Η ανοσολογική απάντηση και κυρίως η κυτταρική ανοσία, κατέχει σημαντικό ρόλο στην παθογένεια της λοίμωξης τόσο από τον ιό της ηπατίτιδας Β όσο και από τον ιό της ηπατίτιδας C. Στην παρούσα μελέτη εκτιμήθηκε η κυτταρική ανοσία, όπως αυτή εκφράζεται από τους Τ λεμφοκυτταρικούς υποπληθυσμούς (CD3, CD4, CD8) στο περιφερικό αίμα και στον ηπατικό ιστό ασθενών με χρόνια ηπατίτιδα Β (ΧΗΒ) και χρόνια ηπατίτιδα C (XHC). Οι ασθενείς με ΧΗΒ χωρίσθηκαν σε δύο κατηγορίες, ανάλογα με την ενεργότητα της νόσου (ασθενείς με χρόνια ενεργό ηπατίτιδα και ασυμπτωματικοί φορείς της νόσου). Επίσης μετρήθηκαν οι κυτταροκίνες του περιφερικού αίματος ( IFN-γ, TNF-a, IL-10, IL-5, IL-12, IL-6, IL-1b, IL-4, IL-8, IL-2) στις παραπάνω ομάδες ασθενών. Μέτρηση των Τ λεμφοκυτταρικών υποπληθυσμών και των κυτταροκινών έγινε στους ασθενείς με ενεργό ΧΗΒ και XHC πριν και μετά την έναρξη της αντιϊκής αγωγής. Όσο αφορά τους Τ κυτταρικούς υποπληθυσμούς του περιφερικού αίματος δεν προέκυψε διαφορά στους ασθενείς με ενεργό ΧΗΒ και ασυμπτωματικών φορέων της νόσου. Αντίθετα, σημαντική αύξηση των Τ κυτταρικών υποπληθυσμών, ιδιαίτερα στο επίπεδο των CD8 κυττάρων διαπιστώθηκε στους ασθενείς με XHC τόσο στο περιφερικό αίμα όσο και στο ηπατικό ιστό σε σχέση με τους ασθενείς με ΧΗΒ. Όσο αφορά τον ηπατικό ιστό υπήρξε άμεση συσχέτιση των CD3 κυττάρων με τη πυλαία φλεγμονή και τη λοβιακή δραστηριότητα και στις δύο ομάδες ασθενών, ενώ άμεση συσχέτιση των CD8 κυττάρων με τη πυλαία φλεγμονή και τη λοβιακή δραστηριότητα παρατηρήθηκε μόνο στους ασθενείς με XHC. Από τη μέτρηση των κυτταροκινών του περιφερικού αίματος προκύπτει αύξηση της IFN-γ, TNF-a, IL-10, IL-5 στους ασυμπτωματικούς φορείς της ηπατίτιδας β σε σχέση με τους ασθενείς με ενεργότητα ενώ σχετικά με τους ασθενείς με XHC και ενεργό ηπατίτιδα β, σημαντική αύξηση του TNF-a και μείωση της IL-4 και IL-12 στους ασθενείς με XHC. Δεν παρατηρήθηκε διαφορά στους Τ κυτταρικούς πληθυσμούς και στις κυτταροκίνες του περιφερικού αίματος στους ασθενείς με ΧΗΒ και XHC πριν και μετά την έναρξη αντιϊκής αγωγής. Από τα αποτελέσματα της μελέτης προκύπτει ότι οι ασθενείς με ΧΗΒ και XHC επιδεικνύουν διαφορετικό ανοσολογικό προφίλ όσο αφορά τους Τ κυτταρικούς υποπληθυσμούς στο περιφερικό αίμα και στον ηπατικό ιστό. Φαίνεται ότι η ανάπτυξη ανεπαρκούς ανοσολογικής απάντησης είναι υπεύθυνη για τη μη αποτελεσματική ιϊκή κάθαρση και την εξέλιξη της ηπατικής βλάβης στους ασθενείς με ΧΗΒ, ενώ αντίθετα στους ασθενείς με XHC η νόσος εξελίσσεται παρά την παρουσία ανοσολογικής απάντησης που είναι πιο έντονη στο επίπεδο των CD8 κυττάρων. Παρόμοια αποτελέσματα προκύπτουν και από τη μέτρηση των κυτταροκινών του περιφερικού αίματος. Έτσι, όσο αφορά την XHC φαίνεται ότι η νόσος εξελίσσεται παρά την παρουσία μιας έντονης Th1 απάντησης, ενώ στους ασθενείς με ενεργό ΧΗΒ φαίνεται ότι υπερτερεί η Th2 απάντηση. Στους ασθενείς με χρόνια ηπατίτιδα β, φαίνεται ότι το υψηλό ιικό φορτίο μπορεί να οδηγήσει σε διαταραχή της λειτουργικότητας των Τ λεμφοκυττάρων, όσο αφορά την παραγωγή IFN-γ που οδηγεί σε εξέλιξη της νόσου και ενεργό ιϊκό πολλαπλασιασμο. / The aim of this study was to evaluate the immune response in peripheral blood and liver, through the measurement of T cell subsets and serum cytokines, in patients with chronic active hepatitis B, asymptomatic HBV carriers and chronic hepatitis C. Thirty four patients with chronic hepatitis B (21 with active hepatitis and 13 asymptomatic carriers) and twenty one patients with chronic hepatitis C were enrolled in the study. We also evaluated 21 biopsies from patients with active CHB and 21 biopsies from patients with CHC. We measured CD3, CD4, CD8 T cell lymphocytes in peripheral blood and liver tissue as well serum cytokines (IFN-γ, TNF-a, IL-10, IL-5, IL-12, IL-6, IL-1b, IL-4, IL-8, IL-2) in these patients. We also evaluated the T – cell subsets and serum cytokines in patients with active CHB and CHC before and after the onset of antiviral therapy. We found no differences in the numbers of all T cells lymphocytes in peripheral blood between patients with active CHB and asymptomatic carriers. In contrast, we found a significant increase in the numbers of T cell subsets in CHC compared to CHB patients. We also found a significant increase in the number of T cell subsets in the area of portal tracts and lobules in CHC patients compared to CHB patients. In both groups there was a direct correlation between CD3 cells in portal tracts and lobules and HAI score but a direct correlation between CD8 cells and HAI score was found only in CHC patients. Regarding cytokine profile, patients with chronic active disease presented significantly decreased levels of IFN-γ, TNF-alpha, IL-10 and IL-5 as compared to inactive carriers. Also, a significant negative correlation between serum hepatitis B viral load and IFN-γ levels was noted. No correlation was found between viral load and the other cytokines. Patients with CHC presented significantly increased levels of TNF-alpha and significantly decreased levels of IL-12 and IL-4 as compared to patients with active hepatitis b infection. We found no difference in T – cell subsets and serum cytokines before and after the onset of antiviral therapy. Insufficient cellular immune response is critical for the ineffective virus clearance and liver damage in active CHB, while in CHC, immune response is present in peripheral blood and liver. However, there is an immunological escape of HCV, which seems to survive in the presence of an adequate immune response. Also, patients with active hepatitis B and HBsAg inactive carriers seem to display different cytokine profile. Decreased Th1 response observed in patients with active hepatitis B could be implicated in the persistence of virus replication and ongoing progression of liver disease. Hepatitis B viral load seems to be an important factor for T cell dysfunction, as expressed through reduced IFN-γ production.

Made available in DSpace on 2014-06-11T19:26:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-02-26Bitstream added on 2014-06-13T20:14:38Z : No. of bitstreams: 1 jardim_acg_me_sjrp.pdf: 3983929 bytes, checksum: 587fc4359397e3ed6de6922651160d80 (MD5) / O HCV é uma das maiores causas de doença do fígado, sendo estimado que mais de 2% da população mundial está infectada. Este vírus possui um genoma de RNA (+) fita simples, que devido à falta de atividade corretiva da polimerase viral apresenta variabilidade genética em vários níveis: genótipos, subtipos e quasispecies. O genótipo 1 é o mais prevalente no Brasil e no mundo, sendo preditivo de uma baixa resposta à terapia antiviral, que atualmente é baseada na administração de PEG-IFN e ribavirina. A variabilidade genética da região viral NS5A tem sido relacionada à sensibilidade ou resistência ao IFN. Este estudo teve como objetivo investigar se a possível relação entre a composição de quasispecies da NS5A e a resposta ao tratamento. Foram selecionados 12 pacientes, sendo 4 respondedores (R), 4 não respondedores (NR) e 4 respondedores ao final do tratamento (RFT). As amostras pré-tratamento destes pacientes foram amplificadas, clonadas e seqüenciadas, resultando em 165 seqüências da NS5A completa. Estas seqüências foram alinhadas, editadas e a construção da topologia da árvore filogenética foi realizada. A NS5A e suas regiões específicas CRS, PKR-binding, ISDR, NLS e V3 foram analisadas quanto às substituições e o grau de variabilidade genético. O grupo de pacientes RFT apresentou uma maior taxa de substituições sinônimas em relação aos demais grupos. Uma maior quantidade de mutações foi observada na região downstream à ISDR, principalmente na região V3. Nenhum sítio específico de mutação foi relacionado a um tipo particular de resposta, e não houve agrupamento filogenético das quasispecies de acordo com o tipo de resposta. Estes resultados sugerem que o número de mutações não é suficiente para predizer a sensibilidade ou resistência à terapia baseada em IFN, sendo necessário avaliar se estas mutações conservaram ou não as propriedades químicas dos aminoácidos. / Hepatitis C virus (HCV) is major causes of liver desease and about 2% of world s population are infected. This virus is a single strain RNA genome of approximately 9.6 kb. Genetics variability of HCV exists at several different levels: genotypes, subtypes and quasispecies. The high mutation rates are related to the low fidelity of viral RNA polymerase. Genotype 1 HCV is the most prevalent in Brazil, as well as worldwide. Genotypes 1a and 1b are predictive of lower sustained virological response in peginterferon (PEG-IFN) plus ribavirin combination therapy. Genetic variability of viral NS5A has been related to IFN sensibility or resistance. To evaluate whether HCV NS5A quasispecies composition are related to responsiveness to combined PEG-IFN and ribavirin therapy, this study analyzed before treatment sample of 12 treated patients (4 sustained responders - SR, 4 non responders - NR and 4 end of treatment responder - ETR). Samples were amplified, cloned and sequenced, resulting in 165 sequences of complete NS5A. Sequences were aligned, edited and phylogenetical tree was constructed. Mutations and mean of genetic distance were analyzed to NS5A and specific regions CRS, PKR-binding, ISDR, NLS and V3. The number of synonymous substitutions per synonymous sites was higher in ETR patients than in other patient groups. Mutations were more common downstream ISDR, mainly concentrated in V3 domain. No single amino acid position or motif was associated with different responses to therapy in any NS5A regions analyzed and phylogenetic analysis did not show clustering of nucleotide sequences of viral isolates from SR, NR or ETR. These results suggest that number of mutations is not sufficient to predict sensibility or resistance to IFN based therapy. Other studies are necessary to evaluate whether chemical characteristics of amino acids were altered for the mutations.

A hepatite C, causada pelo vírus da hepatite C (HCV), afeta milhões de pessoas no mundo. A transmissão do HCV é semelhante ao HIV, justificando a alta taxa de prevalência da coinfecção. Pacientes coinfectados HCV/HIV apresentam maior taxa de progressão da fibrose hepática e da mortalidade, em comparação aos pacientes monoinfectados com HCV. Assim, o estudo de genes e/ou moléculas que controlam a resposta imune é pertinente. No presente estudo, avaliamos o papel do antígeno leucocitário humano G (HLA-G), molécula com reconhecida atividade imunomoduladora, capaz de inibir a ativação das células T e a atividade citotóxica das células Natural Killers (NK) e linfócitos T CD8+, além de induzir a formação células T reguladoras. Nós investigamos 216 pacientes monoinfectados pelo HCV, 135 pacientes coinfectados HCV-HIV e 152 indivíduos não infectados. A variabilidade do gene HLA-G foi avaliada por sequenciamento de Sanger e a expressão hepática da molécula por imunoistoquímica. A expressão de HLA-G foi observada somente no tecido hepático dos pacientes, principalmente nos hepatócitos. O aumento de expressão de HLA-G foi associado com avanço da fibrose e da atividade necroinflamatória no fígado de ambos os grupos de pacientes. Idade igual ou superior a 40 anos e a cor de pele não-branca também foram associados com aumento da expressão hepática da molécula nos pacientes HCV. Outros fatores do hospedeiro analisados como gênero e genótipo do HCV não foram associados com o nível de expressão de HLA-G no fígado. A frequência do alelo HLA-G*01:01:01:01 estava aumentada nos pacientes HCV e do alelo G*01:05N diminuída nos pacientes coinfectados HCV-HIV, porém, não houveram associações significantes entre a variabilidade genética de HLA-G e a expressão hepática de HLA-G. O presente estudo contribui para a ampliar os conhecimentos acerca da participação da molécula HLA-G na hepatite C crônica, associado ou não com infecção pelo HIV. / Hepatitis C, caused by the hepatitis C virus (HCV), affects millions of people worldwide. The transmission of HCV is similar to HIV, which explains the high prevalence of coinfection. HCV-HIV coinfected patients have higher rate of liver fibrosis progression and mortality when compared to HCV monoinfected patients. Thus, the study of genes and/or molecules that control the immune response is relevant. In the present study, we evaluated the role of human leukocyte antigen G (HLA-G), a molecule known by its immunomodulatory activity, which is capable to inhibit T cell activation and cytotoxic activity of natural killer (NK) cells and CD8+ T cells, in addition to inducing the formation of regulatory T cells. We studied 216 HCV patients, 135 HIV-HCV coinfected patients and 152 uninfected individual. The variability of the HLA-G gene was evaluated by Sanger sequencing and the hepatic expression of the molecule by immunohistochemistry. The HLA-G expression was observed only in liver tissue of patients, mainly in hepatocytes. The increased HLA-G expression was associated with increased liver fibrosis and necroinflammatory activity in both groups of patients. The age greater than or equal to 40 years and the non-white skin color were also associated with increased hepatic expression of the molecule in the HCV patients. Other host factors analyzed as gender and HCV genotype were not associated with the level of HLA-G expression in the liver. The frequency of HLA-G*01:01:01:01 allele was increased in HCV patients and G*01:05N decreased in HCV-HIV coinfected patients, however, there was no significant association between the genetic variability of HLA-G and HLA-G liver expression. The present study contributes to expand the knowledge regarding the participation of HLA-G in chronic C hepatitis, associated or not with the HIV infection.

INTRODUCTION: The virus of hepatitis B was classified in eight genotypes that vary with geographic distribution, presenting different clinical manifestations and responses to anti-viral treatment. PURPOSES: This work intends to determine the prevalence of genotypes in Sergipe Brasil and evaluate them according to clinical and histopathological findings. METHODOLOGY: In a transversal search, were evaluated 97 patients, all of them AgHBs chronic porters, with traces of viral replication. From those patients, we got DNA s amplification in 43 samples, that formed the core to genotypical determination. Those were also evaluated on AgHBe positivity, viral load (CV) quantification, aminotransferases (ALT) and histological data. RESULTS: The genotypes A and F, were identified, with 35/43 (81.4%) of genotype A. Twenty Five from 43 patients (58.1%) presented abnormal ALT level, AgHBe negative (23/43 53.5%) and CV below 10.000 copies/ml (20/32 62.5%). In the patients presenting genotype A, 20/32 (62.5%) presented CV below 10,000 copies/ml, but in those with the genotype F, 5/7 (71.4%) presented CV above 10,000 copies/ml (p=0,101). There was no statistic difference between viral genotype and histological findings. CONCLUSION: In Sergipe, the genotypes A and F were found, but predominates the genotype A. Important differences were not found among the genotypes relatively to clinical and laboratorial findings. / INTRODUÇÃO: O vírus da hepatite B foi classificado em oito genótipos que variam de acordo com a distribuição geográfica, apresentando diferentes manifestações clínicas e resposta ao tratamento anti-viral. OBJETIVOS: O estudo visa determinar a prevalência dos genótipos em Sergipe-Brasil, e avaliá-los de acordo com achados clínicos e histopatológicos. METODOLOGIA: Em estudo transversal, foram avaliados 97 pacientes portadores crônicos do AgHBs com sinais de replicação viral. Destes, conseguiu-se amplificação do DNA em 43 amostras, as quais constituíram a casuística para realização de genotipagem. Foram, também, avaliados quanto à positividade do AgHBe, quantificação da carga viral (CV), aminotranferases (ALT) e avaliação histológica. RESULTADOS: Foram identificados os genótipos A e F, sendo 35/43 (81,4%) do genótipo A. Vinte e cinco/43 pacientes (58,1%) apresentaram ALT normais, AgHBe negativo (23/43, 53,5%) e CV inferior a 10.000 cópiasl/ml (20/32 (62,5%). Nos pacientes com genótipo A, 20/32 (62,5%) apresentaram CV inferior a 10.000 cópias/ml enquanto o genótipo F, 5/7 (71,4%) apresentaram CV superior a 10.000 cópias/ml (p=0,101). Não houve diferença estatística entre genótipo viral e características histológicas. CONCLUSÃO: Em Sergipe, foram descritos os genótipos A e F com predomínio do genótipo A. Não foram encontradas diferenças significantes entre os genótipos em relação às manifestações clínico-laboratoriais.

Hepatitis C implications go beyond liver complications, reflecting on systemic metabolic manifestations with consequent deleterious effect on the disease’s clinical course. In view of the pathogenic association between hepatitis C and metabolic dysfunctions, it was justified to perform this study in the care reference center of patients with hepatitis C diagnosis in the State of Sergipe, Brazil, in order to evaluate the anthropometric and metabolic profile evolution of these individuals in triple therapy and nutritional monitoring. This is an observational and descriptive study conducted with data from clinical and nutrition records of patients with chronic hepatitis C, adults or elderly patients in triple therapy attended at the University Hospital of Sergipe’s outpatient clinic. The individual diet plan was delivered after the first nutritional consultation and before the drug therapy start. Anthropometric evaluations were performed, data were collected from the biochemical profile and the extent of sustained virological response was analyzed after the end of drug treatment. It was observed a reduction at the percentage of subjects at risk (p = 0.002) and at substantially increased risk (p <0.001) for waist circumference (WC), and reduction of the percentage of individuals at risk (p <0.001) according to waist-to-height ratio (WHtR). There was a significant reduction in fasting blood glucose (p = 0.014), total cholesterol (p <0.001) and LDL cholesterol (p <0.001).In addition, there was a significant reduction in the prevalence of subjects with altered fasting plasma glucose among patients who achieved sustained virological response and those who did not achieve therapeutic success. Based on these results, it is suggested that nutritional monitoring combined with drug therapy for patients with hepatitis C, provided a positive evolution of the anthropometric and metabolic parameters of the sample, which may represent an effective therapeutic approach in the fight against the systemic manifestations associated with hepatitis C. / As implicações da hepatite C vão além de complicações hepáticas, refletindo em manifestações metabólicas sistêmicas com consequente efeito deletério no curso clínico da doença. Diante da associação patogênica entre hepatite C e disfunções metabólicas, justifica-se a execução desse estudo no centro de referência na assistência a pacientes com diagnóstico de hepatite C no Estado de Sergipe, com objetivo de avaliar a evolução perfil antropométrico e metabólico desses indivíduos em terapia medicamentosa tripla em acompanhamento nutricional. Trata-se de um estudo do tipo observacional e descritivo realizado com dados de prontuários clínicos e registros de nutrição de pacientes com hepatite C crônica, adultos ou idosos em terapia tripla assistidos no ambulatório do Hospital Universitário de Sergipe. O plano alimentar individual foi entregue após a primeira consulta nutricional e antes do início do tratamento farmacológico. Foram realizadas avaliações antropométricas, coletados dados do perfil bioquímico e analisado o alcance da resposta virológica sustentada após o término do tratamento medicamentoso. Observou-se redução do percentual de indivíduos com risco (p = 0,002) e em risco substancialmente aumentado (p < 0,001) para a Circunferência da Cintura (CC) e do percentual de indivíduos em risco (p < 0,001) de acordo com a Relação Cintura Estatura (RCEst). Verificou-se redução nos valores de glicemia de jejum (p = 0,014), colesterol total (p < 0,001) e LDL colesterol (p < 0,001). Além disso, tanto entre os pacientes que alcançaram a resposta virológica sustentada, quanto entre os que não obtiveram sucesso terapêutico, houve redução significativa na prevalência de indivíduos com alterações de glicemia de jejum. A partir destes resultados, sugere-se que acompanhamento nutricional aliado ao tratamento medicamentoso para pacientes com hepatite C, proporcionou uma evolução positiva dos parâmetros antropométricos e metabólicos da amostra, o que pode representar uma abordagem terapêutica eficaz no combate às manifestações sistêmicas associadas à hepatite C. / Aracaju, SE

Introdução: Aproximadamente, 170 milhões de pessoas estão cronicamente infectadas pelo vírus da hepatite C (VHC). A hepatite C é considerada a principal causa de doença hepática, podendo evoluir para cirrose e carcinoma hepatocelular. O tratamento objetiva deter a progressão da doença hepática pela inibição da replicação viral. Objetivo: Avaliar a efetividade e os custos no tratamento da hepatite C. Casuística e Métodos: Estudo retrospectivo de coorte com 161 pacientes acompanhados por meio das prescrições médicas no período de julho de 2005 até outubro de 2007, em uma instituição terciária de assistência, ensino e pesquisa, que utiliza como tratamento interferon alfa (INF), Alfapeginterferona 2a 180mcg (PEG 2a) e Alfapeginterferona 2b 80mcg (PEG 2b). Custo do tratamento calculado com base nos valores apenas dos medicamentos de 2005 até 2010. Resultados: A média de idade foi de 53 anos (23-81, + 11,11); 51,6% dos pacientes eram do gênero feminino; 104 (64,6%) pacientes com genótipo 1, seguidos de 52 (32,3%) com genótipo 3. Cerca de 30 (18,6%) pacientes cirróticos. Foram encontrados cinco grupos de pacientes, de acordo com o tipo de interferon utilizado durante o tratamento; 55 (34,2%) pacientes com resposta virológica sustentada (RVS), 86 (53,4%) não respondedores (NR) e 20 (12,4%) pacientes outras respostas. O uso de terapia de suporte foi maior nos grupos tratados com Alfapeginterferona 24 pacientes (14,9%) quando comparados com interferon alfa, 3 pacientes (1,9%) (p< 0,0001). O custo do tratamento foi maior nos pacientes tratados com Alfapeginterferona 2a 180mcg ao se comparar com as outras alternativas encontradas no estudo. Conclusões: A RVS foi semelhante entre os grupos estudados, o interferon alfa apresentou menor uso de terapia de suporte, e o custo do tratamento do Alfapeginterferona 2b 80mcg foi menor do que o Alfapeginterferona 2a 180mcg. / Introduction: Approximately 170 million people are chronically infected with hepatitis C virus (HCV). Hepatitis C is considered the main cause of liver disease, sometimes progressing to cirrhosis and hepatocellular carcinoma. Treatment aims to halt the progression of liver disease by inhibiting viral replication. Objective: To evaluate the effectiveness and costs in treating hepatitis C. Methods: Retrospective cohort study with 161 patients followed through prescriptions from July 2005 until October 2007 in a tertiary care institution, teaching and research, using treatment as interferon alpha (INF), peginterferon alpha 2a 180mcg (PEG 2a) and peginterferon alpha 2b 80mcg (PEG 2b). Treatment cost calculated based on values from 2005 to 2010 only of the drugs. Results: The mean medium age was 53 years (23-81, + 11.11), 51.6% of patients were female, 104 (64.6%) patients with genotype 1, and 52 (32, 3%) with genotype 3. About 30 (18.6%) patients with cirrhosis. Five groups of patients were found, according to the type of interferon used for the treatment, 55 (34.2%) patients with sustained virological response (SVR), 86 (53.4%) non-responders (NR) and 20 (12.4%) patients other answers. The use of supportive therapy was higher in those treated with peginterferon alfa 24 patients (14.9%) compared with interferon alpha, 3 patients (1.9%) (p<0.0001). The cost of treatment was higher in patients treated with peginterferon alpha 2a 180mcg when compared with other alternatives found in the study. Conclusions: SVR was similar between groups, the interferon alpha showed less use of supportive therapy and the treatment cost of peginterferon alpha 2b 80mcg was lower than the peginterferon alpha 2a 180mcg.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-02-26T11:26:20Z No. of bitstreams: 1 izabellaliguoricorsinovabo.pdf: 625553 bytes, checksum: cb3de105eafd87fb538ddfcec36c8d50 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-03-03T13:37:11Z (GMT) No. of bitstreams: 1 izabellaliguoricorsinovabo.pdf: 625553 bytes, checksum: cb3de105eafd87fb538ddfcec36c8d50 (MD5) / Made available in DSpace on 2016-03-03T13:37:12Z (GMT). No. of bitstreams: 1 izabellaliguoricorsinovabo.pdf: 625553 bytes, checksum: cb3de105eafd87fb538ddfcec36c8d50 (MD5) Previous issue date: 2015-01-29 / Mundialmente a hepatite C crônica é uma das principais causas de hepatopatia crônica. No mundo ocidental, representa a principal causa de cirrose hepática, carcinoma hepatocelular e indicação de transplante hepático. Atualmente, o tratamento utilizado consiste na utilização de interferon alfa peguilado e ribavirina associado ou não aos novos inibidores da protease por 24 a 48 semanas dependendo do genótipo e do grau de fibrose hepática. Além da eficácia longe do ideal, o tratamento da hepatite C crônica é repleto de eventos adversos destacando-se os transtornos neuropsiquiátricos, sobretudo o episódio depressivo. No Brasil existem poucos estudos a respeito da incidência deste episódio na terapia dupla. Diante disso, a proposta deste estudo foi verificar a incidência e os fatores associados ao surgimento de episódio depressivo em pacientes com hepatite C crônica submetidos à terapia antiviral com Interferon peguilado alfa 2a ou 2b e ribavirina, além de avaliar o impacto do surgimento deste episódio sobre a resposta virológica sustentada. Foram incluídos 32 pacientes com Hepatite C Crônica, submetidos à terapia dupla em seguimento regular no Ambulatório de Hepatologia do Serviço de Gastroenterologia do HU/CAS-UFJF, no período de junho de 2012 a junho de 2014. A HADS (Escala Hospitalar de Ansiedade e Depressão) foi utilizada para rastreamento do episódio depressivo, aplicada no baseline e nas semanas 4, 12, 24, 48 e 4 semanas após a interrupção da terapia. O diagnóstico de episódio depressivo foi estabelecido nos pacientes com HADS ≥ 9. Estes foram submetidos ao BDI-II (Inventário de Depressão de Beck) para graduação do episódio depressivo em nível mínimo, leve, moderado e grave. Variáveis clínicas, laboratoriais, histológicas e sócio- demográficas de interesse foram obtidas. Destes pacientes, 25% desenvolveram episódio depressivo sendo o pico de incidência observado na semana 12 de terapia antiviral. O episódio depressivo foi moderado em 87% dos pacientes. Não foi possível identificar preditores de episódio depressivo. A taxa de resposta virológica sustentada foi 75% e 67% nos pacientes com e sem episódio depressivo, respectivamente (p = 0,66). Os resultados permitem concluir que a incidência de episódio depressivo em portadores de hepatite C Crônica submetidas a terapia antiviral é elevada; não foi possível demonstrar fatores relacionados ao aparecimento deste; a presença de episódio depressivo não influenciou a taxa de resposta virológica sustentada. / Chronic Hepatitis C is one of the main causes of chronic liver disease around the world. In the west, it represents the leading cause of liver cirrhosis, hepatocellular carcinoma and indication of liver transplantation. Currently, the usual treatment consists on the use of pegylated interferon alpha and ribavirin, associated or not with the new protease inhibitors, for 24 to 48 weeks, depending on the genotype and the degree of liver fibrosis. Besides the far from ideal effectiveness, the treatment of chronic Hepatitis C is full of adverse events, of which the neuropsychiatric disorders stand out, especially the depressive episode. In Brazil, there are few studies about the incidence of that episode on double therapy. As such, the goal of this study was to verify the incidence and the factors associated with the appearance of the depressive episode in chronic Hepatitis C patients subjected to antiviral therapy with pegylated Interferon alpha 2a or 2b and ribavirin, as well as to evaluate the impact of the appearance of that episode over the sustained viral response. 112 chronic Hepatitis C patients were included, 80 of which were antiviral treatment-naive (control group) and 32 subjected to double therapy (treatment group), regularly followed at the Hepatology Clinic of the Gastroenterology Service of HU/CAS-Universidade Federal de Juiz de Fora, between June 2012 and June 2014. The HADS (Hospital Anxiety and Depression Scale) was used for tracking the depressive episode in both groups, being applied at baseline, at weeks 4, 12, 24 and 48 and 4 weeks after interruption of the therapy on the treatment group. The diagnosis of depression was established at patients with HADS ≥ 9. These were subjected to BDI-II (Beck Depression Inventory) for gradation of the depressive episode in levels minimum, light, moderate and severe. Clinical, laboratory, histological and sociodemographic variables of interest were obtained. On the treatment group, 25% of the patients developed depressive episode, with the peak incidence observed at week 12 of antiviral therapy. The depressive episode was moderate on 87% of the patients. It was not possible to identify predictors for the depressive episode. The sustained viral response rate was 75% and 67% on patients with and without depressive episode, respectively (p = 0,66). The results allow concluding that the incidence of depression on chronic Hepatitis C carriers subjected to antiviral therapy is high and was similar to what the literature describes; it was not possible to demonstrate factors related to the appearance of depression; the presence of depression did not influence the sustained viral response rate.

Systematic discontinuation of long-term treatment with nucleos(t)ide analogues (NAs) is one strategy to increase functional cure rates in patients with chronic hepatitis B e antigen (HBeAg)-negative hepatitis B. Currently, available study results are heterogeneous; however, long-term hepatitis B surface antigen (HBsAg) loss rates of up to 20% have been reported in prospective trials. This review proposes criteria that can be used when considering NA discontinuation in patients with chronic hepatitis B virus (HBV). Discontinuing NA treatment frequently results in a virologic and biochemical relapse that runs through different phases: the lag phase, reactivation phase, and consolidation phase. The HBV-DNA flares observed during the reactivation phase are often transient and most likely represent a trigger for inducing a long-term immune control by specific CD8+ T cells, and therefore do not need immediate interventions but close follow-up evaluation. Low HBsAg levels at the time of treatment cessation predict a positive long-term response to NA discontinuation associated with a higher likelihood of HBsAg clearance. Other host and viral biomarkers are currently under evaluation that may prove to be helpful to further characterize the population that may benefit most from the finite NA treatment concept. Potential harmful biochemical flares during the reactivation phase need to be identified early and can be effectively terminated by reintroducing NA treatment. Hepatic decompensation represents a risk to patients with cirrhosis undergoing NA discontinuation. Therefore, the finite NA approach should only be considered after excluding advanced fibrosis and cirrhosis and if a close follow-up of the patient and supervision by an experienced physician can be guaranteed. Conclusion: For selected patients, NA discontinuation has become a powerful tool to achieve control over HBeAg-negative HBV infections. Its significant effect represents a challenge to novel treatment approaches, but it may also serve as their enhancer.

T cells have a crucial role in viral clearance and vaccine response; however, the mechanisms regulating their responses to viral infections or vaccinations remain elusive. In this study, we investigated T-cell homeostasis, apoptosis, DNA damage, and repair machineries in a large cohort of subjects with hepatitis C virus (HCV) infection. We found that naive CD4 T cells in chronically HCV-infected individuals (HCV T cells) were significantly reduced compared with age-matched healthy subjects. In addition, HCV T cells were prone to apoptosis and DNA damage, as evidenced by increased 8-oxoguanine expression and γH2AX/53BP1-formed DNA damage foci—hallmarks of DNA damage responses. Mechanistically, the activation of DNA repair enzyme ataxia telangiectasia mutated (ATM) was dampened in HCV T cells. ATM activation was also diminished in healthy T cells exposed to ATM inhibitor or to HCV (core protein) that inhibits the phosphoinositide 3 kinase pathway, mimicking the biological effects in HCV T cells. Importantly, ectopic expression of ATM was sufficient to repair the DNA damage, survival deficit, and cell dysfunctions in HCV T cells. Our results demonstrate that insufficient DNA repair enzyme ATM leads to increased DNA damage and renders HCV T cells prone to apoptotic death, which contribute to the loss of naive T cells in HCV infection. Our study reveals a novel mechanism for T-cell dysregulation and viral persistence, providing a new strategy to improve immunotherapy and vaccine responses against human viral diseases.

Le virus de l‘hépatite E (VHE) est endémique mondialement. Dans les pays en voie de développement, le VHE est une cause majeure d'hépatite aiguë et l'hépatite E est une maladie du péril fécal, transmise par la consommation d'eau contaminée. Le taux de mortalité de l'hépatite E aiguë en situation d'épidémie est estimé entre 0,2 et 4%. Dans les pays développés, l'hépatite E d'origine autochtone a émergé au début du XXIème siècle et un réservoir porcin à l'origine de transmissions zoonotiques du VHE a été établi. En 2008, pour la première fois, des formes chroniques de l'hépatite E ont été décrites révélant que le VHE était également une cause d'hépatite chronique et de cirrhose. Ces nouvelles formes d'hépatite E ont été rapportées chez des patients immunodéprimés pour transplantation d'organes solides, par le virus de l'immunodéficience humaine ou par des hémopathies malignes ou les traitements de ces hémopathies. Les travaux de cette Thèse ont eu pour objectifs de décrire les aspects cliniques puis épidémiologiques de l'hépatite E, d'étudier certains aspects immunologiques de l'hôte et certains aspects virologiques des VHE dans le but de comprendre les mécanismes conduisant au développement d'une hépatite E chronique dans la population des patients transplantés d'un rein suivis au CHU de Marseille. Nous avons décrit dans une étude rétrospective les caractéristiques et l'histoire naturelle de 16 infections autochtones diagnostiquées devant une hépatite inexpliquée. Nous avons décrit une évolution majoritairement chronique de l'hépatite E et son potentiel cirrhogène. / Hepatitis E virus (HEV) is endemic worldwide. In developing countries, HEV is a major cause of acute hepatitis and hepatitis E is a disease transmitted by the faecal-oral route through contaminated water. The estimated mortality rate of acute hepatitis E in the setting of outbreaks ranges from 0.2 to 4%. In developed countries, hepatitis E of autochthonous origin emerged at the beginning of twenty-first century and a porcine reservoir for HEV has been established that is a source for zoonotic transmission. In 2008, for the first time, chronic forms of hepatitis E have been reported showing that HEV was also a cause of chronic hepatitis and cirrhosis. These new forms of hepatitis E have been reported in immunocompromised patients due to solid organ transplantation, infection by human immunodeficiency virus, hematological malignancies or treatment of these malignancies. The objectives of this Thesis have been to describe the clinical and epidemiological features of hepatitis E, to examine some immunological aspects of the host and some virological aspects of HEV in order to understand the mechanisms leading to the development of chronic hepatitis E in the population of kidney transplant recipients followed at the University Hospital of Marseille. In a retrospective study, we described the characteristics and natural history of 16 HEV infections diagnosed in patients presenting with unexplained hepatitis. We described that hepatitis E progressed the most frequently towards chronicity and possibly towards liver cirrhosis. We showed that after dose reduction of immunosuppressants, more than half of the chronic infections resolved.