Improved methods for the in situ hybridisation detection of messenger RNA ( mRNA ) in sections of liver tissue, were derived by use of an experimental system. This involved the use of tritiated-poly ( dT ) probes to detect poly ( A ) sequences attached to the 3 ' end of mRNA in sections of mouse liver that had been processed in various ways. The improved - methods were applied to the detection of hepatitis B virus ( HBV ) - and hepatitis delta virus ( HDV ) - RNA. In situ hybridisation and immunostaining techniques were then applied to studies of the pathogenesis of HBV and duck hepatitis B virus ( DHBV ) infection. In situ hybridisation studies of liver biopsy tissue from HBV - infected immunosuppressed renal transplant patients demonstrated an anatomical association between piecemeal necrosis and HBV replication at the cellular level in some patients. However, widespread replicative infection of hepatocytes also occurred in some patients in the presence of normal hepatocyte morphology and mild inflammatory changes indicating that at the cellular level virus replication was not necessarily a direct cytopathic process. These findings supported the view that hepatocyte Injury may : ( i ) result from immune - mediated damage directed against cells undergoing replicative, but not restricted infection ; ( ii ) eliminate cells undergoing replicative infection and favour clonal regeneration of cells undergoing restricted infection. Localisation of interferon - alpha ( IFN - alpha ) expression in liver tissue chronically infected with HBV and HDV, identified mononuclear cells and fibroblasts ( but not hepatocytes ) as the main producers of IFN - alpha. IFN - alpha - positive cells were associated with areas of liver tissue containing cells supporting virus replication and exhibiting the greatest degree of liver damage, suggesting that locally produced IFN - alpha may be a natural regulator of virus replication in chronic liver disease. Experimental DHBV infection of Pekin - Aylesbury ducks showed that virus inoculated either intravenously or intraperitoneally, gained access to randomly distributed hepatocytes without first replicating in other cell types in the liver. Virus was seen to disseminate to contiguous cells following anatomical boundaries by the third day post - inoculation. Markers of DHBV infection in liver and serum showed reproducible kinetics, and duck hepatocytes in this system appeared to be highly permissive as large amounts of DHBV DNA and DHBsAg were produced intracellularly without the development of ongoing cytopathology. Hepatocytes were the major cell type responsible for early significant DHBV replication, in contrast to pancreas, kidney, spleen and circulating mononuclear cells where significant levels of infection were detected only after the first week of infection and the onset of viraemia. / Thesis (Ph.D.)--Department of Microbiology and Immunology, 1989.

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Mikrobiyoloji ve Klinik Mikrobiyoloji Anabilim Dalı, 2002. / Bibliyografya var.

CoordenaÃÃo de AperfeiÃoamento de NÃvel Superior / A regiÃo AmazÃnica à uma das principais Ãreas endÃmicas da hepatite D no Mundo e a Ãnica relacionada com a presenÃa do genÃtipo 3 do vÃrus delta. O objetivo deste estudo foi analisar os resultados do transplante de fÃgado pela cirrose causada pela hepatite D e correlacionar com os transplantados pela monoinfecÃÃo do vÃrus da hepatite B. Foram avaliados 29 pacientes com hepatite D e 40 pacientes com hepatite B, transplantados de fÃgado no Hospital UniversitÃrio Walter CantÃdio da Universidade Federal do Cearà (HUWC/UFC). O grupo de pacientes com hepatite D foi mais jovem (mÃdia 33.9 vs 52.9 anos, p < 0,001), predominante do sexo masculino e todos oriundos da RegiÃo AmazÃnica Brasileira. NÃo houve diferenÃas nos valores dos critÃrios de gravidade, MELD e Child, entre os grupos. A ocorrÃncia de carcinoma hepatocelular (CHC) foi predominante no grupo de pacientes com hepatite B ( frequÃncia 36.8% vs 17.2%, p = 0,05), assim como maior mortalidade ( frequÃncia 25% vs 3.4%, p = 0,019 ). Pacientes com hepatite D, apresentaram mais acentuada plaquetopenia no prÃ-transplante (mÃdia 66.428,57 vs 102.037,50 ÂL, p = 0,02) e no pÃs-operatÃrio imediato (mÃdia 54.242,86 vs 94.063,89 ÂL, p = 0,04). A recuperaÃÃo da lesÃo hepÃtica, avaliada atravÃs dos valores de AST, ALT e BT, mensurados 3 meses apÃs o transplante, nÃo mostrou diferenÃa entre os grupos. A sobrevida analisada pela curva de Kaplan-Meier, no perÃodo de 4 anos, foi de 95% nos pacientes com hepatite D e 75% nos pacientes com a monoinfecÃÃo pelo vÃrus B. Conclui-se que os pacientes com hepatite D possuem excelentes resultados apÃs o transplante hepÃtico e menor incidÃncia para o desenvolvimento do CHC. / The Amazon region is one of the main endemic areas of hepatitis D in the World and the only related to the presence of genotype 3 of delta virus. The objective of this study was to analyze the results of liver transplantation for cirrhosis caused by hepatitis D and correlate with the transplant by monoinfection of hepatitis B. 29 patients were evaluated with hepatitis D and 40 patients with hepatitis B, they were submitted a liver transplantation in the Walter Cantidio University Hospital of the Federal University of Ceara. The group of patients with hepatitis D were younger (mean 33.9 vs 52.9 years, p < 0,001), predominantly male and all from the Brazilian Amazon region. There were no differences in the values of severity criteria, MELD and Child, between groups. The occurrence of hepatocellular carcinoma (HCC) was predominant in patients with hepatitis B (frequency 36.8% vs. 17.2%, p = 0,05), likewise higher mortality (frequency 25% vs 3.4%, p = 0,019). Patients with hepatitis D showed more pronounced thrombocytopenia in pre-transplant (mean 66.428,57 vs 102.037,50 ÂL, p = 0,02) and in the immediate postoperative period (mean 54.242,86 vs 94.063,89 ÂL, p = 0,04). The recovery of liver injury as measured by the values of AST, ALT, and BT, measured 3 months after transplantation showed no difference between groups. The survival analyzed by Kaplan-Meier survival curves, showed a period of four years, the result of 95% in patients with hepatitis D and 75% in patients with monoinfection of hepatitis B. Patients with hepatitis D have excellent results after liver transplantation and lower incidence of HCC development.

Não se tem conhecimento preciso da relevância e magnitude das hepatites em nosso país. Os poucos estudos epidemiológicos estão restritos à populações atendidas em serviços de saúde ou a grupos de risco para as hepatites. A vigilância é um instrumento de saúde pública que tem a capacidade de descrever o comportamento das hepatites virais, bem como identificar seus fatores de risco. Um sistema de vigilância das hepatites A, B, C e E foi implantado em Vargem Grande Paulista em abril de 1997 e mantido até setembro de 1999. O objetivo foi analisar aspectos da operacionalização de um sistema de vigilância nas atuais condições de trabalho da Rede Pública de Saúde e sua potencialidade em descrever o comportamento das hepatites nessa comunidade para oferecer subsídios para elaboração e aprimoramento de estratégias de controle. O sistema incluiu a análise de dados obtidos a partir de notificação de casos suspeitos hepatite A, B, C e E entre residentes no município, assim como dados de soroprevalência de marcadores de infecção para esses mesmos vírus numa população formada pelas gestantes inscritas no Serviço Pré-natal do Município. Considerou-se caso suspeito o indivíduo residente no município de Vargem Grande Paulista e para quem, por critérios clínicos, laboratoriais ou epidemiológicos, foi solicitada a determinação dos níveis de bilirrubinas e transaminases. A confirmação dos casos foi realizada pela identificação dos marcadores sorológicos das hepatites A, B, C e E. Foram identificados 125 casos suspeitos, dos quais 41 (32,8 por cento ) foram confirmados como hepatite A, B, C ou E. A incidência de hepatite A foi 21,1/100.000 hab., 69,3/100.000 hab. e 9,3/100.000 hab. para os anos de 1997, 1998 e 1999, respectivamente. Foi detectado um surto de hepatite A em um dos bairros do município envolvendo 18 casos, no primeiro semestre de 1998. A forma predominante de transmissão do vírus durante o surto foi pessoa a pessoa e a faixa etária mais atingida foi de 5 a 9 anos. A incidência de hepatite B foi de 3,5/100.000 hab. e 9,9/100.000 hab. para os anos de 1997 e 1998 respectivamente. Não foi identificado nenhum caso em 1999. A prevalência de hepatite C foi 3,5/100.000 hab. em 1997 e 9,9/100.000 hab. em 1998. Não foi calculada a incidência de hepatite C, porque não foi possível determinar se a infecção pelo VHC era recente ou não com os testes utilizados. A incidência de hepatite E foi 3,5/100.000 hab., 3,3/100.000 hab. e 3,1/100.000 hab. para 1997, 1998 e 1999. Entre as 793 gestantes que participaram do estudo, a prevalência de anti-VHA foi de 94,7 por cento , de anti-HBc 4,9 por cento , de HBsAg 0,1 por cento , de anti-VHC 0,6 por cento , e anti-VHE 0,8 por cento . Os resultados indicaram que Vargem Grande Paulista apresentou alta endemicidade para hepatite A e baixa endemicidade para hepatite B. A prevalência de hepatite C foi semelhante à encontrada em outros estudos. A prevalência e incidência da hepatite E mostrou que o vírus circulou na região. Os dados demonstraram que o sistema de vigilância pode contribuir com informações importantes no comportamento das hepatites virais no município, oferecendo subsídios para a elaboração de estratégia de prevenção e controle dessas infecções. / A surveillance system of the hepatitis A, B, C and E was implanted in Vargem Grande Paulista In April, 1997 and maintained to September, 1999. The present study was implanted in order to analyze aspects of the surveillance system operation in the current conditions of the Public Health Service and its potentiality in describing the behavior of the hepatitis in that community to be used for elaboration and improvement of control strategies. The system included the analysis of data obtained of the notification of hepatitis A, B, C and E cases among the residents of the Municipal District, as well data of seroprevalence markers in a population formed by the pregnants registered in the Prenatal Service. The system considered suspected case the resident in Vargem Grande Paulista for who was requested the determination of the bilirubin and aminotransferases levels, by clinical, laboratory or epidemiologic criteria. The confirmation of the cases was accomplished by the identification of the hepatitis A, B, C and E serologic markers. Of the 125 suspected cases identified, 41 (32.8 per cent ) were confirmed as hepatitis A, B, C or E. The incidence of hepatitis A was 21.1 per 100,000 population, 69.3 per 100,000 and 9.3 per 100,000 for the years of 1997, 1998 and 1999, respectively. In the first semester of 1998, it was detected a hepatitis A outbreak in one of the neighborhoods, involving 18 cases. The predominant form of transmission, during the outbreak, was person to person and the 5 to 9 age-group was the most affected. The hepatitis B incidence was 3.5 per 100,000 and 9.9 per 100,000 pop. for the years of 1997 and 1998, respectively. It was not identified any case in 1999. The hepatitis C prevalence was 3.5 per 100,000 in 1997 and 9.9 per 100,000 in 1998 and its incidence was not calculated because it was not possible to determine if the HCV infection was recent or not with the used tests. The hepatitis E incidence was 3.5 per 100,000, 3.3 per 100,000 and 3.1 per 100,000 for 1997, 1998 and 1999, respectively. Among the 793 pregnants, the anti-HAV prevalence was 94.7 per cent , anti-HBc 4.9 per cent , HBsAg 0.1 per cent , anti-HCV 0.6 per cent and anti-HEV 0.8 per cent . The results indicated that Vargem Grande Paulista presented high endemicity for hepatitis A and lower for hepatitis B. The hepatitis C prevalence was similar to other studies. The hepatitis E prevalence and incidence showed that the virus circulated in the area. The data demonstrate that the surveillance system can contribute with important information to understand the behavior of the viral hepatitis to the Municipal District, can be subsidies for the elaboration of prevention and control strategy.

Orientador: Maria Inês de Moura Campos Pardini / Coorientador: Rejane Maria Tommasini Grotto / Banca: Alexandre Naime Barbosa / Banca: Atila Iamarino / Resumo: A vulnerabilidade humana à infecção pelo HIV não é uniforme, fatores virológicos e do hospedeiro são determinantes no risco da transmissão e na evolução natural da infecção. Polimorfismos (do hospedeiro) nos genes KIR estão sendo associados à evolução da infecção pelo vírus. Vários estudos vêm sendo realizados em monoinfectados pelo HIV-1, mas pouco se conhece a respeito da relação desses polimorfismos em coinfecção HIV/VHC. A finalidade deste estudo foi analisar a evolução da infecção pelo HIV em pacientes coinfectados HIV/VHC, baseada em parâmetros clínicos, laboratoriais e virológicos, correlacionando polimorfismos de genes KIR. Foram incluídas no estudo 251 amostras, as quais foram distribuídas em três grupos (Grupo 1: 100 indivíduos monoinfectados HIV-1; Grupo 2: 100 indivíduos monoinfectados VHC e Grupo 3: 51 coinfectados HIV/VHC. As determinações dos subtipos (HIV-1) e genótipos (VHC) foram realizadas por sequenciamento. As definições dos polimorfismos dos genes KIR foram determinados por PCR-SSP e do HLA, por sequenciamento. Dados referentes à evolução da infecção pelo HIV-1 e VHC foram analisados a partir dos prontuários médicos dos pacientes. Os resultados obtidos pelo presente estudo com relação aos genes KIR, 2DL2, 2DS2 e 2DL5, sugerem em caráter inédito a correlação destes polimorfismos com a evolução da infecção pelo VHC em indivíduos coinfectados. A inexistência de correlação dos polimorfismos dos genes KIR com a progressão da infecção pelo HIV-1 em coinfectados sugere que nesta condição, a presença do HIV-1 pode estar influenciando muito mais a progressão da doença pelo VHC do que o desenvolvimento de aids propriamente dito / Abstract: Human vulnerability to HIV infection is not uniform, virological and host factors are determinants on the risk of transmission and natural infection progression. KIR genes polymorphisms have been being associated with progression of HIV infection. Several studies have been performed in mono-infected by HIV-1, but few knwoledge is known about the relation of these polymorphisms in coinfection by HIV/HCV. The purpose of this study was to assess the increasing of the infection by HIV in patients coinfected HIV/HCV, based on clinical, laboratory and virological parameters and correlating KIR genes polymorphisms. The study included 251 samples which were divided into three groups (Group 1: 100 HIV mono-infected; Group 2: 100 mono-infected HCV; Group 3: 51 Co-Infected HIV/HCV). Determination of subtypes (HIV) and genotypes (HCV) was held using RNA sequencing. Polymorphisms definitions of KIR genes were determined by PCR-SSP and HLA were accomplished out by sequencing. Clinical and laboratory data, regarding the evolution of HIV and HCV infection were analyzed from the medical records of patients. The results obtained by this study concerning KIR, 2DL2, 2DL5 and 2DS2 genes demonstrate the state-of-the-art on the correlation of these polymorphisms with evolution of HCV infection in coinfected individuals. The absence of correlation between the polymorphism of KIR genes with progression of HIV-1 infection in co-infected, suggests that in this particular condition, the presence of HIV-1 may influence much more the disease progression by the HCV than the aids development in itself / Mestre

Hepatitis B virus (HBV) is a life-threatening pathogen with major economic significance. Acute infection in adults is common, albeit usually self-limiting. Importantly, infection in infants typically results in chronic infection and increased incidence of hepatocellular carcinoma (HCC). Furthermore, the infectious carrier state is perpetuated in chronically infected individuals. Successful immuno-therapeutic vaccination would reduce the incidence of chronic infection and of HCC as well as reduce transmission of the disease. Recovery from acute and chronic HBV infection typically occurs in the presence of robust antigen-specific humoral and cellular immune responses (CMI), whereas these responses are low or absent in chronically HBV-infected individuals. Therefore, it was hypothesised that effective stimulation of both humoral and CMI responses, in conjunction with currently available antiviral therapies, may contribute significantly to development of vaccines for treatment of chronic HBV infection. The duck hepatitis B virus (DHBV) model of HBV infection was used to test novel vaccine strategies that could complement existing antiviral therapeutic approaches to treat chronically HBV-infected humans. To this end, three separate vaccine studies were conducted to investigate potential therapeutic regimes. Methods to assess the efficacies of the vaccine strategies included immunoperoxidase detection of viral antigen and immune cell markers within the liver and development of sensitive assays to monitor levels of DHBV DNA, duck hepatitis B virus surface antigen (DHBsAg), antibodies to duck hepatitis B core (anti-DHBc) and surface antigens (anti-DHBs) in serum were developed and validated which allowed monitoring of the kinetics of the humoral immune response following vaccination and the course and outcome of experimental DHBV infection. The first vaccine study tested the protective efficacy of DNA vaccines encoding either the small form of DHBsAg (DHBs) protein or the larger antigen (DHBpre-S/S), These were administered to ducks at day 4 and 14 of age. On the same day as the second vaccination, ducks were challenged intravenously with DHBV. Immunoperoxidase staining of biopsy tissue collected at day 4 p.i. showed significant decreases in the number of DHBV infected hepatocytes in ducks receiving the DNA vaccines compared to the mock-vaccinated control ducks. Significant protection against development of chronic DHBV infection was observed in ducks vaccinated with DNA vaccines expressing either pre-S/S or S protein. Although anti-DHBs antibodies were not detected prior to DHBV challenge, the decrease in the percentages of DHBV-infected hepatocytes at day 4 p.i is suggestive that neutralisation of the inoculum by low-level anti-DHBs antibodies in cohort with CMI responses induced by vaccination were the most probable mechanisms of action. The second vaccine study examined the protective efficacy of a novel whole-cell vaccine that expressed the DHBV core antigen (DHBcAg). Ducks were vaccinated on day 4 and 14 of age and DHBV challenge was administered 4 days later. Detectable anti-DHBc antibodies were generated as soon as 4 days after the initial vaccination suggesting that this regimen elicited increased immunogenicity than vaccination with DNA vaccines alone. In contrast to the first vaccine study with DNA vaccines expressing DHBsAg, no significant differences in the percentage of DHBV-infected hepatocytes were observed in biopsy tissue collected at day 4 p.i.This finding is confirmation that anti-DHBc antibodies were not neutralising to the initial DHBV inoculum. However, significant protection against development of chronic DHBV infection was observed in the whole-cell vaccinated ducks suggesting that the mechanism of protection was consistent immune-mediated killing of DHBV-infected hepatocytes following CMI responses to determinants of DHBcAg. The final vaccine study involved a combination strategy of antiviral drug Entecavir (ETV) and prime-boost vaccination with DNA vaccines and recombinant fowlpoxvirus (rFPV) expressing DHBV antigens. Immediately following DHBV infection, ducks were dosed by oral gavage with the antiviral drug Entecavir (ETV) and at the same time received the priming DNA vaccines encoding DHBV antigens. Seven days later the boosting vaccination consisting of recombinant fowlpox viruses (rFPV) also expressing DHBV antigens was administered. Extraordinary protection was observed, with 100% of ducks given combination therapy rapidly resolved their DHBV infection while 100% of non-treated ducks developed chronic infection. It was concluded that protection resulted from a combination of at least three factors. First, reduction and control of DHBV levels with the aid of ETV; secondly, stimulation of surface antigen-specific humoral immune responses resulting in neutralisation of newly produced virions; and finally, the combined up-regulation of CMI responses against DHBV core and surface antigens, resulting in elimination of infected hepatocytes. The four manuscripts that comprise this thesis provide insights into the viral kinetics and immune responses that follow DHBV infection and/or vaccination of ducks. The results provide new directions for future vaccine studies aimed at developing effective treatments for chronic HBV infection. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2008

Hepatitis B virus (HBV) is a life-threatening pathogen with major economic significance. Acute infection in adults is common, albeit usually self-limiting. Importantly, infection in infants typically results in chronic infection and increased incidence of hepatocellular carcinoma (HCC). Furthermore, the infectious carrier state is perpetuated in chronically infected individuals. Successful immuno-therapeutic vaccination would reduce the incidence of chronic infection and of HCC as well as reduce transmission of the disease. Recovery from acute and chronic HBV infection typically occurs in the presence of robust antigen-specific humoral and cellular immune responses (CMI), whereas these responses are low or absent in chronically HBV-infected individuals. Therefore, it was hypothesised that effective stimulation of both humoral and CMI responses, in conjunction with currently available antiviral therapies, may contribute significantly to development of vaccines for treatment of chronic HBV infection. The duck hepatitis B virus (DHBV) model of HBV infection was used to test novel vaccine strategies that could complement existing antiviral therapeutic approaches to treat chronically HBV-infected humans. To this end, three separate vaccine studies were conducted to investigate potential therapeutic regimes. Methods to assess the efficacies of the vaccine strategies included immunoperoxidase detection of viral antigen and immune cell markers within the liver and development of sensitive assays to monitor levels of DHBV DNA, duck hepatitis B virus surface antigen (DHBsAg), antibodies to duck hepatitis B core (anti-DHBc) and surface antigens (anti-DHBs) in serum were developed and validated which allowed monitoring of the kinetics of the humoral immune response following vaccination and the course and outcome of experimental DHBV infection. The first vaccine study tested the protective efficacy of DNA vaccines encoding either the small form of DHBsAg (DHBs) protein or the larger antigen (DHBpre-S/S), These were administered to ducks at day 4 and 14 of age. On the same day as the second vaccination, ducks were challenged intravenously with DHBV. Immunoperoxidase staining of biopsy tissue collected at day 4 p.i. showed significant decreases in the number of DHBV infected hepatocytes in ducks receiving the DNA vaccines compared to the mock-vaccinated control ducks. Significant protection against development of chronic DHBV infection was observed in ducks vaccinated with DNA vaccines expressing either pre-S/S or S protein. Although anti-DHBs antibodies were not detected prior to DHBV challenge, the decrease in the percentages of DHBV-infected hepatocytes at day 4 p.i is suggestive that neutralisation of the inoculum by low-level anti-DHBs antibodies in cohort with CMI responses induced by vaccination were the most probable mechanisms of action. The second vaccine study examined the protective efficacy of a novel whole-cell vaccine that expressed the DHBV core antigen (DHBcAg). Ducks were vaccinated on day 4 and 14 of age and DHBV challenge was administered 4 days later. Detectable anti-DHBc antibodies were generated as soon as 4 days after the initial vaccination suggesting that this regimen elicited increased immunogenicity than vaccination with DNA vaccines alone. In contrast to the first vaccine study with DNA vaccines expressing DHBsAg, no significant differences in the percentage of DHBV-infected hepatocytes were observed in biopsy tissue collected at day 4 p.i.This finding is confirmation that anti-DHBc antibodies were not neutralising to the initial DHBV inoculum. However, significant protection against development of chronic DHBV infection was observed in the whole-cell vaccinated ducks suggesting that the mechanism of protection was consistent immune-mediated killing of DHBV-infected hepatocytes following CMI responses to determinants of DHBcAg. The final vaccine study involved a combination strategy of antiviral drug Entecavir (ETV) and prime-boost vaccination with DNA vaccines and recombinant fowlpoxvirus (rFPV) expressing DHBV antigens. Immediately following DHBV infection, ducks were dosed by oral gavage with the antiviral drug Entecavir (ETV) and at the same time received the priming DNA vaccines encoding DHBV antigens. Seven days later the boosting vaccination consisting of recombinant fowlpox viruses (rFPV) also expressing DHBV antigens was administered. Extraordinary protection was observed, with 100% of ducks given combination therapy rapidly resolved their DHBV infection while 100% of non-treated ducks developed chronic infection. It was concluded that protection resulted from a combination of at least three factors. First, reduction and control of DHBV levels with the aid of ETV; secondly, stimulation of surface antigen-specific humoral immune responses resulting in neutralisation of newly produced virions; and finally, the combined up-regulation of CMI responses against DHBV core and surface antigens, resulting in elimination of infected hepatocytes. The four manuscripts that comprise this thesis provide insights into the viral kinetics and immune responses that follow DHBV infection and/or vaccination of ducks. The results provide new directions for future vaccine studies aimed at developing effective treatments for chronic HBV infection. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2008

Made available in DSpace on 2015-07-22T20:50:29Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-02-24. Added 1 bitstream(s) on 2015-08-11T03:26:22Z : No. of bitstreams: 1 Publico-211.pdf: 858378 bytes, checksum: 71178d81ebb4262f204851184441f237 (MD5) / A doença hepática foi um evento negligenciado no paciente infectado pelo HIV por muitos anos, principalmente em virtude da alta mortalidade por doenças oportunistas relacionadas á síndrome da imunodeficiência adquirida (aids). Com o advento da terapia antirretroviral de grande atividade (HAART), a mortalidade relacionada às doenças oportunistas caiu substancialmente e a mortalidade por doenças hepáticas emergiu como uma das principais causas de morte não relacionadas à aids. Desde o reconhecimento de seu impacto na morbidade, muitas modificações vêm ocorrendo. Atualmente, os antirretrovirais disponíveis são menos hepatotóxicos, há um melhor entendimento e busca de aperfeiçoamento no tratamento das hepatites virais, novas tecnologias estão disponíveis para seguimento e diagnóstico da doença hepática, bem como novas formas de avaliar a gravidade desses pacientes. Portanto, avaliar o paciente infectado pelo HIV nesse novo “ambiente” se faz necessário. A presente série de estudos revisa tópicos relacionados á doença hepática em pacientes infectados pelo HIV na atualidade. Primeiramente, comparam-se duas novas técnicas diagnósticas para determinação do grau da fibrose hepática: o Impulso Potente por Radiação Acústica comparado a Elastometria Transitória. Demonstra-se boa correlação diagnóstica entre as duas técnicas e utilizando a elastometria transitória, acessamos a incidência de cirrose em pacientes HIV positivos independente da etiologia. Não surpreendentemente, demonstra-se que atualmente os pacientes que atingem o estádio de cirrose hepática são portadores de hepatite C que não receberam tratamento para essa última ou não atingiram a cura quando tratados. Por último, avaliamos a mortalidade entre pacientes cirróticos infectados pelo HIV. Observa-se uma taxa de mortalidade relativamente elevada quando se compara com dados recentes de literatura que avaliam a mortalidade geral em pacientes HIV positivos. Interessantemente, os fatores associados a uma maior mortalidade foram CD4<200, HIV-RNA>50 cópias/mL, grau de fibrose hepática avaliado por elastometria transitória e o MELD. Sendo assim, nota-se que as inovações apresentadas no campo da coinfecção vêm beneficiando de forma importante os pacientes infectados pelo HIV. Contudo, a mortalidade entre pacientes que possuem cirrose estabelecida segue alta e novos caminhos para acessar a gravidade na cirrose hepática devem ser mais explorados no paciente infectado pelo HIV. / TEDE / BV UNIFESP: Teses e dissertações

Made available in DSpace on 2016-01-13T13:27:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-02-27. Added 1 bitstream(s) on 2016-01-13T13:32:51Z : No. of bitstreams: 1 000854163.pdf: 1976046 bytes, checksum: 9b722e3de2741fb27df9024552ccb885 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A vulnerabilidade humana à infecção pelo HIV não é uniforme, fatores virológicos e do hospedeiro são determinantes no risco da transmissão e na evolução natural da infecção. Polimorfismos (do hospedeiro) nos genes KIR estão sendo associados à evolução da infecção pelo vírus. Vários estudos vêm sendo realizados em monoinfectados pelo HIV-1, mas pouco se conhece a respeito da relação desses polimorfismos em coinfecção HIV/VHC. A finalidade deste estudo foi analisar a evolução da infecção pelo HIV em pacientes coinfectados HIV/VHC, baseada em parâmetros clínicos, laboratoriais e virológicos, correlacionando polimorfismos de genes KIR. Foram incluídas no estudo 251 amostras, as quais foram distribuídas em três grupos (Grupo 1: 100 indivíduos monoinfectados HIV-1; Grupo 2: 100 indivíduos monoinfectados VHC e Grupo 3: 51 coinfectados HIV/VHC. As determinações dos subtipos (HIV-1) e genótipos (VHC) foram realizadas por sequenciamento. As definições dos polimorfismos dos genes KIR foram determinados por PCR-SSP e do HLA, por sequenciamento. Dados referentes à evolução da infecção pelo HIV-1 e VHC foram analisados a partir dos prontuários médicos dos pacientes. Os resultados obtidos pelo presente estudo com relação aos genes KIR, 2DL2, 2DS2 e 2DL5, sugerem em caráter inédito a correlação destes polimorfismos com a evolução da infecção pelo VHC em indivíduos coinfectados. A inexistência de correlação dos polimorfismos dos genes KIR com a progressão da infecção pelo HIV-1 em coinfectados sugere que nesta condição, a presença do HIV-1 pode estar influenciando muito mais a progressão da doença pelo VHC do que o desenvolvimento de aids propriamente dito / Human vulnerability to HIV infection is not uniform, virological and host factors are determinants on the risk of transmission and natural infection progression. KIR genes polymorphisms have been being associated with progression of HIV infection. Several studies have been performed in mono-infected by HIV-1, but few knwoledge is known about the relation of these polymorphisms in coinfection by HIV/HCV. The purpose of this study was to assess the increasing of the infection by HIV in patients coinfected HIV/HCV, based on clinical, laboratory and virological parameters and correlating KIR genes polymorphisms. The study included 251 samples which were divided into three groups (Group 1: 100 HIV mono-infected; Group 2: 100 mono-infected HCV; Group 3: 51 Co-Infected HIV/HCV). Determination of subtypes (HIV) and genotypes (HCV) was held using RNA sequencing. Polymorphisms definitions of KIR genes were determined by PCR-SSP and HLA were accomplished out by sequencing. Clinical and laboratory data, regarding the evolution of HIV and HCV infection were analyzed from the medical records of patients. The results obtained by this study concerning KIR, 2DL2, 2DL5 and 2DS2 genes demonstrate the state-of-the-art on the correlation of these polymorphisms with evolution of HCV infection in coinfected individuals. The absence of correlation between the polymorphism of KIR genes with progression of HIV-1 infection in co-infected, suggests that in this particular condition, the presence of HIV-1 may influence much more the disease progression by the HCV than the aids development in itself

Made available in DSpace on 2016-07-01T13:10:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-08-22. Added 1 bitstream(s) on 2016-07-01T13:14:10Z : No. of bitstreams: 1 000866290.pdf: 647674 bytes, checksum: 4f5b629fd7ab086c433234638ac87a25 (MD5) / Introdução: A seroconversão à vacina contra o vírus da hepatite B (VHB) em indivíduos imunocompetentes varia de 90-95% enquanto nos pacientes em hemodiálise varia de 40-80%. Manter níveis adequados de anticorpos contra o VHB nas unidades de diálise é estratégia importante para diminuição do risco de transmissão do VHB e redução da incidência de complicações crônicas da hepatite B. Objetivo: Avaliar os fatores que influenciam a seroconversão do anticorpo anti- HbS, em pacientes vacinados contra o VHB, em diferentes estádios da doença renal crônica (DRC) e nos tratados por hemodiálise (HD) e diálise peritoneal (DP). Pacientes e Métodos: Foram incluídos pacientes maiores que 18 anos, portadores de DRC prevalentes em dezembro de 2011 e incidentes entre janeiro de 2012 e abril de 2014, que receberam o primeiro esquema de vacinação completo contra o VHB. Os pacientes foram divididos em quatro grupos conforme o estádio da DRC e a modalidade de diálise: grupo DRC (pacientes no estádio IV da DRC), grupo Pré-diálise (pacientes no estádio V da DRC), grupo DP (pacientes tratados por DP) e grupo HD (pacientes tratados por HD). Associações entre fatores demográficos, laboratoriais, clínicos, dialíticos e nutricionais com a seroconversão à vacina contra o VHB (anticorpo anti-Hbs >10 UI/dl) foram analisadas por regressão logística univariada e multivariada. Resultados: Foram incluídos 191 pacientes, 72 no grupo HD, 40 no DP, 36 no DRC e 43 no Pré diálise). A média de idade foi de 59,6 ± 15,1 anos; 49,7% eram masculinos, 83,5% da raça branca e 47,6% diabéticos. A porcentagem geral de seroconversão foi de 72,8%, sendo 76,4% para o grupo HD, 67,5% para o grupo DP, 75% para o grupo DRC e 69,8% para o grupo Pré-Diálise (p=0,72). Os fatores independentemente associados à maior chance de seroconversão foram a contagem total de linfócitos (p=0,02) e o ângulo de fase (p= 0,02), considerando a amostra total de... / Introduction: Seroconversion to the vaccine against hepatitis B virus (HBV) in immunocompetent individuals ranges from 90-95% while in hemodialysis patients varies from 40-80%. The maintenance of adequate levels of antibodies against HBV in the dialysis units is an important strategy for reducing the risk of HBV transmission and of incidence of chronic complications of hepatitis B. Objectives: To evaluate the factors influencing seroconversion of antibody anti-HbS in patients vaccinated against HBV in different stages of chronic kidney disease (CKD) and treated by hemodialysis (HD) or peritoneal dialysis (PD). Patients and Methods: We included patients greater than 18 years, patients with CKD prevalent in December 2011 and 2012 incidents between January and April 2014, who received the first full vaccination scheme against HBV. The patients were divided into four groups according to the stage of CKD and dialysis modality: DRC Group (patients in stage IV of the CKD), Pre-dialysis group (patients in stage V of the CKD), HD group (patients treated by HD), and PD Group (patients treated by PD). Associations between demographic, clinical, laboratory, dialytic, and nutritional factors with seroconversion to the vaccine against HBV (antibody anti-HBS > 10 IU/dl) were analyzed by univariate and multivariate logistic regression. Results: A total of 191 patients were included; 72 in the HD, 40 at DP, 36 in the DRC, and 43 in the Pre dialysis group). The average age was 59.6 ± 15.1 years; 49.7% were male, 83.5% of the white race and 47.6% diabetics. The overall percentage of seroconversion was 72.8%; 76.4% for the HD, 67.5% for DP, 75% for the DRC and 69.8% for Pre dialysis group (p = 0.72). The factors independently associated with the greater chance of seroconversion were the total lymphocyte count (p = 0.02) and the phase angle (p = 0.02), considering the total sample of patients; the total lymphocyte count (p = 0.033) and the use of vitamin D ...