Background: Chronic HBV within the Canadian Arctic is considered endemic (>2% prevalence). To control endemic rates in Nunavut, a vaccination program was initiated approximately 20 years ago, targeted at newborns and grade school students, as an interim catch-up program, such that all individuals born after 1980 are potentially vaccinated. This study investigates the efficacy of these programs and is the first seroepidemiological survey to determine HBV prevalence in Nunavut in the post-vaccination era. Methods: Anonymized serum specimens scheduled for destruction following routine medical testing were collected from individuals granting consent. Specimens were tested for antibodies to HBV (anti-HBs, anti-HBc) and hepatitis C virus. Anti-HBc positive samples were further tested for surface antigen (HBsAg) positivity, and HBV DNA was extracted from HBsAg positive samples in order to perform molecular characterization. Results: 4802 specimens were collected according to the age distribution of Nunavut, with vaccine age cohort specimens comprising just over half of all collected specimens. Overall anti-HCV+ was 0.55%, with all positivity observed among those aged 24 to 69 years old. Total anti-HBc+ prevalence was 9.40%; however, a 10-fold decrease in the rate of HBV exposure was noted among those born after 1980 compared to those born before (1.89% vs 20.1%, p<0.001). HBsAg positivity was primarily documented in individuals born before 1980 (2.55%), although cases still occurred among the vaccine age cohort (0.21%). HBV subgenotype B5 (HBV/B5), known to be unique among Inuit and Alaska Native people, was the most prevalent genotype observed (82%). Vaccine-based antibody as the sole serological marker was evident in the vaccine age cohort, although the rate of decay with increasing age was much greater than anticipated. Conclusion: Nearly two decades after the advent of HBV vaccination in Nunavut, HBV prevalence has decreased to 1.17%, indicating a non-endemic or low risk prevalence. However, the persistence of infection and a lower than expected prevalence of vaccine-based immunity in the vaccine age cohort will require further investigation to understand the causes and consequences.

INTRODUCCIÓN:Diversos estudios epidemiológicos han mostrado la infección crónica por el virus de la hepatitis B (VHB) como factor etiológico del cáncer hepático (CH) y en las dos últimas décadas se ha constatado un incremento de la incidencia de éste en los países industrializados. Sin embargo, los factores de progresión a CH en portadores del VHB han sido estudiados mayoritariamente en países asiáticos, por lo que es importante determinar cuál es su incidencia en Catalunya. OBJETIVOSDeterminar: i) la tendencia de la incidencia y la mortalidad por cirrosis y cáncer hepático en Catalunya en el período 1980-1997; ii) la mortalidad por enfermedad hepática en una cohorte de 2.352 donantes de sangre infectados por el VHB; iii) los factores de riesgo de desarrollar enfermedad hepática en individuos infectados por el VHB.METODOLOGÍAi) los datos de incidencia y mortalidad por cirrosis y CH en Catalunya se recogieron a partir del Registro de Cáncer Poblacional de Tarragona y del Registro de Mortalidad de Catalunya. Las tendencias se evaluaron mediante el análisis joinpoint y el análisis edad-período-cohorte; ii) como grupo control se escogió a 15.504 donantes de sangre no infectados por el VHB. La cohorte y el grupo control se cruzaron con el Registro de Mortalidad de Catalunya para determinar el estado vital y la causa de defunción de los individuos fallecidos. El exceso de mortalidad de la cohorte respecto al grupo control se determinó mediante la Razón de la Mortalidad Estandarizada; iii) se invitó a la cohorte a una visita médica en el periodo 1994-1996, que incluyó una exploración médica, análisis de sangre (función hepática y marcadores serológicos de los virus hepatotrópicos) y un cuestionario epidemiológico. El cuestionario recogió la exposición a diversos factores de riesgo asociados a enfermedad hepática. Los sujetos diagnosticados de hepatopatía fueron los casos y los sujetos con función hepática normal los controles del estudio caso-control anidado en la cohorte. La asociación de cada factor de riesgo y la enfermedad hepática se determinó mediante la razón de las odds (OR). RESULTADOS i) En el período de estudio se constató una disminución de la mortalidad por cirrosis (- 3% anual) en ambos sexos, a excepción de los hombres de 25 a 35 años en que la mortalidad por esta causa aumentó (4.5% de incremento anual). La mortalidad y la incidencia del CH permanecieron estables en ambos sexos y en todos los grupos de edad. Se constató un incremento de la mortalidad por colangiocarcinoma en ambos sexos (10% de incremento anual). ii) Exceso de mortalidad por CH y cirrosis en los hombres infectados por el VHB respecto a los del grupo control (RME CH: 17.7; RME cirrosis: 10.5). En las mujeres, solo se evidenció un exceso de muertes por cirrosis respecto a las del grupo control (RME: 7.2). iii) Los factores de progresión a enfermedad hepática en individuos infectados por el VHB fueron: la replicación del VHB (OR: 20.5 IC95%: 7.9-53.0), historia de episodios de hepatitis agudas (OR: 2.3 IC 95%: 1.3-4.2), el consumo de alcohol (OR: 2.4 IC 95%: 1.5-4.1), la infección por el VHC (OR: 6.9 IC95%: 2.3-20.5). Se constató una interacción entre el consumo de alcohol y la historia de episodios de hepatitis agudas, y posiblemente, entre el consumo de alcohol y diabetes.CONCLUSIONESi) No se ha constatado en Catalunya un aumento de la incidencia y de la mortalidad por CH como en otros países industrializados. Si se ha constatado un incremento de la mortalidad por colangiocarcinoma; ii) Los individuos infectados por el VHB tienen un exceso de mortalidad por enfermedad hepática respecto a los individuos no infectados por el VHB; iii) La replicación del VHB, los antecedentes de episodios de hepatitis agudas, el consumo de alcohol y la coinfección por el VHC incrementan el riesgo de desarrollar enfermedad hepática en individuos infectados por el VHB. / GOALS:To Determine: i) time trends on incidence and mortality by cirrhosis and liver cancer in Catalonia during the period 1980-1997; ii) the mortality by liver disease in a cohort of 2352 blood donors infected by the Hepatitis B Virus (HBV); iii) risk factors to develop liver disease in HBV infected individuals.METHODS: i) Liver cancer incidence and mortality and cirrhosis mortality data were extracted from the population-based cancer registry of Tarragona and from the Catalan Mortality Registry. Statistical analysis: joinpoint analysis and an age-period-cohort modeling. ii) Control Group: 15504 blood donors non-infected by HBV. Record Linkage of the cohort and the control group with the Catalan Mortality Registry. Statistical Analysis: Standardized Mortality Ratios for all causes of death in the cohort. iii) Nested case-control study in the cohort. Cases: ndividuals with liver disease. Controls: individuals without liver disease. Statistical analysis: logistic regression in order to estimate the odds ratios.RESULTS AND CONCLUSIONS:i) During the period of study it has been shown: stability of the incidence and mortality by liver cancer in Catalonia, and a decrease in the mortality by cirrhosis in both sexes excluding males aged 25-35 years old in which mortality by this cause of death increased, and an increase by death of cholangiocarcinoma in both sexes. ii) An excess of risk of death by liver cancer and cirrhosis in the cohort men when they were compared with the control group. It has been observed an excess mortality by cirrhosis in the cohort women. iii) Risk factors associated to de development of liver disease in individuals infected by HBV were replication of HBV, acute hepatitis history, alcohol consumption and Hepatitis C virus infection.

Estudios realizados en diversos países han llegado a la conclusión de que las personas ingresadas en prisión deben ser consideradas como grupos de riesgo de infección por virus de la hepatitis B (VHB). El objetivo fundamental del presente trabajo ha sido investigar la utilidad de las campañas de vacunación anti-hepatitis B en la población reclusa, considerando: l. La inmunogenicidad de la vacuna, y 2. La factibilidad del propio programa (aceptación del cribaje serológico prevacunal y adeherencia al calendario vacunal establecido). Los objetivos adicionales fueron: 1º. Esclarecer si la permanencia en prisión constituye en sí misma un factor de riesgo de infección por los virus de la hepatitis B y D. 2º. Describir el papel que juegan determinadas características personales y otros factores de riesgo de los reclusos sobre la infección por VHB. 3º. Valorar la importancia relativa del consumo de drogas por vía parenteral (CDVP) sobre la infección por VHB y virus de la hepatitis Delta (VHD), y 4º. Interpretar el significado de la presencia aislada de anti-HBc y de anti-HBs, en el examen prevacunal.Previamente a la vacunación, se ha estudiado la prevalencia de marcadores del VHB (HBsAg, anti-HBc y anti-HBs) en 1742 reclusos varones de tres centros penitenciarios (CP) de Cataluña de diferentes características. Ello representa más del 98% de la población total de estos CP (reclusos presentes el día de inicio del estudio, más nuevos ingresos durante un periodo de 4, 5 y 6 meses). En los casos simultáneamente positivos para HBsAg y anti-HBc, se determinó además anti-HBc-IgM, HBeAg, anti-HBe y anti-HD. La presencia de marcadores se ha re1acionado con una serie de vbriab1es (demográficas, penitenciarias y factores de riesgo de infección), obtenidas mediante entrevista personal dirigida.Los reclusos ca1ificados como susceptibles a la infección por VHB (n=705, inc1uyendo 68 casos anti-HBs positivo aislado), fueron vacunados con vacuna recombinante antihepatitis B (20 microgramos, pauta de 0, 1 y 6 meses), practicándose extracciones postvacunales (6º y 9º mes del inicio), para determinar el título de anti-HBs alcanzado.En el examen prevacunal, el 63% de los reclusos presentaron algún marcador del VHB, el 7'1% HBsAg. Tanto el análisis simple como el estratificado (Mantel-Haenszel), mostró que el consumo de drogas por vía parenteral (COVP) era, en cada CP, el factor más fuertemente asociado a la infección por VHB, (para el conjunto de CP, CDVP seropositivos 83'6%, no CDVP seropositivos 41%, OR cruda 7'35, IC 95% 5'84+9'27). Los distintos patrones sero1ógicos de los seropositivos (excepto la prevalencia aislada de anti-HBs), fueron significativamente más comunes en el grupo drogadicto. El 53'9% de los reclusos portadores de HBsAg presentaron anticuerpos anti-HB (65'3% los CDVP vs. 26'7% los no CDVP, OR 5.17).Se consigue vacunar con 2 dosis a 2/3, y con 3 dosis a 1/3 de los reclusos susceptibles, obteniéndose tasas de seroconversión (80% al 9º mes) y títulos de anti-HBs moderadamente más bajos a los logrados en grupos de población sana. Son causa de peor respuesta la mayor edad, el CDVP y la infección por VIH. No inf1uye la presencia previa, aislada, de anti-HBs.La baja adherencia vacunal es fundamentalmente debida a la excarcelación del recluso antes de completar la pauta establecida de 0, l y 6 meses, proponiéndose para mejorar esta adherencia el empleo de pautas flexibles, y la de 0, 1 y 2 meses como pauta de referencia. La vacunación antihepatitis B de los reclusos permite actuar sobre grupos de población muy poco accesibles, de otro modo, a las redes sanitarias convencionales, protegiendo a estas personas dentro de la cárcel y fuera de ella.Se concluye además que el estilo de vida antes, o durante el encarcelamiento, especialmente el CDVP, es la principal causa de propagación de la infección por VHB y VHD, y que el mayor riesgo de los reclusos gitanos se relaciona probablemente con transmisión vertical y horizontal precoz en la infancia. / The fundamental purpose of this study was to investigate the usefulness of anti-hepatitis B vaccination campaigns in the prison population, considering: 1) the vaccine's immunogenicity and 2) the feasibility of the programme itself (acceptance of pre-vaccination serologic screening and compliance of the vaccination schedule).Prior to vaccination, the prevalence of hepatitis B virus (BBV) markers was studied in 1,742 male prisoners in 3 different types of prison centre (PC) in Catalonia. This number of prisoners represents over 98% of these PC's total population. Marker presence was related to a series of variables (demographic, prison and infection risk factors), obtained by means of personal guided interviews.In 63% of prisoners, some kind of HBV marker was detected, which was HBsAg in 7.1%. Parenteral drug consumption (POC) was the factor most strongly associated with BBV infection (raw OR 7.35, IC95% 5.84+9.27) .The different serologic patterns of the seropositive subjects (except the prevalence of anti-HBs alone), were more common in those practising PDC.It was possible to give two thirds of the prisoners 2 vaccine doses, and one-third 3 doses, obtaining seroconversion rates and anti-HBs titres moderately lower than those obtained in groups of healthy population. Advanced age, PDC and BIV infection cause a worse response. The prior presence of anti-HBs alone does not have any influence.Vaccination of prisoners against hepatitis B allows the conventional health networks to act on population groups that otherwise would be difficult to reach, thus protecting these people both inside and outside the prison. In order to improve vaccination schedule compliance, the use of flexible systems is suggested, 0, 1 and 2 months being the reference system.

This thesis investigates the epidemiology of hepatitis B virus infection (HBV) and estimates HBV-related liver disease burden in Vietnam and Australia using a cross-sectional study design and mathematical modelling. A population-based seroprevalence survey was undertaken in rural Northern Vietnam. In a sample of 870 study participants, prevalence of anti-HBV core antibody (anti-HBc) and hepatitis B virus surface antigen (HBsAg) was 68.2% and 19.0%, respectively, and hepatitis B e antigen (HBeAg) was detected in 16.4% of the HBsAg-positive group. Factors associated with HBV infection (anti-HBc and/or HBsAg-positive) were age 60 years or older (adjusted odds ratio (AOR), 3.82; 95% CI, 1.35??10.80; P = 0.01), residence in Vu Thu district (AOR, 3.00; 95% CI, 2.16??4.17; P <0.001), hospital admission (AOR, 2.34; 95% CI, 1.33??4.13; P = 0.003) and history of acupuncture (AOR, 2.01; 95% CI, 1.29??3.13; P = 0.002). Household contact with a person with liver disease (AOR, 2.13; 95% CI, 1.29??3.52; P = 0.003), reuse of syringes (AOR, 1.81; 95% CI, 1.25??2.62; P = 0.002) and sharing of razors (AOR, 1.69; 95% CI, 1.03??2.79; P = 0.04) were independent predictors of HBsAg positivity. Alanine aminotransferase (ALT) level was elevated (>40 IU/L) in 43% of the HBsAg-positive group; the proportion of elevated ALT was higher in HBeAg-positive (65%) compared with HBeAg-negative (39%) (P = 0.02). Based on data from the seroprevalence study, other prevalence estimates and HBV natural history parameters, a mathematical model was used to estimate HBV-related liver disease burden in Vietnam. Estimated chronic HBV prevalence increased from 6.4 million cases in 1990 to around 8.4 million cases in 2005 and was projected to decrease to 8.0 million by 2025. Estimated HBV-related liver cirrhosis and hepatocellular carcinoma (HCC) incidence increased linearly from 21 900 and 9400 in 1990 to 58 650 and 25 000 in 2025. Estimated HBV-related mortality increased from 12 600 in 1990 to 40 000 in 2025. To estimate HBV-related HCC incidence among Australians born in the Asia-Pacific region (APR), a mathematical modelling was developed utilising HBV natural history parameters, HBV prevalence estimates in APR countries and immigration data. Chronic HBV cases among the APR-born population increased rapidly from the late 1970s, reaching a peak of 4182 in 1990. Chronic HBV prevalence increased to more than 53 000 in 2005. Estimates of HBV-related HCC increased linearly from one in 1960 to 140 in 2005, with a projected increase to 250 in 2025. Universal HBV vaccination programs in countries of origin had limited impact on projected HBV-related HCC to 2025. HBV-related HCC survival was analysed in a population-based linkage study in New South Wales (NSW), Australia. Between 1994 and 2002, 278 HCC cases notified to the NSW Cancer Registry were linked to chronic HBV infection notifications to the NSW Health Department. The majority of cases were male (83.5%) and overseas born (93.6%); Asian-born cases accounted for 72.1%. Median survival following HCC diagnosis was 15 months. HCC survival was poorer among older age groups (P <0.001), and among cases with regional spread (HR 3.23; 95% CI, 1.83??5.69; P <0.001) and distant metastases (HR 3.85; 95% CI, 2.44??6.08; P <0.001). Sex, region of birth, and study period (1994??1997 versus 1998??2002) were not associated with HCC survival. The results of these studies show that HBV infection remains a major public health challenge in highly endemic countries such as Vietnam. HBV-related liver disease burden in Vietnam was estimated to increase for at least two decades despite the introduction of a universal infant HBV-vaccination program. Similarly, HBV-related HCC among Australians born in the APR was estimated to continue to increase over the next two decades. Survival for HBV-related HCC even in settings such as Australia continues to be extremely poor. Strategies are required to expand HBV treatment to individuals with chronic HBV infection who are at greatest risk of progression to advanced liver disease.

Bibliography: leaves 184-218. / xx, 218, [135] leaves, [15] leaves of plates : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The research in this thesis describes the development and use of assays to detect cellular immune responses in ducks with application to duck hepatitis B virus (DHBV) infections. This animal model is used to provide an additional area of research which complements the study of hepadnaviruses. The introduction contains an outline of the significance of hepadnavirus research, including hepatitis B virus (HBV) epidemiology, structure, replication and clinical manifestations of the diseases caused by the virus. / Thesis (Ph.D.)--University of Adelaide, Dept. of Microbiology and Immunology, 1997

Hepatitis B virus (HBV) is a global public health problem with an estimated number of 350 million carriers world wide who are at risk of development of severe liver disease and hepatocellular carcinoma. Despite currently available nucleoside analogue therapies no general therapeutic breakthrough, which completely clears infection has been achieved after more then two decades of research. Therefore there is a continuing need to identify new antiviral targets that may be translated into useful therapies. / Hepatitis B fusion represents a possible novel antiviral target. However, its mechanism and the envelope proteins involved remain unknown, due to the lack of an efficient infection system to study the early stages of virus infection. On the other hand, the study of the related duck hepatitis B virus (DHBV) and the ability to carry out an in vitro infection of primary duck hepatocytes has provided some insight into the hepadnaviral mechanism of entry and the role of envelope proteins domains in this process. ( For complete abstract open document)

Bibliography: leaves 184-218. / xx, 218, [135] leaves, [15] leaves of plates : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The research in this thesis describes the development and use of assays to detect cellular immune responses in ducks with application to duck hepatitis B virus (DHBV) infections. This animal model is used to provide an additional area of research which complements the study of hepadnaviruses. The introduction contains an outline of the significance of hepadnavirus research, including hepatitis B virus (HBV) epidemiology, structure, replication and clinical manifestations of the diseases caused by the virus. / Thesis (Ph.D.)--University of Adelaide, Dept. of Microbiology and Immunology, 1997

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

Master of Dental Surgery / This work was digitised and made available on open access by the University of Sydney, Faculty of Dentistry and Sydney eScholarship . It may only be used for the purposes of research and study. Where possible, the Faculty will try to notify the author of this work. If you have any inquiries or issues regarding this work being made available please contact the Sydney eScholarship Repository Coordinator - ses@library.usyd.edu.au

The small envelope of hepatitis B virus (HBV) can self-assembles into virus-like particles (VLPs) and they are highly immunogenic. The use of hepatitis B surface antigen (HBsAg) as a vector to deliver foreign CTL epitopes has met with little success due to the constraints of HBsAg stability and secretion imposed by the insertion of foreign sequence into critical regions. In this study, the efficacy of the small HBsAg envelope protein to deliver foreign CTL epitopes using a protective CTL epitope of human respiratory syncytial virus (RSV) was investigated. The strategy of deleting a DNA sequence encoding HBsAg-specific CTL epitopes at different sites and replacing with DNA sequence encoding RSV CTL epitope resulted in recombinant HBsAg DNA immunogens which elicited effector and memory CTL responses in vitro, and RSV protective responses in vivo when these recombinant HBsAg DNAs were used to immunised mice. These data demonstrate the efficacy of HBsAg DNA as a vector for the delivery of disease relevant protective CTL responses. They also suggest the applicability of the approach to derive recombinant HBsAg DNA immunogens simultaneously encoding protective CTL epitopes for multiple diseases. The use of HBsAg VLPs has been used globally as administered vaccine for hepatitis B virus infection makes it an attractive vector candidate to deliver immunogens for other diseases. Since the HBsAg DNAs we tested formed recombinant HBsAg VLPs, our results have implications for the development of vaccination strategies using either recombinant HBsAg DNA or VLP vaccines.