Introdução: A hepatite C é um grande problema de saúde pública e sua prevalência global está estimada em torno de 3%. O risco de transmissão do VHC via fluído seminal é muito discutida tanto na área de reprodução assistida como em estudos sobre o fator de risco da hepatite C ser ou não uma DST. Foram investigados e analisados 23 pacientes sabidamente infectados pelo VHC. Objetivos: 1.Estabelecer uma técnica para detectar a ausência ou presença do vírus da Hepatite C no sêmen de pacientes infectados; 2.Comparar técnicas de manuseio das amostras de sêmen, procurando diminuir a quantidade de inibidores presentes nas amostras; 3.Comparar técnicas de PCR e detecção do vírus da Hepatite C nas amostras de sêmen, procurando aumentar a sensibilidade dos testes. Métodos: Na primeira fase do estudo foram recrutados 20 pacientes (13 preencheram os critérios de inclusão). Amostras de sêmen e soro foram coletadas. As amostras de sêmen foram processadas com o auxílio do Percoll 90% e 45%. Foi analisada a presença do HCVRNA em soro pelo método Amplicor Roche, teste qualitativo. Se positivas, as amostras de sangue foram genotipadas e as amostras de sêmen foram extraídas, pelo mesmo método, e a PCR executada. Na segunda fase do estudo 23 pacientes foram selecionados, sendo alguns reconvocados da primeira fase (20 preencheram os critérios de inclusão). Amostras de sêmen e soro foram coletadas. As amostras de sêmen foram processadas através de diluições seriadas. Foi analisada a presença do HCV-RNA em soro e sêmen pelo método Amplicor Roche, teste qualitativo e por PCR em Tempo-real. Os dados epidemiológicos e os genótipos foram analisados, assim como os resultados da detecção do soro. Sêmen e frações realizadas pelas 2 (duas) técnicas de processamento estabelecidas foram comparados e analisados. Resultados: Dos 23 pacientes selecionados, a média de idade foi de 40,7 anos, com mediana de 45 anos. O tempo médio de descoberta da infecção pelo VHC foi de 7,15 anos. Dez pacientes (37,1%) não possuíam epidemiologia aparente, oito pacientes (29,6%) adquiriram a infecção pelo VHC através da utilização de drogas injetáveis e/ou inalatórias; seis (22,2%) por transfusão sanguínea; dois (7,4%) apresentaram histórico de transfusão sanguínea e uso de drogas e um (3,7%) relatou ser profissional da saúde. O genótipo 3a foi encontrado em 40,7% dos pacientes, seguido pelo 1a com 26%, 1b com 14,8%, 2b em 11,1% e 1a/1b em 7,4%. Das amostras processadas pelo Percoll, 86,5% apresentaram resultados inibidos, enquanto que nas amostras processadas pela diluição seriada e amplificadas através do PCR convencional, apenas 25,62% das amostras apresentou inibição, 65% não foram detectadas e 9,38% das amostras apresentou positividade. Nas amostras processadas pela diluição seriada na PCR em Tempo-real, 95% das amostras não foram detectadas e somente 5% apresentou positividade. Conclusão: Na tentativa de driblar os inibidores presentes nas amostras de sêmen, o procedimento de diluições seriadas mostrou maior eficácia quando comparado com o processamento através do gradiente descontínuo de concentração. Contudo, a grande quantidade de não detectados mostrou que a carga viral pode ter sido diluída, gerando a necessidade da utilização de técnicas mais sensíveis. Não foi observada diferença significativa entre os resultados da PCR convencional e Tempo-real. Porém o aumento na quantidade dos resultados negativos pode ser conseqüência da ausência de um controle interno nas reações da PCR em Tempo-real. / Introduction: Hepatitis C vírus is a huge problem for public health, and its global prevalence is estimated around 3%. Its transmission by seminal fluid is still in discussion in several fields, such as assisted reproduction and in studies about risk factors, whether the hepatitis C virus is an STD (sexually transmitted disease) or not. Twenty-three patients were investigated. Objectives: 1.Establish a technique to detect the presence or absence of the HCV in semen from chronically infected patients; 2.Compare semen samples handling techniques, in order to decrease the amount of inhibitors on the samples; 3.Compare different PCR and detection techniques for the HCV in semen samples, in order to increase the sensibility of the test. Methods: On the first phase 20 patients were selected (13 filled the inclusion criterion). Semen and serum samples were collected. The semen samples were processed with the help of Percoll® 90% and 45%. The presence of the RNA-HCV were analyzed in serum with Amplicor Roche method, qualitative test. When positive, the serum samples were genotyped and the semen samples were extracted, by the same method, and the PCR was done. On the second phase 23 patients were selected, some of them were old patients from the first phase (20 filled the inclusion criterion). Semen and serum samples were collected. The semen samples were processed through a dilution series. The presence of HCV-RNA was analised by Amplicor Roche, qualitative test and by PCR in Real-time. The epidemiological data and genotypes were analised. Resultados: From the 23 patients selected the mean age was 40,7 years, mean 45 years. The mean time of Discovery was 7,15 years. Ten patients (37,1%) didn´t present any apparent epidemiology, eight patients (29,6%) contracted HCV through injection and inhalatory drug use; six patients (22,2%) through blood transfusion; two patients (7,4%) had history of drug use and blood transfusion and one patient (3,7%) who was a health professional. Genotype 3a was found in 40,7% of the patients, followed by 1a with 26% of the patients, 1b with 14,8%, 2b with 11,1% e 1a/1b in 7,4% of the patients. The samples processed with Percoll, 86,5% presented inhibited results. Whereas on the samples that were processed with dilution series and amplified on the conventional PCR only 25,62% presented inhibited results, 65% were undetected and 9,38% were positive. On the samples processed with dilution series on the Real-time PCR 95% were undetected and only 5% were positive. Conclusion: On the attempt of decreasing the amount of inhibitors found on the semen samples, the procedure of dilution series showed us more efficient results when compared to the Percoll procedure. However, the great amount of undetected showed that the viral load might have being diluted, leading us to the necessity of a more sensitive technique. There was no significant difference between the results of the conventional PCR and the Real-time. These increase on the undetected results may be a consequence of the absence of a internal control on the PCR reactions.

Os vírus da hepatite B (HBV), C (HCV) e Delta (HDV) causam grande impacto para a saúde pública mundial. Noventa e duas, oito e quatro amostras para HBsAg, anti-HD e anti-HCV, respectivamente, foram identificadas em indivíduos no Maranhão. Cinquenta amostras positivas para HBV DNA foram classificadas em subgenótipo D4 (42/86%) e A1 (8/14%). Para o HDV, apenas quatro foram classificadas como HDV-8. As amostras positivas para anti-HCV não apresentaram RNA detectável. O HBV-D4 parece ser o principal vírus representante na região estudada. O estudo filogenético sugere que houve a introdução de uma única cepa do subgenótipo D4 no Maranhão, enquanto que para o subgenótipo A1 existiu introdução de diferentes cepas. A confirmação do achado do HDV-8 em coinfecção com HBV- D4 suporta a hipótese de origem desses vírus na África. A ausência de infecção ativa pelo HCV é provavelmente devido uma introdução recente desse vírus e/ou menor frequência de meios de transmissão eficientes. Mais estudos são necessários em regiões onde é desconhecido o perfil de infecção desses vírus. / Hepatitis B (HBV), C (HCV) and Delta (HDV) viruses cause a great universal public health concern. Ninety-two, eight and four positive individuals for HBsAg, anti-HD and anti-HCV were identified, respectively. Fifty samples for HBV were classified in. subgenotype D4 (42/86%) and A1 (8/14%). Concerning HDV, four samples were identified as HDV-8 genotype. Anti-HCV positive samples were negative for RNA. HBV-D4 seems to be the main representative in the studied region. The phylogenetic tree topology suggests there was the introduction of a single strain of D4 subgenotype in Maranhao, whereas subgenotype A1 had several introductions of different strains. The finding of HDV-8 in coinfection with HBV D4 confirms the hypothesis of origin of these viruses in Africa. The low number of HCV infection in this region may be due to the recent introduction of this virus and / or lower frequency of efficient means of transmission. More studies are necessary in other regions where the infection profile of these viruses is indefinite.

Na prática hemoterápica em todo mundo, a triagem e o diagnóstico da infecção pelo HCV continua sendo um desafio. Desta forma, considerando as variáveis genéticas do vírus da Hepatite C e as variáveis populacionais de cada região, o conhecimento mais profundo da realidade da epidemiologia molecular do vírus da Hepatite C na população de doadores de sangue em regiões específicas se torna cada vez mais imprescindível. Desta forma, este estudo visou realizar a caracterização sorológica e molecular da infecção pelo Vírus da Hepatite C (HCV) em doadores de sangue do Estado do Amazonas a fim de subsidiar conhecimentos para interpretação dos diferentes perfis laboratoriais e clínicos, além de contribuir para o conhecimento das rotas de transmissão e da epidemiologia da infecção do Amazonas. Foram estudados 154 doadores de sangue do Estado do Amazonas com sorologia repetidamente reativa para anti-HCV. Foram realizados testes sorológicos por ELISA e Imunoblot, testes de detecção de RNA viral plasmático por Nested PCR, determinação da carga viral e genotipagem do vírus por sequenciamento. O estudo foi realizado no período de setembro de 2005 a abril de 2007 quando o índice de descarte por anti-HCV reativo foi de 0,37%. Foi observado que 50% dos casos de Imunoblot indeterminado apresentaram positividade no Nested PCR indicando a presença de RNA plasmático. A carga viral baixa foi um fator limitante para a determinação do genótipo viral pelo método de sequenciamento de algumas amostras. A freqüência de casos presumidos de clearance viral plasmático na amostra estudada foi de 18,8%. O genótipo mais prevalente do HCV nos doadores do Estado do Amazonas foi o genótipo 1 (87,5%) seguido do genótipo 3 (12,5%). Considerando as nuances da história natural da Hepatite C e os diversos momentos clínicos que os doadores possam se encontrar devem ser adotadas mudanças de condutas do acompanhamento dos doadores sororeativos para anti-HCV no banco de sangue do Amazonas e no fluxograma de diagnóstico da infecção. / The screening and diagnostic of HCV infection continue to be a challenge on the hemotherapic practice because the unique characteristics of each population and the molecular variability of the virus. The aim of this study was to characterize the serologic and molecular profile of 154 anti-HCV+ Amazon blood donors from the Amazon Hematology and Hemoterapy Foundation. Screening for anti HCV antibody was performed using ELISA and recombinant Imunoblot assay. Seropositive samples were assessed further with Nested PCR, viral load and genotyping techniques. In the study period, 2005-2007 the anti-HCV discard rate was 0,37%. We observed that 50% of the indeterminate Immunoblot cases showed HCV RNA presence in plasma by Nested PCR. The most prevalent genotype between subjects of this study was genotype 1 (87,5%), followed by genotype 3 (12,5%). The presumed plasma clearance frequency was 18,8%. The low viral load was a determinant critical factor to the genotype determination in some samples. Considering the different stages of the HCV natural infection different conducts may be adopted with inclusion of molecular testes as the first option for confirmation to the follow up of the positive anti-HCV blood donors in the Amazon blood bank and in the algorithm of the infection diagnostic, saving resources and providing a better counseling for the reactive donors.

This thesis examines cancer and mortality rates among people diagnosed with hepatitis B (HBV) and C (HCV) infection in New South Wales (NSW) from 1990 through 2002, by linking hepatitis notifications with the NSW Central Cancer Registry (CCR) and National Death Index. Of the 39101 HBV, 75834 HCV and 2604 HBV/HCV co-infection notifications included 1052, 1761 and 85 were linked to cancer notifications and 1233, 4008 and 186 were linked to death notifications respectively. Of 2072 hepatocellular carcinoma (HCC) notifications to the CCR 323, 267 and 85 were linked to HBV, HCV and HBV/HCV co-infection notifications. Incidence of HCC was 6.5, 4.0 and 5.9 per 1000 person years for HBV, HCV and HBV/HCV co-infected groups. Risk of HCC in those diagnosed with hepatitis was 20 to 30 times greater than the standard population. There was a marginally statistically significant increased risk of immunoproliferative malignancies associated with HCV infection (SIR=5.6 95% CI 1.8 ???17.5). Risk of death for those with hepatitis was significantly greater, 1.5 to 5 fold, than the general population with the greatest risk among those with HBV/HCV co-infection. The primary cause of HBV deaths was liver related, particularly HCC, whereas in the HCV groups drug related deaths were most frequent. Among people with HCV, risk of dying from drug related causes was significantly greater than from liver related causes (p=0.012), with the greatest increased risk in females age 15- 24 years (SMR 56.9, 95%CI 39.2???79.9). Median age at diagnosis of HCC varied markedly by country of birth and hepatitis group: HBV 66, 63 and 57years ; HCV 51, 68 and 71 years; unlinked 69, 70 and 64 years for Australian, European, and Asian-born groups, respectively (P<0.0001 for all groups). While the risk of cancer, particularly HCC, is elevated among people with HBV and HCV infection, the absolute risk remains low. Young people with HCV face a higher mortality risk from continued drug use than from liver damage related to their HCV infection. The influence of IDU in the epidemiology of HCC in New South Wales was possibly reflected in the varying distributions of age and country of birth.

Le virus de l’hépatite C (VHC) est une des principales causes d’hépatite chronique. La protéine F du VHC est codée par un cadre de lecture alternatif du gène de la capside, Core. La protéine F a été découverte après que l’on ait associé Core à plusieurs des fonctions pathogènes du VHC. Nous proposons donc que certaines fonctions biologiques et pathogènes attribuées à la protéine Core résultent de l’activité de la protéine F. Nous avons choisi de développer trois lignées de poissons zébrés (Danio rerio) qui expriment différentes versions de la protéine F afin d’étudier les effets de la protéine F et leur incidence dans la pathogenèse du VHC. Deux versions de la séquence codant pour la protéine F (AF11 et AUG26) et une version mutante du gène core (CoremutI) ont été introduites sur les vecteurs d’un système d’expression répressible spécifique au foie. Ces vecteurs ont été co-injectés dans des embryons unicellulaires de poissons zébrés pour générer les poissons fondateurs des lignées transgéniques. 19, 21 et 36 poissons ont été choisis comme fondateurs pour les lignées AF11, AUG26 et CoremutI respectivement. De ce nombre, 9, 11 et 11 poissons ont atteint la maturité, dans l’ordre pour les mêmes lignées, et seront croisés pour donner naissance à des lignées transgéniques stables. Les résultats de ces expériences nous permettront de mieux cerner les propriétés biologiques de la protéine F et de définir son rôle dans la pathogenèse du VHC. / Hepatitis C virus (HCV) is a major cause of liver steatosis, fibrosis and hepatocellular carcinoma. HCV F protein is expressed from an alternative reading frame within the Core sequence. F protein was discovered after many of the pathogenic determinants of HCV had been associated with the effects of Core. Hence, we propose that a part of the functions attributed to Core result from the activity of the F protein. We produced and selected 19, 21 and 36 transgenic zebrafish (Danio rerio) to give rise to 3 independent lines expressing different versions of the F protein. Of these founders, 9, 11 and 11 were raised to maturity and will be bred to generate stable transgenic lines. Characterizing the phenotype of these transgenic fish will help determine the precise role of the F protein in the pathogenesis of hepatitis C.

L'hépatite C pose un problème de santé publique majeur, dans la mesure où le risque de développer une infection chronique est relativement élevé (40 à 60%) et où la résistance au traitement de choix - l’interféron alpha pégylé et la ribavirine - touche près de la moitié des patients. Cette persistence virale repose avant tout sur de puissantes stratégies d’évasion du système immunitaire inné de l’hôte par le virus. Dans ce projet, nous nous sommes intéressés à la caractérisation de la réponse antivirale dans des hépatocytes primaires humains normaux et chroniquement infectés avec le VHC, un domaine encore largement inconnu dû à la difficulté d’obtenir ce type de matériel primaire. Nous avons étudié la fonctionnalité de deux voies majeures de détection des pathogènes viraux suite à l’exposition d’hépatocytes primaires humains à de l’ARNdb intracellulaire, via le récepteur et adaptateur RIG-I/MDA5-CARDIF, et extracellulaire via TLR3-TRIF, mimant ainsi les étapes précoces de la détection d’un virus par la cellule hôte. Nous avons établi par RT-PCR quantitatif et analyse transcriptomique par microarray, que ces deux voies de stimulation sont fonctionnelles dans des hépatocytes primaires normaux et que leur activation entraîne à la fois l’expression de gènes antiviraux communs (ISG56, ISG15, CXCL10, …) mais aussi spécifiques avec les gènes IL28A, IL28B et IL29 qui sont une signature de l’activation de la voie de détection de l’ARNdb intracellulaire. La protéine virale NS3/4A joue un rôle majeur à la fois dans le clivage de la polyprotéine virale initiale, mais aussi en interférant avec les cascades de signalisation engagées suite à la détection par la cellule hôte de l’ARN du VHC. Plus particulièrement, nous avons démontré que l’expression ectopique de NS3/4A dans des hépatocytes primaires humains normaux entraîne une diminution significative de l’induction des gènes antiviraux dûe au clivage de CARDIF au cours de l’activation de la voie de signalisation médiée par RIG-I. Nous avons également démontré que l’expression de la NS3/4A entraîne des modifications de l’expression de gènes-clé impliqués dans la régulation de l’apoptose et du programme de mort cellulaire, en particulier lorsque la voie TLR3 est induite. L’ensemble de ces effets sont abolis en présence de BILN2061, inhibiteur spécifique de NS3/4A. Malgré les stratégies de subversion de l’immunité innée par le VHC, nous avons démontré l’induction significative de plusieurs ISGs et chemokines dans des hepatocytes primaires provenant de patients chroniquement infectés avec le VHC, sans toutefois détecter d’interférons de type I, III ou certains gènes antiviraux précoces comme CCL5. Ces observations, concomitantes avec une diminution de l’expression de CARDIF et une correlation inverse entre les niveaux d’ARNm des ISGs et l’ARN viral révèlent une réponse antivirale partielle dûe à des mécanismes interférents sous-jacents. Cette réponse antivirale détectable mais inefficace est à mettre en lien avec l’échec du traitement classique PEG-IFN-ribavirine chez la moitié des patients traités, mais aussi en lien avec l’inflammation chronique et les dommages hépatiques qui mènent ultimement au développement d’une fibrose puis d’une cirrhose chez une grande proportion de patients chroniquement infectés. / Hepatitis C infection is a worldwide health problem since the risk to develop a persistent infection is relatively elevated (40 to 60%) and nearly half of the infected patients do not respond to the classical anti-HCV therapy based on a combination of PEG-IFNα and ribavirin. Viral persistence is based on powerful evasion strategies of the host’s innate immune system. In our study, we characterized antiviral response in primary human normal and chronically HCV-infected hepatocytes, a cutting-edge in our field due to the difficulty to isolate this particular cell type. In order to better define the antiviral response in freshly isolated human primary hepatocytes, we stimulated these cells with extracellular and intracellular dsRNA to trigger TLR3/TRIF and RIG-I-MDA5/CARDIF-mediated antiviral signaling pathways. By using qRT-PCR and microarray analysis, we report that both detection pathways are functional in normal human hepatocytes, their activation leading to the expression of both common (IFIT1, OASL, ISG15 and CXCL10) and specific genes (IL28A, IL28B and IL29), these last ones being a signature of the intracellular dsRNA-mediated pathway. HCV NS3/4A plays a key role in the viral polyprotein processing and upon viral RNA detection by interfering with the host’s antiviral signalling cascades. We report that major antiviral genes induction following activation of RIG-I mediated pathway are severely impaired in ectopically NS3/4A expressing normal hepatocytes due to CARDIF cleavage, but can be restored by specific NS3/4A inhibitor BILN2061. Our microarray analysis also revealed a role for NS3/4A following TRL3-mediated pathway activation on regulation of apoptosis and programmed cell death, which could be linked to strategies for the virus to persist in its host. Despite HCV strategies to circumvent the host’s immune defense system, we observed significant upregulation of ISGs and chemokines in liver biopsies and corresponding isolated hepatocytes from chronically HCV-infected patients. However, no type I and III interferon, neither key-antiviral genes (e.g., CCL5) were detected, underlying an ongoing –but inefficient- antiviral response unable to eradicate the virus. Moreover, we obtained significant inverse correlations between ISGs mRNAs and viral RNA in addition to CARDIF decrease, clearly unravelling efficient viral interfering strategies in a context of chronic HCV infection. This sustained -albeit incomplete- hepatic innate immune response is certainly associated to the failure of the classical IFN-based therapy in half of the infected patients and to the chronic inflammation causing liver damages and eventually leading to hepatocarcinoma which is often observed at late stage of the disease.

Hepatitis C virus (HCV) is a single-stranded plus-sense RNA virus that is transmitted by blood-to-blood contact, and infects the human liver. HCV has a unique dependence on the liver-specific microRNA miR-122, where miR-122 binds the 5´ un-translated region of the viral RNA at two tandem sites and increases viral RNA abundance. The mechanisms of augmentation are not yet fully understood, but the interaction is known to stabilize the viral RNA, increase translation from the viral internal ribosomal entry site (IRES), and result in increased viral yield. In an attempt to create a small animal model for HCV, we added miR-122 to mouse cell lines previously thought non-permissive to HCV, which rendered these cells permissive to the virus, additionally showing that miR-122 is one of the major determinants of HCV hepatotropism. We found that some wild-type and knockout mouse cell lines – NCoA6 and PKR knockout embryonic fibroblasts – could be rendered permissive to transient HCV sub-genomic, but not full-length, RNA replication upon addition of miR-122, and that other wild-type and knockout cell lines cannot be rendered permissive to HCV replication by addition of miR-122. These knockout cell lines demonstrated varying permissiveness phenotypes between passages and isolates and eventually completely lost permissiveness, and we were unable to achieve sub-genomic RNA replication in PKR knockout primary hepatocytes. Knockdown of NCoA6 and PKR in Huh7.5 cells did not substantially impact sub-genomic replication, leading us to conclude that there are additional factors within the cell lines that affect their permissiveness for HCV replication such as epigenetic regulation during passage or transformation and immortalization. We also added miR-122 to Hep3B cells, a human hepatoma cell line lacking expression of miR-122 and previously thought to be non-permissive to HCV replication. Added miR-122 rendered the cells as highly permissive to HCV replication as the Huh7-derived cell lines commonly used to study the virus. In these cells, we were also able to observe miR-122-independent replication of sub-genomic HCV RNA. This was verified by use of a miR-122 antagonist that had no impact on the putative miR-122-independent replication, and by mutating the miR-122 binding sites to make them dependent on a single nucleotide-substituted microRNA. This replication in the absence of miR-122 was not detected in full-length HCV RNA, but was detectable using a bi-cistronic full-length genomic replicon, suggesting that the addition of a second IRES in sub-genomic and full-genomic replicons altered replication dynamics enough to allow detectable RNA replication without miR-122 binding. Because miR-122 has been implicated in protecting the viral RNA from destabilization and degradation by Xrn1, the main cytoplasmic 5´ to 3´ RNA exonuclease, we employed our miR-122-independent system to test this miR-122-mediated protection. We verified that miR-122 functions to protect the viral RNA from Xrn1, but this was insufficient to account for the overall impact of miR-122 on replication, meaning that miR-122 has further functions in the virus’ life cycle. We showed that the effect of miR-122 on translation is due to stabilization of the RNA by protecting it from Xrn1, through binding at both sites. We further evaluated the role of each miR-122 binding site (S1 and S2) in the virus life cycle, and found that binding at each site contributes equally to increasing viral RNA replication, while binding at both sites exerts a co-operative effect. Finally, we determined that binding of miR-122 at site S2 is more important for protection from Xrn1, suggesting that miR-122 binding at S1 is more important for the additional functions of miR-122 in enhancing HCV RNA accumulation. Altogether, we have shown that miR-122 is partially responsible for the hepatotropic nature of Hepatitis C virus, and that supplementation with this microRNA can render non-permissive cells permissive to viral replication. We have also identified and confirmed replication of both sub-genomic and full-length HCV RNA in the absence of miR-122. Finally, we have characterized the impact of the host RNA exonuclease Xrn1 on the HCV life cycle, and determined the roles of each miR-122 binding site in shielding the viral RNA from this host restriction factor.

This thesis examines cancer and mortality rates among people diagnosed with hepatitis B (HBV) and C (HCV) infection in New South Wales (NSW) from 1990 through 2002, by linking hepatitis notifications with the NSW Central Cancer Registry (CCR) and National Death Index. Of the 39101 HBV, 75834 HCV and 2604 HBV/HCV co-infection notifications included 1052, 1761 and 85 were linked to cancer notifications and 1233, 4008 and 186 were linked to death notifications respectively. Of 2072 hepatocellular carcinoma (HCC) notifications to the CCR 323, 267 and 85 were linked to HBV, HCV and HBV/HCV co-infection notifications. Incidence of HCC was 6.5, 4.0 and 5.9 per 1000 person years for HBV, HCV and HBV/HCV co-infected groups. Risk of HCC in those diagnosed with hepatitis was 20 to 30 times greater than the standard population. There was a marginally statistically significant increased risk of immunoproliferative malignancies associated with HCV infection (SIR=5.6 95% CI 1.8 ???17.5). Risk of death for those with hepatitis was significantly greater, 1.5 to 5 fold, than the general population with the greatest risk among those with HBV/HCV co-infection. The primary cause of HBV deaths was liver related, particularly HCC, whereas in the HCV groups drug related deaths were most frequent. Among people with HCV, risk of dying from drug related causes was significantly greater than from liver related causes (p=0.012), with the greatest increased risk in females age 15- 24 years (SMR 56.9, 95%CI 39.2???79.9). Median age at diagnosis of HCC varied markedly by country of birth and hepatitis group: HBV 66, 63 and 57years ; HCV 51, 68 and 71 years; unlinked 69, 70 and 64 years for Australian, European, and Asian-born groups, respectively (P<0.0001 for all groups). While the risk of cancer, particularly HCC, is elevated among people with HBV and HCV infection, the absolute risk remains low. Young people with HCV face a higher mortality risk from continued drug use than from liver damage related to their HCV infection. The influence of IDU in the epidemiology of HCC in New South Wales was possibly reflected in the varying distributions of age and country of birth.

Ulm, Univ., Diss., 2008.

A infecção pelo vírus da hepatite C (VHC) é uma das mais comuns infecções ao redor do mundo. Aproximadamente, 20% dos pacientes infectados eliminam espontaneamente o vírus, porém a maioria dos indivíduos infectados desenvolve infecção crônica com amplo espectro de lesões hepáticas, desde inflamação leve até cirrose. A resposta imune do hospedeiro exerce grande influência sobre o desfecho da infecção pelo VHC. O objetivo deste trabalho foi analisar a influência dos polimorfismos genéticos de citocinas na susceptibilidade ou persistência da infecção por VHC e no clareamento espontâneo em uma amostra de pacientes da população do Rio de Janeiro (Brasil). Os polimorfismos genéticos das citocinas TNFA (-308), TGFB1 (codon 10 e 25), IL10 (-1082, -592), IL6 (-174) e IFNG (+874) foram analisados por PCR-SSP em 245 pacientes com hepatite C crônica (HCC), 41 pacientes que alcançaram o clareamento viral espontâneo e 189 indivíduos controle saudáveis. Além disso, os polimorfismos próximos ao gene da citocina IL28B (rs12979860, rs12980275 e rs8099917) foram analisados por PCR em tempo real em todos os grupos. O grau de fibrose e inflamação, a resposta ao tratamento e o genótipo do vírus também foram levados em consideração quanto ao desfecho da HCC Os genótipos IL28B rs12979860 CC e CT e rs12980275 AA e AG foram significativamente associados ao clareamento espontâneo e à resposta à terapia anti-viral. Da mesma forma, o alelo C (rs12979860) e o alelo A (rs12980275) foram significativamente maior no grupo Clareamento. O alelo C de IL6 (-174) foi associado com o Clareamento. Nenhuma associação entre as demais citocinas e o desfecho da HCC foi encontrada. O Genótipo TNFA (-308) GG parece estar associado com menor grau de inflamação. Além disso, a etnia auto declarada influencia a distribuição dos polimorfismos em IL6 (-174) e IL28B rs12979860 e rs8099917. Nossas observações indicam que os polimorfismos próximos ao gene da IL28B estão associados com o clareamento viral e resposta ao tratamento na população do Rio de Janeiro. Além disso, nossos resultados podem ser úteis para futuras investigações entre os polimorfismos de citocinas e a infecção por VHC numa população heterogênea como a Brasileira. / Hepatitis C virus infection is one of the most common blood-borne infections worldwide. Approximately, 20% of infected patients successfully eliminate the virus, whereas the majority of patients develop chronic infection with a wide spectrum of liver lesions, ranging from a minimal inflammation to cirrhosis. The host's immune response is an important correlate of HCV infection outcome and disease progression. The aim of this study was to explore the possibility of the inheritance of cytokine gene polymorphisms as a candidate for susceptibility to persistent HCV infection or HCV clearance in a sample of Rio de Janeiro (Brazil) population. Genetic polymorphisms in the cytokines TNFA (-308), TGFB1 (codon 10 and 25), IL10 (-1082, -592), IL6 (-174) and IFNG (+874) were analyzed by polymerase chain reaction-sequence-specific primer (SSP) in 245 chronic hepatitis C (HCC) patients, 41 spontaneous recovery (SR) patients and 189 healthy volunteers. Further, IL28B (rs12979860, rs12980275 and rs8099917) were assessed by real-time PCR in all groups. Liver fibrosis and inflammation staging, response to treatment and virus genotype were also tested to influence in HCV chronic infection. IL28B rs12989760 CC and rs12980275 AA genotypes were significantly associated with spontaneous recovery of HCV infection and response to therapy. Likewise, C allele (rs12979860) and A allele (rs12980275) were also more frequent in SR group, while C allele of IL6 (-174) is associated with persistence to HCC. No association was found between other cytokine gene polymorphism and susceptibility to HCV infection and response to treatment. Multivariate analysis showed male, IL28B rs12979860 CT and TT and TGFB1 (codon 10) TC genotypes to be factors associated with HCC. TNFA (-308) GG genotype seems to be associated with moderate stage of inflammation. Also, ethnicity according self-declared is supposed to influence the distribution IL6 (-174) and IL28B rs12979860 and rs8099917 polymorphisms. These results suggest that the IL28B polymorphisms are associated with spontaneous clearance of HCV and response to therapy in a Brazilian population. Moreover, these results could be useful to further association between cytokine polymorphism and HCV infection outcome in Brazilian admixture population.