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.

Nuevos progresos en el enfrentamiento a la hepatitis C / New progresses in hepatitis C management

RESUMEN El virus de la hepatitis C es la principal infección trasmitida por los derivados de la sangre en los Estados Unidos, con 3.2 millones de individuos infectados. El alfa interferón inyectable ha sido históricamente la piedra angular en la terapia del virus de hepatitis C. Se revisaron las publicaciones los trabajos publicados en Medline, Scielo, PubMed, e Hinari, hasta comienzos del año 2016. Las principales palabras clave utilizadas fueron virus de la hepatitis C, hepatitis C crónica, Interferón, antivirales. Recientes adelantos han llevado a la disponibilidad de nuevos medicamentos antivirales, que con el desarrollo de nuevas terapias orales libres de interferón han convertido la terapia del virus de la hepatitis C más eficaz además de simplificar los regímenes del tratamiento. Aunque estos regímenes de tratamiento aún permanecen complicados, las nuevas recomendaciones y guías evolucionan rápidamente. El rápido desarrollo de nuevas terapias para la hepatitis C, han logrado métodos más eficaces con menos reacciones adversas que optimizan el tratamiento de estos enfermos (AU).

ABSTRACT The hepatitis C virus is the main infection transmitted by blood products in the United States, with 3.2 million of infected individuals. The injected alpha interferon has historically been the key stone in the therapy of the hepatitis C virus. The works published in Medline, Scielo, PubMed and Hinary until the beginning of 2016 were reviewed. The main used key words were HVC, cronic hepatitis C, interferon, antivirals. Recent advances have led to the availability on new antiviral drugs, developing new interferon-free oral therapies that make the therapy of hepatitis C virus more efficacious and make easier the treatment regimens. Although these treatment regimens are still complicated, the new recommendations and guidelines evolve quickly. The fast development of new therapies against hepatitis C has led to more efficacious methods with less adverse reactions, optimizing the treatment of these patients (AU).

Hepatitis C: evaluation of outcomes and georeferencing of cases in Santa Cruz do Sul, Brazil, between 2002 and 2015. A cross-sectional study

ABSTRACT BACKGROUND: Hepatitis C virus infection is one of the main causes of chronic liver disease, with high death rates. The aim here was to analyze case outcomes, sociodemographic and clinical characteristics and spatial distribution among patients diagnosed with hepatitis C in the city of Santa Cruz do Sul (RS), Brazil. DESIGN AND SETTING: Cross-sectional study on 200 cases of hepatitis C in Santa Cruz do Sul that were notified between 2002 and 2015. METHODS: Secondary data including sociodemographic and clinical variables and type of outcome (death, follow-up, abandonment or clinical cure) were gathered. The spatial distribution analysis on hepatitis C virus cases according to outcome was based on information regarding residential address. RESULTS: 58.5% of the patients were 41 years of age and over, 67% were males and 92.5% had the chronic form of the disease. The most frequent transmission route was illicit drug injection (29%); 15.1% of the patients presented coinfection with the human immunodeficiency virus (HIV). Regarding outcomes, 31% achieved clinical cure, 10% died and 20% abandoned follow-up. The cases studied were mainly located in regions of the city characterized by lower socioeconomic status, with high frequency of places used for drug trafficking. CONCLUSION: The population consisted of adults aged 41 years and over, mostly with chronic hepatitis C. The most common transmission routes were illicit drug injection and blood transfusions. There were high rates of HIV coinfection and abandonment of disease monitoring and predominance of cases in neighborhoods with low socioeconomic status.

Risk factors for hepatitis C virus transmission in the municipality of Catanduva, State of São Paulo: a case-control study

Introduction Hepatitis C virus (HCV) is primarily transmitted via contact with the blood of infected patients, although the form of contact has not been identified for a significant percentage of carriers. The present study evaluated possible risk factors for HCV transmission in a medium-sized town located in the northwest region of the State of São Paulo. Methods This was a case-control study, with the case group consisting of 190 chronic HCV carriers older than 18 years residing in the municipality of Catanduva. The control group also consisted of 190 individuals with HCV-negative serology. The groups were paired (1:1) for gender, age range (± five years), and place of residence. The same structured questionnaire was applied to all subjects, who gave written informed consent to participate in the study. The data were statistically analyzed using crude and adjusted logistic regression, and the results were expressed as odds ratios with a 95% confidence interval. Results The demographic profiles of the groups indicated a predominance of males (68.9%) and mean ages of 47.1 years (case group) and 47.3 years (control group). After adjusting for conditional regression, the following factors were found to represent risks for HCV: history of sexually transmitted disease (STD) and blood transfusion; accidents with syringes and/or needles; tattoos; and the use of non-injectable drugs and injectable medications. Conclusions The transmission of HCV via the blood route has been well characterized. Other forms of contact with human blood and/or secretions are likely to transmit the virus, although with a lower frequency of occurrence. .

Mutações nos genes não estruturais do vírus da hepatite C associadas à resistência aos novos antivirais / Mutations in the nonstructural genes of the hepatitis C virus associated with resistance to new antiviral drugs

Introdução e objetivos: Polimorfismos naturais de resistência aos agentes antivirais de atuação direta (DAAs) no vírus da hepatite C (HCV) podem representar um fator limitante para a eficácia dessa terapia. A análise de sequências virais de regiões geográficas distintas pode apresentar diferenças significativas nas frequências de mutações de resistência aos DAAs. Neste contexto, o objetivo deste estudo foi investigar as mutações associadas à resistência aos DAAs nos genes nãoestruturais (NS) do HCV em isolados virais que circulam no Brasil. Métodos: Foram estudados um total de 390 sequências do genótipo 1 do HCV de pacientes brasileiros virgens de tratamento cronicamente infectados. O RNA viral foi extraído, e as regiões abrangendo os genes NS3, NS4 e NS5 foram amplificadas por RT-PCR e sequenciadas. Resultados: No domínio NS3/4A protease, a variação V36L foi encontrada em 5,60 porcento dos isolados do subtipo 1b, e a substituição T54S em 4,16 porcento das sequências do subtipo 1a; na posição 55, 4,16 porcento dos isolados continham a variação V55A, responsável por causar constrição no sítio de ligação do inibidor de protease boceprevir. Em relação à proteína NS4B, um isolado do subtipo 1b apresentou a substituição F98L, responsável por conferir resistência aos inibidores AP80978, PTC725 e silibina. Na proteína NS5A, 3,84 porcento das sequências do subtipo 1a mostraram as mutações de resistência M28T ou Y93H, e 13,46 porcento, as mutações secundárias H58P e E62D. Dentre os isolados do subtipo 1b, 3,70 porcento continham a mutação Y93H, e 14,8 porcento, as mutações secundárias R30Q, L31M, P58S e I280VEm NS5B, 25 porcento das sequências do subtipo 1b brasileiras apresentaram a variação L159F na população viral dominante, mas nenhuma sequência do subtipo 1a exibiu tal substituição...

Background and aims: Natural resistance polymorphisms to direct antiviral agents (DAAs)in hepatitis C virus (HCV) may represent a limiting factor for therapy efficacy. Analysis of viralsequences from distinct geographical regions may show significant differences in the frequencies ofresistance mutations to DAAs. In this context, the aim of this study was to investigate mutationsassociated with resistance to DAAs of HCV non-structural genes (NS) in viral isolates circulating inBrazil. Methods: A total of 390 HCV genotype 1 sequences from therapy-naive Brazilian patientschronically infected. Viral RNA was extracted, and the region encompassing the non-structuralgenes NS3, NS4, and NS5 was RT-PCR amplified and sequenced. Results: In the NS3/4A proteasedomain, a V36L variation was found in 5,60 percent of subtype 1b isolates and a T54S substitution in4,16 percent of subtype 1a sequences; at position 55, 4,16 percent of strains contained the V55A variationwhich is responsible to cause constriction in the binding site of the protease inhibitor boceprevir.Concerning the NS4B protein, one subtype 1b isolate showed the F98L substitution, responsible forconferring resistance to inhibitors AP80978, PTC725 and Silybin. In the NS5A protein, 3,84 percent ofsubtype 1a sequences showed the resistance mutations M28T and Y93H, while 13,46 percent , thesecondary mutations H58P and E62D. Among subtype 1b isolates, 3,70 percent of patients showed theY93H mutation, while 14,8 percent the secondary mutations R30Q, L31M, P58S and I280V. For NS5B,25 percent of Brazilian subtype 1b sequences presented the L159F variation in the dominant viralpopulation, but none of subtype 1a sequence showed such substitution. Moreover, 15 subtype 1bisolates (29 percent ), were observed the C316N variant, responsible to confer resistance to non-nucleosideinhibitors, while only 2,12 percent of subtype 1a isolates showed the C316Y substitution...

Nuevos antivirales frente al VHC: actualidad y perspectivas / New direct acting antiviral for hepatitis C: future perspectives

Aproximadamente 175 millones de personas están infectadas por el virus de la hepatitis C (VHC), lo que representa un 3% de la población mundial. En ausencia de tratamiento eficaz, un 25% de los pacientes desarrollan complicaciones hepáticas tras 25 años de hepatitis crónica C. Hasta hace poco, la única opción terapéutica en estos pacientes era la combinación de interferón pegilado (peg-IFN) y ribavirina (RBV). Alcanzaban la erradicación del VHC un 30-40% de los pacientes infectados con el genotipo 1 del VHC. Recientes avances han permitido desarrollar replicones y sistemas de cultivo tisulares para el VHC. Esto ha facilitado el diseño de fármacos antivirales directos (DAA) que inhiben específicamente la replicación del VHC. Los dos primeros inhibidores de la proteasa del VHC fueron aprobados en mayo de 2011. Permiten obtener tasas de curación en el 70% de los pacientes infectados con el genotipo 1 sin experiencia previa a interferón. La respuesta es menor en pacientes con fracasos previos, excepto en los recidivantes, en los que tasa de curación es del 90%...

Approximately 175 million people worldwide are chronically infected with the hepatitis C virus (HCV), representing 3% of the total world population. In the absence of successful therapy nearly 25% of these patients will develop hepatic complications within 25 years. Until recently, the only available therapeutic option for these patients was the combination of peginterferon-a plus ribavirin. Overall it allowed achievement of eradication in only 30-40% of patients infected by HCV genotype 1. The development of HCV replicons and the chance of producing infectious viral particles in culture systems have both enabled the rational design of direct-acting antivirals (DAA) that specifically inhibit HCV replication. The first two HCV protease inhibitors were marketed in May 2011. Triple therapy has increased the response rate to 70% in HCV genotype 1 carrier naïve to interferon. Although response rates are lower in prior failures, 90% sustained virological response rates are achieved in prior relapsers...

Infección por virus de la hepatitis C en niños / Hepatitis C virus infection in children

La hepatitis C se adquiere por las vías parenteral, materno-fetal y sexual. Afecta al 3 por ciento de la población mundial. La transmisión vertical constituye la principal forma de diseminación del virus actualmente. La mayoría de los niños desarrolla enfermedad crónica asintomática; sin embargo, puede observarse progresión de la enfermedad en la edad pediátrica. Los anticuerpos contra el virus de la hepatitis C no permiten discriminar entre infección activa y resuelta. Se requiere la determinación por PCR del HCV-ARN. La combinación de peginterferón y ribavirina parece ser el tratamiento más eficaz. El desarrollo de nuevos fármacos, así como el de una vacuna, constituyen los próximos desafíos.

The modes of transmission of hepatitis C virus are parenteral, sexual and maternal-fetal. It affects 3 percent of the population worldwide. Currently, vertical infection is the main way of virus spreading. Most children are clinically asymptomatic, but progression of liver disease has been described. The positivity of antibodies against hepatitis C virus does not discriminate between active and resolved infection, so determination of serum HCV-RNA is necessary. The combination of peginterferon and ribavirin appears to be the most effective treatment. Future challenges are the development of new drugs and a vaccine.

Hepatitis C intervention research - where are we now and where should we be heading?

In this paper we outline some of the major pending research questions that lie ahead in hepatitis C intervention research. We argue why these should be answered with randomised clinical trials and we stress how Egypt and other Arab countries can play an important role in this context. We delineate a number of design issues relevant to recent and future hepatitis C randomised clinical trials and provide insights on how and why randomised clinical trial designed in a pragmatic and evidence-based framework will efficiently answer pending research questions

Infecção pelo vírus da hepatite C na região Amazônica brasileira / Hepatitis C virus infection in the Amazon brazilian region

O artigo avalia informações científicas disponíveis sobre a prevalência e características clínicas da infecção pelo virus da hepatite C na Amazônia Brasileira, uma área sabidamente endêmica para infecção pelos vírus das hepatites A, B e D. Toda a informação foi obtida através de extensa revisão bibliográfica de artigos originais e de revisão e de resumos publicados em periódicos conceituados ou em eventos científicos. Na Região Amazônica, a taxa de prevalência de infecção por VHC na população geral varia de 1,1 a 2,4%. Entre doadores de sangue as taxas de prevalência variam de 0,8% a 5,9%. O Estado do Pará (Amazônia oriental) e do Acre (Amazônia ocidental) apresentam as maiores taxas, 2% e 5,9%, respectivamente. Com relação à prevalência da infecção pelo VHC em grupos de risco, observa-se alta prevalência entre hemodiálisados (48,1% - 51,9%), profissionais de saúde (3,2%), contactantes de portadores do VHC (10%) e pacientes com lichen plannus (7,5%). Existe uma predominância significativa do genótipo 1, com maior freqüência do subtipo 1b. A infecção pelo VHC é similar em homens e mulheres e a maioria dos infectados têm mais de 39 anos de idade. A principal via de infecção é a parenteral e os principais fatores de risco são transfusão sangüínea e procedimentos cirúrgicos. O VHC raramente é responsável por hepatite aguda grave nesta região. Por outro lado, de todas as hepatites crônicas, 22,6% são atribuídas ao VHC na Amazônia Ocidental e 25% na Amazônia Oriental. Na Amazônia Brasileira, a infecção pelo VHC parece ter o mesmo comportamento da infecção em outras partes do mundo.

The article evaluates available scientific information concerning the prevalence and clinical characteristics of hepatitis C virus infection in the Brazilian Amazon, a know endemic area for hepatitis A, B and D viruses infection. All the information was obtained through extensive analysis of original and review articles and abstracts published in distinguished journals or in scientific meetings. In the Amazon Region, HCV infection prevalence rate in the general population varies from 1.1 to 2.4%. Among blood donators the prevalence rate varies from 0.8 to 5.9%. Pará (Eastern Amazon) and Acre (Western Amazon) State present the highest rates, 2% and 5.9%, respectively. In respect to the HCV infection prevalence rate in the risk groups, one observates high prevalence In the Brazilian Amazon, infection by HCV seems to cope in the same way of infection in other parts of the world among the hemodialized (48.1 - 51.9%), health professionals (3.2%), HCV carriers contactants (10%) and lichen plannus patients (7.5%). There is a significant predominance of genotype 1, being sub-type 1b the most frequent. The HCV infection is similar in men and women and most of the infected are above 39 years of age. The major route of infection is parenteral and the major risk factors are blood transfusion and surgical procedures. HCV is rarely responsable for acute severe hepatitis in this region. On the other hand, of all chronic hepatitis, 22.6% are attributed to HCV in the Western Amazon and 25% in the Eastern Amazon. In the Brazilian Amazon, infection by HCV seems to cope in the same way of infection in other parts of the world.

Transmisión familiar del virus de la hepatitis C en un grupo de población chilena / Familial transmission of hepatitis C virus infection in Chilean subjects

BACKGROUND: Intravenous drug use, sexual promiscuity and a longer cohabitation period are considered risk factors for familial transmission of hepatitis C virus. The relative importance of this type of transmission is a subject of controversy. AIM: To study familial clustering of hepatitis C virus infection and its risk factors. MATERIAL AND METHODS: HCV positive patients (91 with chronic hepatitis, 88 with cirrhosis, nine with hepatic carcinoma and 29 hemophiliacs) were the index cases. HCV antibodies were measured by ELISA and the type of relationship with the index case was investigated in 317 family members. RESULTS: Positive anti HVC antibodies were detected in 12 of 243 family members of patients with chronic liver disease and in none of the family members of patients with hemophilia. Of these, five were couples of an index case with a long cohabitation period. Ten members had an index case with a severe liver disease (three with Child C cirrhosis and seven with liver carcinoma). CONCLUSIONS: Family transmission of HCV infection is uncommon in Chile. The association of severe liver disease and family transmission could be due to a higher viral load as responsible for transmission during the early periods of a long lasting disease.