[Tratamiento de infección crónica por virus de hepatitis C en niños, ¿perspectiva hacia la curación o lejos de la meta?]

La infección por el virus de hepatitis C es un problema global de salud pública; en México aproximadamente 2 % de la población se encuentra infectada. En niños, los datos de prevalencia son variables según la edad, pero se estima que 0.1 a 2 % de los niños presenta infección crónica por virus de hepatitis C, cuya principal vía de transmisión es la perinatal. Actualmente existen antivirales de acción directa aprobados en adultos con una tasa de respuesta viral sostenida superior a 95 %; sin embargo, en niños aún son pocos los estudios que confirman su seguridad y efectividad. Aunque todavía estamos lejos de la meta, avanzamos rápidamente hacia un tratamiento óptimo de curación también para pacientes pediátricos.

Infection with hepatitis C virus is a global health problem; in Mexico, approximately 2% of the population is infected. In children, data on prevalence are variable according to the age group, but 0.1-2% of children are estimated to have chronic infection with hepatitis C virus, the main way of transmission of which is perinatal. Currently, there are direct-acting antiviral agents approved in adults that offer a sustained viral response rate higher than 95%; however, in children there are still only few studies confirming their safety and effectiveness. Although we are still far from the goal, we are rapidly advancing towards an optimal curative treatment also for pediatric patients.

Tratamiento de infección crónica por virus de hepatitis C en niños, ¿perspectiva hacia la curación o lejos de la meta? / Treatment of chronic hepatitis C virus infection in children, prospect towards cure or far from the goal?

Resumen La infección por el virus de hepatitis C es un problema global de salud pública; en México aproximadamente 2 % de la población se encuentra infectada. En niños, los datos de prevalencia son variables según la edad, pero se estima que 0.1 a 2 % de los niños presenta infección crónica por virus de hepatitis C, cuya principal vía de transmisión es la perinatal. Actualmente existen antivirales de acción directa aprobados en adultos con una tasa de respuesta viral sostenida superior a 95 %; sin embargo, en niños aún son pocos los estudios que confirman su seguridad y efectividad. Aunque todavía estamos lejos de la meta, avanzamos rápidamente hacia un tratamiento óptimo de curación también para pacientes pediátricos.

Abstract Infection with hepatitis C virus is a global health problem; in Mexico, approximately 2% of the population is infected. In children, data on prevalence are variable according to the age group, but 0.1-2% of children are estimated to have chronic infection with hepatitis C virus, the main way of transmission of which is perinatal. Currently, there are direct-acting antiviral agents approved in adults that offer a sustained viral response rate higher than 95%; however, in children there are still only few studies confirming their safety and effectiveness. Although we are still far from the goal, we are rapidly advancing towards an optimal curative treatment also for pediatric patients.

Multicenter Experience using Ledipasvir/Sofosbuvir ± RBV to Treat HCV GT 1 Relapsers after Simeprevir and Sofosbuvir Treatment.

INTRODUCTION AND AIM: Approximately 10%-15% of patients with hepatitis C genotype 1 (HCV GT1) experience virological relapse after all-oral antiviral regimen using simeprevir (SMV) and sofosbuvir (SOF). The efficacy and safety of treating such relapsers using ledipasvir/sofosbuvir (LDV/SOF) with/without ribavirin (RBV) has been limited. OBJECTIVE: Report the virological response and safety of LDV/SOF with/without RBV for 12-24 weeks in treating HCV GT1 relapsers after SMV + SOF. MATERIAL AND METHODS: Patients treated with standardized clinical protocol utilizing LDV/SOF with/without RBV at three transplant centers were retrospectively reviewed. RESULTS: Forty-five patients (29% post-LT, 82% male, 13% non-white, 73% subtype 1a, 86% IL28B CT/TT, 78% F3-4) started LDV/SOF with/without RBV at a median of 22 weeks (range 7-55 weeks) after the last dose of SMV+SOF treatment. Thirty-seven patients received LDV/SOF for 24 weeks (24/37 patients with RBV) and eight patients received LDV/SOF for 12 weeks (5/8 patients with RBV). RBV dose was adjusted for renal function. Sixteen patients who were RBV-ineligible received LDV/SOF without RBV for 12 or 24 weeks. SVR 12 was achieved in 96% (43/45) of patients. Baseline viral load, RBV use, or GT1 subtype did not impact SVR 12. Minimal adverse events were reported in those without RBV; 45% of patients who received RBV developed significant anemia requiring RBV dose reduction and/or discontinuation. In LT recipients, minimal immunosuppression dose adjustments were required and no biopsy-proven acute rejection occurred. CONCLUSIONS: Treatment with LDV/SOF with/without RBV for 12-24 weeks was very well tolerated and resulted in high SVR 12 rates (96%) in HCV GT1 relapsers to SMV + SOF treatment.

The Mexican consensus on the treatment of hepatitis C. / Consenso Mexicano para el Tratamiento de la Hepatitis C.

The aim of the Mexican Consensus on the Treatment of HepatitisC was to develop clinical practice guidelines applicable to Mexico. The expert opinion of specialists in the following areas was taken into account: gastroenterology, infectious diseases, and hepatology. A search of the medical literature was carried out on the MEDLINE, EMBASE, and CENTRAL databases through keywords related to hepatitisC treatment. The quality of evidence was subsequently evaluated using the GRADE system and the consensus statements were formulated. The statements were then voted upon, using the modified Delphi system, and reviewed and corrected by a panel of 34 voting participants. Finally, the level of agreement was classified for each statement. The present guidelines provide recommendations with an emphasis on the new direct-acting antivirals, to facilitate their use in clinical practice. Each case must be individualized according to the comorbidities involved and patient management must always be multidisciplinary.

Access to direct-acting antivirals for the treatment of hepatitis C in a country with limited resources. / Evaluación del acceso a antivirales para el tratamiento de la hepatitis C en un país con recursos limitados.

AIMS: To estimate the number of patients that have access to treatment of hepatitis C with direct-acting antivirals in Argentina and evaluate the factors associated with the lack of access. MATERIALS AND METHODS: A cross-sectional cohort study was conducted that included all the consecutive prescriptions of direct-acting antivirals issued at health centers that participated in the ECHOTM telemedicine project directed by the Hospital Italiano de Buenos Aires, within the time frame of January 2016 and February 2017. RESULTS: A total of 143 treatment prescriptions were included and overall access was 70% (95% CI 62-77%). The only independent factor associated with a lack of treatment access was coverage by a public healthcare system (OR 4.98 [95% CI 2.05- 12.09]). CONCLUSION: Patients with hepatitis C that were covered by a public healthcare system had a 4 times higher chance of not having access to treatment with direct-acting antivirals than patients covered by other healthcare systems (private insurance or the social welfare system).

Rationale for treating hepatitis C virus infection in patients with mild to moderate chronic kidney disease.

Hepatitis C virus infection (HCV) is highly prevalent in patients with chronic kidney disease (CKD) and kidney transplant recipients. Little information exists on treatment in patients with CKD stages 2 to 3, where CKD progression might be slowed by HCV treatment. These patients are not considered a high priority for HCV treatment in most international guidelines. Although some recently published guidelines propose universal treatment, others are still recommending it only in high priority groups. In this review, we evaluate current evidence of HCV infection impact on CKD progression, on cardiovascular and metabolic risk, and the benefits of HCV infection treatment to improve cardiovascular and metabolic outcomes. We made special focus on the benefits of HCV infection treatment in patients with stages 2 to 3 CKD to avoid CKD progression.

Hepatitis C and Its Metabolic Complications in Kidney Disease.

INTRODUCTION: Evidence has been accumulated during the last decade showing that HCV infection plays an important activity at hepatic and extra-hepatic level. Chronic HCV is associated with a large spectrum of extra-hepatic manifestations including lympho-proliferative diseases and metabolic abnormalities (such as insulin resistance and fatty liver disease). MATERIAL AND METHODS: We have performed an extensive review of the medical literature regarding the increased risk of cardiovascular and kidney disease that has been observed in various groups of HCV-infected patients. The potential link between such increased risk and the metabolic consequences of chronic HCV infection has been explored. RESULTS: According to a systematic review with a meta-analysis of longitudinal studies (n = 9 clinical observational studies; n = 1,947,034 unique patients), we found a strong relationship between positive anti-HCV serologic status and increased incidence of chronic kidney disease in the adult general population, the summary estimate for adjusted hazard ratio was 1.43 (95% confidence intervals, 1.23; 1.63, P = 0.0001) (random-effects model) in anti-HCV positive patients. In another meta-analysis of clinical observational studies (n = 145,608 unique patients on long term dialysis; n = 14 observational studies), anti-HCV sero-positive status was an independent and significant risk factor for death in patients on maintenance dialysis. The summary estimate for adjusted relative risk (all-cause mortality) was 1.35 with a 95% confidence interval (CI) of 1.25; 1.47 (P < 0.01) in anti-HCV positive patients on maintenance dialysis. An updated and stratified analysis (n = 4 studies, n = 91,916 patients on maintenance dialysis) resulted in an adjusted HR for cardiovascular mortality among anti-HCV positive patients of 1.21 (95% CI, 1.06; 1.39) (P < 0.01); the homogeneity assumption was not rejected. The mechanisms underlying such relationships remain unclear; it has been suggested that HCV promotes atherogenesis through direct and indirect mechanisms. CONCLUSIONS: Clinical trials are under way to assess whether the clearance of HCV RNA from serum by direct-acting antiviral drugs reduces all cause or disease-specific (cardiovascular) mortality among patients on maintenance dialysis.

Coinfección virus de inmunodeficiencia humana-virus de la Hepatitis C: hacia un nuevo escenario terapéutico / Human Immunodeficiency Virus-Hepatitis C virus coinfection: towards a new therapeutic scenario

Introducción: Las terapias contra el virus de la Hepatitis C han evolucionado vertiginosamente con el desarrollo de los antivirales de acción directa (AADs). Los nuevos regímenes han conseguido igualar las tasas de respuesta al tratamiento en los monoinfectados y los coinfectados con VIH, una población tradicionalmente difícil de tratar debido a la elevada morbimortalidad hepática y sistémica, reacciones adversas e interacciones medicamentosas. Objetivo: Analizar las opciones farmacoterapéuticas más modernas disponibles para los pacientes coinfectados con VIH y VHC, con énfasis en los nuevos antivirales de acción directa, a fin de ofrecer una herramienta útil en el abordaje terapéutico en estos pacientes. Material y métodos: Se revisaron artículos originales, ensayos clínicos y revisiones sistemáticas hasta septiembre de 2016, bases de datos internacionales de interacciones medicamentosas y Guías de Práctica Clínica actualizadas. Desarrollo: Las terapias contra el virus de la Hepatitis C (VHC) han evolucionado vertiginosamente con el desarrollo de los antivirales de acción directa (AADs). Los nuevos regímenes han conseguido igualar las tasas de respuesta al tratamiento en los monoinfectados y los coinfectados con VIH, una población tradicionalmente difícil de tratar que, además, asociaba una elevada morbimortalidad hepática y sistémica, más reacciones adversas y complejas interacciones medicamentosas. Conclusiones: En este nuevo escenario es fundamental dedicar esfuerzos a identificar el elevado porcentaje de infectados no diagnosticados, potenciales interacciones, especialmente con fármacos para patologías asociadas al envejecimiento de los pacientes, reacciones adversas a medio-largo plazos y desarrollo de resistencias, además de garantizar la cobertura universal en todos los contextos clínicos(AU)

Introduction:Therapies for hepatitis C virus (HCV) have rapidly evolved with the development of direct-acting antiviral agents. New regimens, achieve an equate response rates to treatment in cases of HCV mono-infected and HIV/HCV co-infected; a population traditionally difficult to treat due to a high hepatic and systemic morbidity-mortality, adverse reactions and drug interactions. Objective: To analyse the current Pharma-therapeutic options available for co-infected HIV-HCV patients, with emphasis I the new direct-acting antiviral agents, in order to offer a useful tool for the therapeutic approach in these patients. Material and Methods: Original articles, clinical studies and systematic reviews until September 2016 were carried out, as well as international drug interactions databases and updated Practical Guidelines. Development: Therapies for hepatitis C virus (HCV) have rapidly evolved with the development of direct-acting antiviral agents. New regimens achieve an equate response rates to treatment in HCV mono-infected and HIV/HCV co-infected; a population traditionally difficult to treat, which also associate a high hepatic and systemic morbidity-mortality, adverse reactions and complex drug interactions. Conclusions: In this new scenario efforts must be addressed to identify the high percentage of undiagnosed patients; potential interactions, especially with drugs related with patient aging; medium and long-term adverse reactions and development of drug resistances, as well as to guarantee universal coverage in all clinical contexts(AU)

Genetic diversity of NS3 protease from Brazilian HCV isolates and possible implications for therapy with direct-acting antiviral drugs

The hepatitis C virus (HCV) NS3 protease has been one of the molecular targets of new therapeutic approaches. Its genomic sequence variability in Brazilian HCV isolates is poorly documented. To obtain more information on the magnitude of its genetic diversity, 114 Brazilian HCV samples were sequenced and analysed together with global reference sequences. Genetic distance (d) analyses revealed that subtype 1b had a higher degree of heterogeneity (d = 0.098) than subtypes 1a (d = 0.060) and 3a (d = 0.062). Brazilian isolates of subtype 1b were distributed in the phylogenetic tree among sequences from other countries, whereas most subtype 1a and 3a sequences clustered into a single branch. Additional characterisation of subtype 1a in clades 1 and 2 revealed that all but two Brazilian subtype 1a sequences formed a distinct and strongly supported (approximate likelihood-ratio test = 93) group of sequences inside clade 1. Moreover, this subcluster inside clade 1 presented an unusual phenotypic characteristic in relation to the presence of resistance mutations for macrocyclic inhibitors. In particular, the mutation Q80K was found in the majority of clade 1 sequences, but not in the Brazilian isolates. These data demonstrate that Brazilian HCV subtypes display a distinct pattern of genetic diversity and reinforce the importance of sequence information in future therapeutic approaches.