A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy Johannesburg, 2002 / Hepatitis B virus (HBV) infection is endemic to several populous regions and is often complicated by cirrhosis and hepatocellular carcinoma (HCC). Present treatment of chronic HBV infection is usually ineffective and novel therapeutic approaches are an important medical objective. The X open reading frame (ORF) of HBV, HBx, is a conserved sequence that overlaps with the polymerase ORF and viral c/'s-elements, and is present within all viral transcripts. In addition, the HBx ORF encodes a 17 kDa transactivator protein, HBx, which is required for the establishment of viral infection and has been implicated in HBV-associated hepatocarcinogenesis. The HBx sequence thus represents a compelling target for applying nucleic acid hybridisation-based therapeutic agents for the inhibition of HBV gene expression and replication. / IT2018

As hepatites virais A e E estão entre as doenças mais comuns nos seres humanos, relacionadas a países com baixo nível socioeconômico e condições inadequadas de higiene. São transmitidas por via fecal-oral, diretamente pessoa a pessoa ou por contaminação de água e alimentos. Um ciclo zoonótico da hepatite E (genótipo 3) ocorre principalmente pelo consumo de carne ou contato direto com suínos. A incidência de hepatite A vem reduzindo no país, mas pouco tem sido estudado sobre a prevalência em cidades pequenas do interior. Os estudos sobre a hepatite E no país ainda são limitados e sugerem que o genótipo 3 seja o responsável pela infecção. Este estudo buscou estimar a prevalência das hepatites A e E na população adulta de Cássia dos Coqueiros (aprox. 2600 hab.) e levantar possíveis fatores de risco para as infecções. Trata-se de um inquérito soroepidemiológico em 990 habitantes de Cássia dos Coqueiros com mais de 18 anos de idade, aproximadamente 51% de toda a população do município nesta faixa etária, com uma subamostragem de 248 indivíduos especificamente para pesquisa de hepatite E. As amostras de sangue foram coletadas entre os anos de 2011 e 2013 e aplicado um questionário contendo informações demográficas, socioeconômicas e de fatores de risco. Foram realizados exames imunológicos (ELISA) para detecção de anticorpos IgG para as hepatites A e E. As prevalências foram estimadas por faixa etária e calculados seus respectivos intervalos de confiança. Os dados foram submetidos a análises uni e multivariadas, em modelo de regressão logística log-binomial. As associações foram testadas medindo-se as Razões de Prevalência e seus respectivos intervalos de confiança (95%). A prevalência de hepatite A na população total foi 89,1% (IC95%= 87,1 - 90,9), aumentando de acordo com as faixas etárias. Observou-se na análise univariada associação com idade, unidade federada de origem, escolaridade, estrato econômico, antecedentes de hepatite e de contato domiciliar com casos desta doença, bem como história de eliminação de proglotes de Taenia sp nas fezes, mas após ajuste do modelo, apenas a variável idade permaneceu independentemente associada. A prevalência de hepatite E foi 20,7% (IC95%= 15,5 - 25,7), identificando-se associação apenas com a escolaridade na análise univariada, mas que deixou de ser associada após ser ajustada no modelo multivariado. Este é o primeiro estudo soroepidemiológico de base populacional comparando a presença de VHA e VHE numa cidade de porte pequeno com características rurais na região Sudeste do país. Cássia dos Coqueiros apresenta-se como área de baixa endemicidade para VHA, assim como as regiões Sul e Sudeste. A prevalência de VHE foi a maior encontrada em estudo de base populacional ou doadores de sangue no país, mostrando que a infecção ocorre de forma mais frequente do que se acreditava e que mais estudos são necessários para verificar o genótipo circulante e os fatores de risco para infecção, possivelmente pela transmissão zoonótica do VHE3. / Viral hepatitis A and E are among the most common diseases in humans, related to countries with low socioeconomic level and inadequate hygiene conditions. They are transmitted by fecal-oral route, directly person to person or by contamination of water and food. A zoonotic cycle of hepatitis E (genotype 3) occurs mainly through meat consumption or direct contact with swine. The incidence of hepatitis A has been declining in Brazil, but little has been studied about the prevalence in small towns in the interior. Studies on hepatitis E in the country are still limited and suggest that genotype 3 is responsible for the infection. This study aimed to estimate the prevalence of hepatitis A and E in the adult population of Cássia dos Coqueiros (approximately 2600 inhabitants) and to assess possible risk factors for infections. This is a seroprevalence survey of 990 inhabitants of Cássia dos Coqueiros, over 18 years of age, approximately 51% of the entire population of the municipality in this age group, with a subsampling of 248 individuals specifically for hepatitis E screening. Samples were collected between the years 2011 and 2013 and a questionnaire containing demographic, socioeconomic and risk factors information was applied. Immunological tests (ELISA) were performed to detect IgG antibodies to hepatitis A and E. The prevalences of hepatitis A and E were estimated by age group and their respective confidence intervals were calculated. The data were submitted to multivariate analysis using a log-binomial logistic regression model. Associations were tested by measuring the Prevalence Ratios and their respective confidence intervals (95%). The prevalence of hepatitis A in the total population was 89.1% (95% CI = 87.1-90.9), increasing according to age. The univariate analysis identified association with age, federated unit of origin, education level, economic strata, history of hepatitis and home contact with cases of this disease, as well as history of elimination of Taenia sp proglottes in feces. After adjustment of the model, only age remained independently associated. The prevalence of Hepatitis E was 20.7% (95% CI = 15.5 - 25.7), which was only associated with education level in the univariate analysis, but no longer associated with adjustment in the multivariate model. This is the first population-based seroprevalence study comparing the presence of HAV and HEV in a small city with rural characteristics in the Southeastern region of the country. According to the WHO criteria, Cássia dos Coqueiros seems to be as an area of low endemicity for HAV, as well as the South and Southeast regions of Brazil. The prevalence of HEV was the highest found in a population-based study or blood donors in the country, showing that the infection occurs more frequently than previously believed and that more studies are needed to verify the circulating genotype and the risk factors for infection, possibly due to the zoonotic transmission of HEV3.

人類免疫缺陷病毒 (HIV) 是人獲得性免疫缺陷綜合征 (愛滋病，AIDS) 的致病原，2010年全球有180萬人死於愛滋病，HIV/AIDS已成為全球健康的嚴重挑戰。人類免疫缺陷病毒與乙型肝炎病毒 (HBV) ，丙型肝炎病毒 (HCV) 的合併感染非常普遍，已演變成具有嚴重臨床後果的新健康問題。儘管對於人類免疫缺陷病毒的研究已有很大的進展，但由於受研究模型的限制，人體免疫系統對人類免疫缺陷病毒感染的應答，特別是對乙型肝炎病毒，丙型肝炎病毒與人類免疫缺陷病毒合併感染的免疫應答，仍值得進一步的闡明。 / 在本研究中，我們首先對深圳人類免疫缺陷病毒，乙型肝炎病毒，丙型肝炎病毒合併感染的流行情況進行研究。共選取914份人類免疫缺陷病毒感染者的血漿，經過對乙型肝炎病毒表面抗原 (HBsAg) 和抗丙型肝炎病毒抗體 (anti-HCV) 的檢測，發現10.9% (100/914) 的被檢測者是人類免疫缺陷病毒/乙型肝炎病毒合併感染，14.6% (133/914) 為人類免疫缺陷病毒/丙型肝炎病毒合併感染，3.7% (34/914) 為人類免疫缺陷病毒/乙型肝炎病毒/丙型肝炎病毒三重感染。多元邏輯回歸分析證明人類免疫缺陷病毒傳染的危險行為與合併感染顯著相關聯。大多數的人類免疫缺陷病毒/乙型肝炎病毒合併感染者都是通過性接觸感染人類免疫缺陷病毒，包括異性傳播與同性傳播 (95/100, 95%); 大多數的人類免疫缺陷病毒/丙型肝炎病毒合併感染者是靜脈注射吸毒者 (89/133, 66.9%); 人類免疫缺陷病毒/乙型肝炎病毒/丙型肝炎病毒三重感染者中，大多數是靜脈注射吸毒者 (28/34, 82.4%)。靜脈注射吸毒人群中，大部分是男性 (108/122, 88.5%)，約半數人的年齡介乎27至32歲 (56/122, 45.9%) 。有接近一半的經過血液和血液製品傳播人類免疫缺陷病毒的人是人類免疫缺陷病毒/丙型肝炎病毒合併感染者 (10/23, 43.5%) 。性別與人類免疫缺陷病毒感染的危險行為有顯著關係，大部份的靜脈注射吸毒者是男性。 / 進一步，我們利用酶聯免疫吸附測定法 (ELISA) 檢測深圳愛滋病陽性樣本血漿中白細胞介素27 (IL-27) 的濃度。結果顯示，對比健康參照者，人類免疫缺陷病毒單獨感染者，人類免疫缺陷病毒/乙型肝炎病毒合併感染者，人類免疫缺陷病毒/丙型肝炎病毒合併感染者的血漿IL-27濃度顯著升高。隨後我們進一步發現，人類免疫缺陷病毒單獨感染組，人類免疫缺陷病毒/乙型肝炎病毒，人類免疫缺陷病毒/乙型肝炎病毒/丙型肝炎病毒合併感染組之間的血漿IL-27濃度沒有顯著差異，而人類免疫缺陷病毒/丙型肝炎病毒合併感染組與人類免疫缺陷病毒/乙型肝炎病毒/丙型肝炎病毒三重感染組的血漿IL-27濃度差異顯著。我們還發現人類免疫缺陷病毒單獨感染組中，血漿IL-27濃度與CD4⁺ T 淋巴細胞數量顯著正相關 (r = 0.177, P = 0.034)。 / 我們進一步分析了人類免疫缺陷病毒和丙型肝炎病毒的病毒載量對血漿IL-27濃度的影響，發現HIV單獨感染組中人類免疫缺陷病毒載量與血漿IL-27濃度沒有顯著相關 (r = - 0.063, P = 0.679)，而人類免疫缺陷病毒/丙型肝炎病毒合併感染組中，人類免疫缺陷病毒載量與血漿IL-27濃度顯著正相關 (r = 0.362, P = 0.049)。人類免疫缺陷病毒/丙型肝炎病毒合併感染組中，人類免疫缺陷病毒載量與丙型肝炎病毒載量缺少顯著線性關聯 (r = - 0.072, P = 0.704)，而人類免疫缺陷病毒/丙型肝炎病毒合併感染組可根據人類免疫缺陷病毒與丙型肝炎病毒的病毒載量再細分成血漿IL-27濃度差異顯著的三組 (P = 0.014) ， 丙型肝炎病毒載量與血漿IL-27濃度缺少顯著關聯 (r = - 0.119, P = 0.530) 。 / 我們利用TaqMan®等位基因分型技術測定深圳男同性戀人群中IL-27 p28基因的單核苷酸多態性 (SNP)。結果顯示，人類免疫缺陷病毒感染組IL-27 p28 -964A/G 和4603G/A的基因型與健康男同性戀參照組的基因型沒有顯著差異， IL-27 p28 -964A/G 和4603G/A的等位基因比率也沒有顯著差異。結果也顯示，IL-27 p28 2905T/G的TG基因型可減少2.77倍的人類免疫缺陷病毒感染風險，等位基因G可減少2.72倍的人類免疫缺陷病毒感染風險。連鎖不平衡在IL-27 p28 -964A/G 和2905T/G 中存在 ( / 綜上所述， 在本研究中，我們首次調查了深圳人類免疫缺陷病毒，乙型肝炎病毒，丙型肝炎病毒合併感染的流行情況，並分析了合併感染的風險因素。 發現人類免疫缺陷病毒單獨感染者，人類免疫缺陷病毒/乙型肝炎病毒合併感染者， 及人類免疫缺陷病毒/丙型肝炎病毒合併感染者的血漿IL-27濃度比健康參照組顯著地升高；人類免疫缺陷病毒單獨感染組中，血漿IL-27濃度與CD4⁺ T淋巴細胞數量顯著正相關。人類免疫缺陷病毒/丙型肝炎病毒合併感染組中，人類免疫缺陷病毒載量與血漿IL-27濃度顯著正相關 (r = 0.362, P = 0.049)。分析深圳男同性戀人群IL-27 p28基因的單核苷酸多態性，發現IL-27 p28 2905T/G 與人類免疫缺陷病毒感染相關，GGG單型可降低男同性戀人群人類免疫缺陷病毒感染的風險。 / Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS); HIV/AIDS caused 1.8 million deaths world-widely in 2010 and became a major global health challenge. HIV co-infections with Hepatitis B virus (HBV), Hepatitis C virus (HCV) are common and have emerged into new health problems with severe clinical consequences. Since the discovery of HIV, massive progress in understanding of the pathogen has been achieved. Due to the restriction of research model, how human immune system responds to HIV infection, particularly, to HBV or HCV co-infections is still worthy further elucidation. / A cohort study was first conducted in Shenzhen regarding the seroprevalence of HBV, HCV infections among HIV-infected population. Totally 914 HIV positive individuals were recruited in the study and tested for HBsAg and anti-HCV antibodies. The results showed a 10.9% (100/914) HIV/HBV co-infection rate, 14.6% (133/914) HIV/HCV co-infection prevalence and 3.7% (34/914) HIV/HBV/HCV triple-infection prevalence. Multivariate logistic regression revealed that HIV transmission risk behavior was significantly associated with HIV, HBV, HCV co-infections. Most HIV/HBV co-infection cases got HIV through sexual contact including heterosexual and homosexual behaviors (95/100, 95%); while most HIV/HCV co-infection subjects were injection drug users (IDUs) (89/133, 66.9%). In the case of HIV/HBV/HCV triple-infection, IDUs accounted for a large ratio (28/34, 82.4%). Among IDUs, most of them were male (108/122, 88.5%) and nearly half were aged 27 to 32 years old (56/122, 45.9%). Near half people who got HIV through blood and blood products were HIV/HCV co-infected (10/23, 43.5%). Gender has a significant correlation with HIV risk behavior and most IDUs were male. / Next, we applied ELISA to test HIV positive clinical samples and proved that plasma interleukin-27 (IL-27) level was significantly elevated in HIV mono-infected, HIV/HBV co-infected and HIV/HCV co-infected subjects when compared with healthy controls. Later, we further revealed that plasma IL-27 titer was not significantly varied among HIV, HBV and HCV co-infections except between HIV/HCV co-infections and HIV/HBV/HCV triple-infections. We also observed a significant positive correlation between CD4⁺ T cell counts and plasma IL-27 titer within HIV mono-infected group (r = 0.177, P = 0.034). / We further analyzed the impact HIV and HCV viral loads on plasma IL-27 titer. We found there was no significant correlation between HIV viral load and IL-27 titer among HIV mono-infected individuals (r = - 0.063, P = 0.679); while a significant positive correlation was observed between HIV viral load and IL-27 titer in HIV/HCV co-infected individuals (r = 0.362, P = 0.049). In the case of HIV/HCV co-infection, there was no significant linear correlation between HIV and HCV viral loads (r = - 0.072, P = 0.704) but exist obvious subdivision of samples in terms of HIV and HCV viral loads with significant IL-27 titer variance (P = 0.014). No correlation was observed between HCV viral load and IL-27 titer (r = - 0.119, P = 0.530). / IL-27 p28 polymorphisms were genotyped with TaqMan® Allelic Discrimination Assay in Chinese men who have sex with men (MSM) population in Shenzhen and the results revealed that proportions of IL-27 p28 -964A/G and 4603G/A genotypes were not significantly different from the healthy controls; IL-27 p28 -964A/G and 4603G/A allele frequencies were similar between HIV positive MSM group and healthy control MSM group. Results also showed that for IL-27 p28 2905T/G polymorphism, TG genotype has a 2.77-fold decreased risk of HIV susceptibility and subjects with G allele has a 2.72-fold decreased risk of HIV susceptibility. Linkage disequilibrium (LD) coefficients were observed between IL-27 p28 -964A/G and 2905T/G ( / In conclusion, the seroprevalences of HBV and HCV infection among HIV positive population in Shenzhen were surveyed and risk factors associated with co-infections were analyzed. Plasma IL-27 titer was significantly elevated in HIV mono-infected, HIV/HBV co-infected and HIV/HCV co-infected individuals. IL-27 level was correlated with CD4⁺ T cell counts within HIV mono-infected people. A significant positive correlation was found between HIV viral load and IL-27 titer in HIV/HCV co-infected individuals (r = 0.362, P = 0.049). IL-27 p28 2905T/G was associated with individual susceptibility to HIV infection and haplotype GGG showed a protective role in restricting HIV infection in MSM population. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / He, Lai. / "October 2012." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 135-155). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Abstract (English) --- p.iii / Abstract (Chinese) --- p.vi / Acknowledgements --- p.ix / Contents --- p.x / List of Tables --- p.xv / List of Figures --- p.xvi / Abbreviations --- p.xvii / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Human Immunodeficiency Virus --- p.1 / Chapter 1.1.1 --- HIV virology --- p.1 / Chapter 1.1.1.1 --- HIV structure and genome organization --- p.1 / Chapter 1.1.1.2 --- HIV life cycle --- p.3 / Chapter 1.1.1.3 --- HIV genotypes --- p.5 / Chapter 1.1.2 --- HIV epidemiology --- p.6 / Chapter 1.1.2.1 --- Global HIV epidemiology --- p.6 / Chapter 1.1.2.2 --- HIV epidemiology in China --- p.9 / Chapter 1.1.3 --- HIV pathogenesis --- p.13 / Chapter 1.1.3.1 --- Natural history of HIV infection --- p.13 / Chapter 1.1.3.2 --- HIV transmission --- p.15 / Chapter 1.1.3.3 --- HIV tropism --- p.17 / Chapter 1.1.4 --- Immune responses to HIV infection --- p.19 / Chapter 1.1.4.1 --- Innate immune response --- p.19 / Chapter 1.1.4.2 --- Adaptive immune response --- p.21 / Chapter 1.1.5 --- Diagnosis --- p.24 / Chapter 1.1.6 --- HIV prevention --- p.25 / Chapter 1.1.7 --- Anti-HIV therapy --- p.25 / Chapter 1.1.8 --- Hepatitis B virus, Hepatitis C virus infection --- p.26 / Chapter 1.1.8.1 --- HBV infection natural history, diagnosis, disease progression and epidemiology --- p.26 / Chapter 1.1.8.2 --- HCV infection natural history, diagnosis, disease progression and epidemiology --- p.30 / Chapter 1.1.9 --- HIV, HBV, HCV co-infections --- p.32 / Chapter 1.2 --- Interleukin-27 --- p.36 / Chapter 1.2.1 --- Biology of IL-27 --- p.36 / Chapter 1.2.2 --- IL-27 on immune system --- p.37 / Chapter 1.2.3 --- IL-27 anti-tumor properties --- p.38 / Chapter 1.2.4 --- IL-27 antiviral features --- p.40 / Chapter 1.2.5 --- IL-27 with hepatitis --- p.41 / Chapter 1.3 --- Single-nucleotide polymorphisms (SNPs) --- p.42 / Chapter 1.3.1 --- Types of SNPs --- p.43 / Chapter 1.3.2 --- Functions of SNPs --- p.43 / Chapter 1.4 --- Objectives of the study --- p.45 / Chapter Chapter 2 --- Seroprevalence of HBV, HCV infection among HIV positive individuals in Shenzhen --- p.52 / Chapter 2.1 --- Introduction --- p.52 / Chapter 2.2 --- Materials and methods --- p.54 / Chapter 2.2.1 --- Study participants --- p.54 / Chapter 2.2.2 --- Measure of HBV, HCV seroprevalence --- p.55 / Chapter 2.2.3 --- Statistical analysis --- p.60 / Chapter 2.3 --- Results --- p.61 / Chapter 2.3.1 --- HIV infection in Shenzhen --- p.61 / Chapter 2.3.2 --- Seroprevalence of HBV, HCV infection among HIV positive individuals in Shenzhen --- p.61 / Chapter 2.4 --- Discussion --- p.65 / Chapter 2.4.1 --- HIV infection in Shenzhen --- p.65 / Chapter 2.4.2 --- HIV, HBV, HCV co-infections in Shenzhen --- p.68 / Chapter 2.4.3 --- Limitations of the study --- p.71 / Chapter Chapter 3 --- Upregulation of Interleukin-27 titer in HIV infected persons --- p.78 / Chapter 3.1 --- Introduction --- p.78 / Chapter 3.2 --- Materials and methods --- p.80 / Chapter 3.2.1 --- Study participants --- p.80 / Chapter 3.2.2 --- Measure of HIV, HBV, HCV infection --- p.80 / Chapter 3.2.3 --- Detection of IL-27 in plasma --- p.81 / Chapter 3.2.4 --- CD4 counting --- p.84 / Chapter 3.2.5 --- Statistical analysis --- p.84 / Chapter 3.3 --- Results --- p.84 / Chapter 3.3.1 --- Demographics of study participants --- p.84 / Chapter 3.3.2 --- Upregulation of IL-27 levels in HIV infected persons --- p.85 / Chapter 3.3.3 --- Correlation of plasma IL-27 titer with CD4⁺ T cell count --- p.86 / Chapter 3.4 --- Discussion --- p.86 / Chapter Chapter 4 --- Impact of HIV, HCV viral loads on Interleukin-27 titer among Antiretroviral Therapy- Naïve HIV positive Chinese --- p.95 / Chapter 4.1 --- Introduction --- p.95 / Chapter 4.2 --- Materials and methods --- p.96 / Chapter 4.2.1 --- Study participants --- p.97 / Chapter 4.2.2 --- HIV, HBV and HCV Serological assays --- p.97 / Chapter 4.2.3 --- CD4 counting --- p.97 / Chapter 4.2.4 --- Detection of plasma IL-27 --- p.98 / Chapter 4.2.5 --- Quantification of HIV, HCV viral loads --- p.98 / Chapter 4.2.6 --- Statistical analysis --- p.102 / Chapter 4.3 --- Results --- p.102 / Chapter 4.3.1 --- Demographics of study participants --- p.102 / Chapter 4.3.2 --- Plasma IL-27 was elevated in HIV-positive persons --- p.103 / Chapter 4.3.3 --- Correlation of IL-27 titer and CD4⁺ T cell count --- p.103 / Chapter 4.3.4 --- Correlation of HIV viral load and IL-27 titer --- p.104 / Chapter 4.3.5 --- Correlation of HCV viral load and IL-27 titer --- p.104 / Chapter 4.4 --- Discussion --- p.105 / Chapter Chapter 5 --- Association of Interleukin-27 polymorphisms with the susceptibility to HIV infection in a Chinese men who have sex with men population --- p.116 / Chapter 5.1 --- Introduction --- p.116 / Chapter 5.2 --- Materials and methods --- p.118 / Chapter 5.2.1 --- Study participants --- p.118 / Chapter 5.2.2 --- HIV screening --- p.118 / Chapter 5.2.3 --- Genomic DNA extraction --- p.119 / Chapter 5.2.4 --- IL-27 p28 -964A/G, 2905T/G and 4603G/A genotyping --- p.120 / Chapter 5.2.5 --- Statistical analysis --- p.121 / Chapter 5.3 --- Results --- p.122 / Chapter 5.3.1 --- Demographics of study participants --- p.122 / Chapter 5.3.2 --- IL-27 genotypes and allele frequencies in HIV MSM and healthy MSM controls --- p.122 / Chapter 5.3.3 --- LD analysis and haplotype analysis --- p.123 / Chapter 5.4 --- Discussion --- p.124 / Chapter Chapter 6 --- Summary and perspectives --- p.130 / Chapter 6.1 --- Summary --- p.130 / Chapter 6.2 --- Perspectives --- p.132 / Bibliography --- p.135

As hepatites virais A e E estão entre as doenças mais comuns nos seres humanos, relacionadas a países com baixo nível socioeconômico e condições inadequadas de higiene. São transmitidas por via fecal-oral, diretamente pessoa a pessoa ou por contaminação de água e alimentos. Um ciclo zoonótico da hepatite E (genótipo 3) ocorre principalmente pelo consumo de carne ou contato direto com suínos. A incidência de hepatite A vem reduzindo no país, mas pouco tem sido estudado sobre a prevalência em cidades pequenas do interior. Os estudos sobre a hepatite E no país ainda são limitados e sugerem que o genótipo 3 seja o responsável pela infecção. Este estudo buscou estimar a prevalência das hepatites A e E na população adulta de Cássia dos Coqueiros (aprox. 2600 hab.) e levantar possíveis fatores de risco para as infecções. Trata-se de um inquérito soroepidemiológico em 990 habitantes de Cássia dos Coqueiros com mais de 18 anos de idade, aproximadamente 51% de toda a população do município nesta faixa etária, com uma subamostragem de 248 indivíduos especificamente para pesquisa de hepatite E. As amostras de sangue foram coletadas entre os anos de 2011 e 2013 e aplicado um questionário contendo informações demográficas, socioeconômicas e de fatores de risco. Foram realizados exames imunológicos (ELISA) para detecção de anticorpos IgG para as hepatites A e E. As prevalências foram estimadas por faixa etária e calculados seus respectivos intervalos de confiança. Os dados foram submetidos a análises uni e multivariadas, em modelo de regressão logística log-binomial. As associações foram testadas medindo-se as Razões de Prevalência e seus respectivos intervalos de confiança (95%). A prevalência de hepatite A na população total foi 89,1% (IC95%= 87,1 - 90,9), aumentando de acordo com as faixas etárias. Observou-se na análise univariada associação com idade, unidade federada de origem, escolaridade, estrato econômico, antecedentes de hepatite e de contato domiciliar com casos desta doença, bem como história de eliminação de proglotes de Taenia sp nas fezes, mas após ajuste do modelo, apenas a variável idade permaneceu independentemente associada. A prevalência de hepatite E foi 20,7% (IC95%= 15,5 - 25,7), identificando-se associação apenas com a escolaridade na análise univariada, mas que deixou de ser associada após ser ajustada no modelo multivariado. Este é o primeiro estudo soroepidemiológico de base populacional comparando a presença de VHA e VHE numa cidade de porte pequeno com características rurais na região Sudeste do país. Cássia dos Coqueiros apresenta-se como área de baixa endemicidade para VHA, assim como as regiões Sul e Sudeste. A prevalência de VHE foi a maior encontrada em estudo de base populacional ou doadores de sangue no país, mostrando que a infecção ocorre de forma mais frequente do que se acreditava e que mais estudos são necessários para verificar o genótipo circulante e os fatores de risco para infecção, possivelmente pela transmissão zoonótica do VHE3. / Viral hepatitis A and E are among the most common diseases in humans, related to countries with low socioeconomic level and inadequate hygiene conditions. They are transmitted by fecal-oral route, directly person to person or by contamination of water and food. A zoonotic cycle of hepatitis E (genotype 3) occurs mainly through meat consumption or direct contact with swine. The incidence of hepatitis A has been declining in Brazil, but little has been studied about the prevalence in small towns in the interior. Studies on hepatitis E in the country are still limited and suggest that genotype 3 is responsible for the infection. This study aimed to estimate the prevalence of hepatitis A and E in the adult population of Cássia dos Coqueiros (approximately 2600 inhabitants) and to assess possible risk factors for infections. This is a seroprevalence survey of 990 inhabitants of Cássia dos Coqueiros, over 18 years of age, approximately 51% of the entire population of the municipality in this age group, with a subsampling of 248 individuals specifically for hepatitis E screening. Samples were collected between the years 2011 and 2013 and a questionnaire containing demographic, socioeconomic and risk factors information was applied. Immunological tests (ELISA) were performed to detect IgG antibodies to hepatitis A and E. The prevalences of hepatitis A and E were estimated by age group and their respective confidence intervals were calculated. The data were submitted to multivariate analysis using a log-binomial logistic regression model. Associations were tested by measuring the Prevalence Ratios and their respective confidence intervals (95%). The prevalence of hepatitis A in the total population was 89.1% (95% CI = 87.1-90.9), increasing according to age. The univariate analysis identified association with age, federated unit of origin, education level, economic strata, history of hepatitis and home contact with cases of this disease, as well as history of elimination of Taenia sp proglottes in feces. After adjustment of the model, only age remained independently associated. The prevalence of Hepatitis E was 20.7% (95% CI = 15.5 - 25.7), which was only associated with education level in the univariate analysis, but no longer associated with adjustment in the multivariate model. This is the first population-based seroprevalence study comparing the presence of HAV and HEV in a small city with rural characteristics in the Southeastern region of the country. According to the WHO criteria, Cássia dos Coqueiros seems to be as an area of low endemicity for HAV, as well as the South and Southeast regions of Brazil. The prevalence of HEV was the highest found in a population-based study or blood donors in the country, showing that the infection occurs more frequently than previously believed and that more studies are needed to verify the circulating genotype and the risk factors for infection, possibly due to the zoonotic transmission of HEV3.

This thesis examines the effect of hepatitis C virus infection (HCV) on health-related quality of life (HRQOL) to define burden of disease at individual and population levels. A systematic review of HCV HRQOL studies was undertaken with translation of Short Form-36 (SF-36) Health Survey data into community-weighted health state utilities using three different methods. Derived estimates of health utilities were 0.87 for HCV treatment-induced sustained virological response (SVR); 0.81 for pre-cirrhosis; 0.76 for compensated cirrhosis; 0.69 for decompensated cirrhosis; 0.67 for hepatocellular carcinoma (HCC); and 0.77 for liver transplant. The HCV health state utilities varied considerably from expert estimates, with relatively lower estimates for early liver disease and higher estimates for advanced liver disease, but were comparable to direct patient-elicited utilities. A study utilising data from population-based health surveys incorporating HCV screening among prisoners at Australian correctional centres in 1996 and 2001 showed no measurable effect of HCV on HRQOL, including that attributable to HCV viraemia. Compared to uninfected Australian norms, prisoners had lower HRQOL irrespective of HCV status. Several non-HCV factors such as age, co-morbidity, severity of depressive symptoms, and medical care utilization influenced HRQOL. A prospective study of health outcomes among HCV monoinfected and HIV/HCV coinfected individuals conducted at Sydney tertiary level hepatitis clinics between 2003 and 2005 found similar cognitive function, mood, and HRQOL patterns in these two HCV groups in the context of pegylated interferon (PEG-IFN) alfa-2a and ribavirin therapy. The HCV groups had similar levels of pre-treatment HRQOL impairment, further on-treatment deterioration, and posttreatment improvements. SVR was associated with significant HRQOL improvements, but mental HRQOL improvement was also seen in individuals not achieving an SVR. The impact of HCV treatment uptake on HCV-related burden of disease at a population level in Australia was examined using a mathematical model. The model estimated that in 2004, there were ~181,500 cases of chronic HCV infection, 7,020 with HCV-related cirrhosis, and annual incidence of 238 cases of HCV-related liver failure and 70 cases of HCV-related HCC. Compared to no treatment, current treatment levels (~1% of HCV-infected individuals per annum) would reduce projected HCV-related cirrhosis and advanced liver disease numbers by ~30% at 2020 and a gain of ~122,200 Quality-Adjusted Life Years (QALYs). Even with a five-fold increase from current treatment levels, advanced liver disease numbers will continue to increase through 2020 but will be reduced by ~55% and a gain of ~483,200 QALYs.

Offprints of author's four journal articles in pocket / Bibliography: leaves 131-147 / x, 148 leaves, [13] leaves of plates : ill. (1 col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, 1986

Thesis (Ph. D.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

The Hepatitis B virus (HBV) chronically infects 350 million individuals worldwide, leading to mortality by end-stage liver disease, liver cirrhosis, and hepatocellular carcinoma. The vaccine to prevent HBV infection is highly effective but is not extensively available in endemic areas, resulting in high infection rates. Nucleoside analogue treatment of HBV has allowed for higher rates of viral clearance in infected individuals, but most patients must remain on therapy long term and viral resistance to the drugs is growing. The HBV viral genome is an episome in the nucleus of infected hepatocytes. It is called covalently closed circular (ccc) DNA and is highly stable, has a long half-life, and is the template for all viral transcription and progeny production. Nucleoside analogues do not directly target cccDNA, therefore many patients experience rebound when antiviral therapy is stopped. I have designed novel DNA binding proteins called zinc finger proteins (ZFPs) to specifically bind to the cccDNA in infected cells and inhibit viral transcription. Seven ZFPs targeting the model duck HBV (DHBV) and ten ZFPs targeting HBV were developed. Kinetic analyses of the purified ZFPs were performed, characterizing their specificity and binding properties. Using the DHBV tissue culture model system, I have demonstrated that the DHBV-specific ZFPs can specifically inhibit transcription from the viral template, resulting in reduced viral RNA, protein products and progeny virions. The DHBV-specific ZFPs were tested in primary duck hepatocytes (PDH) and in vivo in the Pekin duck model. ZFPs failed to express in PDH transduced by baculovirus vectors when DHBV was present in the cells. In vivo gene delivery of the ZFPs was carried out by portal vein injection of chitosan-based nanospheres. Unfortunately, non-specific reductions in viral levels masked any direct effect by the ZFPs. Testing of the HBV-specific ZFPs in tissue culture was hindered by a lack of transfectable cell culture model. A number of different transfection methods were tested to express the HBV-specific ZFPs, all without success. Further work is being carried out using baculovirus vectors to deliver the HBV-specific ZFPs to HBV-harbouring cell lines and HBV-infected scid-Alb/uPA chimeric mice with human liver cells. / Virology

Background: An estimated 50,000 adults in the United States (U.S.) die each year from one of 10 vaccine preventable diseases. For those who survive vaccine preventable infections, health care costs and loss of income become more significant. While children in the U.S. aged 0-2 exhibit vaccine prevalence rates of almost 90%, some adult vaccine prevalence rates in the U.S. population are reported to be nearly 30-40% less than the goals set forth by Healthy People 2010. The purpose of this study was to examine the associations between socio-demographic characteristics of U.S. adults and adult vaccination prevalence for pneumococcal, hepatitis A, hepatitis B, tetanus, and pertussis. Methods: Data from the 2008 National Health Interview Survey were assessed examining various health indicators and characteristics of non-institutionalized adults and children. The sample was restricted to adults ≥18 years of age. Odds ratios were calculated and multivariate logistic regression was also conducted. P-values of Results: There were 21781 total observations; 19.3% received the pneumococcal vaccine, 9.4% received the hepatitis A vaccine, 27.2% received the hepatitis B vaccine, 55.1% received the tetanus vaccine, and 15.2% received the pertussis vaccine. Of the socio-demographic characteristics examined, age, health insurance, marital status, and education were significant for either all five or at least four of the vaccines included in this study. As one might expect those who reported health insurance and those who had a higher level of education usually had a higher likelihood of vaccine receipt as compared to those without health insurance and those with less than a high school education. Age associations varied due to age-related recommendations for certain vaccines such as pneumococcal (recommended for adults ≥65). Compared to the married population (referent), marital status results varied, but for reasons unclear. Whites, the referent group, were the most likely to be vaccinated as compared to Blacks, Hispanics/Latinos, and Asians. Hispanics/Latinos typically had the lowest likelihood of vaccination in this examination. Conclusions: This study further explores the impact of socio-demographic disparities on vaccination status and adds new information to the literature regarding adult vaccination rates for preventable diseases. While research exists related to strengthening interventions such as patient reminder systems, those who do not see the same health care providers on a regular basis remain at risk for lower vaccination prevalence. It is important to better understand the role of social determinants of health, specifically in terms of vaccinations. Future research is needed to further characterize the association of socio-demographic factors with receipt of optional vaccines in adults.

Chronic liver disease is an important disease which affects national healthy in Taiwan. Hepatitis B or C virus infection is strongly relative to chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. However, the early effective treatment can decrease the progression of liver cirrhosis and hepatocellular carcinoma and increase the recovery rate. In order to promote the health care quality for the patients with hepatitis, Bureau of National Health Insurance (BNHI) implemented the ¡§Enhance Hepatitis B or C Health Care Program¡¨ in October of 2003. The new policy sets up the standard treatment models and pay medical costs to encourage the patients to participate this program and fit cost-effectiveness. Therefore, aims of the study are to estimate the effects of the new policy on health care utilization and expenditures for the patients with hepatitis B or C. The study used the database from Bureau of National Health Insurance (BNHI) in 2002 and 2004. The study sample is the patients with hepatitis B or C who enrolled the program from January to June in 2004. We compared the differences of health care utilization and expenditures with these statistics in 2002. Besides, we also analyzed the difference in the characteristics of the patients and hospitals. In health care utilization, we found that number of visits was increased but interval between visits was decreased. Total costs, costs of treatments, prescriptions, total claim amount, and averages of prescription costs in health care expenditures were all increased significantly after the new policy implemented. Otherwise, there were not different on health care utilization and expenditures between different gender and level of the hospitals. On the other hand, there were significantly correlation of ages and number of comorbility. It means that the patients¡¦ ages are older, and their number of visits and total costs are higher but interval between visits is shorter than younger. Furthermore, number of comorbility increases and then interval between visits become short. The new policy certainly affects the health care utilization and expenditures of patients with hepatitis B or C. Implementing the new program can encourage patients adopt treatment actively and physicians have standard treatment protocols to follow. Understanding the changes on health care utilization and expenditures can give a health care guideline of cost-effectiveness. In conclusion, the results can provide the information about payments on patients with hepatitis to BNHI and then use it to be a basis after the new program implemented. Moreover, other countries also can evaluate the implementation of the new policy based on our results.