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Pessôa, Mário Guimarães. ""Hepatite colestática associada ao vírus da hepatite C pós-transplante hepático: estudo virológico, histopatológico e imuno-histoquímico"." Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/5/5144/tde-04042006-090453/.
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A evolução da recorrência da hepatie C pós-transplante hepático pode ter um curso bastante variável. Raramente a doença pode progredir para uma forma conhecida como hepatite recorrente colestática grave, cuja patogenia ainda não é bem conhecida. Nós estudamos nesse trabalho alguns aspectos virológicos, histológicos e imunohistoquímicos de seis pacientes com essa forma rara de recorrência da doença, tendo como comparação um grupo pareado de seis pacientes transplantados com a forma leve de hepatite C recorrente, e como controle imunocompetente, cinco pacientes não transplantados com hepatite crônica pelo vírus C. Foram avaliados como possíveis fatores preditivos de gravidade da progressão da recorrência: viremia do VHC, evolução de quasispécies, parâmetros histopatológicos, e imunoreatividade para o antígeno core do VHC.Following liver transplantation (OLT) HCV-related disease severity is highly variable, with a minority of cases progressing to an extremely severe form of cholestatic hepatitis, in which the pathogenesis is not yet understood. We aim to compare virological, histological and immunohistological changes in patients developing mild and severe post-OLT HCV recurrence. Twelve patients with recurrent HCV infection were studied (6 with severe and 6 with mild disease). Five HCV-infected immunocompetent patients were used as controls. We looked at viral load, quasispecies evolution of HCV, several histological parameters and immuno-reactivity of core antigens at three time-points (pre-OLT, early post-OLT and late post-OLT) as predictors of severity of recurrence post-OLT.
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Zaver, Himesh, Momani Laith Al, Kalpit Devani, and Chakradhar M. Reddy. "Ledipasvir/sofosbuvir induced nephrotic syndrome: A challenging case of Hepatitis C management." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/asrf/2018/schedule/80.
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ABSTRACT:
Hepatitis C virus (HCV) is associated with various glomerulopathies and nephrotic syndrome. However nephrotic syndrome following treatment is rare. Ledipasvir/sofosbuvir (L/S) has recently come into favor in treating HCV due to its relatively mild side effects compared to the more traditional interferon therapy. To the best of our knowledge, there are no reported cases of nephrotic syndrome following treatment with L/S. We present a case of nephrotic syndrome suspected secondary to L/S in a patient with chronic kidney disease. Increased vigilance when assessing therapeutic options in HCV patients with renal comorbidities can improve patient outcomes. A 63 year-old male patient presented to the hospital with shortness of breath, and a two-week history of bilateral lower extremity edema. Past medical history was significant for liver cirrhosis secondary to Hepatitis C genotype Ia, hepatocellular carcinoma status post liver transplantation 6 months prior to admission and Stage 3b chronic kidney disease with baseline creatinine (Cr) approximately 1.5 mg/dl. Medications included L/S for HCV and tacrolimus and prednisone for post-transplant treatment. Patient’s vitals were stable and physical exam was remarkable for facial swelling, mainly on the eyelids, decreased breath sounds bilaterally, distended abdomen with a fluid wave, and 2-3+ pitting edema up to the knees on lower extremities bilaterally. Laboratory work-up was remarkable for low albumin of 3.0 g/dl, and total protein of 5.6 g/ dl. Creatinine of 1.8 mg/dl was elevated from patient’s baseline. HCV viral load was undetectable and electrolytes, transaminases and the complete blood count were within normal limits. Subsequently, urine protein to creatinine ratio was measured because of generalized swelling and hypoproteinemia, which was found to be significantly high at 8.80, compared to 0.04 one year prior. 24-hour total urine protein was found to be 2065 mg/day. Renal ultrasonography showed no hydronephrosis and was otherwise unremarkable. Renal biopsy however, revealed changes suggestive of membranoproliferative glomerulonephritis (MPGN] most likely secondary to HCV. No immune complexes, lambda/kappa light chains, or cryogloblin were appreciated. Nephrotoxic agents such as diuretics and corticosteroids were held. Tacrolimus trough was appropriate to dose level and was continued along with L/S. As admission progressed the patient’s creatinine continued to get worse and rose up to 4.3 mg/dl with persistent proteinuria. With tacrolimus trough levels within normal limits and given L/S was the most recently initiated drug, L/S was thought to be the culprit and was thus held. The renal function began to improve gradually, and the patient was discharged in stable condition with close follow up. Follow up one month later found creatinine and renal function return to baseline and proteinuria resolved. Our case shows that Ledipasvir/sofosbuvir may possibly be related to nephrotic syndrome in HCV patients. Although further studies are needed to prove the causality our case seeks to raise clinical suspicion and increase vigilance when assessing therapeutic options in HCV patients with renal comorbidities such as chronic kidney disease.
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Pereira, Haydée Marina do Valle. "Características de pacientes com hepatite C crônica e transaminases normais." Universidade de São Paulo, 2005. http://www.teses.usp.br/teses/disponiveis/5/5134/tde-08102014-103411/.
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Hepatite C tem evolução progressiva, persiste na maioria dos pacientes (85%) e leva a uma doença crônica assintomática.A maioria dos pacientes apresenta nível de ALT elevada e aproximadamente 25% normal. Estes geralmente são mulheres e não há associação entre genótipo e severidade da lesão hepática. Histologicamente apresentam lesão mínima e leve fibrose, embora cirrose tenha sido relatado.Visando estimar a prevalência, características demográficas, genotípicas e anatomopatológicas em pacientes com ALT normal, realizamos um estudo de série de 68 casos entre janeiro de 1997 a abril de 2000. A prevalência foi de 13,82%, 45,6% do gênero masculino e 54,4% feminino, média de idade 38 +/- 13 anos. Genótipo 1 em 84,75%, 2 em 6,78% e o 3 em 8,47%. Em 52,9% dos casos biópsia hepática revelou fígado reacional, porém uma importante proporção (29%) dos nossos pacientes com transaminases normais mostrou sinais de fibrose. Estes resultados sugerem a necessidade de revisar os algoritimos da prática de biópsia hepática nessa populaçãoHepatitis C evolves progressively persisting in the majority of patients (85%) resulting in na asymptomatic chronic disease.Most patients have high ALT levels and approximately 25% normal ALT.The latter are usually female and there is no association between genotype and severity hepatic lesion.Histology shows small lesion and low amount of fibrosis, despite cirrhosis having been reported.Aiming at assessing prevalence, demographic, genotypical and anatomopathological characteristics in patients with normal ALT levels, we studied a series of 68 cases between January 1997 and April 2000.There was a prevalence of 13,82%, 45,6% of which were male and 54,4% female, average age of 38+/-13 years.Genotype 1 in 84,75%, 2 in 6,78% and 3 in 8,47%.In 52,9% of the cases revealed liver reaction, however, an important proportion of patients showed histologic signs of fibrosis (29%).Theses results suggest the need to revisit the algorithm for liver biopsy practice
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Ribeiro, Maria de Fatima Gomes de Sá. ""Fatores prognósticos na evolução da hepatite C"." Universidade de São Paulo, 2005. http://www.teses.usp.br/teses/disponiveis/5/5144/tde-12082005-155039/.
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O consumo alcoólico pode levar à deterioração da lesão hepática em pacientes com hepatite C. A progressão da doença na hepatite C crônica depende de vários outros fatores relacionados com o hospedeiro, vírus e o meio ambiente embora os mecanismos patogênicos ainda não sejam bem conhecidos. OBJETIVOS: avaliar os dados demográficos, epidemiológicos, clínicos e bioquímicos dos pacientes com hepatite C crônica em relação ao consumo alcoólico e relacionar as variáveis clínicas, epidemiológicas e bioquímicas em relação às alterações histopatológicas ausente e leve em comparação às intensas. MÉTODOS: Nós estudamos os dados demográficos, clínico-epidemiológicos e laboratoriais comparando-os às alterações histopatológicas em 120 doadores voluntários de sangue com hepatite C, divididos em três grupos de acordo com a ingestão alcoólica: (i) grupo abstêmio: n=41; (ii) grupo consumo alcoólico leve: n=36; (iii) grupo consumo alcoólico acentuado: n=43. Os parâmetros histopatológicos como alterações estruturais ou fibrose, atividade periportal e lobular e infiltrado portal foram graduados de 0 a 4 e divididas em leve (0/1/2) e intensa (3/4). RESULTADOS: Quase 70% dos pacientes eram homens e a maior proporção deles (83,5%) era de alcoolistas (leve e acentuado).Por outro lado, as mulheres eram habitualmente abstêmias (58,5%). Transfusão, como fator de risco para hepatite C foi mais freqüente em abstêmios (p=0,056) enquanto que o uso de drogas predominou no grupo de consumo alcoólico acentuado (p < 0,001). Com relação aos grupos, não foram observadas diferenças quando analisados o tempo de ingestão alcoólica, abstinência alcoólica, cirurgia e outros modos de contaminação, níveis séricos de alanina aminotransferase, aspartato aminotransferase, gama-glutamiltransferase, graus de fibrose, atividade lobular e infiltrado portal.Atividade periportal leve foi relevante nos grupos abstêmios e consumo alcoólico leve enquanto a atividade periportal intensa foi maior no consumo alcoólico acentuado (p=0,033). Quando comparamos os diferentes parâmetros histopatológicos, a idade mais avançada foi associada de modo significativo com fibrose (p=0,004), atividade periportal (p=0,001) e infiltrado portal intensos (p=0,001). Valores mais altos de índice de massa corpórea correlacionaram significativamente (p=0,013) com fibrose intensa enquanto maior tempo de ingestão alcoólica foi relacionado com atividade periportal intensa (p=0,001). Níveis de alanina aminotransferase foram maiores significativamente com intensas fibrose (p < 0,001), atividade periportal (p=0,031) e atividade lobular (p=0,013), enquanto níveis elevados de aspartato aminotransferase correlacionaram com fibrose (p < 0,001), atividade periportal (p < 0,001), atividade lobular (p=0,001) e infiltrado portal intensos (p < 0,018). Valores de gama-glutamiltransferase foram significativamente maiores com intensas fibrose (p=0,012), atividade periportal (p=0,013 e atividade lobular (p=0,003) e níveis mais altos de imunoglobulina G correlacionaram com intensas fibrose (p=0,040) e atividade lobular (p=0,048). A contagem de plaquetas foi significativamente menor quando comparada com intensas fibrose (p < 0,001) e atividade periportal (p=0,049). Análise de regressão logística identificou aspartato aminotransferase e contagem de plaquetas como fatores preditivos independentes de intensa fibrose. CONCLUSÕES: Nosso estudo mostrou correlação entre consumo de álcool e atividade periportal mas não com fibrose que está relacionada com idade, índice de massa corpórea, alanina aminotransferase, aspartato aminotransferase, gama-glutamiltransferase e menor contagem de plaquetas. Níveis de aspartato aminotransferase e contagem de plaquetas foram os melhores fatores preditivos de fibrose intensaINTRODUCTION: The interaction of hepatitis C with alcohol consumption is thought to be a deleterious one. Progression of liver disease in chronic hepatits C depends on several other factors related to the host, virus and the enviroment but, these factors are not well understood yet. AIMS:To analyze demographic, epidemiological, biochemical and histopathological data of patients with hepatitis C according to heavy, light or no alcohol consumption.To assess the behavior of clinical, epidemiological and biochemical variables in relation to absent or mild histopathological alterations in contrast to severe alterations. METHODS: We have studied the demographic, epidemiological and laboratory data and then compared them to the histopathological alterations in 120 volunteer blood donors with hepatitis C virus divided into three groups according to alcohol intake: abstainers: n=41, light drinkers: n=36 and heavy drinkers: n=43. Liver histopathology alterations, namely architectural staging, periportal and lobular inflammation as well as portal inflammatory infiltrate were graded from 0 to 4 and afterwards divided into light (0 to 2) and severe (3 to 4). RESULTS: Almost 70% (83/120) of the patients were men and a high proportion of men (83.5 %) were drinkers (light and heavy). Women, on the other hand were more likely to be abstainers: 58.5% of them did not drink. Transfusion as risk factor for HCV was more frequent in abstainers (p= 0.056) whereas drug addiction predominated in heavy drinkers (p < 0.001). Regarding these groups no differences were found when duration of alcohol intake, abstinence of alcohol, surgery, other contamination factors, ALT, AST, GGT, degree of fibrosis, lobular inflammation and portal infiltrate were consider.Regarding three groups, mild periportal inflammation was significantly related with abstainers and light drinkers groups whereas severe periportal inflammation was more predominant in heavy drinkers (p=0.033). When we compared mild with severe histopathological alterations older age was significantly associated with severe fibrosis (p=0.004), periportal inflammation (p=0.001) and portal inflammatory infiltrate (p=0.001). Higher BMI values correlated significantly (p=0.013) with severe fibrosis whereas higher duration of alcohol intake was related to severe periportal inflammation (p=0.001). ALT level was significantly higher in severe fibrosis (p < 0.001), periportal inflammation (p=0.031) and lobular inflammation (p=0.013), whereas higher levels of AST correlated with severe fibrosis (p < 0.001), periportal inflammation (p < 0.001), lobular inflammation (p=0.001) and portal inflammatory infiltrate (p=0.018) . GGT values were significantly higher in severe fibrosis (p=0.012), periportal inflammation(p=0.013) and lobular activity (p=0.003) and higher levels of IgG correlated with fibrosis (p=0.040) and lobular inflammation (p=0.048). In the end, platelets were significantly lower (p < 0.001) in severe fibrosis and periportal inflammation (p=0.049). Logistic regression analysis identified AST and platelet count as independent predictors of severe fibrosis.CONCLUSIONS: Our study has shown a correlation between alcohol consumption and periportal inflammation, but not with fibrosis, which is correlated with age, high enzymes levels and low platelet count. AST and platelet count were the best predictors of severe fibrosis
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Trepo, Eric. "Role of genetic factors in the progression of fibrosis in alcoholic liver disease and chronic hepatitis C." Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209659.
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La maladie alcoolique du foie (MAF) et l’hépatite C chronique (HCC) sont les causes les plus fréquentes de cirrhose, carcinome hépatocellulaire (CHC) et transplantation hépatique dans les pays industrialisés. La fibrose hépatique est le stigmate lésionnel de la progression de la maladie vers la cirrhose comme dans toutes les hépatopathies chroniques. Certains facteurs de risque cliniques environnementaux ont été identifiés. Toutefois, ils n’expliquent pas l’extrême variabilité individuelle de la progression de la fibrose. L’influence ethnique à développer une maladie plus sévère ainsi que les études de concordance des jumeaux mono- et di-zygotiques sur la prévalence de la cirrhose alcoolique ont suggéré l’existence de facteurs génétiques associés. Les nombreuses études de gènes candidats réalisées n’ont identifié que très peu de variants associés de manière reproductible. Pour l’HCC par exemple, le score de risque de cirrhose ou « CRS » a montré sa capacité à prédire une fibrose avancée dans diverses cohortes caucasiennes. Récemment, une étude d’association pangénomique (GWAS) dans la stéatohépatopathie non-alcoolique (NAFLD) a mis en évidence un singleton (single nucleotide polymorphism [SNP]) particulier (rs738409 C>G) dans le gène PNPLA3. Ce dernier s’est révélé être, dans diverses études, le SNP ayant l’impact le plus robuste et le plus reproductible dans cette maladie. Par ailleurs, ce même variant a également été significativement associé à la cirrhose alcoolique chez les hispaniques.Les travaux réalisés dans le cadre de cette thèse ont permis de montrer que :
1) Le CRS avait la capacité de prédire la progression de la fibrose chez des patients caucasiens ayant une HCC dans 2 cohortes européennes indépendantes.
2) Par ailleurs, dans la MAF, nous avons répliqué chez des patients caucasiens l’association entre le SNP rs738409 dans le gène PNPLA3 et la cirrhose. Nous avons également montré pour la première fois, que l’expression de PNPLA3 était significativement diminuée chez les patients avec une fibrose plus avancée. De plus, nous avons observé dans 2 cohortes européennes que rs738409 était également associé à la prévalence du CHC.
3) Enfin, nous avons également mis en évidence l’impact de ce même SNP sur la stéatose hépatique et la fibrose dans l’HCC sans toutefois qu’il influence la réponse à la thérapie antivirale dans 3 cohortes caucasiennes indépendantes.
Ainsi de manière remarquable, un même SNP (rs738409) apparait associé à des lésions hépatiques sévères dans les trois pathologies hépatiques chroniques les plus fréquentes (la MAF, l’HCC et la NAFLD). Ceci suggère des voies pathogéniques communes de la fibrogénèse hépatique. Par ailleurs, ces travaux soulignent indirectement que les GWAS ont la capacité d’ouvrir de nouvelles voies physiopathologiques et d’identifier de nouveaux variants, gènes ou région génétiques capables de constituer de nouveaux biomarqueurs et cibles thérapeutiques dans l’HCC et la MAF.
Doctorat en Sciences médicales
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Deltenre, Pierre. "Hépatite C: contribution à l'évaluation de l'histoire naturelle et à la prise en charge thérapeutique de l'hépatite chronique." Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209708.
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L’hétérogénéité de l’histoire naturelle de l’hépatite C est expliquée par l’existence de facteurs environnementaux ou liés au malade qui influencent l’évolution de la maladie. L’obtention d’une réponse virologique soutenue est l’objectif principal de la prise en charge thérapeutique car c’est la seule façon de réduire l’incidence de la cirrhose et la mortalité liée au virus de l’hépatite C. Pour être efficaces, les stratégies thérapeutiques doivent être élaborées à deux niveaux. A l’échelle individuelle, elles doivent optimaliser les chances de réponse virologique tout en limitant l’exposition aux effets secondaires. A l’échelle d’une population, la meilleure stratégie est celle qui aura l’impact le plus important sur l’incidence de la cirrhose et sur la mortalité liées au virus de l’hépatite C.Les travaux réalisés dans le cadre de cette thèse ont permis d’identifier des critères virologiques autorisant l’arrêt d’un traitement inefficace dès le terme de la 4ème semaine chez les malades présentant des transaminases normales et chez les malades non répondeurs à un premier traitement, de quantifier la perte de chance de réponse virologique lorsque la durée du traitement est limitée à 24 semaines chez les malades infectés par un génotype 1, d’évaluer la place de l’amantadine dans l’arsenal thérapeutique, de quantifier l’impact d’une insulino-résistance sur le taux de réponse virologique, de contribuer à l’élaboration d’une stratégie thérapeutique permettant une meilleure tolérance hématologique chez les malades hémodialysés et de quantifier l’impact des polymorphismes de l’interleukine 28B sur le taux réponse virologique des malades infectés par un génotype 2 ou 3. Nos travaux ont également permis de mesurer l’impact d’une consommation excessive d’alcool sur la morbi-mortalité liée au virus de l’hépatite C à l’échelle d’une population et de quantifier l’impact des mesures thérapeutiques actuelles et de stratégies thérapeutiques alternatives sur cette morbi-mortalité.
Au cours de la prochaine décennie, le traitement de l’hépatite chronique C sera articulé autour des molécules antivirales spécifiques agissant directement contre le virus de l’hépatite C. De nouvelles stratégies thérapeutiques intégrant la cinétique virale et les marqueurs génétiques prédictifs de la réponse virologique soutenue devront être élaborées afin d’offrir les meilleures chances d’éradication virologique au plus grand nombre de malades.
Doctorat en sciences médicales
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Savage, Anne Kay. "The pathology of hepatitis C virus infection." Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362544.
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Lim, Teegan Reina. "Metabolic effects of hypoxia and chronic hepatitis C." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8535/.
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Hypoxia has been linked to the pathogenesis of hepatic steatosis in murine and human models. There is an abundance of data suggesting that HIFs play a central role in regulating hepatic lipid metabolism. This study suggested that hypoxia-induced hepatic lipid accumulation is through de novo lipogenesis and free fatty acid uptake, and is dependent on hypoxia inducible factors la and 2a. On the contrary, hepatitis C infection reduced de novo lipogenesis and free fatty acid uptake in both normoxic and hypoxic conditions in vitro, and this inhibition is viral strain-dependent. In the clinical setting, chronic hepatitis C {CHC) and non-alcoholic fatty liver diseases {NAFLD) are associated with hepatic steatosis and insulin resistance. Using an integrative physiological approach that measures lipid and carbohydrate flux in vivo we demonstrated that patients with CHC had modest increase in insulin resistance and that the relative contribution of tissue specific insulin sensitivity in patients with CHC and NASH varied. Furthermore, curing HCV infection improved hepatic and subcutaneous adipose tissue insulin resistance. The improvement in hepatic and adipose tissue insulin resistance was more pronounced in patients infected with genotype 3 HCV, whilst the improvement in skeletal muscle insulin resistance was more evident in genotype 1 infection, demonstrating a genotype-specific effect in the metabolic perturbation in CHC. Further studies are required to confirm that genotype specific effect of HCV on insulin resistance and its link with NASH.
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Christie, John Michael Landale. "Viral persistence in hepatitis C virus infection." Thesis, University of Southampton, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268465.
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HAYASHI, HISAO, TOSHIKUNI TAKlKAWA, KATSUMI KATO, SATOSHI TAKIYA, TSUNEAKI TAGAYA, JUNSUKE KURIKI, MOTOHIRO ARAO, and SHOSHI KATO. "BIOCHEMICAL IMPROVEMENT OF CHRONIC HEPATITIS C AFTER GASTROINTESTINAL BLEEDING." Nagoya University School of Medicine, 1994. http://hdl.handle.net/2237/16077.
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Verbaan, Hans. "Chronic hepatitis C infection with special reference to prevalence, aggravating factors and longterm outcome /." Lund : Gastroenterology and Hepatology Division, Dept. of Medicine, University Hospital, Lund University, 1997. http://books.google.com/books?id=SBdrAAAAMAAJ.
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Hui, Chee-kin, and 許志堅. "Chronic hepatitis C infection: diagnosis, fibrosis progression and interferon therapy." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B29756972.
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Abbas, Amro M. "Pathogenesis of disease associated with chronic hepatitis C virus infection." Thesis, University of Nottingham, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368251.
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Veldt, Bartholomeus Johannes. "Long-term clinical outcome of treatment for chronic hepatitis C." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2008. http://hdl.handle.net/1765/12624.
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Dolman, Grace E. "Tissue biomarkers of fibrosis progression in chronic hepatitis C infection." Thesis, University of Nottingham, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.718462.
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Chronic infection with hepatitis C virus leads to liver fibrosis. In some individuals this can progress to cirrhosis and its clinical complications. As such, chronic hepatitis C is a major burden to healthcare systems globally. As fibrosis progression rates are highly variable, it would be useful to be able to identify those individuals at greatest risk of rapid progression. Efficacious therapies for hepatitis C are now available, but are expensive, and will not be available to all. Fibrosis progression is challenging to study due to the long duration of the disease. We have used data from the Trent Study of Patients with Hepatitis C Virus Infection to determine the factors associated with fibrosis progression in patients with advanced fibrosis and cirrhosis. This prospective cohort study contains a wealth of information and has ethical permission to collect clinical outcome data and access a large biobank of liver biopsies. Fibrosis progression is a non-linear process and our data suggest that the factors driving the process may change as fibrosis advances. We describe the development of a semi-automated digital image analysis algorithm to quantify collagen and elastin in archived liver biopsies and we have evaluated these tissue biomarkers as predictors of subsequent clinical outcomes. Elastin shows promise as a novel biomarker of progression to clinical outcomes in liver cirrhosis. Measuring gene expression profiles has the potential to be a sensitive indicator of fibrogenesis, not just fibrosis. We have measured the gene expression profile of archived hepatic biopsy tissue in patients with cirrhosis and we have identified a small number of target genes that have increased expression in those who reach clinical outcomes at 5 years. This work furthers our understanding of the factors that are predictive of progression to clinical outcomes in chronic hepatitis C infection, an area of increasing clinical importance.
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Carlsson, Tony. "Hepatitis C virus kinetics during antiviral treatment /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-588-3/.
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Mohamed, Ajayeb Dakhelallah. "The influence of HLA in chronic hepatitis B and C and analysis of a new subtype of hepatitis C virus." Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243795.
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Oriolo, Giovanni. "Mood, immunity and brain connectivity in patients with chronic hepatitis C." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/668025.
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INTRODUCTION. Sickness behavior is a highly organized adaptive strategy elicited by inflammation to support the organism’s defense against pathogens. It is characterized by changes in behavior, mood and cognition similar to those observed in patients with major depressive disorder. Despite its adaptive function, sickness behavioral changes may become prolonged and dysfunctional when the pathogen stimulus cannot be removed and may contribute to the development of depression in vulnerable patients. The study of the mechanisms linking inflammation to sickness behavior and depression would be crucial for a better understanding of the pathophysiology of depression and to develop new therapeutic approaches.
HYPOTHESIS AND OBJECTIVES. Patients with a low-degree chronic inflammatory disease such as chronic hepatitis C (CHC), compared to healthy controls, would present changes in brain morphology, activity, connectivity and metabolism in areas linked to sickness behavior and depression, and that such alterations would be related to mood symptoms and inflammatory markers. The main objective of this thesis was to elucidate the clinical and neurobiological correlates of a prolonged sickness condition associated with chronic inflammation, such as CHC.
STUDY 1: METHODS AND RESULTS. A systematic review with meta-analysis of neuroimaging research was conducted in CHC treatment naïve patients. A computerized literature search was performed in main databases from inception up until 1 May 2017 for peer-reviewed studies on structural or functional neuroimaging assessment of no treated patients without cirrhosis or encephalopathy, neuropsychiatric disease or substance use disorder with control group. The primary measures of interest varied according to the neuroimaging technique used and the secondary outcome were the correlation of these measures with neuropsychiatric symptoms. Meta-analysis was conducted when possible. Of 1403 records, 32 full-text articles were assessed for eligibility. The final sample was of 25 studies. The whole sample was of 509 patients of mild liver disease, and 491 healthy controls. A meta‐analysis of magnetic resonance spectroscopy studies showed increased levels of choline/creatine ratio, creatine and glutamate plus glutamine in basal ganglia and increased levels of choline/creatine ratio in centrum semiovale white matter in CHC patients. Other structural and functional brain abnormalities were also reported by individual studies as marker of neuroinflammation, oxidative stress and neuron-glia or axon-myelin integrity disruption. Central nervous system metabolic changes were mainly correlated with neurocognitive impairment and fatigue symptoms, thought controversial results were observed.
STUDY 2: METHODS AND RESULTS. A cross-sectional, case-control study of 35 CHC no treated patients, and 30 healthy controls, age and sex matched. Exclusion criteria were decompensated cirrhosis or hepatocarcinoma, any chronic disease or inflammatory condition, any neuropsychiatric and substance use disorder. All patients were evaluated for perceived stress (PSS), depression (PHQ-9), fatigue and irritability through a visual analog scale (VAS), as well as serum levels of interleukin-6 (IL-6), prostaglandin E2 (PGE2) and oxidative stress markers. Functional magnetic resonance imaging was performed, measuring resting-state functional connectivity using a region-of-interest (seed)-based approach focusing on the bilateral insula, subgenual anterior cingulate cortex (sgACC) and bilateral putamen. Between-group differences in functional connectivity patterns were assessed with two-sample t-tests, while the associations between symptoms, inflammatory markers and connectivity patterns were analyzed with multiple regression analyses. We observed that CHC patients had higher PSS, PHQ-9 and VAS scores for fatigue and irritability, as well as increased IL-6 levels, PGE2 concentrations and antioxidant system activation compared to controls. Increased perceived stress and depressive symptoms were associated with changes in inflammatory marker levels and in functional connectivity between the insula and putamen, areas involved in interoceptive integration, emotional awareness, and orientation of motivational state. Of note, PGE2 and PSS scores accounted for 46% of the variance in functional connectivity between the anterior insula and putamen.
CONCLUSIONS. The results supported the hypothesis of a direct or indirect involvement of hepatitis C virus in central nervous system disturbances and provide valuable information on the brain areas involved in perceived stress, fatigue and subclinical depressive symptoms during chronic inflammation, highlighting the crucial role of interoception in coordinating prolonged sickness behavior. Using the CHC disease as a model of low-grade inflammation, new neurobiological and neuroanatomical links between sickness behavior and chronic inflammatory conditions have been elucidated. These findings may be crucial in understanding pathophysiological mechanisms related with psychiatric diseases such as depression and open new research perspectives centered on the development of new therapeutic targets.INTRODUCCIÓN. La conducta de enfermedad es una estrategia adaptativa y coordinada que tiene la finalidad de defender el organismo en contra de agente patógenos. Los cambios conductuales pueden persistir de forma prolongada y volverse disfuncionales. El estudio de los mecanismos subyacentes que relacionan la inflamación, conducta de enfermedad y depresión mejoraría el conocimiento de la fisiopatología de la depresión. HIPÓTESIS Y OBJETIVOS. Los pacientes con hepatitis C crónica (HCC) podrían presentar cambios cerebrales a nivel estructural, funcional, conectividad y metabolismo en áreas asociadas con la conducta de enfermedad y la depresión, y dichas alteraciones podrían estar relacionadas con síntomas anímicos y marcadores inflamatorios. El objetivo de esta tesis es elucidar los correlatos clínicos y neurobiológicos de la conducta de enfermedad prolongada asociada a HCC. ESTUDIO 1: MÉTODOS Y RESULTADOS. Realizamos revisión sistemática con meta-análisis de estudios sobre neuroimagen en pacientes con HCC no tratados. Se llevó a cabo una búsqueda computerizada de los estudios de neuroimagen publicados en las principales bases de datos. La variable primaria dependió de la técnica de neuroimagen utilizada. De 1403 estudios encontrados, 25 fueron seleccionados. La muestra final comprendió 509 pacientes con HCC y 491 controles sanos. En los meta-análisis de los estudios de espectroscopia se observaron niveles incrementados de la ratio entre colina y creatina, de la creatina y de glutamato plus glutamina en los ganglios basales de pacientes. Las alteraciones metabólicas en el sistema nervioso central estaban relacionadas a alteraciones neurocognitivas de forma controvertida. ESTUDIO 2: MÉTODOS Y RESULTADOS. Estudio transversal, caso-control, que compara 35 pacientes de ambos sexos, entre 18 y 55 años, con HCC sin tratar y 30 controles sanos. Se evaluaron el estrés percibido (PSS), depresión (PHQ-9), fatiga e irritabilidad mediante escala visual analógica (VAS), así como las concentraciones séricas de interleuquina-6 (IL-6), prostaglandina E2 (PGE2) y marcadores de estrés oxidativo. Se realizó una resonancia magnética cerebral funcional estudiando la conectividad cerebral en estado de reposo, mediante la selección a priori de regiones de interés: ínsula bilateral, cortex cingulado anterior subgenual (sgACC), y el putamen bilateral. Las asociaciones entre síntomas clínicos, marcadores inflamatorios y patrones de conectividad funcional fueron analizadas mediante regresión múltiple. Los pacientes con HCC presentaban puntuaciones mayores en las escalas de PSS, PHQ-9, VAS-F y VAS-I, un incremento de las concentraciones séricas de IL-6 y PGE2 y una mayor activación del sistema anti-oxidativo comparado con los controles sanos. El incremento del estrés percibido y los síntomas depresivos estaban asociados a alteraciones de los marcadores inflamatorios y de la conectividad entre ínsula y putamen. Los niveles de PGE2 y los valores de PSS eran responsables del 46% de la variación de la conectividad funcional entre ínsula anterior y putamen. CONCLUSIONES. Los resultados observados proporcionan información importante sobre las áreas cerebrales involucradas en el estrés percibido y los síntomas depresivos subclínicos durante un estado de inflamación crónica. Se han podido ilustrar nuevos enlaces neurobiológicos y neuroanatómicos entre la conducta de enfermedad e la inflamación crónica que podrían ayudar en la comprensión de mecanismos fisiopatológicos relacionados con la depresión, y abrir nuevas perspectivas de investigación centradas en el desarrollo de nuevas dianas terapéuticas.
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Okwor, Chisom Ifeoma Adaeze. "Understanding Immune Suppression in Patients with Chronic Hepatitis C Virus Infections." Thesis, Université d'Ottawa / University of Ottawa, 2021. http://hdl.handle.net/10393/41856.
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Hepatitis C Virus (HCV) is a small RNA virus that progresses to chronicity in 50-80% of infected individuals. Direct-acting antivirals (DAAs) are revolutionary treatments for HCV with 90-98% cure rates. However, over time, chronic HCV infections can result in advanced liver disease, including cirrhosis. Patients with advanced fibrosis experience a poor response to vaccination, recurrent infections and increased risk for hepatocellular carcinoma (HCC). These outcomes are, in part, a consequence of immune dysfunction. Increased inhibitory receptor and Galectin-9 (GAL-9) expression is a possible mechanism promoting lymphocyte dysfunction.
In this study, blood samples were collected from chronic HCV patients with different degrees of liver fibrosis. I conducted a 13-parameter flow stain on the peripheral blood mononuclear cells (PBMC) of these patients. Next, I measured the expression of inhibitory receptors (PD-1, CTLA-4, LAG-3, TIGIT and TIM-3) and GAL-9 on bulk T cell and NK cells of 15 chronic HCV patients with no to moderate fibrosis (F0-F2) and 15 with advanced fibrosis (F3-F4). To analyze receptor co-expression, I employed t-distributed stochastic neighbor embedding (t-SNE) analysis to dimensionally reduce the multi-parametric data.
Notably, I found that F3-F4 patients had higher frequencies of >3 inhibitory receptor co-expression on NK cells. Moreover, t-SNE analysis of bulk T cells revealed that F3-F4 patients manifest a higher frequency of cells in the clusters with CD25+TIGITmed-hi CD4+ T cells and PD-1medLAG-3med-hiGAL-9med-hi CD4+ T cells. t-SNE analysis of NK cells also showed that F3-F4 patients manifest a higher frequency of cells in the cluster with CD25+TIGITmed-hiTIM-3med-hi CD56Dim NK cells and CCR7+ PD-1medLAG-3med-hiGAL-9med-hi CD56Dim NK cells. Lastly, the frequency of cells in these clusters was found to positively correlate with patient’s extent of liver damage. In conclusion, I identified phenotypes of immune dysregulation that could explain the increased susceptibility to infection and HCC in chronic HCV patients with advanced fibrosis. These phenotypes could identify targets for combinatorial checkpoint blockade therapy to potentially improve immune function in these patients.
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Hoang, Xuan Su. "The control of immune responses in chronic hepatitis C virus infection." Thesis, Grenoble, 2014. http://www.theses.fr/2014GRENV011/document.
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L'infection par le virus de l'hépatite C implique des processus d'interaction complexe entre l'hôte et le virus. Plusieurs facteurs de l'hôte incluant des polymorphismes génétiques et les réponses immunitaires influent sur l'infection et les réponses au traitement. Aussi, il est important d'identifier en amont les facteurs pour prédire la réponse au traitement. L'objectif de la thèse est d'étudier l'influence de certains polymorphismes génétiques de l'hôte sur la réponse à la bithérapie et sur le statut immunitaire du foie dans l'infection chronique par le VHC. L'étude a porté sur les polymorphismes des gènes de l'interféron lambda 3 et 4, l'interféron gamma, l'interleukine 10, et l'interleukine 17, conjointement à la réponse au traitement avec le peg-IFNα et la RBV et aux réponses immunitaires du foie chez les patients. Nous avons établi une méthode PCR-RFLP simple et fiable pour le typage de deux polymorphismes de l'IFNL3. En utilisant les enzymes de restriction BstUI et BrsDI permet le génotypage de deux variantes de IFNL3 (rs12979860 C/T et rs8099917 T/G, respectivement). Les résultats indiquent que cette méthode PCR-RFLP donne des résultats similaires à ceux des méthodes standard et présente un intérêt pour des analyses de routine en laboratoire clinique car elle est peu coûteuse. Nous avons analysé l'association des polymorphismes avec la réponse au traitement antiviral sur une cohorte de 108 patients infectés par le VHC de génotype 1 traités par la bithérapie. Nous avons ainsi démontré que le génotype de l'IFNL4 TT/TT de ss469415590 et une réponse virologique rapide sont des facteurs prédictifs indépendants pour atteindre un taux de réponse virologique soutenue (OR = 3,93, p = 0,004 et OR = 6,74, p = 0,021). D'autre part, une charge virale initiale haute est associée à l'échec au traitement (OR = 0,34, p = 0,023). Ainsi, ces paramètres sont utiles pour la définition d'un traitement personnalisé. Pour expliquer l'influence de ces polymorphismes dans l'infection chronique par le VHC, nous avons étudié l'association des polymorphismes IFNL3 et 4 avec la réponse immunitaire du foie chez les patients atteints d'une infection chronique par le VHC. En utilisant l'expression de CD107a comme marqueur de l'activité sécrétoires des lymphocytes, nous avons observé une activité de dégranulation des lymphocytes du foie plus importante les patients porteurs des génotypes de IFNL4 favorables en comparaison avec les patients porteurs de l'allèle défavorable. En utilisant des analyses de régression, les taux d'ALT sont en corrélation avec la fréquence des cellules NKT CD107a+ dans le foie. Enfin, chez les patients traités par la bithérapie, une forte activité de dégranulation est observée chez les patients avec les génotypes favorables IFNL3 et 4. Nous suggérons que les polymorphismes des gènes de l'interféron lambda sont associés à l'activité de la dégranulation des lymphocytes intra-hépatiques et contribuent à un mécanisme de clairance du VHC sous la bithérapie. Nous avons également étudié l'impact de plusieurs polymorphismes génétiques sur la gravité de l'hépatite C chronique. Les résultats montrent une association significative observée entre le polymorphisme de l'IFN-γ et la gravité de l'hépatite C chronique. Pour l'analyse de régression logistique, l'allèle T et la présence d'une stéatose sont des facteurs prédictifs indépendants de la sévérité de la maladie hépatique chronique associée au VHC. L'utilisation du génotypage de l'IFN-γ pourrait être utile dans la prise en charge des patients. En conclusion, nous avons montré que les polymorphismes des gènes des IFNL3 et 4 et de l'IFN-γ de l'hôte jouent un rôle important dans l'efficacité du traitement et les réponses immunitaires hépatiques. Ces résultats aident à définir un traitement personnalisé pour le contrôle de l'infection chronique par le VHC, en particulier dans les régions aux ressources limitées où les nouveaux traitements ne sont pas accessiblesHepatitis C virus (HCV) infection is a complex interaction process between the host and viral factors. The host immune responses and genetic polymorphisms have been shown to be associated with the outcome of HCV infections and the responses to treatments. Thus, it is very important to identify pre-treament factors to predict treatment outcomes. The overall aim of the thesis study is to investigate the role of host genetic polymorphisms on response to combination therapy and immune response in the liver in chronic HCV infection. The study has focused on polymorphisms in the interferon lambda (IFNL) genes, interferon gamma, interleukin 10, and interleukin 17 in relation to response to therapy with peg-IFNα and Ribavirin (RBV) and liver immune responses in patients with chronic HCV infection.First, we have established a simple and reliable method for genotyping of the IFNL3 polymorphisms. We designed primers and selected restriction enzymes BstUI and BrsDI for genotyping 2 variants rs12979860 C/T and rs8099917 T/G, respectively. The results indicate that this PCR-RFLP method yields to identical data than standard sequencing method and commercial kit. We suggest that PCR-RFLP method could be used routinely in conventionally clinical laboratory for genotyping of IFNL3 polymorphisms. Next, we analysed the association of these variants with response in combination therapy of peg-IFNα and RBV. Among 108 treated patients infected with HCV genotype 1, by using logistic regression model analyses, we showed that patients who had favorable IFNL4 genotype (genotype TT/TT of ss469415590) and presented a rapid virological response (RVR) were independent predictors of achieving sustained virological response rate (OR = 3.93, CI = 1.53 -10.08, p = 0.004 and OR = 6.74, CI = 1.33 - 34.06, p= 0.021), whereas patients with high baseline viral load level were associated with failure to treatment (OR = 0.34, CI = 0.13 - 0.87, p = 0.023). We suggest that patients had favorable IFNL4 genotype and achieved RVR should benefit an individualized treatment of combination therapy of peg-IFNα and RBV. To explain the influence of these polymorphisms in chronic HCV infection, we investigated the association of IFNL4 polymorphisms with immune response in the liver in patients with chronic HCV infection. By using marker CD107a, a marker expressing degranulation activity of cytotoxic lymphocytes, we indicated that degranulation process was found in liver lymphocytes in patients carrying favourable IFNL4 genotypes compared with patients with unfavourable genotypes. By using multiple regression analyses, we demonstrated that ALT levels correlate with frequency of CD107a+ NKT cells in the liver. Finally, in patients treated by peg-IFNα and RBV, high degranulation activity observed in patients with favourable genotypes of IFNL3 and IFNL4 (CC of rs12979860 and TT/TT of ss469415590). We suggest that polymorphisms in the interferon lambda genes associated with intrahepatic lymphocyte degranulation activity and contribute to clearance mechanism of HCV under combination treatment of peg-IFNα and RBV.We investigated the impact of several genetic polymorphisms on the severity of chronic hepatitis C. We showed a significant association observed between polymorphism of IFN-γ and the severity of chronic hepatitis C. By using logistic regression analysis, T allele of IFN-γ and the presence of steatosis are independent predictive factors of severity of HCV-1 - related liver disease. This suggests we can use genetic variant of IFN-γ in classification and management of chronic hepatitis C. In conclusion, we indicated that host genetic polymorphisms play critical roles both in responses to treatment and in the immunopathogenesis of chronic HCV infection. This study can help to reach a closer step to individualized medicine for the control of chronic HCV infection in resource-limited regions when new treatment regimens are not available
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Taal, Maarten Willem. "Control of Hepatitis B and C virus infection in chronic haemodialysis patients." Master's thesis, University of Cape Town, 1997. http://hdl.handle.net/11427/25675.
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Chronic haemodialysis patients have a high prevalence of Hepatitis B and C virus infections both of which are associated with chronic liver disease and hepatocellular carcinoma Hepatitis B virus (HBV) was identified as a frequent cause of hepatitis during the early years of chronic haemodialysis therapy and strict adherence to infection control measures alone proved inadequate to control the transmission of infection between patients. A policy of regular screening of all patients and blood donations for hepatitis B surface antigen together with isolation of positive patients to separate dialysis units resulted in a significant decline in the incidence of new infections. Hepatitis B vaccination provided an important new means of protection. Despite the finding that haemodialysis patients did not respond to the vaccine as well as normal adults, randomized controlled trials showed significant protection in units with a previously high incidence of infection. Studies have identified both monocyte dysfunction and B cell inhibition by elevated levels of parathyroid hormone (PTH) as possible mechanisms for the reduced response in dialysis patients. Other factors which have been associated with this poor response include increased age, male gender, specific human leukocyte antigens, shorter time on a dialysis programme and poor nutritional status. One study has shown an increased response in patients receiving recombinant human erythropoietin and. there is in vitro evidence that nifedipine improves B cell proliferation in dialysis patients with hyperparathyroidism. Hepatitis C virus (HCV) infection in haemodialysis patients has been associated with blood transfusions in many studies. However, evidence exists that transmission between patients also occurs. There is disagreement as to what measures are necessary to prevent possible nosocomial spread. Some authors recommend isolation of HCV -infected patients to separate dialysis machines or units. There is also concern over the potential of dialyzer reuse to transmit the virus. A protocol for surveillance 0f hepatitis B and C infections was established in the dialysis unit at Groote Schuur Hospital while HCV positive patients were not isolated and reuse of dialyzers was continued for all patients. HBV -infected patients are dialyzed in a separate unit and their dialyzers are not reused. A trial of hepatitis B vaccination of all antibody negative patients was undertaken using four doses of a plasma-derived vaccine given intramuscularly at month 0,1 ,2 and 4.
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Hayashi, Hisao, Toshikuni Takikawa, Noriko Arai, and Motoyoshi Yano. "The Advantage of Gastrectomized Patients in Management of their Chronic Hepatitis C." 名古屋大学医学部, 1997. http://hdl.handle.net/2237/6187.
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Lindahl, Karin. "Ribavirin - dose and concentration in treatment of chronic hepatitis C infected patients /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-348-5/.
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Bulteel, Naomi Sarah. "Predictors of disease progression and outcome in chronic hepatitis C virus infection." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/9079/.
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Chronic HCV infection (CHC) is a significant cause of both liver related and non-liver related morbidity and mortality worldwide. Disease progression through to cirrhosis and hepatocellular carcinoma is highly variable, and once chronicity of infection has been established, the likelihood of spontaneous clearance without antiviral treatment is extremely low. Safe and highly effective oral antiviral therapy is now available for the treatment of CHC, however price and accessibility may limit the global use of these agents. Furthermore, concerns have been raised regarding the incidence of hepatocellular carcinoma in HCV-infected individuals receiving oral antiviral regimens, and there appears to be a ‘point of no return’ beyond which cirrhotic HCV-infected individuals fail to benefit from antiviral treatment. Thus, there remain a number of unanswered questions on the natural history of HCV infection. Ageing of the immune system, or immunosenescence, appears to contribute to poorer clinical and treatment outcomes, however robust, non-invasive, clinically relevant biomarkers are lacking. MicroRNAs (miRNAs) are short, endogenous non-coding RNAs responsible for post-transcriptional control of host gene expression. Specific patterns of miRNA deregulation have been described in the serum, liver tissue and peripheral immune cells of HCV-infected subjects, and it is hypothesised that they may be suitable as both diagnostic and prognostic biomarkers. We interrogated 3 patient cohorts (providing access to local and national clinical data) to identify patient factors associated with disease progression and both spontaneous and treatment-associated clearance of CHC. We found that chronological age and elevated BMI had the strongest association with hepatic cirrhosis. Co-morbid type 2 diabetes mellitus was associated with poor clinical outcomes during antiviral therapy. Spontaneous clearance of CHC occurred rarely (0.36 per 100 person-years follow up), and was associated with female gender, earlier age at infection, low HCV viral load and co-infection with HBV. Current injecting drug use was negatively associated with spontaneous clearance. We also explored the use of miRNAs as biomarkers in these cohorts. We correlated miRNA expression with cellular markers of immunosenescence to identify novel prognostic biomarkers for disease outcomes in CHC. Our findings demonstrated that CHC was associated with a distinct miRNA signature in the serum and peripheral immune cells. Serum miR-21-5p, miR-122-5p and miR-885-5p levels correlated with the expression of previously described biomarkers of ageing, however these miRNAs performed poorly as biomarkers of cirrhosis in CHC. Elevated serum miR-21-5p expression was an independent predictor of virologic relapse following antiviral therapy, together with HCV genotype. MiR-21-5p also appeared to predict the likelihood of an adverse clinical event during treatment. We identified a further microRNA, miR-345-5p, elevated baseline expression of which correlated with negative clinical outcome during treatment, and was associated with the presence of both hepatic and extra-hepatic malignancy. We explored the regulation of miRNA expression in an in vitro model, and found that interferon-stimulated gene expression is necessary for IFN-induced miR-21-5p expression. Finally, we performed pathway analysis for target genes regulated by miRNAs deregulated during CHC, and found that pathways in cancer were highly enriched. Pathway enrichment was similar between HCV-infected cirrhotic subjects and non-cirrhotic, immunosenescent subjects, suggesting that non-cirrhotic individuals with elevated biomarkers of immunosenescence may be at an increased risk of hepatocellular carcinoma and may benefit from enhanced surveillance and prioritisation for antiviral treatment. Overall, the wealth of clinical and molecular data provided the opportunity to explore possibilities for integrating novel biomarkers into clinical decision-making for monitoring liver-related disease in HCV-infected subjects.
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Haydon, Geoffrey H. "The severity and activity of liver disease in chronic hepatitis C infection." Thesis, University of Edinburgh, 1999. http://hdl.handle.net/1842/28213.
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The aims were twofold. Firstly, to assess the clinical significance of staging investigations; in particular the significance of molecular virological investigations in terms of disease diagnosis and prognosis. The role of non-invasive investigations in staging the disease process was also considered. Secondly, the impact of chronic hepatitis C infection was assessed in two populations; patients diagnosed as having hepatocellular carcinoma and those immunocompromised chronic HIV infection. In the Scottish population studied, both serum and intrahepatic virus levels were not determined by host factors (age of patient, mode or duration of infection) or by virus factors (HCV genotype). Likewise, there was no correlation between serum and liver HCV RNA levels demonstrated; however, those data did demonstrate that repetitive negative RT-PCR for HCV RNA in serum did not indicate absence of HCV from the liver. Pilot studies of the two non-invasive investigations in this population showed both to be reliable in predicting the presence of hepatic cirrhosis in patients infected with HCV. Amongst the intravenous drug abusers with chronic HIV infection, HCV did not influence either the clinical progression of HIV disease to AIDS and it was not associated with a more rapid immunological decline. Chronic HCV infection was identified as a major risk factor for the development of hepatocellular carcinoma. Molecular virological staging investigations should be interpreted with caution in chronic HCV infection; their most significant role is likely to be the initiation and monitoring of therapy rather than the inference of disease prognosis. Non-invasive investigations of hepatic cirrhosis are likely to be useful tests when a liver biopsy is contraindicated, although they should be first validated in larger, well described populations.
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Pembroke, Thomas. "Natural killer cell activation and evasion during chronic hepatitis C virus infection." Thesis, Cardiff University, 2014. http://orca.cf.ac.uk/58428/.
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Hepatitis C virus (HCV) infects 3% of the global population and HCV-related liver inflammation is a major cause of liver failure and hepatocellular carcinoma. Current treatments are based upon long courses of interferon-α (IFNα) injections, which have significant side effects and are only effective in 40-80% of individuals depending on viral genotype. Natural killer (NK) cells are innate lymphocytes, which can kill virally infected cells and are stimulated by IFNα. To establish a chronic infection HCV must evade immune responses. I hypothesised that NK cells are important for the successful eradication of HCV and that chronic HCV infection impinges upon NK cell function to prevent viral clearance. I found that NK cell function was reduced in chronic HCV and correlated with the proportion of NKp46+ NK cells in vitro. In keeping with these findings NKp46-rich intrahepatic NK cell populations were more activated and the proportion of these cells correlated with liver inflammation. During interferon-α treatment individuals who had the greatest increase in NK cell function in response to increasing stimulation had the fastest rate of viral clearance and were most likely to successfully clear the virus. Using a novel adenovirus vector expressing HCV proteins I have discovered that NS5B protein reduces NK cell cytotoxicity and cytokine production. Therefore, in this thesis I have described novel insights into the mechanisms of HCV immunoevasion, HCV-related disease pathogenesis with implications for viral eradication therapy.
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Yuen, Man-fung. "Role of hepatitis B virus genotypes B and C on chronic liver disease in the Chinese." Click to view the E-thesis via HKUTO, 2004. http://sunzi.lib.hku.hk/hkuto/record/B33710089.
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Falconer, Karolin. "HIV-1/HCV co-infection immunity and viral dynamics /." Stockholm, 2010. http://diss.kib.ki.se/2010/978-91-7409-762-7/.
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Frelin, Lars. "Development of vaccines and experimental models for chronic infections caused by the hepatitis C virus /." Stockholm : Karolinska institutet, 2004. http://diss.kib.ki.se/2004/91-7349-906-4/.
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Hora, Caroline. "Connective tissue growth factor, steatosis and fibrosis in patients with chronic hepatitis C /." Bern : [s.n.], 2008. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Suddle, Abid Raza. "A clinical and virological study of chronic hepatitis C infection in East London." Thesis, Queen Mary, University of London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406652.
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Whiteley, David James. "Recontextualising the lived experience of hepatitis C and its treatment." Thesis, Edinburgh Napier University, 2016. http://researchrepository.napier.ac.uk/Output/979740.
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BACKGROUND: Rapid advances in the treatment of the hepatitis C virus (HCV) have been witnessed in clinical practice over the last five years. Pharmacological developments have ended the reliance on the drug interferon-α as a component of successful therapy, heralding the dawn of a new era in the fight against the disease. How this new era is being understood and experienced by those individuals living with the virus is currently unknown. METHODS: A purposive sample of 20 individuals participated in face-to-face semi-structured interviews exploring their experience of living with HCV. Eight of these participants were interviewed again following a period of interferon-free treatment. All interviews were conducted between June 2015 and March 2016. The interviews were transcribed verbatim and explored using thematic analysis, underpinned by social phenomenological theory. RESULTS: Analysis of the corpus of data resulted in three overarching themes entitled ‘positioning HCV', ‘beyond a physical burden' and ‘reconstructing uncertainty'. These themes offer original insight into how this new era of therapy is being realised by those living with the virus. The experience of interferon-free treatment was also explored through the narratives of those individuals who participated in a further post-treatment interview. Three further themes entitled ‘expectations and realisations', ‘an honour and a pleasure' and ‘treatment needs' encapsulate their experience. DISCUSSION: The findings from this study recontextualise the lived experience of HCV within a new era of treatment. In doing so, they expose social and emotional spheres of illness, and a perception of illness chronicity, which remain untouched by the treatment revolution. Further, this work emphasises how treatment inequalities fundamentally underpin multiple aspects of the daily lived experience, and are integral to how those living with HCV articulate the disease. The implications of this work challenge current HCV policy and clinical practice.
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Yuen, Man-fung, and 袁孟峰. "Role of hepatitis B virus genotypes B and C on chronic liver disease in the Chinese." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2004. http://hub.hku.hk/bib/B33710089.
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Qattan, I. "Mechanisms involved in resistance to interferon alpha therapy in chronic hepatitis C virus infection." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1415966/.
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Chronic hepatitis C virus infection is a massive worldwide healthcare burden, which is estimated to cost in the USA alone over $5 billon per annum. Until recently, the only current effective treatment was combination therapy with peg-interferon alpha and ribavirin (peg-I FNα+RBV), which is expensive and has significant side-effects, and is only effective in up to 50% of those infected with HCV genotype 1. In this thesis, a method was evaluated for detecting genotype 1b infections using a 5’non coding region sequence based approach (TRUEGENE). This allowed the identification of genotype 1b patients who could then be analysed for mutations in key regions of the genome associated with interferon resistance. A total of 14 patients with HCV genotype 1 were prescribed peg-IFNα+RBV and subjected to detailed sequence analysis of their interferon sensitivity determining region (ISDR) Following PCR amplification and sequence analysis there was no evidence for significant mutations occurring in the ISDR in patients who did not respond to therapy either at the start of therapy of during therapy. The recognition that host genetics may play a role in HCV infection and the success of treatment with interferon based therapies is now firmly established through the identification of single nucleotide polymorphisms (SNPs) in the IL28 gene which encodes a lambda interferon. I used an allele specific SNP detection system for two loci in the IL28B gene region (rs12979860C/T and rs8099917G/T) in a large population of Gulf region, and particularly Saudi Arabian, HCV infected patients (n=315) some of whom were co-infected with either HBV (n=1 01) or HIV (n=1 00). The results showed that the genotype distribution at both SNP loci were different to other studies based on North American and European populations. In addition, when the patients were separated into responders, non-responders and transient responders, marked differences in genotype frequencies was observed together with associations between specific alleles and HCV load. The inclusion of co-infected individuals allowed me to show that IL28B polymorphisms at these two loci are not evenly distributed between patients with HCV mono-infection and co-infections. In the final phase of the thesis, I used a proteomic approach to indentify novel proteins that may be useful as biomarkers for treatment response. After optimization of the electrophoretic procedure the patients who had been used for the earlier ISDR studies were analysed. Although preliminary, the data identified haptoglobulin as a protein whose expression pattern inversely correlated with the control of replication after therapy. In conclusion this thesis has attempted to identify viral and host genetic markers that contribute to treatment success and failure in HCV and has shown that differences in the prevalence of IL28B polymorphisms exist between Saudi Arabia and elsewhere and between patients harbouring dual infections compared to single HCV infection.
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Juttla, Vicky Satinderpal. "Analysis of the evolution and phenotype of hepatitis C virus glycoproteins during chronic infection." Thesis, University of Nottingham, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.442271.
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Alvarez, Italo, Juan C. Urbina, and Romina A. Tejada. "Chronic hepatitis C and health-related quality of life in patients with cognitive impairment." S. Karger AG, 2018. http://hdl.handle.net/10757/624654.
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Suzuki, Saori. "Basic research for the development of hepatitis C vaccine." 京都大学 (Kyoto University), 2016. http://hdl.handle.net/2433/215372.
Full textAbstract:
Contents of the present thesis were published in the following articles. 1. Suzuki S, Mori K, Higashino A, Iwasaki Y, Yasutomi Y, Maki N, Akari H. 2016. Persistent replication of a hepatitis C virus genotype 1b-based chimeric clone carrying E1, E2 and p6 regions from GB virus B in a New World monkey. Microbiol Immunol 60:26-34. Copyright © 1999-2016 John Wiley & Sons, Inc.2. Yoshida T, Suzuki S, Iwasaki Y, Kaneko A, Saito A, Enomoto Y, Higashino A, Watanabe A, Suzuki J, Inoue K, Kuroda T, Takada M, Ito R, Ito M, Akari H. 2013. Efficient in vivo depletion of CD8+ T lymphocytes in common marmosets by novel CD8 monoclonal antibody administration. Immunol Lett 154:12-17.Copyright © 2013 Elsevier B. V.Kyoto University (京都大学)
0048
新制・課程博士
博士(理学)
甲第19546号
理博第4206号
新制||理||1604(附属図書館)
32582
京都大学大学院理学研究科生物科学専攻
(主査)教授 明里 宏文, 教授 岡本 宗裕, 教授 中村 克樹
学位規則第4条第1項該当
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Bruchfeld, Annette. "Hepatitis C in chronic kidney disease and kidney transplantation : with special reference to epidemiology and treatment /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-701-0/.
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Maia, Sarah Cristina Oliveira Machado. "Análise de custo-efetividade do tratamento da hepatite C crônica genótipo 1: comparação da adição do boceprevir a terapia padrão (interferon-α peguilado e ribavirina)." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/9/9139/tde-16062015-140318/.
Full textAbstract:
A hepatite C afeta cerca de 150 milhões de pessoas no mundo e é a razão mais comum de transplantes de fígado. A erradicação viral, por meio de tratamento medicamentoso, é a única intervenção que pode deter a progressão da doença, reduzir a mortalidade e melhorar a qualidade de vida dos pacientes. Em 2011, foi aprovado o boceprevir, um inibidor de protease, que passou a ser adicionado à terapia padrão dupla (interferon peguilado e ribavirina) pelo Protocolo Clínico brasileiro para tratamento de Hepatite C genótipo 1 em pacientes com grau de fibrose maior que F2. Devido ao alto custo de aquisição deste medicamento e à produção cada vez maior de novas tecnologias para essa área terapêutica, foi proposta essa pesquisa que tem como objetivo analisar o custo-efetividade da terapia tripla em relação à terapia dupla, no tratamento da hepatite C crônica genótipo 1 em pacientes virgens de tratamento para todos os graus de fibrose. Para tanto, foi construído um modelo de Markov com 15 estados de saúde representando a história natural da Hepatite C crônica. O modelo seguiu uma coorte hipotética pela vida toda, em que os custos foram expressos em Reais e os desfechos em anos de vida ganhos. A perspectiva adotada foi a do SUS. A RCEI calculada, com taxa de desconto de 5% para custos e desfechos, foi R$ 201.504,92 por ano de vida ganho. Considerando um limiar de custo efetividade de 3 vezes o valor do PIB per capita, segundo recomendação da OMS, a adição do boceprevir não foi custo-efetiva no tratamento de pacientes virgens em todos os graus de fibrose. Pela análise de sensibilidade, nenhuma variável teve grande impacto na RCEI, exceto quando a taxa de desconto aplicada em desfechos foi zerada, em que a terapia tripla passou a ser custo-efetiva.The Hepatitis C virus affects around 150 million of people worldwide and it is the most common reason for liver transplantation. Viral eradication, by drug treatment, is the only therapeutic intervention that may halt the disease progression, reduce HCV-related mortality and improve the quality of life of infected patients. Boceprevir, a protease inhibitor, was approved in 2011, being to be added to standard of care (peguilated interferon-α and ribavirin) by the Brazilian Protocol of treatment of genotype 1 Hepatitis C, in patients with degree of fibrosis greater than F2. Due to the high cost of acquisition of this drug and the increasing production of new technologies in this therapeutic area, the aim of this work was develop a cost-effectiveness analysis, comparing the triple therapy with the standard of care (double therapy) for treatment of genotype 1 chronic hepatitis C in treatment-naïve patients of all degrees of fibrosis. It was constructed a Markov Model with 15 health states representing the natural history of chronic Hepatitis C. The model followed a hypothetic cohort by lifetime, where costs were expressed in Reais and outcomes in life-years gained, under the perspective of Brazilian public health system. The calculated ICER, with discount rate of 5% to costs and outcomes, was R$201.504, 92 by life-years gained. Considering three times GDP per capita for cost-effectiveness threshold, according WHO recommendation, boceprevir was not cost-effective, when considered treatment-naïve patients of all degrees of fibrosis. By sensitivity analysis, none of the variables had a big impact in the ICER, except when it was stopped applying the discount rate in outcomes, in which the triple therapy became cost-effective.
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Serag, Hani. "Barriers to accessibility to antiviral treatment for patients with Chronic Viral Hepatitis C in Egypt." University of Western Cape, 2014. http://hdl.handle.net/11394/6070.
Full textAbstract:
Magister Public Health - MPH (Public Health)Egypt has the highest burden of Hepatitis C Viral infection (HCV) in the world with 10% between 15- 60 years old having HCV antibodies and 7% having chronic HCV infection. HCV is more concentrated among rural, aged, less educated, and poor population groups in addition to patients who require frequent blood transfusion or on renal dialysis, and injection drug users. Despite advancement in antiviral treatments with higher than 90% sustained virologic response (efficacy), access remains limited. The government strategy tied expanding the access to antiviral treatment to a price reduction through subsidies, but an expansion of HCV treatment coverage was not observed. This suggests a broader range of barriers in addition to the financial affordability.
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Giuggio, Vicki M. "Characterization of Intrahepatic T-lymphocytes in Patients with Chronic Hepatitis C Virus Infection: a Dissertation." eScholarship@UMMS, 2000. https://escholarship.umassmed.edu/gsbs_diss/203.
Full textAbstract:
Hepatitis C virus (HCV) is a positive strand RNA virus that is the leading cause of chronic hepatitis. HCV infections are an important health problem because >80% of patients become chronically infected and many develop chronic hepatitis. With approximately 400 million chronic HCV infections worldwide, understanding the pathogenesis of this disease is of critical importance in order to develop appropriate therapies and/or vaccine strategies.
Strong proliferative and cytotoxic T cell responses that target multiple HCV proteins are detected in patients with self-limited infection. Conversely, HCV-specific T cell responses are minimal during acute infection in patients who become chronically infected. It is thought that the genetic diversity of HCV plays a crucial role in establishing persistence.
Chronic viral hepatitis is characterized by infiltration of T lymphocytes in the liver, which are thought to play a pivotal role in disease progression. Although virus-specific T cells can be isolated from both peripheral blood and from liver biopsy samples of chronically infected patients, there appears to be a compartmentalization of HCV-specific T cells in the liver. However, the presence of virus-specific T cells is inefficient for viral clearance. Because HCV is known to be highly variable in sequence, the detailed characterization of the interaction of individual HCV-specific CTL clones with autologous viral sequences might be important for understanding the mechanisms by which HCV is able to establish a chronic infection.
We isolated three intrahepatic CD8+ CTL clones from two individuals with chronic HCV infection and compared the recognition of prototype and autologous HCV sequences. These CTL recognized epitopes within the NS2 (amino acids 957-964) or NS3 (amino acids 1402-1410 and 1406-1415) proteins in the context of HLA B37, B8, or A2.1, respectively. The corresponding predominant autologous HCV sequences (SDWAANGL, ELAAKLVGL, ALRGMGLNAV, respectively) differed from the HCV-1 prototype sequences used for screening (RDWAHNGL, ELAAKLVAL, KLVALGINAV, respectively) at one to five residues. For each CTL clone, recognition of the autologous HCV sequence required significantly higher peptide concentrations than did recognition of the HCV-1 sequence; for two of the clones, recognition was minimal or absent at peptide concentrations as high as 25μM.
When the HLA A2.1-restricted HCV NS3-specific T cell clone was analyzed further, we found that it was cross-reactive with peptide sequences from at least three other HCV strains. The clone recognized target cells loaded with synthetic peptides derived from sequences of genotype 1b; HCVTW (KLSALGIHAV), HCVJA (KLTGLGLNAV),and HCVBK (KLSGLGINAV). This HCV-specific T cell clone was also able to recognize target cells that were loaded with a peptide derived from an autologous protein, cellular retinoic acid binding protein I (CRABP I). When we generated HLA A2.1-restricted HCV NS3-specific T cell lines from the peripheral blood of two additional patients, almost one half of the cell lines could lyse target cells loaded with the CRABP I peptide. These data show that intrahepatic HCV-specific CD8+ CTL clones can be relatively inefficient at recognizing autologous viral epitopes and that some viral-specific CTL can recognize autoantigens in vitro.
There is little information regarding the composition and stability of the liver-infiltrating T cell repertoire during chronic HCV infection. To address this issue, we used TCR complimentarity determining region 3 (CDR3) length analysis to examine the T lymphocytes in sequential biopsy samples from five individuals chronically infected with HCV. We found that although almost all TCRBV families were represented in the liver, 25-85% had skewed spectratype profiles, indicative of the presence of clonally expanded T cells. Further analysis using TCRBJ-primed run-off reactions revealed that the intrahepatic repertoires were not stable, as many expansions that existed in one biopsy sample were not detected in the other. Some expansions persisted, however, and sequencing of TCRBV-J transcripts identified CDR3 sequences that were maintained in two individuals for 10 or 45 months. Furthermore, although some expansions were found in the periphery, most were represented only in the liver. These data suggest that there is an evolution of the immune response during chronic HCV infection and that the response is largely concentrated in the liver of these individuals.
Based on our observations regarding the function of intrahepatic HCV-specific CTL and the dynamics of the intrahepatic repertoire during chronic HCV infection, we propose a model in which the co-evolution of HCV quasispecies and HCV-specific T cells contribute to both viral persistence and immunopathology.
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Giuggio, Vicki M. "Characterization of Intrahepatic T-lymphocytes in Patients with Chronic Hepatitis C Virus Infection: a Dissertation." eScholarship@UMMS, 2011. http://escholarship.umassmed.edu/gsbs_diss/203.
Full textAbstract:
Hepatitis C virus (HCV) is a positive strand RNA virus that is the leading cause of chronic hepatitis. HCV infections are an important health problem because >80% of patients become chronically infected and many develop chronic hepatitis. With approximately 400 million chronic HCV infections worldwide, understanding the pathogenesis of this disease is of critical importance in order to develop appropriate therapies and/or vaccine strategies.
Strong proliferative and cytotoxic T cell responses that target multiple HCV proteins are detected in patients with self-limited infection. Conversely, HCV-specific T cell responses are minimal during acute infection in patients who become chronically infected. It is thought that the genetic diversity of HCV plays a crucial role in establishing persistence.
Chronic viral hepatitis is characterized by infiltration of T lymphocytes in the liver, which are thought to play a pivotal role in disease progression. Although virus-specific T cells can be isolated from both peripheral blood and from liver biopsy samples of chronically infected patients, there appears to be a compartmentalization of HCV-specific T cells in the liver. However, the presence of virus-specific T cells is inefficient for viral clearance. Because HCV is known to be highly variable in sequence, the detailed characterization of the interaction of individual HCV-specific CTL clones with autologous viral sequences might be important for understanding the mechanisms by which HCV is able to establish a chronic infection.
We isolated three intrahepatic CD8+ CTL clones from two individuals with chronic HCV infection and compared the recognition of prototype and autologous HCV sequences. These CTL recognized epitopes within the NS2 (amino acids 957-964) or NS3 (amino acids 1402-1410 and 1406-1415) proteins in the context of HLA B37, B8, or A2.1, respectively. The corresponding predominant autologous HCV sequences (SDWAANGL, ELAAKLVGL, ALRGMGLNAV, respectively) differed from the HCV-1 prototype sequences used for screening (RDWAHNGL, ELAAKLVAL, KLVALGINAV, respectively) at one to five residues. For each CTL clone, recognition of the autologous HCV sequence required significantly higher peptide concentrations than did recognition of the HCV-1 sequence; for two of the clones, recognition was minimal or absent at peptide concentrations as high as 25μM.
When the HLA A2.1-restricted HCV NS3-specific T cell clone was analyzed further, we found that it was cross-reactive with peptide sequences from at least three other HCV strains. The clone recognized target cells loaded with synthetic peptides derived from sequences of genotype 1b; HCVTW (KLSALGIHAV), HCVJA (KLTGLGLNAV),and HCVBK (KLSGLGINAV). This HCV-specific T cell clone was also able to recognize target cells that were loaded with a peptide derived from an autologous protein, cellular retinoic acid binding protein I (CRABP I). When we generated HLA A2.1-restricted HCV NS3-specific T cell lines from the peripheral blood of two additional patients, almost one half of the cell lines could lyse target cells loaded with the CRABP I peptide. These data show that intrahepatic HCV-specific CD8+ CTL clones can be relatively inefficient at recognizing autologous viral epitopes and that some viral-specific CTL can recognize autoantigens in vitro.
There is little information regarding the composition and stability of the liver-infiltrating T cell repertoire during chronic HCV infection. To address this issue, we used TCR complimentarity determining region 3 (CDR3) length analysis to examine the T lymphocytes in sequential biopsy samples from five individuals chronically infected with HCV. We found that although almost all TCRBV families were represented in the liver, 25-85% had skewed spectratype profiles, indicative of the presence of clonally expanded T cells. Further analysis using TCRBJ-primed run-off reactions revealed that the intrahepatic repertoires were not stable, as many expansions that existed in one biopsy sample were not detected in the other. Some expansions persisted, however, and sequencing of TCRBV-J transcripts identified CDR3 sequences that were maintained in two individuals for 10 or 45 months. Furthermore, although some expansions were found in the periphery, most were represented only in the liver. These data suggest that there is an evolution of the immune response during chronic HCV infection and that the response is largely concentrated in the liver of these individuals.
Based on our observations regarding the function of intrahepatic HCV-specific CTL and the dynamics of the intrahepatic repertoire during chronic HCV infection, we propose a model in which the co-evolution of HCV quasispecies and HCV-specific T cells contribute to both viral persistence and immunopathology.
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Wada, Masaya. "Association of genetic polymorphisms with interferon-induced haematologic adverse effects in chronic hepatitis C patients." Kyoto University, 2009. http://hdl.handle.net/2433/124295.
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Forton, Daniel Michael. "The cerebral manifestations of chronic hepatitis C infection : cognitive, magnetic resonance spectroscopy and molecular virology studies." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.414983.
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Caronia, Simona. "Chronic hepatitis C infection : relation to apoptosis and the role of novel prognostic and therapeutic approaches." Thesis, University of London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.511351.
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Patel, Keyur. "The influence of host factors on hepatic fibrosis and virolologic response in chronic hepatitis C infection." Thesis, University of Southampton, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485034.
Full textAbstract:
Chronic hepatitis C (CHC) infection affects an estimated 170 million people worldwide, and is characterized by varying degrees of inflammation and progressive hepatic fibrosis leading to . cirrhosis and complications of end-stage liver disease in a proportion of patients over 20 to 40 years. CHC infection is now the leading indication for liver transplantation in developed nations. Several host and viral factors have been implicated disease progression and predicting response to therapy. The aims of this thesis were to characterize host determinants of progressive fibrosis and assess virologic responses in a large cohort ofCHC patients linked to an extensive and pedigreed biorepository. Our studies indicate that HLA class 1 allelic diversity has a relatively weak influence on disease severity and fibrosis progression compared to standard host factors such as age, gender and alcohol intake. However, steatosis is an important host variable that is associated with fibrosis, and also reduces both early and sustained virologic responses to therapy in genotype-l infected patients. Myeloperoxidase gene polymorphisms also appear to be associated with fibrosis severity, thus implicating oxidative stress in this regard. Non-invasive alternatives to a needle liver biopsy to stage and follow disease progression in CHC patients would be a useful clinical tool. We have developed and validated a serodiagnostic panel of matrix proteins to differentiate mild from moderate-to-severe stages of fibrosis that could provide an alternative to liver biopsy for binary disease staging in a proportion ofCHC patients. At present, there are no reliable host, or viral, predictors of relapse following an end-of-treatment viral response. Our studies indicate that hepatic HCV RNA measurement has minimal clinical utility in following virologic responses to therapy, although residual intrahepatic virus may be present in a minority of patients that relapse following an apparent sustained virologic response. Whole blood extraction methods for viral detection also do not appear to provide any clinical benefit over conventional serum based assays during therapy, or in predicting relapse after an end-of-treatment response. Our ongoing studies will plan to better define the role of host immune response in hepatic injury, and develop accurate and reliable non-invasive markers of fibrosis.
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Rushbrook, Simon Matthew. "The role of T-regulatory lymphocytes in the pathogenesis of chronic viral Hepatitis B and C." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611894.
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Vilar, Janaina LeitÃo. "Autoantibodies profile in patients with chronic hepatitis C and the influence of Interferon-alfa plus Ribavirin." Universidade Federal do CearÃ, 2006. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=386.
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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel SuperiorChronic hepatitis C has been associated with non-organ-specific autoantibodies (NOSA) production. Despite of increasing number of researches about this subject, there is no agreement among the authors of which autoantibodies are produced during combinated therapy of interferon and ribavirin or the clinical relevance of NOSA in patientâs organism. Our aim was to evaluate the profile of NOSA in patients with chronic hepatitis C who attended to Walter CantÃdio Hospital (HUWC) and received combinated antiviral therapy (interferon-ribavirin). A total of 34 patients with hepatitis C were studied. Anti-nuclear antibody (ANA), anti-smooth muscle antibody (SMA), anti-liver/kidney microsomal antibody type 1 (LKM-1) and anti-mitochondrial antibody (AMA) were detected by indirect immunofluorescence. The presence of NOSA was related to clinical and epidemiological variables and to the outcome of antiviral combination therapy with interferon-alfa and ribavirin. Patients were classified as nonresponders, relapsers or long-term responders depending on the outcome of treatment. In our study, before therapy, 23 patients were NOSA positive (SMA was detected in 6 patients, SMA and AMA in 10 and SMA, AMA and ANA in 7). On the 24th week of treatment, 24 patientes were NOSA positive (SMA was detected in 4 patients, SMA and AMA in 10, ANA and SMA in 1, ANA and AMA in 1 and SMA, AMA and ANA in 8). NOSA behavior did not show significant variation during treatment. The overall rate of long-term response was 26,5% (9/34). Long-term response occurred in 17,4% (4/23) of NOSA positive patients and 45,5% (5/11) of NOSA negative patients. Positivity of autoantibodies was not associated with gender, age, viral genotype or aminotransferase levels. In conclusion, ANA was the only NOSA associated with treatment outcome. The absence of NOSA might indicate a significantly higher chance for viral clearance in response to combination therapy for chronic hepatitis C infection.
A hepatite crÃnica pelo vÃrus C tem sido associada à produÃÃo de autoanticorpos nÃo-ÃrgÃo especÃficos (NOSA). Apesar do aumento do nÃmero de pesquisas nessa Ãrea, ainda nÃo existe um consenso entre quais autoanticorpos tÃm seus nÃveis elevados devido ao tratamento combinado de interferon e ribavirina, nem sua influÃncia no desfecho do mesmo ou a relevÃncia clÃnica da presenÃa desses autoanticorpos no organismo do pacientes. O objetivo do presente estudo foi avaliar o perfil de NOSA em pacientes com hepatite C crÃnica atendidos no Hospital UniversitÃrio Walter CantÃdio (HUWC) e submetidos à terapia combinada de interferon-alfa e ribavirina. Para isso, um total de 34 pacientes com hepatite C foram estudados. Os anticorpos anti-nuclear (FAN), anti-mÃsculo liso (SMA), anti-microssomal de fÃgado e rim do tipo 1 (LKM-1) e anti-mitocÃndria (AMA) foram detectados atravÃs de imunofluorescÃncia indireta. A presenÃa de NOSA foi relacionada a variÃveis clÃnicas e epidemiolÃgicas e à resposta ao tratamento. Os pacientes foram classificados, em relaÃÃo à resposta ao tratamento, como nÃo respondedores, recidivantes ou respondedores (resposta virolÃgica sustentada). Em nosso estudo, 23 pacientes foram NOSA reagentes (SMA foi detectado em 6 pacientes, SMA e AMA em 10 e SMA, AMA e FAN em 7). Na 24 semana de tratamento, 24 pacientes foram NOSA reagentes (SMA foi detectado em 4 pacientes, SMA e AMA em 10, FAN e SMA em 1, FAN e AMA em 1 e SMA, AMA e FAN em 8). A variaÃÃo dos tÃtulos dos autoanticorpos durante o tratamento nÃo foi significativa. O percentual total de respondedores foi de 26,5% (9/34). A resposta virolÃgica sustentada foi obtida por 17,4% (4/23) dos pacientes NOSA reagentes e 45,5% (5/11) dos pacientes nÃo reagentes para NOSA. A presenÃa de autoanticorpos nÃo foi associada a gÃnero, idade, genÃtipo viral ou nÃveis de transaminases. Conclui-se que o FAN foi o Ãnico NOSA significativamente associado à resposta à terapia. A ausÃncia de NOSA indica uma tendÃncia à resposta virolÃgica sustentada no tratamento da hepatite C crÃnica.
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Viso, Ana Teresa Rodriguez. "Hepatite C crônica e citocinas - estudo no soro e no fígado." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/5/5134/tde-19082010-103153/.
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INTRODUÇÃO: A patogênese da hepatite C crônica resulta principalmente de mecanismos imuno-mediados com a atuação central das citocinas tanto na lesão hepatocelular como na eliminação e na persistência do vírus da hepatite C (VHC). OBJETIVOS: Investigar a resposta imune adaptativa da hepatite C crônica através da expressão das células inflamatórias no tecido hepático e de citocinas no tecido hepático e no sangue, relacionando-os com dados demográficos, laboratoriais e histológicos. MÉTODOS: Pacientes com hepatite C crônica, virgens de tratamento foram selecionados no ambulatório de Moléstias Infecciosas do Hospital das Clínicas. Foram utilizados dois grupos controles para comparação: de doadores de sangue saudáveis e fragmentos de biópsia hepática de doadores de órgãos. Todos os controles selecionados não tinham evidência de hepatopatia. As seguintes citocinas foram analisadas no sangue pelo método quantitativo de ELISA no sangue dos casos e dos doadores de sangue: interleucina (IL) 1, IL2, IL4, IL6, IL 10, interferon (IFN) , fator de necrose tumoral (TNF) e fator de crescimento e transformação (TGF) . As mesmas citocinas e as populações celulares CD4+, CD8+, CD45RO+, CD57+, CD68+ e S100 foram quantificadas através de método imuno-histoquímico no espaço portal e no lobo hepático dos casos e dos doadores de fígado. Esses dados foram posteriormente associados às alterações histológicas pela classificação de Ishak. RESULTADOS: Foram selecionados 51 pacientes com hepatite C crônica, 58% do gênero masculino; 66,6% brancos e média de idade de 39 anos (variando de 20 a 59). Foram selecionados 33 doadores de órgãos e 51 doadores de sangue. Comparando com os doadores de sangue, os casos apresentaram maiores níveis séricos de IL2 (p <0,001), IL10 (p <0,001), INF (p 0,018) e TGF (p <0,001). Na análise das biópsias hepáticas, os casos apresentaram maior expressão de LTCD4+ portais (p <0,001), LTCD8+ portais (p <0,001), IL4 lobular (p 0,001), IL10 lobular (p 0,007), INF lobular (p <0,001), TNF portal (p <0,001) e lobular (p <0,001), TGF portal (p <0,001) e lobular (p <0,001) do que os doadores de órgãos. Entre os casos, houve correlações significantes diretas entre os seguintes marcadores e as alterações histológicas: CD4+ portal com a atividade peri portal (p 0,004); CD4+ lobular com a atividade lobular (p 0,017); TGF lobular com a atividade lobular (p 0,016); IL1 portal com atividade peri portal (p 0,009) e IL8 do sangue e fibrose (p 0,036). As populações celulares foram correlacionadas às citocinas no fígado dos casos e houve significância direta entre: CD4+ portal e TNF portal (p 0,004); CD8+ portal e TGF portal (p 0,030); CD57+ portal e IL10 portal (p 0,008); CD57+ lobular com TGF lobular (p 0,040) e IL2 lobular (p 0,048); S100 portal e IL10 portal (p 0,014). Não houve correlação significante entre as citocinas do fígado e as citocinas do sangue nos pacientes com hepatite C crônica. A carga viral do VHC teve correlação indireta com LTCD8+ lobulares (p 0,020), IL2 portal (p 0.049) e lobular (p 0.004). DISCUSSÃO: O comando da resposta imune nesta casuística foi orquestrado pelos linfócitos T CD4+ e CD8+, com predomínio da resposta Th1 e o principal local dos eventos foi o espaço portal. A compartimentalização da resposta imune ao VHC foi evidenciada pela ausência de correlações significantes entre as citocinas do tecido hepático e do sangue nos pacientes com hepatite C crônica.BACKGROUND: The pathogenesis of chronic hepatitis C results mainly of immunological mechanisms with cytokines playing a central role in hepatocellular necrosis and in the immunopathogenic process involved in viral clearance and persistence. AIM: To investigate immune response to hepatitis C virus (HCV) through expression of inflamatory cells in liver and cytokines in liver and serum, and assess the relationship with demografic, laboratorial and histological features. METHODS: Naïve patients with chronic hepatitis C were selected from Infectious Diseases Division at a University Hospital. Two sets of controls were selected for comparison: healthy blood donors and liver biopsy specimens from liver donors. All controls had no evidence of hepatic disease. The following cytokines were analyzed by quantitative ELISA method in serum of cases and healthy blood donor controls: interleukin (IL) 1, IL2, IL4, IL6, IL10, interferon (IFN) , tumor necrosis factor (TNF) , and transforming growth factor (TGF) . The same cytokines and cellular populations of CD4+ T lymphocytes (TL), CD8+ TL, CD45+, CD57+, CD68+ and S100 were quantified by immunohistochemistry in acinar and portal spaces in liver biopsies of cases and liver donor controls. These data were additionally associated to histological parameters by Ishak Score. RESULTS: Were selected 51 patients with chronic hepatitis C, 58% were males; 66,6% white and the median age was 39 (range 20 to 59) years. Were selected 33 liver donors and 51 blood donors. Compared with heathy blood donor controls, cases showed higher levels of IL2 (p <0.001), IL10 (p <0.001), INF (p 0.018) and TGF (p <0.001). In liver biopsy analyses, cases showed greater expression of the following cell populations and cytokines: portal CD4+ TL (p <0.001), portal CD8+ (p <0.001), acinar IL4 (p 0.001), acinar IL10 (p 0.007), acinar INF (p <0.001), portal TNF (p <0.001), acinar TNF (p <0.001), portal TGF (p <0.001) and acinar TGF (p <0.001). Among cases, significant positive correlations were found between the following markers and Ishak graded patterns: portal CD4+TL and periportal inflammation (p 0.004); acinar CD4+ and focal inflammation (p 0.017); acinar TGF and focal inflammation (p 0.016); portal IL1 and periportal inflammation (p 0.009) and IL8 in blood and fibrosis (p 0.036). The cellular populations were correlated to cytokines in liver of hepatitis C patients and there was significant positive correlation between: portal CD4+ and portal TNF (p 0.004); portal CD8+ TL and portal TGF (p 0,030); portal CD57+ and portal IL10 (p 0,008); acinar CD57+ and acinar TGF (p 0,040) and acinar IL2 (p 0,048); portal S100 and portal IL10 (p 0,014). No significant correlation was found between liver and serum cytokines in cases. Hepatitis C viremia was inversely correlated to acinar CD8+ TL (p 0.020); portal (p 0.049) and acinar IL2 (p 0.004). DISCUSSION: The command of the immune response in this casuistic was orchestrated by CD4+ TL and CD8+ T lymphocytes, with predominance of Th1 answer, and the main site where of the events ocurred was the portal space. The compartimentalization of immune response to HCV was evidenced by the absence of significant correlations between cytokines in hepatic tissue and blood from patients with chronic hepatitis C.
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Delcorde, Julie. "Investigating Host-Viral Interactions in Liver Lipid Homeostasis and HCV Pathology." Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31184.
Full textAbstract:
Hepatitis C virus (HCV) infects an estimated 170 million people worldwide and is a major cause of chronic hepatitis and hepatocellular carcinoma. As there are limited treatment options, the elucidation of novel host-viral interactions during HCV pathogenesis will be critical for the development of new therapeutics. My thesis work has identified cell death-inducing DFF45-like effector B (CIDEB) as a host factor that is disregulated during HCV infection, and has delineated the relevance of CIDEB’s dual roles in apoptosis and lipid metabolism in the context of the HCV lifecycle. Moreover, additional host factors necessary for the HCV lifecycle were investigated using unnatural amino acid (UAA) technology. With this technique, the photo-cross-linking UAA p-azido-phenlyalanine (AZF) and 3’-azibutyl-N-carbamoyl-lysine (Abk) were incorporated into viral proteins by expanding the genetic code of the host organism. This conferred diverse physicochemical and biological properties to these proteins that were exploited to investigate protein structure and function in vitro and in vivo. In summary, gaining insight into the numerous host-viral interactions that take place during HCV infection will both advance our understanding of HCV pathogenesis and uncover potential therapeutic targets.