People who experience structural violence are an increased risk for health conditions including HIV and Hepatitis C. Particularly they are at greater risk for experiencing known syndemic interactions between these two chronic infectious diseases. The risks are mediated bio-socially through the ways that structural inequality increases social and biological vulnerability to illness and suffering. Structural inequalities, or experiences of structural violence shape environments of risk; environments of risks increase social and biological vulnerability to the structures of risk promoting syndemic interactions between biological, behavioral, and psychological conditions. The lived experiences of people diagnosed with a combination of HIV, HCV, and mental health conditions (MHC) (e.g., mood disorders and depression) are, however, thus far understudied. Many aspects and consequences of structural violence and social suffering; poverty, homelessness, substance use, lack of access to healthcare, and structural risks for HIV, HCV, MHC and interactions between the three. Through this mixed-methods, primarily qualitative, ethnographic fieldwork with individuals in the Boston area living with HIV, HCV, or both HIV and HCV, or suffering from MHC I ethnographically explore people’s perceptions of their vulnerability to these syndemic interactions. I also investigate their experiences of being at-risk for these conditions. Through this process, I seek to illuminate individuals’ understandings of the impact structures of risk (i.e., substance use, food insecurity and unstable housing) have on lived experiences with HIV/HCV, HIV/MHC, and HCV/MHC syndemics. The perceptions of the lived realities of disease-behavioral-psychological interactions and health consequences are analyzed in the context of substance use. Substance use’s biological and social dimensions have a role in promoting syndemic interactions for each of the syndemics experienced within this population. Therefore, substance use is a syndemogenic factor because of its role as a mediator for environments of risks, and as a structural risk factor in all three of these syndemics. These interactions, and consequential health outcomes, in sufferers’ own words, enrich the landscape of syndemics research, producing a clearer picture regarding the structures of risks affecting this vulnerable group in the greater Boston area.

Background: Decentralization and task-shifting of hepatitis C virus (HCV) infection testing and management from specialty services to primary care is vital to achieve global and Canadian HCV elimination targets since direct-acting antiviral therapy revolutionized HCV management. Primary care providers are instrumental in enabling more accessible and sustainable community-based HCV management. Understanding primary care providers' experiences and beliefs on provision of HCV treatment in primary care is vital to optimize primary care-directed HCV treatment. Purpose: We aimed to use best practices from implementation science to determine the key factors influencing primary care physicians' provision of HCV treatment and to synthesize the published evidence on the barriers and enablers to optimizing primary care-directed HCV treatment to inform future implementation interventions. Method: In Study 1, we conducted theory-informed interviews with family physicians practicing in Ontario, Canada to identify perceived barriers of and enablers to their provision of HCV treatment. The interviews and data analysis were guided by the Theoretical Domains Framework (TDF), which incorporates 33 theories of behaviour change into 14 domains to systematically identify cognitive, affective, social, and environmental influences on health behaviours. In Study 2, we conducted a systematic review of the barriers and facilitators to optimizing primary care-directed HCV treatment using the TDF as the organising framework. We characterized key determinants of primary care-directed HCV treatment by using the theoretical constructs, generating themes, and mapping themes to relevant TDF domains to identify potential targets for future implementation interventions. Results: We conducted semi-structured TDF-based interviews with 20 family physicians and found 'knowledge gap of HCV treatment guidelines', 'time and resource constraint and competing priorities in primary care', and 'clarity of primary care physicians' professional role in HCV treatment cascade' were the key barriers and enablers to provision of HCV treatment in primary care. The systematic review included 20 studies which suggested 'enabling environment', 'primary care capacity', and 'knowledge deficit in HCV treatment guidelines' were the key factors coded to 'Environmental context and resources', 'Social influences', 'Identity and social professional role', and 'Knowledge' as the most relevant TDF domains to influencing the optimization of primary care-directed HCV treatment. Conclusion: Our results provided practical insights into the barriers and enablers to better primary care-based HCV management. Future research will focus on developing implementation strategies to tackle the barriers and fortify the enablers to optimal HCV treatment in primary care.

Bakgrund och problemformulering: Patienter med blodsmitta riskerar att bli sedda utifrån sin blodsmitta. Det kan bero på stigmatisering och förlegade synsätt som är formade utifrån vårdinrättningarnas vårdkultur. Patienten kan bli identifierad med sin blodsmitta och kan därmed få sämre vårdande möten eller utebliven vård. Fokus skiftas från den primära sökorsaken till blodsmittan i sig. Omvårdnaden som ska bedrivas utifrån Caritas brister på grund av rädsla för blodsmitta och vårdandet kan bli till ett vårdlidande. Syfte: Syftet är att beskriva blodsmittade patienters upplevelse i mötet med vårdpersonal.   Metod: Litteraturöversikt med nio kvalitativa artiklar som analyserats och granskats. Resultat: Presenteras utifrån två huvudteman: Diskriminering och stigmatisering med ett undertema sekretess och attityder med två underteman negativa attityder och positiva attityder. Slutsatser: Blodsmittade patienters upplevelse av vårdpersonalens bemötande innefattade negativa attityder, diskriminering och stigmatisering. Detta resulterade i utebliven behandling, vårdlidande och rädsla för att avslöja sin blodsmitta. Negativa attityder, diskriminering och stigmatisering yttrade sig i form av nedvärdering, utebliven behandling, onödiga hygienrutiner och sämre vård samt omvårdnad. Genom ökad kunskap om blodsmitta kan lidandet lindras för dessa patienter.

Current methods for studying RNA binding proteins (RBPs) combine the use of ultraviolet (UV) crosslinking and immunoprecipitation (CLIP) to analyze RNA-protein interactions. An underexplored alternative approach is using site-specific incorporation of photoactivatable non-canonical amino acids (ncAAs) to enhance the crosslinking efficiency of many CLIP protocols. This thesis describes the incorporation of the photo-crosslinking unnatural amino acid p-azido-L-phenylalanine (AzF) into the Hepatitis C Virus (HCV) non-structural protein 3 helicase (NS3h) for photo-crosslinking and in vitro analysis of the potential binding sites found within the HCV RNA genome. From the five potential sites identified from the NS3h crystal structure for AzF incorporation, two sites, E503AzF and Q580AzF, allowed for nucleic acid photo-crosslinking with fluorescently labelled DNA substrates. We further tested if these mutations adversely affected NS3h and binding activity through a molecular beacon helicase assay and fluorescence polarization methods. We found that E503AzF unexpectedly had a faster unwinding rate than wild type (WT) NS3h and managed to have a similar binding affinity to the tested DNA substrate. Finally, we found that there was a 5-fold increase in the photo-crosslinking efficiency of nucleic acids for E503AzF NS3h mutant compared to our WT NS3h at 254 nm UV light. We are currently working on methods for our CLIP-based protocol to ensure quality RNA footprint generation and purification from photo-crosslinked NS3h. Other work contained in this thesis consists of using Prevotella sp. P5-125 Cas13b (PspCas13b), a clustered regularly interspaced short palindromic repeats (CRISPR) RNA-targeting system, which has been previously shown to knockdown viral RNA and mRNA through designable guide CRISPR RNA (crRNA). Here we incorporated the photo-crosslinking ncAA AzF into PspCas13b to irreversibly bind the crRNA in an attempt to enhance knockdown efficiency and longevity of viral and mRNA targets. We were able to design a crRNA that produced significant knockdown targeting the luciferase mRNA of a luciferase rennilla reporter system. When targeting an HCV subgenomic replicon luciferase reporter system, knockdown was not observed. Additionally, the WT PspCas13b had photo-crosslinking to the bound crRNA and requires further optimization for future use.

Hepatitis C virus (HCV) infection is common among injection drug users (IDUs). There is accumulating evidence that circulating microRNAs (miRNAs) are related to HCV infection and disease progression. The present study was undertaken to determine the in vivo impact of heroin use on HCV infection and HCV-related circulating miRNA expression. Using the blood specimens from four groups of study subjects (HCV-infected individuals, heroin users with/without HCV infection, and healthy volunteers), we found that HCV- infected heroin users had significantly higher viral load than HCV-infected non-heroin users (p=0.0004). Measurement of HCV-related circulating miRNAs in plasma showed that miRs-122, 141, 29a, 29b, and 29c were significantly increased in the heroin users with HCV infection, whereas miR-351, an HCV inhibitory miRNA, was significantly decreased in heroin users as compared to control subjects. Further investigation identified a negative correlation between the plasma levels of miR-29 family members and severity of HCV infection based on aspartate aminotransferase to platelet ratio index (APRI). Heroin use and/or HCV infection also dysregulated a panel of plasma miRNAs. Taken together, these data for the first time revealed in vivo evidence that heroin use and/or HCV infection alter circulating miRNAs, which provides a novel mechanism for the impaired innate anti-HCV immunity among IDUs. Recent studies revealed that extracellular miRNAs were able to incorporate into cell-derived exosomes as a method of cell-to-cell interaction. Exosomes are a class of cell-released small vesicles that mediate intercellular communication by delivering functional factors to recipient cells. During HCV infection, the interaction between liver resident macrophages and hepatocytes is important for host defense and viral elimination, triggered by innate immune activation, especially Toll like receptors (TLR). In our study, we explored the role of macrophage-derived exosomes in the transmission of innate immune responses against HCV infection in hepatocytes, and the involvement of exosomal miRNAs in transferring the anti-HCV activities. We reported that upon TLR3 activation, macrophages shed exosomes that were able to attenuate HCV-JFH1 infection in Huh7 cells. We further demonstrated that exosomes from poly I:C treated macrophages were internalized by Huh7 cells, which induced the intercellular anti-HCV responses (type I interferon, interferon stimulated genes, etc.) and thus drastically inhibited HCV infection in Huh7 cells. Moreover, using an in vitro macrophage and Huh7 cell co-culture model, we also found exosomes mediated HCV suppression in Huh7 cells after TLR3 activation. The presence of exosome inhibitor in co-culture compromised the anti-HCV activity by TLR3-activated macrophages. Interestingly, the miRNA-29 family, which was reported to suppress HCV infection, was significantly increased in the macrophage exosomes after TLR3 activation. The inhibition of miRNA-29 partially compromised the anti-HCV activity of TLR3-activated macrophages, indicating the potential involvement of exosomal miRNAs in the transmission of anti-HCV activity from macrophages to Huh7 cells through exosomes. In conclusion, this study proposed an antiviral mechanism of TLR3 activation that involves the intercellular communication between immune cells and hepatic parenchymal cells via exosomes, and exosomal miRNAs. This discovery sheds light on exploiting the therapeutic potential of new drugs against HCV infection. / Pathology

Η πολυλειτουργική πρωτεΐνη core του ιού της ηπατίτιδας C (HCV) εμπλέκεται στην ανάπτυξη ηπατοκυτταρικού καρκινώματος (HCC) που προκαλείται από τον ιό της ηπατίτιδας C, αλλά ο μηχανισμός με τον οποίο συμβαίνει αυτό δεν είναι κατανοητός. Η ενεργοποίηση του μονοπατιού Wnt/ β-κατενίνη, παίζει ένα σημαντικό ρόλο στην ανάπτυξη ηπατοκυττταρικού καρκίνου, και τροποποιείται από την πρωτεΐνη core του ιού της ηπατίτιδας C. Ο ιός της ηπατίτιδας C χαρακτηρίζεται από εκτεταμένη γενετική ποικιλομορφία και διαφορετικά κλινικά δείγματα διαφέρουν όσον αφορά την μολυσματικότητα τους και την παθογένεια που προκαλούν. Σκοπός αυτής της μελέτης είναι να καθοριστεί ο ρόλος της γενετικής ποικιλομορφίας της πρωτεΐνης HCV core στην ενεργοποίηση του μονοπατιού Wnt/ β-κατενίνη και να μελετηθεί ο μοριακός μηχανισμός με τον οποίο η πρωτεΐνη HCV core ρυθμίζει την ενεργοποίηση αυτή. Η ενεργότητα του μονοπατιού Wnt/β-κατενίνη μελετήθηκε σε HEK 293T και Huh 7.5 κυτταρικές σειρές που εκφράζουν παροδικά τις πρωτεΐνες core των γενοτύπων 1a, 1b, 3a, 4a, 4f και από ένα μοναδικό δείγμα του γενοτύπου 1a που προέρχεται από έναν ασθενή από την Καμπότζη (1aCam). Μελέτες βασισμένες στη μέτρηση ενεργότητας της λουσιφεράσης, Western blot ανάλυση και qPCR, χρησιμοποιήθηκαν για την μέτρηση των επιπέδων έκφρασης γονιδίων και πρωτεϊνών. Βρέθηκε ότι η HCV core πρωτεΐνη ρυθμίζει θετικά την μεσολαβούμενη από τη β-κατενίνη Tcf-εξαρτώμενη ενεργότητα της λουσιφεράσης σε ένα γενοτυπο-εξαρτώμενο τρόπο. Σε συμφωνά με τα αποτελέσματα αυτά βρέθηκε ότι η πρωτεΐνη HCV core σταθεροποίει τα επίπεδα της β-κατενίνης, τόσο σε παροδικά μετασχηματισμένα κύτταρα, όσο και σε κύτταρα που μολύνονται με βακουλοϊούς που εκφράσουν τις πρωτεΐνες core των υποτύπων 4a και 4f. Τέλος, βρέθηκε ότι η πρωτεΐνη HCV core συμβάλει στην θετική ρύθμιση των γονιδίων c-myc, αξίνης και Tbx3, τα οποία είναι καθοδικά γονίδια στόχοι του μονοπατιού Wnt/β-κατενίνη και εμπλέκονται στην ανάπτυξη ηπατοκυτταρικού καρκινώματος. Συμπερασματικά, οι πρωτεΐνες HCV core διαφορετικών γενοτύπων του ιού ρυθμίζουν διαφορετικά το μονοπάτι σηματοδότησης Wnt/β-κατενίνη και η διαφορετική αυτή ρύθμιση μπορεί να σχετίζεται με ικανότητα των διαφόρων γενοτύπων του ιού της ηπατίτιδας C να επάγουν την ανάπτυξη ηπατοκυτταρικού καρκινώματος. / The multifunctional HCV core protein is implicated in the development of hepatocellular carcinoma (HCC) caused by HCV infection, but the underlying mechanism is not fully understood. Activation of the Wnt/ β-catenin pathway plays a major role in HCC and is modulated by the HCV core protein. HCV is characterized by extensive genetic diversity and different clinical isolates do vary in their infectivity and pathogenesis mainly due to variations in the structure/function relationships of individual viral proteins. The aim of this study is to determine the possible influence of genetic variability in HCV core protein in enhancing the Wnt/ β-catenin signaling activity and to elucidate the molecular mechanisms by which HCV core modulates activation of β-catenin. The Wnt/β-catenin activity was investigated in transiently transfected HEK 293T and Huh 7.5 cell lines transiently expressing HCV core proteins from HCV genotypes 1a, 1b, 4a, 4f and from a unique isolate of genotype 1a obtained from a Cambodian patient (1aCam). Luciferase-based reporter assay, Western blot, and qPCR, were used to measure gene and protein expression levels. We found that, HCV core protein upregulates β-catenin-mediated Tcf-dependent luciferase activity in a genotype specific manner. Consistent to these findings, HCV core stabilizes β-catenin levels. Finally, we showed that HCV core contributes to the upregulation of Tbx3 gene expression, a downstream target gene of Wnt/ β-catenin pathway contributing to HCC development. In conclusion, HCV core protein from different genotypes appears to differentially regulate the Wnt/β-catenin signaling pathway and this finding may contribute to different potential of HCV genotypes to induce HCC.

O transplante de fígado é definido como a terapêutica de escolha para as doenças hepáticas em estágio terminal. Por muitos anos, o sucesso deste procedimento foi mensurado pelas taxas de mortalidade e a freqüência de complicações nas anastomoses biliares e complicações infecciosas. No entanto, mais recentemente um novo foco de preocupação voltou-se para a avaliação da qualidade de vida no grupo de pacientes transplantados. Os benefícios do transplante hepático sobre a qualidade de vida dos pacientes é um evento já demonstrado previamente em alguns estudos que utilizaram questionários genéricos de avaliação de qualidade de vida. A qualidade de vida em saúde também pode ser acessada através de questionários específicos, como o LDQOL (Liver Disease Quality of Life). Este é um instrumento voltado especificamente para sintomas relacionados às doenças hepáticas, desenvolvido nos Estados Unidos e recentemente traduzido para o Português e adaptado culturalmente para à população brasileira. Objetivo Aplicar este novo instrumento na população de pacientes em lista de espera de transplante de fígado e naqueles submetidos a transplante, reavaliando diferentes aspectos da qualidade de vida destes pacientes e avaliando o impacto da recidiva da doença de base após o transplante hepático. Método: Foram aplicados os questionários LDQOL e SF?36 a 126 pacientes em acompanhamento ambulatorial regular no Serviço de Transplante e Cirurgia do Fígado do Hospital das Clínicas da Universidade de São Paulo, dos quais 65 eram pacientes cirróticos em lista de espera de transplante de fígado e 61 deles eram pacientes submetidos a transplante hepático há pelo menos 6 meses e no máximo há 60 meses. Também foi aplicado o questionário SF-36 a um grupo de doadores de sangue sadios, pareados por sexo e idade e que funcionou como grupo controle. As avaliações, realizadas a partir da formação destes 3 grupos, incluiram a comparação da qualidade de vida entre cirróticos e transplantados, a comparação entre indivíduos saudáveis e portadores de hepatopatia e a influência de outros aspectos como etiologia da doença hepática, escore do MELD, classificação de Child-Pugh, presença de co-morbidades, tempo decorrido do transplante e efeito da recidiva da doença hepática sobre a qualidade de vida do paciente transplantado. O método estatístico aplicado foi o teste de Mann- Whitney. Resultados: As pontuações atingidas para os pacientes em lista de transplante hepático para mensuração da qualidade de vida foram significantemente mais baixas do que aquelas atingidas pelo grupo controle. Na comparação entre cirróticos com MELD <= 15 e cirróticos com MELD > 15, tanto o SF-36 como o LDQOL mostraram pior qualidade de vida nos pacientes com MELD mais elevado. A comparação entre indivíduos antes e depois do transplante evidenciou melhor qualidade de vida no grupo de pacientes transplantados. Isto ficou evidenciado tanto pelo LDQOL como SF-36. No grupo de pacientes pré-transplante, o questionário LDQOL mostrou maior comprometimento da qualidade de vida naqueles pacientes com cirrose por VHC, quando comparado a outras etiologias, enquanto o SF-36 não teve a mesma acurácia em demonstrar esta diferença. Nos pacientes transplantados, a recidiva da hepatite C determina comprometimento da qualidade de vida, quando avaliados pelo LDQOL, mas não pelo SF-36. Conclusões: O uso de um instrumento de medida de qualidade de vida - o LDQOL - pôde demonstrar, com maior acurácia, o seu comprometimento nos pacientes cirróticos, a melhora observada nos pacientes transplantados e o impacto negativo da recidiva da hepatite C no pós-transplante. / Liver transplantation has been established as the standard treatment for patients with end stage liver disease and for many years the outcomes of its procedure has been measured as mortality rates and biliary and infectious complications. More recently a new issue has been raised and many studies have been changing the focus to analyze the health related quality of life among the population of transplanted patients. A positive effect of liver transplantation on health-related quality of life (HRQOL) has been documented in many studies using generic instruments. Health-related quality of life can also be assessed with specific instruments, as the Liver Disease Quality of Life(LDQOL), a questionnaire targeted to symptoms of hepatic disease, that has been recently translated to Portuguese and culturally adapted to Brazilian population. Our aim was to reevaluate different aspects of HRQOL before and after liver transplantation with this new instrument, and determinate the impact of liver disease recurrence after the surgical procedure. Methods: The LDQOL and SF-36 questionnaires were applied to 126 patients at the Service of Transplant and Liver Surgery of Clinical Hospital of University of São Paulo, 65 of them on the transplant waiting list and 61 of them after 6 to 60 months of liver transplantation. It was also analyzed the quality of life, by using the SF-36 questionnaire, of health blood donors, paired by sex and age, to serve as control group. Multiple comparisons were made concerning etiology of cirrhosis, co-morbidities, MELD scores, time elapsed of transplant, recurrence of liver disease after liver transplantation, using the Mann-Whitney test. Results: HRQOL scores for patients waiting for transplantation were significantly lower than those for the control group. Patients with MELD scores > 15 showed worse healthrelated quality of life than patients with MELD scores <= 15, both with SF-36 and LDQOL. When the group of transplanted patients was compared with patients before transplant, an improvement of HRQOL was found in the transplanted group with both SF-36 and LDQOL. Quality of life in pretransplant patients was found to be worse in those with cirrhosis due to hepatitis C than in those with cirrhosis due to other etiologies; the reduction in quality of life was found to be greater using LDQOL than using SF-36. Transplanted patients with recurrence of hepatitis C had worse HRQOL when measured with LDQOL, but not with SF-36. Conclusions: LDQOL, a specific instrument for measuring quality of life is more reliable than SF-36 in showing quality of life impairment. A deterioration in health-related quality of life after recurrence of hepatitis C could be observed with LDQOL.

This thesis aimed to describe the epidemiology of HCV in South Australian prisons - prevalence, transmission and risk factors. This thesis also aimed to determine the impact of incarceration on reported risk behaviours. A related objective was to evaluate the epidemiological effectiveness of the ELISA - 3 HCV antibody test using PCR as the gold standard. Finally, this thesis aimed to explore the potential for minimising HCV risk in the South Australian prison population. Methods: Two case note audits were conducted at each of eight publicly operated SA prisons ( in summer and winter ) to identify any documented HCV - antibody test results. Prisoners recruited at entry to prison were offered tests for HCV - antibody and completed a pre - entry risk factor survey. Participants completed additional risk factor surveys and ( if HCV - negative at last test ) underwent further antibody tests at three - monthly intervals for up to 15 months. A sample of participants also provided blood specimens for HCV - RNA testing. Limited stakeholder consultations with prison officers and nurses were also conducted. Quantitative data were analysed using univariate and multivariate techniques. Results: 1347 case notes were audited in summer, and 1347 in winter and an overall HCV prevalence of 42 % was estimated. In both univariate and multivariate analyses, HCV prevalence was significantly higher in female prisoners ( 65 % ), those aged above 28 years ( 48 % ), and in Indigenous prisoners originating from metropolitan areas ( 56 % ). Indigenous prisoners originating from remote areas had significantly lower HCV prevalence ( 20 % ). 666 prisoners were recruited at entry, and 42 % were estimated to be HCV - antibody positive. Three seroconversions were noted in 151 initially HCV - seronegative negative individuals followed up for a median time of 121 days - a rate 4.6 per 100 person years - but community exposure could not be ruled out. Overall agreement between HCV - antibody and HCV - RNA assays was 86 % ( 100% in the HCV negative samples ) - kappa = 0.71. Injecting history was highly prevalent in prison entrants ( 70 % ) and both community and prison injecting ( but not tattooing ) were independent predictors of entry HCV status. Prison history was also independently associated with entry HCV status. Injecting in prison during the study was infrequently reported, but significantly more likely in those testing HCV - antibody positive at prison entry ( risk ratio = 2.48, P = 0.046 ). Stakeholders were most supportive of strategies to increase education and to minimise risks associated with hair clippers, but did not support most other suggested preventive strategies. Other issues related to communicable diseases and infection control were explored in the stakeholder interviews. Conclusions: HCV prevalence in South Australian prisoners is extremely high and may have contributed to a ' ceiling effect ' , minimising the seroconversion rate observed in this population. Injecting is relatively infrequently reported in prison, but more likely in those already infected with HCV. Thus, contaminated injecting equipment represents a significant threat to other prisoners and prison staff. Strategies aimed at reducing HCV risk in prisons, which address the concerns of those expected to implement them, are proposed in this thesis. / Thesis (Ph.D.)--School of Population Health and Clinical Practice, 2006.

I) Hintergrund Die chronische Hepatitis-C-Infektion stellt global ein wesentliches Gesundheitsproblem dar. Diese Virusinfektion kann bei unbehandelten Patienten zur Leberzirrhose und im weiteren Verlauf bis hin zur Entwicklung eines hepatozellulären Karzinoms führen. Die einzige Behandlungsoption mit der Aussicht auf dauerhafte Viruselimination besteht in modernen Kombinationstherapien, die das Zytokin Interferon alfa enthalten. Wesentliche Merkmale sind – neben inzwischen sehr hohen Ansprechraten – eine Behandlungsdauer zwischen 24 und 48 Wochen, hohe Therapiekosten und ein Nebenwirkungsprofil, das sowohl somatische als auch psychopathologische Symptome umfassen kann. II) Untersuchungsgegenstand und Fragestellungen Sowohl die chronische Virusinfektion an sich als auch die aktuell verfügbaren Therapieverfahren bergen ein erhebliches psychisches Belastungspotential. Hauptgegenstand dieser Dissertation ist die Erfassung der psychologischen Aspekte der Erkrankung und der psychischen und psychopathologischen Nebenwirkungen einer Interferonbehandlung. Wesentliche bearbeitete Fragestellungen sind: - Welchen Belastungsfaktoren sind Hepatitis-C-Patienten bereits ohne aktuelle antivirale Interferontherapie ausgesetzt bzw. welche psychopathologischen Symptome zeigen diese Patienten? - Wie ist der zeitliche Verlauf psychopathologischer Symptome bei Hepatitis-C-Patienten vor, während und nach einer antiviralen Therapie? - Wie wirksam und wie sicher ist eine medikamentöse Behandlung der Interferon-induzierten Depression mit selektiven Serotonin-Wiederaufnahmehemmern (SSRI) unter Fortführung der antiviralen Therapie? III) Patienten und Methoden Studienteilnehmer waren Hepatitis-C-Patienten, die sich ambulant vorstellten bzw. in unsere Ambulanz überwiesen wurden und die jeweiligen Einschlusskriterien erfüllten. Zu den wichtigsten verwendeten psychometrischen Selbstbeurteilungsskalen zählen: HADS (Depressivität, Angst), SCL-90-R (psychopathologische Symptome), SF-36 (Lebensqualität) und FKV (Krankheitsverarbeitung). IV) Wesentliche Forschungsergebnisse Bereits ohne Einfluss des Zytokins Interferon bestehen starke Krankheits-assoziierte psychische bzw. psychosoziale Belastungen der Patienten, die sich in einem erhöhten Depressionsrisiko ausdrücken. Die erhobenen Depressionsscores stehen in signifikantem Zusammenhang mit der Erkrankungsdauer und den individuell bestehenden Optionen und Erfolgsaussichten einer antiviralen Interferontherapie. Prospektive Erfassungen der Auftretenshäufigkeit klinisch relevanter Interferon-assoziierter Depressionen ergeben Raten von ca. 30 %. Diese Größenordnung wurde sowohl in einer eigenen prospektiven Studie als auch im Rahmen einer vorgestellten Übersichtsarbeit bestätigt. Die Umstellung der verwendeten Formulierung des Medikaments von herkömmlichem Interferon alfa auf die pegylierte Variante brachte keine Verbesserung der Verträglichkeit z.B. im Hinblick auf die interferonassoziierte Depression. Ein rechtzeitiges Erkennen der entsprechenden Symptome vorausgesetzt, ist die antidepressive Behandlung der Interferon-assoziierten Depression mit Hilfe von selektiven Serotonin-Reuptake-Inhibitoren auch ohne generelle Prophylaxe sehr effektiv und sicher möglich. V) Diskussion Empfohlen wird ein engmaschiges psychometrisches Monitoring aller Hepatitis-C-Patienten im Therapieverlauf. Ausführliche Aufklärung, enger Arzt-Patienten-Kontakt während der Therapie, sowie die Betreuung durch einen festen Ansprechpartner während der bis zu einem Jahr dauernden Therapie sind wichtige Rahmenbedingungen für eine solche Behandlung. Für die medikamentöse Behandlung der Interferon-induzierten Depression gilt: Bei besonderer Indikation (z.B. Interferon-assoziierte Depression bei früheren Therapieversuchen) sollte eine SSRI-Sekundärprophylaxe in Betracht gezogen werden. Ansonsten ist eine entsprechende SSRI-Intervention beginnend mit dem Einsetzen einer klinisch relevanten Depression ausreichend.

This thesis aimed to describe the epidemiology of HCV in South Australian prisons - prevalence, transmission and risk factors. This thesis also aimed to determine the impact of incarceration on reported risk behaviours. A related objective was to evaluate the epidemiological effectiveness of the ELISA - 3 HCV antibody test using PCR as the gold standard. Finally, this thesis aimed to explore the potential for minimising HCV risk in the South Australian prison population. Methods: Two case note audits were conducted at each of eight publicly operated SA prisons ( in summer and winter ) to identify any documented HCV - antibody test results. Prisoners recruited at entry to prison were offered tests for HCV - antibody and completed a pre - entry risk factor survey. Participants completed additional risk factor surveys and ( if HCV - negative at last test ) underwent further antibody tests at three - monthly intervals for up to 15 months. A sample of participants also provided blood specimens for HCV - RNA testing. Limited stakeholder consultations with prison officers and nurses were also conducted. Quantitative data were analysed using univariate and multivariate techniques. Results: 1347 case notes were audited in summer, and 1347 in winter and an overall HCV prevalence of 42 % was estimated. In both univariate and multivariate analyses, HCV prevalence was significantly higher in female prisoners ( 65 % ), those aged above 28 years ( 48 % ), and in Indigenous prisoners originating from metropolitan areas ( 56 % ). Indigenous prisoners originating from remote areas had significantly lower HCV prevalence ( 20 % ). 666 prisoners were recruited at entry, and 42 % were estimated to be HCV - antibody positive. Three seroconversions were noted in 151 initially HCV - seronegative negative individuals followed up for a median time of 121 days - a rate 4.6 per 100 person years - but community exposure could not be ruled out. Overall agreement between HCV - antibody and HCV - RNA assays was 86 % ( 100% in the HCV negative samples ) - kappa = 0.71. Injecting history was highly prevalent in prison entrants ( 70 % ) and both community and prison injecting ( but not tattooing ) were independent predictors of entry HCV status. Prison history was also independently associated with entry HCV status. Injecting in prison during the study was infrequently reported, but significantly more likely in those testing HCV - antibody positive at prison entry ( risk ratio = 2.48, P = 0.046 ). Stakeholders were most supportive of strategies to increase education and to minimise risks associated with hair clippers, but did not support most other suggested preventive strategies. Other issues related to communicable diseases and infection control were explored in the stakeholder interviews. Conclusions: HCV prevalence in South Australian prisoners is extremely high and may have contributed to a ' ceiling effect ' , minimising the seroconversion rate observed in this population. Injecting is relatively infrequently reported in prison, but more likely in those already infected with HCV. Thus, contaminated injecting equipment represents a significant threat to other prisoners and prison staff. Strategies aimed at reducing HCV risk in prisons, which address the concerns of those expected to implement them, are proposed in this thesis. / Thesis (Ph.D.)--School of Population Health and Clinical Practice, 2006.