Submitted by Marlene Santos (marlene.bc.ufg@gmail.com) on 2014-11-04T19:15:44Z No. of bitstreams: 2 Dissertação - Natália Alberto Alves Brandão.pdf: 2752228 bytes, checksum: f1f4834b88d60df4f5620fe3e16ff30d (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Jaqueline Silva (jtas29@gmail.com) on 2014-11-05T09:19:23Z (GMT) No. of bitstreams: 2 Dissertação - Natália Alberto Alves Brandão.pdf: 2752228 bytes, checksum: f1f4834b88d60df4f5620fe3e16ff30d (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2014-11-05T09:19:23Z (GMT). No. of bitstreams: 2 Dissertação - Natália Alberto Alves Brandão.pdf: 2752228 bytes, checksum: f1f4834b88d60df4f5620fe3e16ff30d (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2013-05-06 / Hepatitis B and C viruses are responsible for the most common chronic viral infections worldwide. The prevalence of these viruses is higher among HIV-infected individuals, due to common route of transmission. Coinfections HBV / HIV and HCV / HIV seems to be associated with a worst liver disease prognosis. Studies evaluating these coinfections in the mid-western Brazil are scarce. Objectives: To estimate the prevalence and the risk factors associated with HBV and HCV coinfections in HIV-positive patients in Goiânia – Goiás. Methods: A cross-sectional study was conducted including 495 adults, recruited from the Centro de Referência em Diagnóstico e Terapêutica de Goiânia in 2011. After signing the informed consent, participants were interviewed and material was collected for research markers for HBV (anti-HBc, HBsAg, anti-HBs and HBV DNA) and HCV (anti-HCV and HCV RNA). Prevalence of HBV and HCV infection was estimated. Univariate and multivariate analysis to evaluate factors associated with positivity for both viruses were performed. Odds and adjusted odds ratios were calculated with 95% confidence intervals (CI95%) and a significance level of p<0.05. Results: Participants mean age was 40.2 years (standard deviation =10. 4) with a male predominance (73.9%). Injecting drugs usage was reported by 3.6% of participants. The prevalence of markers for hepatitis B exposure was 33.5% (CI95% 29.4-37.9). Nineteen patients (3.8%, CI95% 2.4-6.0) were diagnosed as hepatitis B carriers. Prevalence of anti-HCV was 9.7% (CI95% 7.3-12.7). The distribution of HCV genotypes was: 1a (72.7%), 3 (13.6%) and 1b (9.1%). Coinfection by the three viruses was 4.4% (CI95% 2.9-6.8). Male, age ≥ 40 years, previous history of sexually transmitted disease (STD) and homo or bisexuality were associated with exposure to HBV. History of injecting drugs and STD were associated with HCV seropositivity. Over half of the coinfected patients were not aware of being HBV or HCV positive. Conclusion: Seromarkers for previous HBV and/or HCV infections are common among individual HIV positives in Goiânia. A significant proportion of them are unaware of their serological status. These findings suggest the need for better screening and guidance improvements for this population / Os vírus das hepatites B (HBV) e C (HCV) são responsáveis pelas infecções crônicas virais mais comuns em todo o mundo. A prevalência dessas infecções é maior entre indivíduos infectados pelo HIV, devido às vias comuns de transmissão desses vírus. As coinfecções HBV/HIV e HCV/HIV parecem estar associadas a um pior prognóstico da doença hepática. Estudos avaliando essas coinfecções, na região centro-oeste do Brasil, são escassos. Objetivos: Estimar a prevalência e analisar fatores sócio-demográficos e comportamentais associados às infecções pelo HBV e HCV em pacientes HIV positivos. Métodos: Estudo transversal, com inclusão de 495 pacientes adultos, recrutados no Centro de Referência em Diagnóstico e Terapêutica de Goiânia, em 2011. Após assinatura do termo de consentimento livre e esclarecido, os participantes foram entrevistados e coletouse material para pesquisa de marcadores para o HBV (anti-HBc, HBsAg, anti-HBs e HBV DNA) e HCV (anti-HCV e HCV RNA). Estimou-se a prevalência das infecções pelo HBV e HCV. Foi realizada análise uni e multivariada para avaliar fatores associados com a positividade para os dois vírus. Foram calculados os Odds Ratios brutos e ajustados com respectivos intervalos de 95% de confiança (IC95%) e nível de significância de p<0,05. Resultados: A média de idade dos participantes foi de 40,2 anos (desvio padrão=10,4), com predomínio de homens (73,9%). O relato de uso de drogas injetáveis foi feito por 3,6% dos participantes. A prevalência de exposição ao vírus da hepatite B foi de 33,5% (IC95% 29,4-37,9). Dezenove pacientes (3,8%, IC95% 2,4-6,0) foram diagnosticados como portadores do vírus da hepatite B. A prevalência de anti-HCV foi 9,7% (IC95% 7,312,7). A distribuição dos genótipos do HCV nessa população foi: 1a (72,7%), 3 (13,6%) e 1b (9,1%). A coinfecção pelos três vírus foi de 4,4% (IC95% 2,9-6,8). Sexo masculino, idade ≥ 40 anos, relato de doença sexualmente transmissível (DST) e homo ou bissexualismo mostraram-se associados à presença de marcadores de exposição ao HBV. Antecedentes de drogas injetáveis e DST mostraram associação com soropositividade para HCV. Cerca da metade dos pacientes coinfectados não sabia ser HBV ou HCV positivos. Conclusões: Marcadores de exposição prévia ao HBV e ao HCV são frequentes entre os pacientes HIV positivos, em Goiânia. Uma parcela significativa dessa população desconhece seu status sorológico, sugerindo a necessidade de medidas de triagem e de orientação mais efetivas.

Introducción: La prevalencia de tuberculosis (TB) siempre se ha mantenido como un problema de salud pública a nivel mundial, sin embargo, con la aparición de la enfermedad del coronavirus (COVID-19) y su alto índice de contagios, ha causado que la problemática se vea acrecentada considerablemente. La similitud entre los síntomas de ambas enfermedades puede causar un mal diagnóstico, por ende, un tratamiento inadecuado hacia este grupo de pacientes, aumentando los índices de mortalidad entre ellos. Los valores de laboratorio pueden dar un indicio de la COVID-19, sin embargo, los medicamentos contra la TB pueden causar irregularidades en los mismos. Objetivo: Describir la evolución clínica y de laboratorio de los pacientes con comorbilidad de tuberculosis que contrajeron COVID-19 en Lambayeque. Material y Métodos: Estudio de tipo descriptivo, no experimental, transeccional y retrospectivo, con una muestra censal de 32 historias clínicas. Se recolectaron los datos clínicos y de laboratorio referentes a casos de coinfección de TB y COVID-19 mediante la revisión y observación de historias clínicas. Conclusiones: Respecto a la evolución clínica y de laboratorio de los pacientes con coinfección COVID-19 y TB, el 84,4 % de ellos lograron sobrevivir, mientras que el 56,3 % presentó anemia leve, el 93,8 % presentó leucocitosis y el 81,3 % presentó linfocitosis durante la enfermedad.

Pour faire face à des perturbations environnementales, les organismes ont développé des défenses antitoxiques couramment utilisés comme biomarqueurs dans l'évaluation de la qualité des milieux. Cependant, de nombreux facteurs confondants comme la température ou le genre, influencent la réponse de ces biomarqueurs. Il est ainsi nécessaire de connaitre les effets de ces facteurs afin d'imputer correctement la réponse biologique mesurée à la présence de polluants. Dans ce contexte, nous avons choisi d'étudier l'influence d'un parasite acanthocéphale, Polymorphus minutus, transmis horizontalement et de microsporidies à transmission verticale, sur les réponses physiologiques de leur hôte, Gammarus roeseli, un crustacé amphipode d'eau douce d'intérêt écotoxicologique. Pour cela, nous avons choisi d'étudier le glutathion, tripeptide jouant un rôle central dans les systèmes antitoxiques, sa synthèse (i.e. activité gamma-glutamylcystéine ligase), les réserves énergétiques (i.e. lipides, glycogène, protéines) et un biomarqueur d'effets toxiques, le malondialdéhyde. L'influence du parasitisme a été appréhendé dans différents cas d'études: (i) chez G. roeseli infecté par P. minutus, (ii) chez G. roeseli infecté par des microsporidies (Dictyocoela roeselum essentiellement) et (iii) chez G. roeseli co-infecté par ces deux types de parasite. Chaque cas d'étude a été réalisé en absence de stress et lors d'une exposition au cadmium. Nous avons mis en évidence qu'en absence de contamination, la présence de P. minutus et une co-infection par P. minutus et D. roeselum affectent les biomarqueurs de G. roeseli. Après exposition au cadmium, la présence de parasites (i.e. infection simple ou co-infection) modifie la mobilisation des défenses antitoxiques et accentue les effets toxiques subits par l'hôte. Les résultats obtenus au cours de ce travail mettent en avant le caractère confondant du parasitisme en écotoxicologie et souligne l'importance de prendre en compte ce paramètre lors de l'évaluation de la qualité des milieux / To cope with environmental disturbances, organisms have developed antitoxic defenses commonly used as biomarkers in environmental risk assessment. However, many confounding factors such as temperature and gender could influence biomarker responses. It seems hence necessary to investigate their effects, in order to attribute biological responses only to pollutants. In this context, we investigated the influence of parasitism by studying the acanthocephalan parasite Polymorphus minutus, horizontally transmitted, and microsporidia parasites, vertically transmitted, on the physiological responses of their common host, the freshwater amphipod Gammarus roeseli, a classical model used in ecotoxicology. We investigated the glutathione, a tripeptide having a key role in antitoxic systems, its synthesis (i.e. gamma-glutamylcysteine ligase activity), energy reserves (i.e. lipids, glycogen, proteins) and a toxicity biomarker, the malondialdehyde. The influence of parasitism was considered in different studies: (i) in G. roeseli infected by P. minutus only, (ii) in G. roeseli infected by microsporidia (mainly Dictyocoela roeselum) and (iii) in G. roeseli coinfected by both parasites. Each study was carried out in absence of pollutants and under cadmium stress. We highlighted that, in the absence of contamination, only P. minutus and the co-infection affect the G. roeseli biomarker assessments. After cadmium exposure, the presence of parasites (i.e. single infection or co-infection) influences the mobilization of antitoxic defences, and accentuates toxic effects in their hosts. Our results underline the confounding nature of parasitism in ecotoxicology and thus, highlight the importance to take into account this parameter in the environmental risk assessment

Le traitement du virus de l'hépatite C (VHC) a connu une révolution récente, rapide et exemplaire grâce à l'arrivée des agents antiviraux directs (AAD) en plusieurs vagues depuis 2011, détrônant ainsi la bithérapie interféron-pégylé/ribavirine. Ces nouveaux traitements ont été rapidement confrontés à des limites concernant leur efficacité et leur tolérance notamment à leurs débuts avec les inhibiteurs de la protéase NS3/4A de première génération. L'arrivée de nouveaux AAD sur le marché lors d'une 2ème vague en 2014 a permis toutefois de surpasser celles-ci et de devenir le traitement de référence du VHC.Leur efficacité remarquable a laissé naître l'idée d'une potentielle élimination du VHC grâce à l'utilisation universelle de ces traitements. Cependant, leur coût élevé et les comportements à risque observés dans des sous-groupes de population (utilisateurs de drogues intraveineuses et homosexuels) restent encore des problématiques cruciales à surmonter pour espérer atteindre les objectifs fixés par l'Organisation Mondiale de la Santé en 2030 concernant l'élimination du VHC. De plus ces traitements, permettant l'élimination virale quasi-systématique et donc consécutivement une diminution du risque de complications hépatiques, ont été récemment confrontés à une polémique concernant un potentiel risque de récidive précoce de carcinome hépatocellulaire (CHC) suite à une exposition à ces derniers.Le travail présenté dans cette thèse s'articule autour de trois problématiques ayant toutes pour objectif principal d'optimiser l'utilisation de ces traitements dans l'optique de contrôler l'histoire naturelle de la maladie à l'échelle individuelle et à l'échelle populationnelle par l'intermédiaire de diverses méthodes statistiques.Nos résultats ont permis de montrer au sein d’une première problématique ayant exploré l'efficacité et la tolérance de ces traitements antiviraux à l’échelle individuelle: (i) une efficacité antivirale moindre que celle annoncée dans les essais de phase III des inhibiteurs de protéase de première génération(télaprévir et bocéprévir), (ii) un effet indésirable significatif des inhibiteurs de protéase de première génération sur la fonction rénale, (iii) une tolérance moins bonne de ces premières molécules que lors du traitement par bithérapie avec une incidence accrue d'anémie probablement liée à un surdosage en ribavirine induit par les inhibiteurs de protéase et (iv) une efficacité antivirale remarquable des AAD arrivés depuis 2014 sans impact des caractéristiques du patient ni des dosages pharmacologiques sur la réponse virologique. Dans un second temps, la problématique d'un risque de récidive de CHC accru après un traitement par AAD a également été explorée par l'analyse d'une cohorte locale, celle-ci ayant conclu à l'absence de risque accru comparé à un groupe de patients non exposés. Enfin, nos travaux basés sur la modélisation de la transmission du VHC en France dans la population coinfectée VIH-VHCont montré qu'un taux annuel de traitement par AAD de 50% était nécessaire dans la population homosexuelle ayant des pratiques à haut-risque de transmission pour contrer l'épidémie actuellement observée.Nos travaux ont donc permis d'apporter des données pour optimiser l'utilisation des nouveaux traitements anti-VHC par l'intermédiaire de diverses approches statistiques et ont apporté des éléments de réponse aux grandes problématiques actuelles. L'efficacité exemplaire et la tolérance quasi-parfaite des dernières molécules antivirales permettent une utilisation universelle de ces traitements dans toutes les populations de patients. Des études complémentaires robustes sont cependant nécessaires pour apporter des arguments à la question de la récidive du CHC. Des efforts sont également attendus concernant l'accès au traitement, la diminution des coûts associés et un dépistage renforcé du VHC pour espérer pouvoir éradiquer un jour cette maladie. / The arrival of direct-acting antivirals agents (DAAs) has spurred a rapid revolution in the treatment of hepatitis C virus (HCV), supplanting the previous standard of care, i.e. pegylated interferon and ribavirin. These new treatments are associated with an increased rate of virological response however they rapidly faced some limits more particularly at the beginning with the first generation NS3/4A protease inhibitors. From 2014 on the second wave of DAA was available for treatment of chronic HCV infection and surpassed previous encountered limits. These treatments are nowadays the gold standard for HCV treatment in high-income countries.The idea of HCV eradication recently emerged since DAA treatment are highly effective. However, their associated high cost and recent high-risk behaviors associated with an increased risk of HCV transmission (among intravenous drug users and homosexuals) have been reported. These issues need therefore to be addressed in order to achieve the objectives of the World Health Organization for 2030 of an HCV eradication. Moreover, these treatments allow a sustained virological response in almost all patients and consequently reduce the risk of liver-related complications, but a recent controversy regarding a potential increased risk of hepatocellular carcinoma after DAA treatment has been raised.Three issues will be extensively discussed in this manuscript regarding how these treatments can be used to optimize their effect on HCV natural history at the individual and population level through different statistical approaches.As regards the first issue, this project allowed us to demonstrate regarding the tolerance and efficacy of DAA treatment: (i) a lower antiviral efficacy than previously reported in the phase III trials for first generationprotease inhibitor regimen (telaprevir and boceprevir), (ii) impairment of renal function during first generation protease inhibitor treatment, (iii) an increased rate of reported side effects during first-generation protease inhibitor treatment and more particularly anemia, potentially related to an increased ribavirin biodisponibility induced by protease inhibitor intake and (iv) a remarkable antiviral efficacy of second generation DAAs without impact of patients' characteristics norpharmacology on virological response rate. The recent issue regarding a higher risk of HCC recurrence after DAA treatment was also explored through a local cohort study and no impact of DAA treatment was observed when comparing DAA-exposed vs non DAA-exposed patients. Finally, we conducted amodelling study on HCV transmission in the coinfected HIV-HCV French population and our results suggested that an annual DAA treatment coverage rate of 50% was required in the homosexual population with high-risk behaviors to counter the recent observed epidemic in this population.Our different works provide new insights on how to optimize the use of DAA treatment through several statistical approaches and bring new elements for discussion on the recent controversy. The new DAA have an excellent efficacy and tolerance profile and should be universally used in all populations without restriction. However, further studies are required to explore on a deeper level the question regarding HCC recurrence after DAA treatment. Efforts are also still needed regarding DAA treatment access, associated costs and HCV screening to reach the objective of HCV eradication

Plus de 170 millions d'individus sont infectés par le VHC dans le monde et 37 millions par le VIH. La coinfection VIH/VHC est fréquente et représente un élément clé de la prise en charge des patients infectés par le VIH. Depuis l'arrivée des HAART, les maladies du foie sont devenues la cause principale de mortalité chez les patients coinfectés VIH/VHC. L'évolution naturelle et le pronostic de l'hépatite C sont plus sévères en cas de coinfection par le VIH du fait d'une fibrose accélérée et d'une évolution rapide vers la cirrhose et ses complications. Certains facteurs accélérant la fibrose hépatique sont clairs aujourd'hui comme: l'absence de recours au traitement anti-VHC, la réplication active du VHC et la consommation excessive d'alcool. De plus, il existe de plus en plus de preuves que les variants génétiques contribuent à la fibrose hépatique chez les patients monoinfectés par le VHC, mais cet aspect a été peu étudié dans la coinfection VIH/VHC.Durant ma thèse, j'ai eu accès aux données d'un échantillon de 494 patients coinfectés génotypés issu de la cohorte ANRS CO13 HEPAVIH. L'histoire naturelle du VIH et du VHC y est renseignée de manière très détaillée et le suivi clinique des patients permet d'avoir des informations précises sur l'état de fibrose hépatique. J'ai pu alors réaliser deux études d'association « génome-entier » pour identifier des polymorphismes associés à la sévérité de la fibrose à l'aide de données complètes de 292 patients. La première étude a mis en évidence une association entre la quantification de l'élasticité hépatique par Fibroscan® et un locus, également répliqué dans la monoinfection par le VHC. Cette association a permis d'identifier deux gènes impliqués dans des mécanismes de maintien de structure et de signalisation cellulaire (CAV3) mais aussi dans la réplication du VHC (RAD18). La seconde étude a identifié deux associations significatives en comparant deux groupes de scores METAVIR (F0F1F2 vs F3F4), en particulier dans le gène CTNND2 qui est impliqué dans un réseau d'interaction associé à des mécanismes moléculaires lié à des maladies hépatiques.Ces deux études sont en cours de publication dans des revues scientifiques internationales à comité de lecture. Ces nouvelles perspectives dans la compréhension des mécanismes de fibrose dans le contexte de la coinfection VIH/VHC pourraient aider à l'identification de nouvelles cibles pour la création de médicaments ou de tests diagnostiques afin d'améliorer les soins des patients. / Over 170 million people worldwide are infected by HCV and 37 million by HIV. Both viruses share the same modes of transmission, and HIV/HCV coinfection is common and represents a key element in the management of patients infected with HIV. Since the appearance of HAART, liver diseases have become the leading cause of death in HIV/HCV coinfected patients. The natural history and prognosis of hepatitis C are more severe in case of coinfection with HIV due to accelerated rate of fibrosis progression and rapid progression to cirrhosis and its complications. Factors accelerating liver fibrosis are known today such as the lack of recourse to anti-HCV treatment, active HCV replication and excessive alcohol consumption. There is increasing evidence that genetic variants contribute to liver fibrosis in HCV monoinfection, but this aspect has been little studied in HIV/HCV coinfection.I have exploited the genotype information from 494 coinfected patients from the cohort ANRS CO13 HEPAVIH. These patients are very-well documented regarding the history of their HIV/HCV infection and are very carefully followed-up, especially regarding the status of liver fibrosis. I have performed two genome-wide association studies to identify polymorphisms associated with the severity of fibrosis from complete data of 292 patients. The first study has dealt with the quantification of liver stiffness by Fibroscan® and an association with the 3p25 region has been identified, also replicated in monoinfection HCV. Two genes involved in cell signaling and structure of holding mechanisms (CAV3) but also in HCV replication (RAD18) appear as good candidates. The second study has unraveled two significant associations by comparing the METAVIR score group (F0F1F2 vs F3F4), especially in the CTNND2 gene implicated in a network of interactions with molecular mechanisms involved in liver diseases.These results are under publications in peer-review international scientific journals. These new insights into the molecular mechanisms of liver fibrosis in patients with HIV/HCV co- infection may help to define new targets for drug development or new diagnostic tests, to improve patient care.

Les virus du Chikungunya (CHIKV) et de la dengue (DENV) sont deux virus émergents qui sévissent dans les régions tropicales et subtropicales du monde entier et qui sont transmis par les moustiques du genre Aedes. Ces dernières années, leur transmission a surtout progressé dans les zones urbaines et périurbaines touchant des millions d’individus et faisant de ces deux pathogènes des sujets majeurs de préoccupation pour la santé publique. Le Chikungunya et la Dengue sont des infections dites aiguës entrainant une mise en place rapide de la réponse immunitaire innée qui joue un rôle majeur dans le contrôle et l’évolution de la maladie. Les cellules Natural Killer (NK) représentent une population cellulaire clé de la réponse innée et jouent un rôle crucial dans les mécanismes de défense mis en place. A travers une étude ex vivo et in vitro, nous nous sommes intéressées à la caractérisation des cellules NK à travers (i) une étude phénotypique et fonctionnelle des cellules NK chez des patients infectés en phase aiguë par le CHIKV, DENV-2 ou par les deux virus et (ii) à la caractérisation des interactions entre les cellules NK et les cellules cibles infectées par le virus. L’ensemble de ces données contribue à mieux identifier l’implication des cellules NK dans le contrôle des infections par le CHIKV et DENV-2 permettant ainsi de mieux comprendre les mécanismes à l’origine des dérèglements de la réponse immunitaire. Au cours des dernières épidémies, plusieurs cas de patients coinfectés par les deux virus ont été répertoriés. De plus, l’expansion géographique des moustiques Aedes pourrait amener à une augmentation du nombre de cas de coinfections sans que les mécanismes sous jacents aux coinfections ne soient étudiés. Afin de pouvoir réponse à certaines questions concernant ce phénomène, nous avons mis en place un modèle expérimental de coinfection par CHIKV et DENV-2 chez le macaque Rhésus. / Chikungunya (CHIKV) and Dengue (DENV) virus are both re-emerging viruses transmitted by Aedes mosquitoes and responsible of widespread outbreaks in tropical and subtropical country. Recently, transmission of both viruses had emerged in urban and peri-urban area infecting millions of persons. Chikungunya and Dengue are both acute infections where innate immunity rapidly takes place and play a crucial role in the control and in the evolution of the disease. Natural Killer cells (NK) represent one of the major cellular population of innate immunity and play a crucial role in defense mechanism. By way of ex vivo and in vitro studies, we characterized NK cells by (i) a phenotypic and functional study of NK cells in CHIKV, DENV-2 infected patients or CHIKV/DENV-2 co-infected patients and (ii) characterization of NK cells interactions with infected target cells. During last outbreaks, several cases of co-infected patients were reported. Moreover, geographic spread of Aedes mosquitoes could increase number of coinfection cases without underlying mechanisms being explored. In order to respond to certain questions regarding coinfections, we realized a co-infected CHIKV and DENV-2 experimental model in Rhesus macaques.Together, these data will contribute to better identify NK cells implication in the control of CHIKV and DENV-2 infections allowing a better comprehension of mechanisms that causes immune system disorder.

Introdução - A tuberculose (TB) e a Síndrome da Imunodeficiência Adquirida (AIDS) são os agravos de origem infecciosa com maior mortalidade no mundo. O vírus da imunodeficiência humana (HIV) compromete o sistema imunológico e favorece o adoecimento por TB e, nesta perspectiva, a coinfecção TB-HIV constitui uma associação potencialmente fatal. Objetivos - Descrever os casos novos de TB coinfectados pelo HIV e analisar os padrões de distribuição espacial e temporal da coinfecção no município de São Paulo. Método - Estudo descritivo, analítico e de série temporal com dados do Sistema de Notificação e Acompanhamento dos Casos de Tuberculose (TBWEB). Foram incluídos todos os casos novos de TB coinfectados pelo HIV residentes no município de São Paulo, no período de 2007 a 2015. Foram calculadas as proporções de infecção pelo HIV entre os casos novos de TB e as taxas anuais de incidência de coinfecção TB-HIV, e a tendência temporal foi analisada por regressão de Prais-Winsten. Casos foram descritos segundo as características sociodemográficas, clínicas e epidemiológicas, e casos com e sem residência fixa foram comparados pelo teste de qui-quadrado de Pearson ou teste exato de Fisher. Casos sem residência fixa foram espacialmente distribuídos segundo o distrito administrativo de tratamento da TB. Casos com residência fixa foram geocodificados pelo endereço de residência, e foram utilizados para o cálculo das taxas brutas de incidência e taxas suavizadas pelo Método Bayesiano Empírico Local. Índices de Moran Global e Local avaliaram a autocorrelação espacial dos dados. O nível de significância adotado foi de 5%. Resultados - Foram analisados 6.092 casos novos de coinfecção TB-HIV: 5.609 indivíduos com residência fixa e 483 sem residência fixa. A proporção de coinfecção TB-HIV variou de 13,7%, em 2007, a 10,5%, em 2015, com queda de 3,0%/ano. A proporção de coinfecção pelo HIV entre casos de TB sem residência fixa foi maior em todo o período, com queda de 4,3%/ano, enquanto na população com residência fixa a diminuição anual foi de 3,3%. As taxas brutas de incidência de coinfecção TB-HIV apresentaram diminuição de 3,6% ao ano, passando de 7,0 em 2007, para 5,3 em 2015 (por 100 mil habitantes/ano). A população coinfectada por TB-HIV alcançou baixas taxas de cura (<60,0%), e o óbito e o abandono foram desfechos de tratamento para uma parcela importante dos casos (>20,0%). O perfil dos indivíduos sem residência fixa diferiu em alguns aspectos daqueles com residência, e foram, sobretudo, atendidos nas regiões Centro, Oeste e Sudeste do município. A incidência da coinfecção TB-HIV na população com residência fixa apresentou autocorrelação espacial positiva e significativa em todo o período, com um padrão espacial heterogêneo, e com um aglomerado de alto risco na região central do município. Conclusões - A tendência de queda na coinfecção TB-HIV indica importante avanço no controle da TB e do HIV/AIDS entre 2007 e 2015 no município de São Paulo. As análises revelaram áreas que se apresentaram contínua e desigualmente afetadas pelo agravo, e que devem ser priorizadas nas formulações de políticas para o aprimoramento das ações de prevenção e controle da coinfecção TB-HIV. / Introduction - Tuberculosis (TB) and the Acquired Immunodeficiency Syndrome (AIDS) are the infectious diseases with the highest mortality in the world. Human immunodeficiency virus (HIV) affects the immune system and facilitates the progress to active TB, therefore TB-HIV coinfection is a potentially fatal association. Objectives - Describing the new TB-HIV coinfected cases and analyzing the spatial and temporal patterns of coinfection in the city of São Paulo. Method - Descriptive, analytical and time series study with data from the reporting and monitoring system of TB cases (TBWEB). All new cases of TB with HIV coinfection living in the city of São Paulo were included, in the period from 2007 to 2015. The HIV infection proportions among new TB cases and annual incidence rates of TB-HIV coinfection were calculated, and temporal trends were analyzed by Prais-Winsten regression. The cases were described according to sociodemographic, clinical and epidemiological characteristics, and cases with fixed residence and homeless cases were compared by the Pearson\'s chi-square test or Fisher\'s exact test. Homeless cases were spatially distributed according to the district of TB treatment. Cases with fixed residence were geocoded by the home address, and used to calculate the crude incidence rates and the Empirical Bayes smoothed rates. Global and Local Moran indexes evaluated the spatial autocorrelation. The level of significance was 5%. Results - A total of 6,092 new cases of TB-HIV coinfection were analyzed: 5,609 had fixed residence and 483 were homeless. The proportion of TB-HIV coinfection ranged from 13.7% in 2007 to 10.5% in 2015, with a decrease of 3.0%/year. Coinfection by HIV among homeless TB cases was higher in the entire period, but decreasing 4.3% per year, while in the population with fixed residence the annual decline was equal to 3.3%. The incidence rates of TB-HIV coinfection presented a decrease of 3.6% per year, ranging from 7.0 in 2007 to 5.3 in 2015 (per 100 thousand people/year). The TB-HIV coinfected population achieved low rates of cure (<60.0%), and death and treatment dropout were final outcomes for an important portion of cases (> 20.0%). The profile of homeless cases differed in some aspects from those with a fixed residence, and they were mainly attended in the Central, West and Southeast regions of the city. Incidence rates of TB-HIV coinfection among the population with fixed residence presented positive and significant spatial autocorrelation throughout the period, with a heterogeneous spatial pattern, and a high-risk cluster in the central region of the city. Conclusions - Decreasing trend of TB-HIV coinfection indicates an important advance in TB and HIV/AIDS control from 2007 to 2015 in the city of São Paulo. Spatial and temporal analyzes revealed areas continuously and unequally affected by disease, and should be prioritized for guiding policy formulation in order to improve prevention and control actions of TB-HIV coinfection.

Made available in DSpace on 2016-08-10T10:54:18Z (GMT). No. of bitstreams: 1 ROBERPAULO ANACLETO NEVES.pdf: 3157130 bytes, checksum: 0cf8ffe81408930e67e0854181733521 (MD5) Previous issue date: 2014-03-14 / Durante anos a hepatite C foi conhecida sob a designação de hepatite não-A e não- B. Somente após sua identificação em 1989 tornou-se evidente que um considerável número de pessoas estavam infectadas pelo HCV. A transmissão ocorre principalmente pela via sexual e pelo uso de drogas injetáveis. Dentro da mesma visão epidemiológica o HIV e o HCV apresentam-se hoje como um importante problema mundial de saúde pública. A coinfecção pelos vírus HCV e HIV, tende a agravar o quadro clínico do infectado. O HCV dificulta a reconstituição do sistema imunitário, eleva o risco de hepatotoxicidade e diminui o tempo para o aparecimento da AIDS e morte. O objetivo principal deste estudo foi identificar a prevalência da infecção pelo Vírus da Hepatite C e coinfecção pelo vírus da Imunodeficiência Humana na população de detentos do Complexo Prisional de Aparecida de Goiânia, apontar os comportamentos de riscos e os fatores associados às infecções. Estudo transversal, descritivo e de abordagem quantitativa. Os detentos participantes foram submetidos à punção venosa para obtenção de amostras de soro e plasma, as quais foram submetidas a testes laboratoriais para a pesquisa do marcador sorológico anti-HCV, sendo os testes reagentes, submetidos à pesquisa do anti-HIV. O complexo prisional apresenta uma população total de 3250 indivíduos privados de liberdade. Destes, 1157 indivíduos aceitaram participar da pesquisa, sendo, 1015 do sexo masculino e 142 do sexo feminino. Utilizaram-se os testes Qui-Quadrado e Exato de Fisher (ambos com nível de significância estatística de 5%) e a razão de prevalência com intervalo de confiança de 95%. Foram identificados 51 indivíduos detentos sororreagentes para o anti-HCV, sendo 44 homens e 7 mulheres, o que correspondeu a 4,4% quando comparado com a população total de participantes. Destes 51 indivíduos, 3 apresentavam como comorbidade o HIV, o que correspondeu a 5,9% de coinfecção HCV/HIV. Os resultados indicam que a condição de marginalização, o baixo nível socioeconômico dos detentos, a superpopulação das prisões e a precária condição de saúde contribuem para a disseminação de doenças nas prisões, sendo necessária a implantação de programas de saúde contínuos a fim de possibilitar medidas de controle e prevenção dessas infecções no ambiente prisional.

Introdução - A tuberculose (TB) e a Síndrome da Imunodeficiência Adquirida (AIDS) são os agravos de origem infecciosa com maior mortalidade no mundo. O vírus da imunodeficiência humana (HIV) compromete o sistema imunológico e favorece o adoecimento por TB e, nesta perspectiva, a coinfecção TB-HIV constitui uma associação potencialmente fatal. Objetivos - Descrever os casos novos de TB coinfectados pelo HIV e analisar os padrões de distribuição espacial e temporal da coinfecção no município de São Paulo. Método - Estudo descritivo, analítico e de série temporal com dados do Sistema de Notificação e Acompanhamento dos Casos de Tuberculose (TBWEB). Foram incluídos todos os casos novos de TB coinfectados pelo HIV residentes no município de São Paulo, no período de 2007 a 2015. Foram calculadas as proporções de infecção pelo HIV entre os casos novos de TB e as taxas anuais de incidência de coinfecção TB-HIV, e a tendência temporal foi analisada por regressão de Prais-Winsten. Casos foram descritos segundo as características sociodemográficas, clínicas e epidemiológicas, e casos com e sem residência fixa foram comparados pelo teste de qui-quadrado de Pearson ou teste exato de Fisher. Casos sem residência fixa foram espacialmente distribuídos segundo o distrito administrativo de tratamento da TB. Casos com residência fixa foram geocodificados pelo endereço de residência, e foram utilizados para o cálculo das taxas brutas de incidência e taxas suavizadas pelo Método Bayesiano Empírico Local. Índices de Moran Global e Local avaliaram a autocorrelação espacial dos dados. O nível de significância adotado foi de 5%. Resultados - Foram analisados 6.092 casos novos de coinfecção TB-HIV: 5.609 indivíduos com residência fixa e 483 sem residência fixa. A proporção de coinfecção TB-HIV variou de 13,7%, em 2007, a 10,5%, em 2015, com queda de 3,0%/ano. A proporção de coinfecção pelo HIV entre casos de TB sem residência fixa foi maior em todo o período, com queda de 4,3%/ano, enquanto na população com residência fixa a diminuição anual foi de 3,3%. As taxas brutas de incidência de coinfecção TB-HIV apresentaram diminuição de 3,6% ao ano, passando de 7,0 em 2007, para 5,3 em 2015 (por 100 mil habitantes/ano). A população coinfectada por TB-HIV alcançou baixas taxas de cura (<60,0%), e o óbito e o abandono foram desfechos de tratamento para uma parcela importante dos casos (>20,0%). O perfil dos indivíduos sem residência fixa diferiu em alguns aspectos daqueles com residência, e foram, sobretudo, atendidos nas regiões Centro, Oeste e Sudeste do município. A incidência da coinfecção TB-HIV na população com residência fixa apresentou autocorrelação espacial positiva e significativa em todo o período, com um padrão espacial heterogêneo, e com um aglomerado de alto risco na região central do município. Conclusões - A tendência de queda na coinfecção TB-HIV indica importante avanço no controle da TB e do HIV/AIDS entre 2007 e 2015 no município de São Paulo. As análises revelaram áreas que se apresentaram contínua e desigualmente afetadas pelo agravo, e que devem ser priorizadas nas formulações de políticas para o aprimoramento das ações de prevenção e controle da coinfecção TB-HIV. / Introduction - Tuberculosis (TB) and the Acquired Immunodeficiency Syndrome (AIDS) are the infectious diseases with the highest mortality in the world. Human immunodeficiency virus (HIV) affects the immune system and facilitates the progress to active TB, therefore TB-HIV coinfection is a potentially fatal association. Objectives - Describing the new TB-HIV coinfected cases and analyzing the spatial and temporal patterns of coinfection in the city of São Paulo. Method - Descriptive, analytical and time series study with data from the reporting and monitoring system of TB cases (TBWEB). All new cases of TB with HIV coinfection living in the city of São Paulo were included, in the period from 2007 to 2015. The HIV infection proportions among new TB cases and annual incidence rates of TB-HIV coinfection were calculated, and temporal trends were analyzed by Prais-Winsten regression. The cases were described according to sociodemographic, clinical and epidemiological characteristics, and cases with fixed residence and homeless cases were compared by the Pearson\'s chi-square test or Fisher\'s exact test. Homeless cases were spatially distributed according to the district of TB treatment. Cases with fixed residence were geocoded by the home address, and used to calculate the crude incidence rates and the Empirical Bayes smoothed rates. Global and Local Moran indexes evaluated the spatial autocorrelation. The level of significance was 5%. Results - A total of 6,092 new cases of TB-HIV coinfection were analyzed: 5,609 had fixed residence and 483 were homeless. The proportion of TB-HIV coinfection ranged from 13.7% in 2007 to 10.5% in 2015, with a decrease of 3.0%/year. Coinfection by HIV among homeless TB cases was higher in the entire period, but decreasing 4.3% per year, while in the population with fixed residence the annual decline was equal to 3.3%. The incidence rates of TB-HIV coinfection presented a decrease of 3.6% per year, ranging from 7.0 in 2007 to 5.3 in 2015 (per 100 thousand people/year). The TB-HIV coinfected population achieved low rates of cure (<60.0%), and death and treatment dropout were final outcomes for an important portion of cases (> 20.0%). The profile of homeless cases differed in some aspects from those with a fixed residence, and they were mainly attended in the Central, West and Southeast regions of the city. Incidence rates of TB-HIV coinfection among the population with fixed residence presented positive and significant spatial autocorrelation throughout the period, with a heterogeneous spatial pattern, and a high-risk cluster in the central region of the city. Conclusions - Decreasing trend of TB-HIV coinfection indicates an important advance in TB and HIV/AIDS control from 2007 to 2015 in the city of São Paulo. Spatial and temporal analyzes revealed areas continuously and unequally affected by disease, and should be prioritized for guiding policy formulation in order to improve prevention and control actions of TB-HIV coinfection.

Utilizando modelo de coinflamação tuberculose e alergia (TB/OVA), nosso grupo mostrou que camundongos BALB/c coinflamados apresentaram diminuição significativa no número de bacilos, associada com diminuição no infiltrado granulomatoso no pulmão, aumento na produção de leucotrieno B4 e no número de células CD8+, quando comparados ao grupo infectado com Mycobacterium tuberculosis (TB). No presente estudo, nosso objetivo foi avaliar os mecanismos envolvidos na restrição ao crescimento dos bacilos nos animais do grupo TB/OVA. Quatro estratégias foram usadas: I) Para avaliar o papel dos linfócitos CD8+ no modelo TB/OVA, foram utilizados camundongos deficientes para a molécula CD8 (CD8KO). Foi observado que não houve diferenças significativas no crescimento do bacilo no pulmão dos animais CD8KO-TB/OVA e WT-TB/OVA. No entanto, nos pulmões dos animais WT-TB/OVA houve maior crescimento de bacilos em relação aos animais WT-TB, diferente do previamente observado com os animais TB/OVA da linhagem BALB/c. Para avaliar o papel dos leucotrienos foram usadas as seguintes estratégias: II). Camundongos da linhagem 129Sv tratados com MK886, inibidor da enzima 5-lipoxigenase (5LO), envolvida na síntese de mediadores lipídicos; III) animais 129Sv, deficientes para a expressão da 5LO (5LOKO). Foi observado que o tratamento com MK886 não afetou o número de bacilos no pulmão do grupo coinflamado TB/OVA quando comparado ao grupo TB/OVA. Além disso, diferente do que foi previamente observado em animais BALB/c, os animais 129Sv coinflamados foram mais susceptíveis que os animais 129Sv infectados. Do contrário, animais 5LOKO-TB/OVA foram mais resistentes que os camundongos WT-TB/OVA. Para avaliar se alterações no infiltrado granulomatoso estavam relacionadas com o infiltrado de macrófagos no pulmão, usamos a quarta estratégia: IV) quantificação das populações de macrófagos M1 e M2. Foi observado que os animais TB/OVA apresentaram aumento da população de macrófagos M2 no pulmão, enquanto a população de macrófagos M1 manteve-se inalterada comparado-se ao grupo apenas infectado. A diminuição no crescimento de bacilos nos animais TB/OVA foi dependente dos macrófagos M2, pois animais deficientes para a expressão do receptor de IL-33 submetidos ao protocolo de coinflamação tiveram diminuição da população de macrófagos M2, e foram susceptíveis à infecção. Esses resultados mostram que a diminuição no crescimento de bacilos nos animais coinflamados TB/OVA é dependente do aumento da população de macrófagos M2. / Using model of coinfection allergy and tuberculosis (TB / OVA), our group showed that coinfected BALB/c showed a significant decrease in the number of bacilli, associated with a decrease in granulomatous infiltrate the lung, increased production of leukotriene B4 and the number of cells CD8+, compared to the group infected with Mycobacterium tuberculosis (TB). To evaluate the mechanisms involved in reducing the growth of bacilli in group TB/OVA, were used four strategies: I) To assess the role of CD8+ lymphocytes in model TB/OVA, we used mice deficient for the molecule CD8 (CD8KO).We was observed that the number of bacilli in the lungs of animals in the group CD8KO-TB/OVA and WT-TB/OVA was similar. However, the lungs of animals WT-TB/OVA growth of bacillus was higher compared to WT animals, TB, unlike what was previously observed with background genetic BALB/c. To evaluate the role of leukotrienes, we use the following strategies: II) strain 129Sv mice treated with MK886, an inhibitor of the enzyme 5-lipoxygenase (5LO), involved in the synthesis of lipid mediators, III) 129Sv animals deficient for the expression of 5LO (5LOKO). We observed that treatment with MK886 did not affect the number of bacilli in the lung of the coinfected group TB/OVA. Moreover, unlike what was previously observed in animals BALB/c mice, coinfected 129Sv were more susceptible than the animals infected 129Sv. On the contrary, 5LOKO-TB/OVA animals were more resistant than mice WT-TB/OVA. To assess whether changes in granulomatous infiltrates were related to macrophages, we use the fourth strategy: IV) quantification of macrophage populations M1 and M2. We observed that M2 population in animals TB/OVA showed increased lung. The decrease in bacilli growth of animals TB/OVA was dependent on macrophage M2, since animals deficient for the expression of IL-33 protocol submitted to coinfected protocol had decreased macrophage population M2, and were susceptible to infection. These results show that the reduction in growth of bacilli in coinfected animals TB/OVA is dependent increase in macrophage population M2.