ribavirin, although the development of new direct-acting antiviral agents such as sofosbuvir and simeprevir will change the strategies used in these patients. The decision to wait for the new treatments is complex because their release date is unknown; likewise, their high cost will limit the possibilities for their use.

Drug-induced liver damage is one of the most complex liver diseases due to its similar presentation to other acute or chronic liver processes, its potential severity and the absence of specific biomarkers to confirm diagnosis, which is based on clinical suspicion and exclusion of alternative causes. Because the drug development process fails to completely screen out hepatotoxic molecules and identify susceptible individuals, postmarketing pharmacovigilance remains essential. Hepatotoxicity registries are the ideal instrument for systematic and continual data collection, using preestablished criteria based on consensus. The present article briefly describes the contributions of the Spanish Hepatotoxicity Registry and those of other international registries. Hopefully, Latin American registries will be incorporated into existing initiatives, which will stimulate research and improve understanding of the complex mechanisms involved in this adverse reaction.

Resumen Fundamento y objetivo La monoterapia con adefovir dipivoxil en pacientes resistentes a lamivudina se asocia con mayor desarrollo de resistencias que en naive. La respuesta virologica durante el tratamiento predice el riesgo de resistencias. Los objetivos de este estudio son evaluar la eficacia del tratamiento con adefovir dipivoxil en pacientes naive y resistentes a lamivudina y valorar si la respuesta virologica predice el desarrollo de resistencias a adefovir. Pacientes y metodo Se ha incluido a 82 pacientes con hepatitis cronica B (HCB) HBeAg negativo tratados con adefovir dipivoxil. Durante el tratamiento se determino ADNVHB por reaccion en cadena de la polimerasa y en los casos de breakthrough virologico, se estudio la presencia de mutaciones asociadas a resistencia a adefovir. Resultados La respuesta virologica a los 12 y 24 meses fue del 59 y el 73% en naive y del 40 y el 67% en resistentes a lamivudina. El breakthrough virologico a los 24 meses fue del 9,5% en naive y el 20% en resistentes a lamivudina. El 4% de los naive con respuesta virologica a los 12 meses presento breakthrough virologico entre 12 y 40 meses de tratamiento frente al 29,4% de los pacientes sin respuesta virologica (p = 0,03). En resistentes a lamivudina la respuesta virologica a los 12 meses no predijo el breakthrough virologico. Conclusiones La monoterapia con adefovir dipivoxil en pacientes resistentes a lamivudina se asocia con mayor tendencia al desarrollo de breakthrough virologico no predecible por la respuesta virologica a los 12 meses de tratamiento. En pacientes naive la carga viral no detectable a los 12 meses de tratamiento predice la ausencia de breakthrough virologico hasta los 40 meses de tratamiento.

Immunosuppressants are among the pharmacological agents with the greatest potential to cause adverse reactions, although induction of hepatotoxicity is paradoxical from the pathogenic point of view, since the response of the innate and acquired immune system is a key element in the chain of events leading to chemical liver damage. Hepatotoxicity induced by immunosuppressants is difficult to evaluate since these drugs are sometimes used to treat liver diseases, or in combination with other drugs that can also cause hepatotoxicity, or in the context of liver transplantation, in which rejection or biliary complications can act as confounding factors. In addition, immunosuppressant therapy can favor the development of infections, which by themselves can cause liver damage, or reactivate latent chronic viral hepatitis. Corticosteroids and calcineurin inhibitors only exceptionally cause hepatotoxicity. Methotrexate at high doses and in patients with risk factors can induce advanced fibrosis and cirrhosis. Thiopurine agents can cause a spectrum of hepatic lesions, including hepatocellular of cholestatic lesions, and hepatic vascular alterations. Leflunomide has high hepatotoxic potential, especially when combined with methotrexate. Anti-tumor necrosis factor-alpha agents have rarely been associated with hepatotoxicity, often with detectable autoantibodies, and most of the reactions - some severe - have been linked to infliximab, especially when used in patients with rheumatological diseases.

Introduccion La prevalencia de homocigosidad para C282Y en pacientes con hemocromatosis hereditaria (HH) originarios de algunos paises de la cuenca mediterranea puede ser sustancialmente inferior a la observada en el norte de Europa. Los datos referidos a Espana son contradictorios y basados en series pequenas de ambito regional. El objetivo de nuestro estudio es determinar la prevalencia de las 2 principales mutaciones del gen HFE en una serie de pacientes espanoles con HH, no relacionados y de diferente procedencia geografica. Pacientes y mEtodo Los criterios para el diagnostico de HH fueron: indice de saturacion de transferrina superior al 45% en 2 determinaciones y homocigosidad para C282Y y/o indice de hierro hepatico mayor de 1,9 de tejido hepatico seco en pacientes no cirroticos o superior a 4,1 en presencia de cirrosis. Se excluyeron los casos detectados en familiares. Se evaluaron los datos demograficos, la expresion clinica, los parametros del hierro y las mutaciones C282Y y H63D del gen HFE en un total de 222 pacientes. Resultados El 83,3% de los pacientes fueron homocigotos para C282Y y el 5% dobles heterocigotos (C282Y/H63D). No se observaron diferencias significativas en la expresion fenotipica ni en la frecuencia de homocigosidad para C282Y en los pacientes nacidos en el norte o en el sur de Espana. Conclusion El patron genotipico y la expresion fenotipica de la HH en Espana son muy similares a los observados en el norte de Europa. Por tanto, la heterogeneidad genetica descrita en algunas regiones del sur de Europa no puede considerarse una caracteristica comun a todos los paises de la cuenca mediterranea.

Sr. Director: Alfuzosina es un derivado de quinazolina cuyo mecanismo de accion es antagonizar de forma competitiva y selectiva los receptores ?1-adrenergicos implicados en la contraccion del tracto urinario bajo1. Es usado exclusivamente para el tratamiento de la hiperplasia prostatica benigna2. Este agente es metabolizado principalmente por el higado y un 11% del compuesto es excretado de forma inalterada en la orina1. El perfil de seguridad de alfuzosina es similar al de placebo si se tiene en cuenta la globalidad de los incidentes adversos asociados a ambos1,3. Ademas, presenta una eficacia y seguridad similar a otros bloqueantes alfa-1 como doxazosina y tamsulosina2. La incidencia de efectos adversos es baja, siendo los mas comunes cardiovasculares, especialmente en pacientes ancianos y pacientes tratados con farmacos para el aparato cardiovascular (antihipertensivos, inhibidores de la enzima conversora de la angiotensina, bloqueantes de los canales del calcio y diureticos)4,5. Otros efectos reportados han sido los gastrointestinales: nauseas, vomitos, dispepsia y diarrea6,7. Alfuzosina ha sido muy raramente involucrado en reacciones hepatotoxicas8,9,10. Presentamos un caso de lesion hepatocelular recurrente por alfuzosina. Varon de 55 anos que fue evaluado por hipertransaminasemia. Habia tomado alfuzosina (10mg/24h, formulacion de liberacion prolongada) desde el 18 abril de 2007 hasta el 15 enero de 2008, siendo interrumpido por hipertransaminasemia ALT 109 UI/l (VN

Drug-induced liver damage is one of the most complex liver diseases due to its similar presentation to other acute or chronic liver processes, its potential severity and the absence of specific biomarkers to confirm diagnosis, which is based on clinical suspicion and exclusion of alternative causes. Because the drug development process fails to completely screen out hepatotoxic molecules and identify susceptible individuals, postmarketing pharmacovigilance remains essential. Hepatotoxicity registries are the ideal instrument for systematic and continual data collection, using preestablished criteria based on consensus. The present article briefly describes the contributions of the Spanish Hepatotoxicity Registry and those of other international registries. Hopefully, Latin American registries will be incorporated into existing initiatives, which will stimulate research and improve understanding of the complex mechanisms involved in this adverse reaction.

Adefovir dipivoxil monotherapy in lamivudine-resistant patients is associated with more frequent development of resistance than in naïve patients. The virological response during treatment predicts the risk of developing resistance. The aims of this study were to assess the efficacy of adefovir dipivoxil treatment in naïve and lamivudine-resistant patients and to determine whether virological response predicts the development of adefovir resistance.This study included 82 patients with HBeAg-negative chronic hepatitis B (CHB) who received adefovir dipivoxil therapy. During active treatment, HBV-DNA values were determined by polymerase chain reaction; in addition, the presence of adefovir resistance-associated mutations was studied in cases of virological breakthrough.Virological response at 12 and 24 months was 59% and 73% in naive patients compared with 40% and 67% in lamivudine-resistant patients, whereas virological breakthrough at 24 months was 9.5% in naïve patients compared with 20% in lamivudine-resistant patients. A small percentage (4%) of patients with virological response at 12 months showed virological breakthrough between 12 and 40 months versus 29.4% of patients without virological response (P=.03). In lamivudine-resistant patients, virological response at 12 months was not a predictive factor for the development of virological breakthrough.Adefovir dipivoxil monotherapy in lamivudine-resistant patients is associated with an increased tendency to develop virological breakthrough, which cannot be predicted by virological response at 12 months of treatment. In naive patients, an undetectable viral load at 12 months of treatment ensures the absence of virological breakthrough at 40 months of treatment.

Immunosuppressants are among the pharmacological agents with the greatest potential to cause adverse reactions, although induction of hepatotoxicity is paradoxical from the pathogenic point of view, since the response of the innate and acquired immune system is a key element in the chain of events leading to chemical liver damage. Hepatotoxicity induced by immunosuppressants is difficult to evaluate since these drugs are sometimes used to treat liver diseases, or in combination with other drugs that can also cause hepatotoxicity, or in the context of liver transplantation, in which rejection or biliary complications can act as confounding factors. In addition, immunosuppressant therapy can favor the development of infections, which by themselves can cause liver damage, or reactivate latent chronic viral hepatitis. Corticosteroids and calcineurin inhibitors only exceptionally cause hepatotoxicity. Methotrexate at high doses and in patients with risk factors can induce advanced fibrosis and cirrhosis. Thiopurine agents can cause a spectrum of hepatic lesions, including hepatocellular of cholestatic lesions, and hepatic vascular alterations. Leflunomide has high hepatotoxic potential, especially when combined with methotrexate. Anti-tumor necrosis factor-alpha agents have rarely been associated with hepatotoxicity, often with detectable autoantibodies, and most of the reactions - some severe - have been linked to infliximab, especially when used in patients with rheumatological diseases.