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Salvador, BA, Brasil / INTRODUÇÃO: A hepatite B (VHB) é uma infecção dinâmica crônica, que apesar de existir programas de imunização e tratamento antiviral disponível, existe o risco de emergência de mutações de resistência aos análogos de núcleos(t)ídeos (AN) que devem ser rastreadas, devido as suas implicações clínicas. O Brasil disponibiliza pelo SUS cinco drogas para o tratamento antiviral: IFN, LAM, ADF, ETV e TDF e um guia de conduta clínica para orientar o tratamento no território nacional, o Protocolo de Diretrizes Terapêuticas para Hepatite B e co-infecções. OBJETIVO: O objetivo do presente estudo foi avaliar as mutações de resistência aos AN, mutações de escape vacinal e genótipos circulantes em pacientes com hepatite B crônica em dois centros de referencia em Hepatites, na Bahia (região Nordeste) e no Acre (região Norte) do Brasil. MATERIAL E MÉTODOS: Foi utilizadas ferramentas de biologia molecular e bioinformática, através de nested PCR e sequenciamento direto das amostras, para rastrear as mutações de resistência, a região alvo foi a transcriptase reversa (RT) do gene P e as mutações de escape vacinal foi a região do gene S do VHB, como também os genótipos e subgenotipos do VHB. RESULTADOS: Foram incluídos 527 pacientes durante o período de 2011-2015, sendo 320 pacientes do HUPES/BA e 207 do FUNDHACRE/AC. Os pacientes que representam a região Nordeste foram 59,3 % do sexo masculino e uma média de idade de 44,75±12,4 DP, os pacientes da região Norte 42% foram do sexo masculino e a média de idade foi de 40,36±13,9 DP. Todos os pacientes incluídos apresentaram AgHBs persistente por mais de seis meses e 86,1% apresentaram AgHBe negativo. Foram sequenciadas 296 amostras dos pacientes com VHB crônica. Foram encontradas mutações de resistência aos AN na Região Norte 1,2% (2), Região Nordeste 7,4%(8) e no global 3,8%(20). Os padrões de mutações de resistência primária encontrados foram: rtA194T, (3) rtL180M+M204V, rtL180M+M204I, rtS202I, rtM204I, rtA181S, rtA181E e rtA184S. Em relação ao escape vacinal a frequencia para a Região Norte foi de 7,1% (11), Região Nordeste 8,4% (9) e no global 7,6% (20). Nos pacientes virgens de tratamento (n=189), a frequência de mutações de resistência foi de 6%, somente nas amostras da região Nordeste. Não houve diferença estatisticamente significante entre o grupo com ou sem mutação dos pacientes virgens de tratamento. Não foram encontradas mutações de resistência nas amostras da região Norte. Os genótipos circulantes nas duas regiões foram A, D e F, e a região Nordeste foi encontrada o genótipo C (C2). CONCLUSÃO: Os resultados demonstram a importância de rastrear e monitorar as mutações de resistência aos AN e de escape vacinal devido a importância epidemiológica e clínica na conduta terapêutica. / INTRODUTION: Hepatitis B virus (HBV) is a chronic dynamic infection, which although there immunization programs and antiviral therapy available, there is a risk of emergence of resistance mutations cores analogs (t) ide to be screened, because of their implications clinics. The Brazil offers the SUS five drugs for antiviral treatment: IFN, LAM, ADF, ETV and TDF and clinical guide of conduct to guide treatment in the country, the Therapeutic Guidelines Protocol for Hepatitis B and co-infections. AIM: The aim of this study was to evaluate the resistance mutations core analogues (t) ide, vaccine escape mutations and circulating genotypes in patients with chronic hepatitis B in two reference centers in Hepatitis, Bahia (Northeast) and Acre (Northern region) of Brazil. MATERIAL AND METHODS: Was used tools of molecular biology and bioinformatics by nested PCR and direct sequencing of samples to track resistance changes, the target region is the reverse transcriptase (RT) P gene and vaccine escape mutations was region of the gene S of HBV, as well as the HBV genotypes and subgenotipos. RESULTS: 527 patients were included during the period 2011-2015, with 320 patients HUPES / BA and 207 FUNDHACRE / AC. Patients representing the Northeast were 59.3% male and an average age of 44.75 ± 12.4 PD patients in the northern region 42% were male and the average age was 40, 36 ± 13.9 DP. All patients had persistent HBsAg for more than six months and 86.1% were HBeAg negative. We were sequenced 296 samples from patients with chronic HBV. the cores of similar resistance mutations were found (t) ide in the North 1.2% (2), Northeast 7.4% (8) and 3.8% overall (20). The patterns of primary resistance mutations were: rtA194T (3) rtL180M + M204V, M204I + rtL180M, rtS202I, rtM204I, rtA181S, and rtA181E rtA184S. Regarding vaccine escape the frequency for the Northern Region was 7.1% (11), Northeast 8.4% (9) and the global 7.6% (20). In treatment-naïve patients (n = 189), the frequency of resistance mutations was 6%, only the samples in the Northeast. There was no statistically significant difference between the groups with or without mutation of naive patients. There were no resistance mutations in samples from the North. Circulating genotypes in the two regions A, D and F, and the Northeast found the C genotype (C2). CONCLUSION: The results demonstrate the importance of tracking and monitoring the resistance mutations similar cores (t) ide and vaccine escape due to epidemiological and clinical importance in the therapeutic approach.

Introdução: A vacinação contra a hepatite B, aliada às precauções padrão, é um importante instrumento para a prevenção deste agravo em profissionais de saúde, que podem sofrer exposição a material biológico potencialmente contaminado. Objetivos: Estimar a cobertura da vacinação contra a hepatite B, a prevalência de imunizados e de exposição ocupacional a material biológico por acidentes perfurocortantes nos profissionais de saúde do município de Santa Rosa/RS/Brasil. Metodologia: Foram pesquisados, através de um estudo transversal, 322 profissionais de saúde que atuam em hospitais, no banco de sangue e nas unidades de saúde (Médicos, Enfermeiros, Técnicos e Auxiliares de Enfermagem, Odontólogos, Auxiliares de Consultório Dentário (ACD), Farmacêuticos e Auxiliares de Laboratório). A significância estatística das associações foi avaliada usando-se o teste de qui-quadrado para a comparação de variáveis categóricas, e regressão logística para a análise multivariável. Resultados: A média de idade dos entrevistados foi de 38,1 anos, com média de 13 anos de atuação na profissão. 24,8% eram do sexo masculino e 75,2 do sexo feminino. A cobertura vacinal nestes profissionais foi de 87,9% (IC 95% 83,8 a 91,2%). As coberturas de vacinação foram maiores em profissionais com nível médio e que não atuam em hospitais. A taxa de acidentabilidade com instrumento perfurocortante foi de 40,5% na amostra. A prevalência de imunizados com testagem realizada até 6 meses foi de 78,8%. Conclusão: A cobertura de vacinação e a prevalência de imunizados foram inferiores ao preconizado pelo Ministério da Saúde e Centers for Diseases Control and Prevention. Há necessidade de maiores investimentos na prevenção da infecção ocupacional pelo vírus da hepatite B para esses profissionais. / Introduction: The vaccination against hepatitis B, together with standard precautions, is an important tool for the prevention of this disease in health professionals, who can suffer exposure to biological potentially contaminated. Goals: Estimate the coverage of vaccination against hepatitis B, the prevalence of immunized and the occupational exposure to biological material from perforating injuries in health professionals located in city of Santa Rosa/RS/Brazil. Methodology: 322 health professionals who work in hospitals, in blood bank and in health services (Phisicians, Nurses, Technicians and Assistants in Nursing, Dentists, Dental Office Assistants (DOA), Pharmacists and Laboratory Assistants) were investigated, through an cross-sectional study. The statistic significance of the associations was evaluated by using the chi-square test to compare categorical variables and logistic regression for multivariable analysis. Results: The interviewed are, on average, 38,1 years old, and have been working in the profession for around 13 years. 24,8% werw male and 75,2 female. The vaccination in those professional was 87.9% (IC 95% 83.8 to 91.2%). The vaccination was larger in professionals with high school and that do not work in hospitals. The rate of injury due perforating instrument was 40.5% in the sample. The prevalence on immunized with testing performed up to 6 months was 78.8%. Conclusion: The vaccination and the prevalence of immunization were below the recommended by Brazilian Ministry of Health and Centers for Diseases Control and Prevention. More investments in the prevention of occupational infection by Hepatitis B virus for those professionals are necessary.

Introdução: A vacinação contra a hepatite B, aliada às precauções padrão, é um importante instrumento para a prevenção deste agravo em profissionais de saúde, que podem sofrer exposição a material biológico potencialmente contaminado. Objetivos: Estimar a cobertura da vacinação contra a hepatite B, a prevalência de imunizados e de exposição ocupacional a material biológico por acidentes perfurocortantes nos profissionais de saúde do município de Santa Rosa/RS/Brasil. Metodologia: Foram pesquisados, através de um estudo transversal, 322 profissionais de saúde que atuam em hospitais, no banco de sangue e nas unidades de saúde (Médicos, Enfermeiros, Técnicos e Auxiliares de Enfermagem, Odontólogos, Auxiliares de Consultório Dentário (ACD), Farmacêuticos e Auxiliares de Laboratório). A significância estatística das associações foi avaliada usando-se o teste de qui-quadrado para a comparação de variáveis categóricas, e regressão logística para a análise multivariável. Resultados: A média de idade dos entrevistados foi de 38,1 anos, com média de 13 anos de atuação na profissão. 24,8% eram do sexo masculino e 75,2 do sexo feminino. A cobertura vacinal nestes profissionais foi de 87,9% (IC 95% 83,8 a 91,2%). As coberturas de vacinação foram maiores em profissionais com nível médio e que não atuam em hospitais. A taxa de acidentabilidade com instrumento perfurocortante foi de 40,5% na amostra. A prevalência de imunizados com testagem realizada até 6 meses foi de 78,8%. Conclusão: A cobertura de vacinação e a prevalência de imunizados foram inferiores ao preconizado pelo Ministério da Saúde e Centers for Diseases Control and Prevention. Há necessidade de maiores investimentos na prevenção da infecção ocupacional pelo vírus da hepatite B para esses profissionais. / Introduction: The vaccination against hepatitis B, together with standard precautions, is an important tool for the prevention of this disease in health professionals, who can suffer exposure to biological potentially contaminated. Goals: Estimate the coverage of vaccination against hepatitis B, the prevalence of immunized and the occupational exposure to biological material from perforating injuries in health professionals located in city of Santa Rosa/RS/Brazil. Methodology: 322 health professionals who work in hospitals, in blood bank and in health services (Phisicians, Nurses, Technicians and Assistants in Nursing, Dentists, Dental Office Assistants (DOA), Pharmacists and Laboratory Assistants) were investigated, through an cross-sectional study. The statistic significance of the associations was evaluated by using the chi-square test to compare categorical variables and logistic regression for multivariable analysis. Results: The interviewed are, on average, 38,1 years old, and have been working in the profession for around 13 years. 24,8% werw male and 75,2 female. The vaccination in those professional was 87.9% (IC 95% 83.8 to 91.2%). The vaccination was larger in professionals with high school and that do not work in hospitals. The rate of injury due perforating instrument was 40.5% in the sample. The prevalence on immunized with testing performed up to 6 months was 78.8%. Conclusion: The vaccination and the prevalence of immunization were below the recommended by Brazilian Ministry of Health and Centers for Diseases Control and Prevention. More investments in the prevention of occupational infection by Hepatitis B virus for those professionals are necessary.

Orientadores: Fernando Lopes Gonçales Junior, Neiva Sellan Lopes Gonçales / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-08T15:36:18Z (GMT). No. of bitstreams: 1 Jardim_RuthNogueiraCordeirodeMoraes_M.pdf: 4267075 bytes, checksum: e1769c6758a1c8847d53c93bc31bd35a (MD5) Previous issue date: 2006 / Resumo: A infecção oculta pelo VHB é caracterizada pela presença do DNA-VHB em indivíduos com o antígeno de superfície (HBsAg) indetectável. A prevalência e significado clínico desta infecção ainda não são totalmente conhecidos. Este trabalho teve por objetivo determinar a prevalência de infecção oculta pelo VHB em dois grupos de pacientes imunossuprimidos (pacientes em tratamento por hemodiálise e pacientes HIV positivos) com anti-HBc positivo co-infectados ou não pelo vírus da hepatite C (VHC). Foi investigada uma possível correlação entre prevalência do DNA-VHB e carga viral, níveis de CD4, fatores de risco e administração de lamivudina no grupo de HIV positivos. O primeiro grupo (G1) foi formado por 34 pacientes hemodialisados que eram HBsAg negativo/anti-HIV negativo. O segundo grupo (G2) formado por 159 pacientes infectados pelo vírus da imunodeficiência humana (anti-HIV positivo) e HBsAg negativo. Foi utilizado como grupo controle (G3), 150 doadores de sangue com marcadores sorológicos negativos para o HBsAg e para o HIV, mas reagentes para o anti-HBc. A pesquisa do DNA do VHB foi realizada pela PCR ?in house? , segundo a técnica de Kaneko et al. (1989), utilizando-se ?primers? específicos da região do core do VHB (limite de detecção 100 cópias/ml). Entre os pacientes hemodialisados, a infecção oculta não esteve presente, talvez devido ao controle da infecção pelo VHB nestes centros, pela adoção das medidas de precauções universais e imunização específica por vacinação contra o VHB que possivelmente, foram eficazes para evitar a presença de infecção oculta pelo VHB. A prevalência de positividade do VHB-DNA entre os pacientes HIV positivos foi de 5,03% (8/159). Este dado mostrou que não houve diferença significativa entre o grupo HIV positivo e o grupo controle (5,03% x 4%). De acordo com estes resultados, provavelmente, a imunossupressão nestes pacientes HIV positivos não foi fator determinante na prevalência de infecção oculta. O DNA-VHB foi observado independente da presença do anti-HBs nos pacientes HIV positivos coinfectados ou não pelo VHC. Esta observação sugere que o anti-HBs não foi capaz de proteger, na totalidade, os pacientes. A prevalência de infecção oculta pelo vírus da hepatite B não foi diferente entre os grupos estudados, HIV positivos e doadores de sangue. Não foi observada associação entre contagem de CD4, carga viral, fator de risco e nem à utilização da lamivudina como parte do tratamento anti-retroviral e ocorrência de hepatite B oculta / Abstract: Occult hepatitis B virus infection is characterized by presence of HBV-DNA in individuals with undetectable hepatitis B surface antigen (HBsAg). The prevalence and clinical significance of this infection remain incompletely defined. The aim of this study was to determinate the prevalence of occult HBV infection between two immunosuppressed populations (maintenance haemodialysis patients and HIV positive patients) with anti-HBc positive, co-infected or not with hepatitis C virus (HCV). Possible correlations were investigated between prevalence of HBV-DNA, viral load, CD4 levels, risk factors and lamivudina administration in the HIV group. The first group (G1) was formed by 34 hemodialysed patients that were HBsAg negative/anti-HIV negative. The second group (G2) formed by 159 human immunodeficiency virus infected patients (anti- HIV positive) and HBsAg negative. Used as a control group (G3), 150 blood donors with serologic markers negative to HBsAg and HIV, but positive for anti-HBc. HBV-DNA testing was performed using ?in house? nested PCR as described by Kaneko et al. and was detected using specific primers derivated from core regions of HBV genome (detection limit 100 copies / ml). Occult hepatitis B virus infection was absent in hemodialysis patients may be due the control of HBV infection in these centers, by adoption universal precautions measures and specific immunization by hepatitis B vaccination perhaps were effective to avoid occult HBV infection. The prevalence of HBV-DNA in HIV positive patients was 5,03% (8/159). This data showed that there was not significant difference between group HIV positive and control (5,03% x 4%). According these results probably the Immunosuppression in this HIV positive patients were not a determinant factor in prevalence of occult infection. The HBV-DNA was observed independent the presence of anti-HBs in HIV positive patients co-infected or not by HCV. This observation suggest that anti-HBs was not able to protect in the totality this patents. The prevalence of occult hepatitis B virus infection was not different among the group studied HIV positive patients and blood donors. It was not observed association between CD4 cell count, viral load, risk factor or treatment antiretroviral with lamivudine and occurrence of occult hepatitis B / Mestrado / Ciencias Basicas / Mestre em Clinica Medica

Made available in DSpace on 2015-04-11T13:55:03Z (GMT). No. of bitstreams: 1 Monica Moresco.pdf: 1380196 bytes, checksum: a4c9d499289cc3b851dcc2691af82caf (MD5) Previous issue date: 2012-10-30 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A epidemiologia da infecção pelo vírus da hepatite B (VHB) demonstra uma distribuição diversificada no mundo, afetando cerca de 2 bilhões de pessoas com alta frequência de infecção crônica. A segurança transfusional depende da avaliação clínico-epidemiológica apropriada de candidatos à doação de sangue e do uso de testes de seleção adequados para excluir e evitar a transmissão de agentes infecciosos tais como o VHB. A ocorrência de infecção oculta pelo VHB em doadores de sangue assintomáticos abriu uma nova lacuna a ser preenchida principalmente em hemocentros de regiões de alta prevalência como na Amazônia brasileira, que são desafiados a buscar estratégias de garantia de estoques considerando o alto impacto do descarte de hemocomponentes anti-HBc reativos. Este estudo buscou analisar nas doações de sangue do interior do estado do Amazonas a presença da infecção oculta pelo vírus da hepatite B em amostras anti-HBc total positivas com ou sem o marcador anti-HBs. A população de estudo foi composta por candidatos à doação de sangue que se apresentaram nas Unidades de Coletas Transfusionais (UCT s) nas regionais de saúde do Baixo Amazonas, Entorno de Manaus, Médio Amazonas, Rio Negro e Solimões e Triângulo, no período de junho/2011 a junho/2012. Foram analisados dois grupos de doadores negativos para HBsAg: os que apresentaram reatividade para anti-HBc com e sem a presença do anti-HBs. Foram utilizados métodos sorológicos qualitativos e quantitativos dos marcadores para a infecção e moleculares para detecção e quantificação da carga viral do DNA-VHB. A prevalência do anti-HBc total reativo no interior do estado do Amazonas entre os doadores de sangue foi de 24,4%. Foram analisadas 179 amostras anti-HBc reativas e HBsAg negativas, destas, 04 foram positivas para o DNA-VHB, caracterizando infecção oculta pelo vírus B com uma prevalência de 2,2%. Das 179 amostras, 03 apresentaram anti-HBs ≥100 mUI/mL, indicando que o marcador protetor mesmo em altos títulos não evidencia a ausência do vírus. Não houve correlação entre os títulos do anti-HBs e anti-HBc com a carga viral encontrada. A maior frequência dos doadores foi do sexo masculino com 90% em ambos os grupos de estudo e não houve relato de exposição aos fatores clássicos de risco para a infecção entre os doadores com DNA-VHB. A evidência da presença de IOB entre os doadores de sangue do interior do Estado do Amazonas abre espaço para discussão das melhores estratégias a serem utilizadas na triagem de doadores de sangue em regiões de alta prevalência e de perfil de transmissão peculiar como o caso da Amazônia. Atualmente, tanto os testes de triagem sorológica, quanto o teste NAT precisam ser redesenhados no intuito de aprimorar as estratégias de controle da transmissão transfusional buscando um algoritimo balanceado entre a rejeição de doadores potenciais, descarte de unidades, razões econômicas e segurança desejada.

Background The Hepatitis B Virus (HBV) is a blood-borne infection affecting around 2 billion people at any given time and is commonly transmitted through Mother to Child Transmission (MTCT). Preventative measures include vaccinations, particularly the timely Birth Dose (TBD) given within 24 hours of birth. Timing is crucial for the efficacy of the TBD, and is influenced by various factors. São Tomé and Príncipe is one of seven sub-Saharan African countries with a TBD policy. This study aims to observe the different proportions of children receiving adequate or inadequate vaccinations against HBV, as well as to analyse the risk factors that may lead to inadequate vaccination. Methods Secondary data from the São Tomé and Príncipe Demographic Health Survey from 2008-2009 was analysed in this study. Dose delays for all children and those at risk were described. An associative analysis looked at the potential risk factors for inadequate TBD vaccination. Results A high coverage rate for vaccinations was found (>85%), however, the majority were delayed, with only 1% and 4% on time, and mean a TBD administration of 2(SD±2) months after birth, in all children, versus children at risk. Children born to mothers with positive HBV status and low wealth were significantly more likely to receive the TBD on time. Conclusion The majority of vaccinations, including the TBD were inadequately administered, denoting a concern of transmission to children born at risk. Additionally, socioeconomic factors were found to be factors influencing the provision of the TBD

Les traitements actuels contre le virus de l’hépatite B (VHB) combinent un ou plusieurs analogues de nucléos(t)ides qui inhibent directement la réplication virale en bloquant l’étape de transcription inverse. Ces traitements très efficaces sont pourtant confrontés à l’émergence de virus résistants à ces traitements. Ces résistances sont la conséquence de l’émergence et la sélection de mutants parfois complexes présentant des mutations à la fois dans le gène de la polymérase (pol) et de l’enveloppe virale. Les objectifs principaux de ce doctorat ont été d’étudier la sensibilité des variants résistants du VHB vis-à-vis d’analogues de nucléos(t)ides et de nouveaux composés nonnucléos(t)idiques agissant contre la nucléocapside, mais également de comparer les performances virales de différents mutants afin de comprendre le processus de sélection des mutants qui s’opère chez le patient sous pression thérapeutique. Ces études ont caractérisé la sensibilité de certaines mutations de résistance aux analogues de nucléos(t)ides, de souligner l’importance des modifications de l’enveloppe dues aux mutations de résistance dans le processus d’émergence et de sélection des variants dans la quasi-espèce virale et d’identifier de nouvelles molécules antivirales efficaces permettant, en combinaison avec les analogues de nucléos(t)ide, de diminuer fortement les phénomènes de résistance du VHB. Mieux comprendre les phénomènes de résistance, les procédés d’émergence, de sélection et de transmission des mutants du VHB pour élaborer les meilleures stratégies cliniques de combinaisons thérapeutiques peut réduire considérablement le nombre de personnes touchées par ce virus / Current therapies against the hepatitis B virus (HBV) combine one or more nucleoside analogues that directly inhibit viral replication by blocking reverse transcription step. These treatments are very effective, however, faced with the emergence of viruses resistant to these treatments. These resistances are the result of the emergence and selection of mutants with mutations can be complex in both the polymerase gene (pol) and the viral envelope. The main objectives of this PhD was to study the sensitivity of resistant HBV variants vis-à-vis similar nucleos(t)ides and new compounds non-nucleos(t)idic acting against the nucleocapsid, but also compare the performance of different viral mutants to understand the process of selection of mutants that occurs in patients under therapeutic pressure. These studies have characterized the sensitivity of some resistance mutations to nucleoside analogues, to highlight the importance of the envelope changes due to resistance mutations in the process of emergence and selection of variants in the quasispecies virus and to identify new effective antiviral drugs may allow, in combination with nucleoside analogues, to greatly reduce the phenomenon of HBV resistance. Better understanding the phenomenon of resistance, the processes of emergence, selection and transmission of HBV mutants to develop the best clinical strategies of combination therapy can significantly reduce the number of people affected by this virus

L’hépatite B, causée par le virus de l’hépatite B (VHB), est responsable d’un à deux millions de morts chaque année dans le monde. Le VHB occasionne des lésions importantes au niveau du foie, pouvant amener à la cirrhose et au carcinome hépatocellulaire. Ce virus, de la famille des hepadnavirus, contient une capside formée de 240 copies d’une même protéine : la protéine core. Des biopsies de patients infectés par le VHB montrent que la protéine de capside se localise soit dans le noyau soit dans le cytoplasme des cellules infectées. On s’accorde à dire qu’une localisation majoritairement cytoplasmique est liée à une aggravation de la maladie. Nous avons observé que, dans des cellules HuH-7, la protéine core seule est nucléaire alors qu’en contexte viral, elle se localise dans le cytoplasme. Après avoir vérifié que nos observations ne sont pas dues aux conditions de culture des cellules, nous avons démontré que la relocalisation de core est due à des facteurs viraux : la polymérase virale grâce à son domaine TP ainsi que la Tige/Boucle  présente sur l’ARN prégénomique. La localisation de core est aussi influencée par l’état de phosphorylation de ses sérines 157, 170 et 172.Ainsi, nous avons pu montrer à quel point le trafic de core était complexe et qu’il était régulé par divers facteurs viraux et cellulaires. Ces travaux permettront une étude plus approfondie des régulations du trafic intracellulaire de la protéine core et ainsi de faire évoluer plus favorablement l’hépatite B chez les patients infectés. / Hepatitis B is a liver inflammation caused by the Hepatitis B virus (HBV). It is responsible of one to two millions deaths per year in the world. HBV is the cause of important liver damages and may lead to cirrhosis and hepatocellular carcinoma.HBV is a member of hepadnaviral family. It has a capsid composed of 240 copies of the same protein: the core protein. In literature, patients’ biopsies showed that capsid is found either in the nucleus or in the cytoplasm or both compartments of hepatocytes. In general, a cytoplasmic localization is related to an advanced state of the disease.In our study, we observed that in HuH-7 cells, core protein alone has a nuclear localization, whereas in viral context it is essentially found in the cytoplasm. We verified that these observations were not due to culture conditions. Then, we demonstrated that the cytoplasmic localization of core was due to viral factors. The viral polymerase is implied by its TP domain. The second component is the viral pregenomic RNA, by its Epsilon stem loop structure. At last, core localization is also influenced by the phosphorylation state of its serines 157, 170 and 172.Thus, we demonstrated that the core protein traffic is very complex and regulated by different viral and cellular factors. This work will further study the regulation of intracellular trafficking of the core protein and allow a better outcome for the infected patients.

L'épidémiologie des infections sexuellement transmissibles (IST) à Mayotte est peu documentée notamment chez les femmes enceintes (FE) et la connaissance des déterminants favorisants les IST sur l'île dans un contexte socio-économique et sanitaire très particulier est nécessaire. Les objectifs de ce travail étaient d'estimer les fréquences et facteurs de risque associées au VIH, au VHB, et à la syphilis, d'étudier la vaccination anti-VHB et de décrire les connaissances, attitudes, croyances et comportements liées aux VIH/SIDA-IST chez les FE. Une étude transversale prospective a été réalisée auprès de 671 FE suivies dans les centres de Protection Maternelle et Infantile (PMI) de Mayotte. Aucun cas de séropositivité au VIH n'a été observé. La prévalence de l'antigène HBs du VHB était de 3,4% et celle de la syphilis active était de 2,1%, mais la prévalence de l'infection au VHB et de la vaccination anti-VHB était respectivement de 35.5% et 18.6%. L'infection par le VHB était associée au lieu de naissance (Comores), à des facteurs comportementaux et à des antécédents d'IST. La syphilis était plutôt associée au manque d'éducation et aux antécédents d'IST. La vaccination anti-VHB était associée à des déterminants sociodémographiques. L'étude socio-comportementale a montré qu'il existe une bonne connaissance du VIH/SIDA-IST chez les FE malgré la pratique de certains comportements sexuels à risque. Ce travail a permis de dresser un état des lieux du VIH et des IST, et de leurs déterminants chez les femmes enceintes à Mayotte, et permettra la mise en place de méthodes de prévention adaptées à ce contexte / The epidemiology of sexually transmitted infections (STIs) is poorly documented in Mayotte especially among pregnant women (PW) and knowledge of determinants that increased STI in the island, and in this particular socio-economic and health situation, is needed. The objectives of this study were to estimate the frequency and risk factors associated with HIV, HBV, and syphilis, to study the HBV vaccination and describe the knowledge, attitudes, beliefs and behaviors related to HIV/AIDS-STIs in PW. A prospective cross-sectional study was conducted among 671 PW followed in Mayotte public prenatal clinic (Protection Maternelle et Infantile (PMI)) services. No case of HIV seropositivity was observed. The prevalence of HBsAg of HBV was 3.4% and of active syphilis was 2.1%, but the prevalence of HBV infection and HBV vaccination was respectively 35.5% and 18.6%. The HBV infection was associated with birthplace (Comoros), behavioral factors and history of STIs. Syphilis was rather associated with lack of education and history of STIs. The HBV vaccination was associated with sociodemographic determinants. The socio-behavioral study showed that there is a good knowledge of HIV/AIDS-STIs in PW despite the practice of some risky sexual behaviors. This work has helped to draw up an update of HIV and STIs, and their determinants among PW in Mayotte, and could lead to the development of prevention methods adapted to this context

The clearance of viruses is largely dependent upon the activation of T cells to generate a robust immune response. However, host responses are suppressed during chronic viral infections. In this thesis, we explored the role of Top2α in DNA topology in individuals with chronic HBV, HCV, and HIV infections. We found that Top2α protein expression and activity were low in T cells derived from chronically virus-infected individuals compared to healthy subjects. Using CD4+ T cells treated with Top2α inhibitor or poisoner as a model, we demonstrated that Top2α inhibition disrupts the DNA topology, suppresses DNA repair kinase (ATM), and telomere protein (TRF2) expression, and induces T cell dysfunction. These findings reveal that Top2α inhibition is a mechanism by which viruses evade the host responses and establish persistent infection, and thus, restoring Top2α levels could be a way of boosting immune responses during chronic viral infections.