Perfiles de expresión génica en las primeras doce semanas de tratamiento en pacientes con hepatitis C crónica / Gene expression profiling in the first twelve weeks of treatment in chronic hepatitis C patients

Introducción Los perfiles de expresión génica (PEG) en las primeras semanas de tratamiento de pacientes con hepatitis C crónica pueden servir para evaluar la eficacia de la terapia basada en interferón. El objetivo de este trabajo fue estudiar los PEG de pacientes respondedores y no respondedores precoces antes y tras 12 semanas de tratamiento con peginterferón alfa y ribavirina. Métodos Estudio observacional donde se analizaron los PEG de 12 pacientes con hepatitis C crónica candidatos a recibir tratamiento con peginterferón alfa y ribavirina. Resultados De los 12 pacientes estudiados, seis mostraron una respuesta virológica precoz completa, mientras que seis no lograron controlar la viremia. En respondedores precoces, el tratamiento con peginterferón y ribavirina indujo un aumento de la expresión de un mayor número de genes de respuesta al interferón (ISG15, IFI6, IFI44L, IFI27, MX1, OASL, IRF7, IFIT3, IFITM1, EIF2AK2, HERC5 y APOBEC3A) que en no respondedores (ISG15, IFI44L, IFI27, IRF7, USP18) (p<0,05). En ambos grupos, se observaron cambios en los niveles de algunos genes hasta ahora escasamente descritos en el tratamiento de la hepatitis C.Conclusiones Los PEG descritos en este trabajo pueden ayudar a comprender mejor la patogénesis de la infección, así como las bases fisiológicas de la respuesta al tratamiento. Así, el mayor efecto del tratamiento sobre la expresión de genes de respuesta al interferón observado en respondedores podría explicar su mejor control de la carga viral (AU)

Introduction: Gene expression profiling in the first weeks of treatment of patients with chronic hepatitis C may contribute to better evaluate the response to interferon-based therapy. The objective of this study was to evaluate the gene expression profiles of early responders and non-responders before, and after12 weeks of treatment with peginterferon alfa and ribavirin. Methods: Gene expression profiles were analysed in 12 patients with chronic hepatitis C, and scheduled for treatment with peginterferon alpha and ribavirin. Results: Of the 12 patients studied, six showed a complete early virological response, while six failed tocontrol viremia. In early responders, treatment with peginterferon and ribavirin induced an increasedexpression of a larger number of interferon-induced genes (ISG15, IFI6, IFI44L, IFI27, MX1, OASL, IRF7,IFIT3, IFITM1, EIF2AK2, HERC5 and APOBEC3) than in non-responders (ISG15, IFI44L, IFI27, IRF7, USP18)in the first twelve weeks of treatment (P<0.05). In both groups, there were changes in the levels of certaingenes poorly described in the treatment of hepatitis C so far (AU)

[Gene expression profiling in the first twelve weeks of treatment in chronic hepatitis C patients]. / Perfiles de expresión génica en las primeras doce semanas de tratamiento en pacientes con hepatitis C crónica.

INTRODUCTION: Gene expression profiling in the first weeks of treatment of patients with chronic hepatitis C may contribute to better evaluate the response to interferon-based therapy. The objective of this study was to evaluate the gene expression profiles of early responders and non-responders before, and after 12 weeks of treatment with peginterferon alfa and ribavirin. METHODS: Gene expression profiles were analysed in 12 patients with chronic hepatitis C, and scheduled for treatment with peginterferon alpha and ribavirin. RESULTS: Of the 12 patients studied, six showed a complete early virological response, while six failed to control viremia. In early responders, treatment with peginterferon and ribavirin induced an increased expression of a larger number of interferon-induced genes (ISG15, IFI6, IFI44L, IFI27, MX1, OASL, IRF7, IFIT3, IFITM1, EIF2AK2, HERC5 and APOBEC3) than in non-responders (ISG15, IFI44L, IFI27, IRF7, USP18) in the first twelve weeks of treatment (P<0.05). In both groups, there were changes in the levels of certain genes poorly described in the treatment of hepatitis C so far. CONCLUSIONS: The gene expression profiles described in this study provide a new insight to understanding the pathogenesis of the disease and treatment effect. The more marked effect of the treatment on the expression of interferon-response genes observed in early responders could explain their better control of viral load.

Increased Th1, Th17 and pro-fibrotic responses in hepatitis C-infected patients are down-regulated after 12 weeks of treatment with pegylated interferon plus ribavirin.

Hepatitis C virus causes significant morbidity and mortality worldwide. The infection induces up-regulation of cytokine and chemokines commonly linked to the development of cellular and pro-inflammatory antiviral responses. The current standard in hepatitis C treatment consists of combination regimens of pegylated interferon-alpha plus ribavirin. The impact of combined treatment in the host immune response is still poorly understood. In the present study, we profiled 27 cytokines, chemokines and growth factors involved in the innate and adaptive responses to the virus in the serum of 27 hepatitis C virus-infected patients, before and after 12 weeks of combined treatment, and compared them to 10 healthy controls. Hepatitis C virus infection induced not only the secretion of chemokines and cytokines participating in Th1 responses (MIP-1 alpha, IP-10, TNF-alpha, IL-12p70, IL-2), but also cytokines involved in the development of Th17 responses (IL-6, IL-8, IL-9 and IL-17) and two pro-fibrotic factors (FGF-b, VEGF). The most important increases included MIP-1 alpha (4.7-fold increase compared to the control group), TNF-alpha (3.0-fold), FGF-b (3.4-fold), VEGF (3.5-fold), IP-10 (3.6-fold), IL-17 (107.0-fold), IL-9 (7.5-fold), IL-12p70 (7.0-fold), IL-2 (5.6-fold) and IL-7 (5.6-fold). Combined treatment with pegylated interferon-alpha plus ribavirin down-modulated the secretion of key Th1 and Th17 pro-inflammatory mediators, and pro-fibrotic growth factors as early as 12 weeks after treatment initiation. MIP-1 alpha, FGF-b, IL-17 decreased in a more dramatic manner in the group of responder patients than in the group of non-responders (fold-change in cEVR; fold-change in NcEVR): MIP-1 alpha (4.72;1.71), FGF-b (4.54;1.21), IL-17 (107.1;1.8). Correlation studies demonstrated that the decreases in the levels of these mediators were significantly associated with each other, pointing to a coordinated effect of the treatment on their secretion (r coefficient; p value): [ FGF-b versus IL-17 (0.90; 0.00), IL-17 versus VEGF (0.88; 0.00), MIP-1 alpha versus IL-17 (0.84;0.00), FGF-b versus MIP-1 alpha (0.96;0.00), FGF-b versus IL-12p70 (0.90; 0.00), VEGF versus IL-12p70 (0.89; 0.00)]. Th17 immunity has been previously associated with autoimmune diseases and asthma, but this is the first work reporting a role for this profile in viral hepatitis. These results provide an opportunity to evaluate the impact of the treatment with Peg-INF-alpha and RBV on the prevention of immune-driven tissue damage in infected patients.