Vinte e seis pacientes portadores de Hepatite C crônica e co-infectados pelo HIV, sem outras causas para hepatopatia e virgens para a terapia do VHC, foram tratados com Interferon Peguilado Alfa 2a de 40 KDa associado a Ribavirina por 48 semanas. Coletamos 20 amostras - horas 0, 4, 8, 12, 18, 24, 30, 36, 42, 48, dias 3, 4,7, 8, 15, 22, 29, 43, 57 e semana 12 - para quantificação do HCV (TaqMan®) e do HIV após o início da terapia. Os dados basais evidenciavam que o Genótipo 1 correspondia a 15 pacientes, enquanto o Genótipo 3 a 11. A mediana do VHC foi de 1.285.000 UI/ml, CD4 médio 573/mm3 e a média da carga viral do HIV 1109 cp/ml. Em uma análise por intenção de tratamento, o percentual obtido de resposta virológica sustentada (RVS) foi 26,9%. A única correlação estatisticamente significativa entre as variáveis analisadas e parâmetros cinéticos calculados, e a obtenção de RVS ocorreu entre RVS e Genótipo 3 (p < 0,04). Houve ajuste para os parâmetros cinéticos calculados para 18 pacientes. Pacientes com RVS apresentaram maiores taxas de eficiência do Interferon, eliminação de células infectadas e eliminação de vírions livres, assim como as Fases 1 e 2 foram mais rápidas entre eles. A ausência de redução do VHC de um log10 em 24 ou 48 horas, obteve um VPN de 100% para RVS. Ausência de queda de dois log10 nos dias oito e 29 obteve VPN de 92,31% e 100%, havendo associação entre a presença dessa resposta virológica precoce (RVP) e a obtenção de RVS (p=0,003 e p=0,01). A cinética viral mostra-se uma ferramenta útil no manejo clínico e predição muito precoce da ausência de RVS, o que é muito importante, particularmente para os co-infectados com o HIV, ante o complexo manuseio clínico dessa situação. / Twenty six co-infected patients were treated with PegIFN A2A and Ribavirin for 48 weeks. Twenty samples were drew at hours 0, 4, 8, 12, 18, 24, 30, 36, 42, 48, days 3, 4, 7, 8, 22, 29, 43, 57 and week 12 to HIV and HCV (TaqMan®) quantification after began medication. Basal data showed Genotype 1 in 15 patients, 3 in 11. Median HCV were 1.285.000 UI/ml, mean CD4 573/mm3 and mean HIV 1109 cp/ml. SVR was associated only with Genotype 3 (p<0,04). Overal SVR (ITT) were 26,9%. We obtained fitted viral kinetics parameters for 18 patients. Patients with SVR showed higher Interferon efficacy, infected cells clearance, free virion clearance and faster phase 1 and 2. Reduction on HCV load of less than one log10 at 24 or 48 hs had a NPV of 100% for SVR. Less than two log decay at days 8 and 29 had 92,31 and 100% of NPV and the presence of those reduction were associated with SVR p=0,003 and p=0,01). Viral kinetics are an important tool regarding clinic management and very early prediction of absence of SVR, wich is very important for the HIV co-infected patients for whom the clicical management is very complex.

Sia Sin Fun. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 105-121). / Abstracts in English and Chinese. / STATEMENT --- p.i / ACKNOWLEDGEMENTS --- p.ii / ABSTRACT --- p.iii / ABSTRACT (CHINESE VERSION) --- p.v / TABLE OF CONTENTS --- p.vi / ABBREVIATIONS --- p.xi / LIST OF FIGURES --- p.xv / LIST OF TABLES --- p.xvi / Chapter CHAPTER ONE: --- INTRODUCTION / Chapter 1.1 --- The interferon / Chapter 1.1.1 --- Classification of interferons --- p.1 / Chapter 1.1.1.1 --- Type IIFN --- p.2 / Chapter 1.1.1.2 --- Type II IFN --- p.3 / Chapter 1.1.2 --- Biosynthesis of IFN --- p.3 / Chapter 1.1.3 --- IFN-α/β receptor and signal transduction --- p.8 / Chapter 1.1.4 --- Functions induced by IFN / Chapter 1.1.4.1 --- Antiviral activity of IFN-α/β --- p.11 / Chapter 1.1.4.1.1 --- PKR (double-stranded RNA-dependent protein kinase) --- p.11 / Chapter 1.1.4.1.2 --- The 2-5A synthetase/RNase L system (The 2-5A system) --- p.16 / Chapter 1.1.4.1.3 --- Mx proteins --- p.17 / Chapter 1.1.4.2 --- Immunomodulatory function of IFN-α/β --- p.18 / Chapter 1.1.4.3 --- Inhibition of cell growth --- p.18 / Chapter 1.1.4.4 --- Control of apoptosis --- p.19 / Chapter 1.1.5 --- The significance of IFN system --- p.20 / Chapter 1.1.6 --- Subtype of murine IFN-α --- p.21 / Chapter 1.1.7 --- Production of IFN in response to infection --- p.23 / Chapter 1.1.8 --- Existing methods to determine the IFN-α subtypes productionin response to stimulus --- p.24 / Chapter 1.2 --- Influenza virus --- p.27 / Chapter 1.2.1 --- Classification --- p.27 / Chapter 1.2.2 --- The structure of influenza virus --- p.29 / Chapter 1.2.3 --- The viral genome and proteins --- p.29 / Chapter 1.2.4 --- Replicative cycle of influenza virus / Chapter 1.2.4.1 --- "Virus adsorption, entry and uncoating" --- p.31 / Chapter 1.2.4.2 --- Transcription and replication of vRNA --- p.31 / Chapter 1.2.4.3 --- Synthesis of viral proteins --- p.32 / Chapter 1.2.4.4 --- Packaging and budding of progeny virus --- p.33 / Chapter 1.2.5 --- Viral inhibition of the IFN response --- p.33 / Chapter 1.3 --- Aim of study --- p.35 / Chapter CHAPTER TWO: --- MATERIALS AND METHODS / Chapter 2.1 --- Overall procedures --- p.37 / Chapter 2.2 --- Materials / Chapter 2.2.1 --- "Cell line, bacterial strain and vector" --- p.40 / Chapter 2.2.2 --- Chemicals --- p.40 / Chapter 2.2.3 --- "Culture media, buffer and other solutions" --- p.41 / Chapter 2.2.4 --- Reagents and nucleic acids --- p.41 / Chapter 2.2.5 --- Reaction kits --- p.42 / Chapter 2.2.6 --- Solutions --- p.42 / Chapter 2.2.7 --- Solutions of reaction kits --- p.43 / Chapter 2.2.8 --- Major equipments --- p.44 / Chapter 2.2.9 --- Primers --- p.44 / Chapter 2.2.10 --- Cell lysate --- p.45 / Chapter 2.3 --- Methods / Chapter 2.3.1 --- Design of IFN-α whole coding region and subtype specific primers using OLIGO´ёØ ver 50 --- p.46 / Chapter 2.3.2 --- Construction of plasmid DNA with the whole coding region of IFN-α gene / Chapter 2.3.2.1 --- Isolation of genomic DNA from L929 cells --- p.46 / Chapter 2.3.2.2 --- Amplification of whole coding region of IFN-α subtypes --- p.47 / Chapter 2.3.2.3 --- Preparation of plasmid DNA --- p.48 / Chapter 2.3.2.4 --- Restriction digestion of the vector pBluescript SKII (-) with SmaI --- p.48 / Chapter 2.3.2.5 --- Purification of DNA fragments from agarose gel --- p.49 / Chapter 2.3.2.6 --- Blunt end ligation --- p.49 / Chapter 2.3.2.7 --- Transformation --- p.49 / Chapter 2.3.2.8 --- Screening by polymerase chain reaction --- p.50 / Chapter 2.3.2.9 --- DNA sequencing --- p.50 / Chapter 2.3.3 --- Test on IFN-α subtype specific primers / Chapter 2.3.3.1 --- Determination of the specificity of IFN-α subtype specific primers by PCR --- p.51 / Chapter 2.3.3.2 --- Determination of the amplification of a particular subtype in the presence of excess of other templates --- p.51 / Chapter 2.3.4 --- Induction of expression of IFN in fibroblast L929 cells / Chapter 2.3.4.1 --- By chemical agents Poly(I) Poly(C) and DEAE --- p.52 / Chapter 2.3.4.2 --- By infection with influenza virus (A/NWS/33 and B/Lee/40) --- p.52 / Chapter 2.3.5 --- Detection of IFN-α subtypes expression / Chapter 2.3.5.1 --- Isolation of total RNA by guandidium thiocyanate - cesium chloride ultracentrifugation --- p.53 / Chapter 2.3.5.2 --- Synthesis of first strand cDNA --- p.54 / Chapter 2.3.5.3 --- Normalization of RNA samples --- p.54 / Chapter 2.3.5.4 --- RT-PCR amplification of the IFN-α subtypes --- p.54 / Chapter 2.3.5.5 --- "RT-PCR amplification of IFN-γ, IFN-α receptor 1，IFN-α receptor 2 (transmembrane and soluble form) and IFN-(3" --- p.55 / Chapter CHAPTER THREE: --- RESULTS / Chapter 3.1 --- Designing of primers for IFN-α genes --- p.56 / Chapter 3.1.1 --- Design of IFN-α primers for amplification of whole coding region --- p.56 / Chapter 3.1.2 --- Design of IFN-α subtype specific primers --- p.58 / Chapter 3.2 --- Cloning of the IFN-α subtype genes / Chapter 3.2.1 --- Purification of genomic DNA --- p.59 / Chapter 3.2.2 --- PCR conditions used for amplification of whole coding region of mIFN-α subtypes --- p.61 / Chapter 3.2.3 --- Subcloning the whole coding region of IFN-α genes from amplified fragments --- p.63 / Chapter 3.3 --- Optimization of specific amplification condition for subtype specific primers by cross-PCR --- p.64 / Chapter 3.4 --- Determination of the amplification of a particular subtype in the excess of other templates --- p.67 / Chapter 3.5 --- Determination of the gene expression in poly (I) poly (C) treated L929 cells / Chapter 3.5.1 --- Spectrophotometric analysis of total RNA --- p.70 / Chapter 3.5.2 --- Agarose gel electrophoresis of RNA --- p.72 / Chapter 3.5.3 --- Normalization of RNA sample --- p.73 / Chapter 3.5.4 --- Detection of IFN-α subtypes mRNA in L929 cell induced with poly(I) poly(C)-DEAE dextran --- p.74 / Chapter 3.5.5 --- "Detection of IFN-γ, IFN-α/β receptor and IFN-β expressionin Poly(I) Poly(C)-DEAE dextran or DEAE dextran treated L929 cells" --- p.70 / Chapter 3.6 --- Measurement of gene expression in L929 cells infected with influenza virus / Chapter 3.6.1 --- Spectrophotometric analysis of total RNA --- p.83 / Chapter 3.6.2 --- Agarose gel electrophoresis of RNA samples --- p.84 / Chapter 3.6.3 --- Normalization of RNA samples --- p.86 / Chapter 3.6.4 --- Detection of IFN-α subtypes mRNA in L929 cell infected with influenza A/NWS/33 virus --- p.87 / Chapter 3.6.5 --- Detection of IFN-α subtypes mRNA in L929 cells infected with influenza B/Lee/40 virus --- p.90 / Chapter 3.6.6 --- "Detection of IFN-γ, IFN-α/β receptor and IFN-β expression in L929 cells infected with A/NWS/33 and B/Lee/40" --- p.93 / Chapter CHAPTER FOUR: --- DISCUSSION --- p.97 / REFERENCES --- p.105 / APPENDIX --- p.122

Vinte e seis pacientes portadores de Hepatite C crônica e co-infectados pelo HIV, sem outras causas para hepatopatia e virgens para a terapia do VHC, foram tratados com Interferon Peguilado Alfa 2a de 40 KDa associado a Ribavirina por 48 semanas. Coletamos 20 amostras - horas 0, 4, 8, 12, 18, 24, 30, 36, 42, 48, dias 3, 4,7, 8, 15, 22, 29, 43, 57 e semana 12 - para quantificação do HCV (TaqMan®) e do HIV após o início da terapia. Os dados basais evidenciavam que o Genótipo 1 correspondia a 15 pacientes, enquanto o Genótipo 3 a 11. A mediana do VHC foi de 1.285.000 UI/ml, CD4 médio 573/mm3 e a média da carga viral do HIV 1109 cp/ml. Em uma análise por intenção de tratamento, o percentual obtido de resposta virológica sustentada (RVS) foi 26,9%. A única correlação estatisticamente significativa entre as variáveis analisadas e parâmetros cinéticos calculados, e a obtenção de RVS ocorreu entre RVS e Genótipo 3 (p < 0,04). Houve ajuste para os parâmetros cinéticos calculados para 18 pacientes. Pacientes com RVS apresentaram maiores taxas de eficiência do Interferon, eliminação de células infectadas e eliminação de vírions livres, assim como as Fases 1 e 2 foram mais rápidas entre eles. A ausência de redução do VHC de um log10 em 24 ou 48 horas, obteve um VPN de 100% para RVS. Ausência de queda de dois log10 nos dias oito e 29 obteve VPN de 92,31% e 100%, havendo associação entre a presença dessa resposta virológica precoce (RVP) e a obtenção de RVS (p=0,003 e p=0,01). A cinética viral mostra-se uma ferramenta útil no manejo clínico e predição muito precoce da ausência de RVS, o que é muito importante, particularmente para os co-infectados com o HIV, ante o complexo manuseio clínico dessa situação. / Twenty six co-infected patients were treated with PegIFN A2A and Ribavirin for 48 weeks. Twenty samples were drew at hours 0, 4, 8, 12, 18, 24, 30, 36, 42, 48, days 3, 4, 7, 8, 22, 29, 43, 57 and week 12 to HIV and HCV (TaqMan®) quantification after began medication. Basal data showed Genotype 1 in 15 patients, 3 in 11. Median HCV were 1.285.000 UI/ml, mean CD4 573/mm3 and mean HIV 1109 cp/ml. SVR was associated only with Genotype 3 (p<0,04). Overal SVR (ITT) were 26,9%. We obtained fitted viral kinetics parameters for 18 patients. Patients with SVR showed higher Interferon efficacy, infected cells clearance, free virion clearance and faster phase 1 and 2. Reduction on HCV load of less than one log10 at 24 or 48 hs had a NPV of 100% for SVR. Less than two log decay at days 8 and 29 had 92,31 and 100% of NPV and the presence of those reduction were associated with SVR p=0,003 and p=0,01). Viral kinetics are an important tool regarding clinic management and very early prediction of absence of SVR, wich is very important for the HIV co-infected patients for whom the clicical management is very complex.

Orientador: Raquel Mantuaneli Scarel Caminaga / Banca: Elisa Maria Aparecida Giro / Banca: Paula Cristina Trevilatto / Resumo: A doença periodontal (DP) em indivíduos com Síndrome de Down (SD) se desenvolve com alta prevalência, precocemente, de modo rápido e generalizado em comparação com indivíduos não-sindrômicos. Foi demonstrado que portadores da SD apresentam resposta imune diminuída em relação aos cromossomicamente normais. O objetivo desta pesquisa foi investigar diferenças nos parâmetros clínicos periodontais e níveis de expressão dos genes Interferon-gama (IFNG), Interferon-gama receptor 1 (IFNGR1), Interferon-gama receptor 2 (IFNGR2), Interferon-alfa (IFNA), Interferon-alfa receptor 1 (IFNAR1), Interferon-alfa receptor 2 (IFNAR2), Janus-quinase 1 (JAK1), Transdutor de sinal e ativador da transcrição 1 (STAT1) e Fator de regulação de interferon 1 (IRF1) em indivíduos com SD que apresentam ou não DP e em indivíduos cromossomicamente normais. Fizeram parte deste estudo 80 indivíduos entre 7 e 57 anos de idade subdivididos em 4 grupos: SD com DP (A); indivíduos com SD sem DP (B); indivíduos não-sindrômicos (Controle) com DP (C) e indivíduos Controle sem DP (D). A expressão gênica foi investigada por meio de quantificação relativa utilizando a técnica da Reação em Cadeia da Polimerase (PCR) em Tempo Real. Para o índice sangramento à sondagem (SS) não houve diferença entre os grupos A e 21 C. A periodontite crônica localizada foi o tipo prevalente tanto entre indivíduos com SD como Controle. Considerando os parâmetros clínicos, não foram encontradas diferenças na periodontite crônica localizada entre os indivíduos com SD e Controle, assim como para a periodontite crônica generalizada. Com relação à análise genética, observou-se que indivíduos dos grupos com SD em relação aos grupos cromossomicamente normais (A+B-C+D) tiveram uma expressão de IFNG semelhante ao observado entre indivíduos do grupo... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Periodontal disease (PD) in individuals with Down Syndrome (DS) has an early, quickly and widespread onset and high prevalence when compared with individuals without the Syndrome. Only poor oral hygiene does not explain the severe periodontal destruction seen in DS patients. It has been shown that DS patients have a weaker immune response than people with normal number of chromosomes. The aim of this study was to investigate differences in periodontal clinical parameters and the expression levels of the genes Interferon-gamma (IFNG), Interferon-gamma receptor 1 (IFNGR1), Interferon-gamma receptor 2 (IFNGR2), interferon-alpha (IFNA), interferon-alpha receptor 1 (IFNAR1), Interferon-alpha receptor 2 (IFNAR2), Janus-kinase 1 (JAK1), Signal transducers and activators of transcription 1 (STAT1) and Interferon regulatory factor 1 (IRF1) in DS patients with and without periodontal disease in comparison with chromossomically normal individuals. A total of 80 individuals aged 7 to 57 years participated in this study and were divided into 4 groups: DS with PD (A); DS without PD (B); individuals without DS (control) with PD (C) and individuals without DS (control) and without PD (D). A quantitative RT-qPCR was used to investigate gene expression. There was no difference between groups A and C regarding the bleeding on probing 25 (BOP) index. The most prevalent type of periodontitis seen in this study was the localized chronic periodontitis, both in individuals with and without DS. Considering the clinical parameters, localized and generalized chronic periodontitis did not differ between individuals with and without DS. Regarding genetic analysis, individuals of the groups with DS in relation to the groups without DS (A+B-C+D) showed an IFNG expression similar to that seen among the individuals of groups control with PD (C-D). However, individuals... (Complete abstract click electronic access below) / Mestre

Le ciblage de l’activité de l’IFNα est une stratégie développée afin d’augmenter l’index thérapeutique de cette cytokine, dont l’efficacité requiert de fortes doses au site d’action, responsables d’une toxicité systémique. Du fait de l’expression ubiquitaire de son récepteur, le ciblage de l’IFNα par immunocytokine est limité. En se basant sur le concept d'immunocytokine et utilisant un IFNα muté, peu actif, une efficacité de ciblage de 3 log a pu être obtenue, dans le système humain et murin, grâce au rétablissement de l'activité de l'IFNα sur les cellules ciblées. Ces IFNα ciblés sont doués d'une activité biologique, notamment antitumorale, dont la cible cellulaire reste à déterminer. Une stratégie inverse, en cours d'optimisation, permet d'inhiber l’activité des IFN-I spécifiquement sur les cellules ciblées. Cette double stratégie de ciblage de l’activité et de l’inhibition de l’IFN devrait permettre de déterminer les cibles des effets bénéfiques et néfastes des IFN-I, avec des applications thérapeutiques éventuelles. / Targeting IFN activity is a strategy developed to increase the therapeutic index of thiscytokine, whose efficiency requires high doses to site of action, responsible for systemictoxicity. Due to the ubiquitous expression of its receptor, the targeting efficiency of IFNbasedimmunocytokine is limited. Using a mutated IFNα, poorly active, a 3 log targetingefficiency was achieved, in the human and mouse system, by restoring the activity of IFNα ontargeted cells. The biological activity of these targeted IFNα include an antitumoral effect,the cellular target remains to be determined. A reverse strategy being optimized, can inhibitIFN-I activity specifically on targeted cells. This dual targeting strategy of the activity andinhibition of IFN should identify the targets of beneficial and deleterious effects of IFN-I,with possible therapeutic applications.

No description available.

No description available.

Introdução: Estima-se que a infecção pelo vírus da hepatite C (VHC) acometa 3% da população global constituindo a maior causa de cirrose hepática e hepatocarcinoma. Nos pacientes infectados pelo genótipo 1 do VHC, a terapia em vida real com interferon peguilado (PEG-IFN) e ribavirina (RBV) resulta em 30% a 50% de resposta virológica sustentada (RVS). Este desfecho é determinado por fatores de associados ao VHC (carga viral, genótipo, quasispécies), características do hospedeiro (etnia, gênero, fatores genéticos, comorbidades, adesão) e fatores ligados aos medicamentos. Estudos de associação genética ampla (GWAS) têm demonstrado que a presença dos polimorfismos (SNP) no gene da interleucina 28B (IL-28B) associam-se a resposta à terapia baseada em interferon. Os SNPs rs12979860, rs8099917 e rs12980275 têm sido amplamente estudados e pacientes com o perfil favorável têm maiores chances de alcançar a RVS ou a eliminação espontânea do VHC. Objetivos: Avaliar a frequência relativa e a influência dos polimorfismos rs12979860 (C > T), rs8099917 (T > G) e rs12980275 (A > G) no gene IL-28B em brasileiros portadores de infecção crônica pelo VHC tratados com PEGIFN/ RBV em uma casuística de pacientes atendidos pelos médicos do Ambulatório de Hepatites DMIP/LIM-47 e avaliar retrospectivamente a possibilidade de predição de resposta à partir do perfil IL-28B na população estudada. Materiais e Métodos: Após aprovação ética, foram selecionados 171 pacientes com coleta retrospectiva e sistematizada das informações de interesse. O DNA destes pacientes foi purificado e foram desenhados primers e sondas específicas para a genotipagem dos SNPs através da técnica de reação em cadeia de polimerase em tempo real. Resultados: entre os SNPs selecionados na análise univariada rs12979860 e rs12980275 associaram-se com RVS (p < 0,05). rs8099917 não teve associação com RVS. Na análise multivariada apenas rs12980275 manteve associação com RVS (p < 0,05). Conclusão: Ao contrário do descrito na Literatura Internacional nos pacientes brasileiros apenas o pouco estudado SNP rs12980275 associou-se à RVS / Introduction: Currently, infection with hepatitis C virus (HCV) affects 3% of people worldwide, and is the major cause of chronic hepatitis C, liver cirrhosis and hepatocellular carcinoma. In patients infected by genotype 1 of HCV, 30%- 50% of patients achieve sustained virological response, when they are treated with pegylated interferon (PEG-IFN) and ribavirin (RBV). This outcome is determined by VHC factors (mutations, genotype, quasispecies), host factors (gender, ethnic, genetic factors, comorbidities, adherence to treatment) and factors related to drugs. Genome wide association studies (GWAS) demonstrated that the presence of polymorphisms in interleukin 28B gene (IL- 28B) are associated with response to interferon based therapy. SNPs rs12979860, rs8099917 and rs12980275 have been widely studied and patients with the favorable profile are more likely to achieve SVR. Objectives: To evaluate the relative frequency and influence of the polymorphisms rs12979860 (C > T), rs8099917 (T > G) and rs12980275 (A > G) in Brazilian patients treated for chronic hepatitis C with PEG-IFN/RBV, and to evaluate, retrospectively, the prediction of the response possibility from IL-28B profile in the selected patients. Material and Methods: It was selected 171 patients. Medical history was evaluated retrospectively. A real time polymerase chain reaction assay was realized in order to analyze the polymorphisms. Results: In univariate analysis the polymorphisms rs12979860 and rs12980275 were associated with SVR (p < 0,05). The SNP rs8099917 was not associated with SVR. Multivariate analysis revealed that only rs12980275 maintained an association with SVR (p < 0,05). Conclusion: It is described on international literature that rs12979860 is strongly associated with SVR, however in Brazilian patients only the less studied SNP rs12980275 was associated with SVR

Introdução: Estima-se que a infecção pelo vírus da hepatite C (VHC) acometa 3% da população global constituindo a maior causa de cirrose hepática e hepatocarcinoma. Nos pacientes infectados pelo genótipo 1 do VHC, a terapia em vida real com interferon peguilado (PEG-IFN) e ribavirina (RBV) resulta em 30% a 50% de resposta virológica sustentada (RVS). Este desfecho é determinado por fatores de associados ao VHC (carga viral, genótipo, quasispécies), características do hospedeiro (etnia, gênero, fatores genéticos, comorbidades, adesão) e fatores ligados aos medicamentos. Estudos de associação genética ampla (GWAS) têm demonstrado que a presença dos polimorfismos (SNP) no gene da interleucina 28B (IL-28B) associam-se a resposta à terapia baseada em interferon. Os SNPs rs12979860, rs8099917 e rs12980275 têm sido amplamente estudados e pacientes com o perfil favorável têm maiores chances de alcançar a RVS ou a eliminação espontânea do VHC. Objetivos: Avaliar a frequência relativa e a influência dos polimorfismos rs12979860 (C > T), rs8099917 (T > G) e rs12980275 (A > G) no gene IL-28B em brasileiros portadores de infecção crônica pelo VHC tratados com PEGIFN/ RBV em uma casuística de pacientes atendidos pelos médicos do Ambulatório de Hepatites DMIP/LIM-47 e avaliar retrospectivamente a possibilidade de predição de resposta à partir do perfil IL-28B na população estudada. Materiais e Métodos: Após aprovação ética, foram selecionados 171 pacientes com coleta retrospectiva e sistematizada das informações de interesse. O DNA destes pacientes foi purificado e foram desenhados primers e sondas específicas para a genotipagem dos SNPs através da técnica de reação em cadeia de polimerase em tempo real. Resultados: entre os SNPs selecionados na análise univariada rs12979860 e rs12980275 associaram-se com RVS (p < 0,05). rs8099917 não teve associação com RVS. Na análise multivariada apenas rs12980275 manteve associação com RVS (p < 0,05). Conclusão: Ao contrário do descrito na Literatura Internacional nos pacientes brasileiros apenas o pouco estudado SNP rs12980275 associou-se à RVS / Introduction: Currently, infection with hepatitis C virus (HCV) affects 3% of people worldwide, and is the major cause of chronic hepatitis C, liver cirrhosis and hepatocellular carcinoma. In patients infected by genotype 1 of HCV, 30%- 50% of patients achieve sustained virological response, when they are treated with pegylated interferon (PEG-IFN) and ribavirin (RBV). This outcome is determined by VHC factors (mutations, genotype, quasispecies), host factors (gender, ethnic, genetic factors, comorbidities, adherence to treatment) and factors related to drugs. Genome wide association studies (GWAS) demonstrated that the presence of polymorphisms in interleukin 28B gene (IL- 28B) are associated with response to interferon based therapy. SNPs rs12979860, rs8099917 and rs12980275 have been widely studied and patients with the favorable profile are more likely to achieve SVR. Objectives: To evaluate the relative frequency and influence of the polymorphisms rs12979860 (C > T), rs8099917 (T > G) and rs12980275 (A > G) in Brazilian patients treated for chronic hepatitis C with PEG-IFN/RBV, and to evaluate, retrospectively, the prediction of the response possibility from IL-28B profile in the selected patients. Material and Methods: It was selected 171 patients. Medical history was evaluated retrospectively. A real time polymerase chain reaction assay was realized in order to analyze the polymorphisms. Results: In univariate analysis the polymorphisms rs12979860 and rs12980275 were associated with SVR (p < 0,05). The SNP rs8099917 was not associated with SVR. Multivariate analysis revealed that only rs12980275 maintained an association with SVR (p < 0,05). Conclusion: It is described on international literature that rs12979860 is strongly associated with SVR, however in Brazilian patients only the less studied SNP rs12980275 was associated with SVR

Techn. Universiẗat, Diss., 2005--München.