Hepatitis C is a public health crisis in both developing and developed countries. Direct acting antiviral therapies have revolutionized the fight against Hepatitis C, making the worldwide eradication of the disease feasible. However, screening and access to care for vulnerable patients – especially for patients experiencing homelessness – are lacking. Homelessness exacerbates the effects of Hepatitis C, leading to poor health outcomes for individual patients and high costs for health providers and taxpayers. One potential solution is investing in affordable housing and the housing first model that provide the stability needed to address both acute and chronic health conditions, including Hepatitis C. Partnerships between patients and providers facilitated by supportive housing can benefit individual outcomes and decrease the financial and social costs to communities.

The human immunodeficiency virus (HIV)-hepatitis C virus (HCV) coinfection is one of the most common coinfections across the globe. There are over 2 million people living with both HIV and HCV worldwide. In the United States, HIV-HCV coinfections present a huge public health issue. There are several risk factors associated with developing this coinfection. One of the greatest risk factors is injection drug use and the practice of sharing needles. With the advent of the opioid epidemic, the number of people contracting both infections have skyrocketed. Despite the large prevalence rate, people with HIV-HCV coinfections can be treated for both infections. Medical professionals have begun successfully controlling HIV infections through antiretroviral therapies and treatments. These HIV regimens have worked well to increase the cluster of differentiation 4 (CD4) cell counts to manageable levels in many patients. Clinicians have used several different HIV medications that are easily categorized into five separate categories: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase strand transfer inhibitors, protease inhibitors, and C-C chemokine receptor type 5 (CCR5) antagonists. Of these medications, nucleoside reverse transcriptase inhibitors and protease inhibitors have been commonly used with direct-acting antivirals. Like antiretroviral treatments, these direct-acting antivirals (or HCV regimens) have been largely successful in reducing HCV ribonucleic acid (RNA) levels and effectively “curing” the HCV infection. However, some serious complications occurred in several cases because of drug-drug interactions between antiretroviral and direct-acting antiviral medications. This study was dedicated (1) to exploring the many benefits that these medications have for coinfected patients and (2) to analyzing the significant consequences of these drug-drug interactions. To achieve both goals, a review of various research studies, websites, and textbooks was instigated through PubMed, Google Scholar, and the Boston University library system. The resulting research studies spanned a period from the 1980s to the 2010s. The implications from these sources suggest that more extensive testing of medications, regimens, and drug combinations is needed to allow for a more individualized and simplified HIV-HCV treatment plan for each patient. Additional testing may also lead to more generalizable findings that could be applied to a large swath of the population in the United States.

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.

京都大学 / 新制・課程博士 / 博士(社会健康医学) / 甲第23120号 / 社医博第116号 / 新制||社医||11(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 今中 雄一, 教授 中山 健夫, 教授 佐藤 俊哉 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

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Le virus de l'hépatite C (HCV) représente un problème de santé publique à l'échelle mondiale. Les thérapies actuelles ne permettent pas de guérir tous les patients infectés par le HCV et certains antiviraux ont des effets secondaires importants. Dans la première partie de ma thèse, nous avons identifié des combinaisons d'antiviraux à action directe (DAA) et d'inhibiteurs d'entrée caractérisés par un effet synergique dans la prévention et le traitement du HCV dans des modèles de culture cellulaire et les souris uPA-SCID avec un foie chimérique. Ceci représente une nouvelle stratégies de lutte contre l'infection par le HCV. Dans la seconde partie de ma thèse, nous avons démontré que le mode de transmission du HCV de cellule à cellule est la voie de transmission dominante dans les modèles de culture cellulaire. De plus, les virus résistant aux DAA se propagent efficacement grâce à la transmission de cellule à cellule. L'inhibition de la transmission de cellule à cellule en utilisant des inhibiteurs d'entrée est un moyen efficace pour empêcher l'émergence de virus résistant aux DAA et pour potentialiser l'efficacité antivirale des DAA pour éradiquer l'infection par le HCV. / Hepatitis C virus (HCV) poses a threat to global health with infecting about 170 million people. Current therapies cannot cure all the patients infected with HCV and have obvious side effects. In the first part of my thesis, we uncovered combinations of direct-acting antivirals (DAAs) and entry inhibitors caracterized by a synergistic effect in prevention and treatment of HCV infection using HCV cell culture models and human liver chimeric uPA-SCID mice, thereby providing a new strategy to control HCV infection. In the second part of my thesis, we demonstrated that HCV cell-cell transmission is the dominant transmission route in cell culture models and that DAA-resistant HCV spread efficiently through cell-cell transmission to develop viral resistance. Blocking cell-cell transmission using entry inhibitors allows to prevent the emergence of DAA-resistant virus and potentiates the antiviral efficacy of DAAs to clear HCV infection. In summary, we provide novel strategies to enhance antiviral efficacy by combining entry inhibitors and DAAs and to prevent viral resistance by blocking viral cell-cell transmission.

L’infection par le virus de l’hépatite C (VHC) est l’un des principaux problèmes de santé publique chez les utilisateurs de drogues injectables (UDI). Actuellement, plusieurs outils sont disponibles pour réduire le fardeau du VHC dans cette population. Ceux-ci incluent des programmes de réduction des méfaits, tels que le traitement par un opioïde agoniste (TAO), pouvant réduire le risque d'infection par le VHC, ainsi que des traitements antiviraux extrêmement efficaces pour éradiquer le virus parmi les infectés. Plus récemment, il y a eu un intérêt national et international à éliminer le VHC en tant que menace pour la santé publique d'ici 2030, tout en priorisant les UDI dans les efforts de prévention et traitement. Parallèlement à ce mouvement, plus globalement, le fardeau des méfaits liés aux pratiques d’injection chez les UDI, tels que la surdose, soulignent la nécessité d’adopter une vision plus large sur leur santé. Dans l’ensemble, cette thèse vise à combler certaines lacunes dans les connaissances vis-à-vis de l’élimination du VHC chez les UDI. Premièrement, puisque le lien entre l’adéquation du dosage des TAO et le risque d’infection au VHC est peu connu, j’examine cette relation dans un échantillon d’UDI suivis dans la cohorte HEPCO à Montréal. Les résultats indiquent que le risque d'infection par le VHC ne serait pas systématiquement réduit chez toutes les personnes recevant des TAO, mais plutôt que ce risque varie en fonction de la dose prescrite et de l’adéquation du dosage telle que perçue par le patient. Ces résultats soulignent qu’un élargissement de l'accès aux TAO ne serait pas suffisant pour atteindre les objectifs de prévention et d'élimination du VHC, et que l’adéquation du dosage devrait être prise en compte dans le cadre de nos efforts de prévention. Deuxièmement, l’accès aux traitements antiviraux est faible chez les UDI, en partie à cause des préoccupations des prestataires et des décideurs politiques qui craignent une augmentation de la consommation de drogues et des comportements à risque après le traitement. En capitalisant sur deux études différentes - la cohorte IMPACT à Montréal et les essais SIMPLIFY / D3FEAT menés dans plusieurs pays - je montre que les comportements liés à la drogue diminuent ou restent stables après le traitement du VHC. Ensemble, ces deux études suggèrent que les préoccupations liées à une consommation élevée de drogue ou à une hausse des comportements à risque après le traitement ne seraient pas fondées. Ainsi, ces résultats appuient davantage une augmentation de l’accès au traitement chez les UDI. Troisièmement, allant au-delà du VHC en tant que problématique principale, en capitalisant une fois de plus sur les données collectées dans HEPCO, j’examine les associations entre trois facteurs - le TAO, le logement et le revenu - et la fréquence d’injection chez les UDI. Puisque la consommation de drogues est dynamique dans le temps, j'examine dans quelle mesure ces trois facteurs sont liés à la fréquence d’injection chez des UDI ayant des trajectoires d’injection variées. Nos résultats indiquent que la stabilité socioéconomique et le TAO seraient systématiquement liés à une fréquence d'injection inférieure chez les UDI, quelles que soit leurs trajectoires d’injection sous-jacentes. Globalement, ces résultats suggèrent qu’il y aurait des moyens de soutenir tous les UDI à atteindre de petits changements comportementaux qui pourraient réduire les risques liés aux pratiques d’injection, qu’ils soient ou non en mesure d’arrêter l’injection de drogues. En conclusion, alors que presque tous les pays ont lancé un effort mondial pour éliminer le VHC, des efforts sont nécessaires pour optimiser les programmes de réduction des méfaits bien établis afin de réduire la transmission du VHC, et d’accroître l’accès au traitement chez ceux qui sont infectés, tout en considérant les besoins et les préoccupations des communautés touchées. Cette thèse a fourni des données permettant d’éclairer (i) l’optimisation des TAO dans la prévention de la transmission du VHC, (ii) l’élargissement de l’accès au traitement du VHC et (iii) l’accès à des logements et revenus stables afin de réduire plus globalement les risques liés aux pratiques d’injection chez les UDI. Ainsi, ces résultats pourraient aider à réduire le fardeau du VHC chez les UDI et à soutenir le progrès vers l'élimination du VHC. / Infection with hepatitis C virus (HCV) is one of the main public health concerns affecting people who inject drugs (PWID). Although no effective prophylactic vaccine currently exists to prevent acquisition of HCV, a number of other tools are available to curb the HCV burden among PWID. These include harm-reduction programs, such as opioid agonist treatment (OAT), which can reduce the risk of HCV infection among those susceptible, and highly effective antiviral therapies to eradicate the virus among those who are infected. In recent years, there has been national and international interest in eliminating HCV as a public health threat by 2030, prioritising PWID in prevention and treatment efforts given that they are the population most affected. In parallel to this global effort, the high prevalence of injection-related harms among PWID that are unrelated to HCV, such as overdose, highlight a need to adopt a broader view on drug user health. Overall, this thesis is concerned with addressing some of the knowledge gaps and barriers that remain to achieving HCV elimination in PWID. First, because little is known about the importance of OAT dosage in influencing the risk of HCV acquisition, I examine this relationship in a sample of PWID followed in the Hepatitis Cohort (HEPCO) in Montreal. Findings indicate that the risk of HCV infection may not be systematically reduced for everyone receiving OAT and rather, that the risk of infection varies considerably according to the level of the prescribed OAT dosage and patient-perceived dosage adequacy. These findings suggest that simply scaling-up OAT access may not be sufficient to achieving the HCV elimination goals, and that the dosage of treatment should be considered as part of prevention efforts. Second, uptake of HCV treatment is low among PWID, partly due to concerns among providers and policymakers that drug use and injection risk behaviours may increase following treatment, thereby negating the benefits of therapy. Capitalising on two different studies - the IMPACT Cohort in Montreal and the SIMPLIFY/D3FEAT trials conducted in several countries - I illustrate that drug-related behaviours decrease or remain stable following HCV treatment. Together, these two studies suggest that concerns of escalating drug use or risk behaviours following HCV treatment are unfounded, further supporting the importance of expanding access to therapy among PWID. Third, moving beyond HCV as the primary focus of research, and capitalising once more on data collected in HEPCO, I examine the associations between three factors- OAT, housing and income, and patterns of injection frequency among PWID. Recognizing that injection patterns are dynamic over time, I examine the extent to which these three factors relate to injection frequencies among PWID with diverse trajectories of injection drug use, followed over a period of 7.5 years. Our findings indicate that socioeconomic stability and OAT are consistently associated with a lower injection frequency among all PWID, irrespective of their underlying injection trajectory and whether or not they are on a path to cessation. These findings suggest that there may be ways to support PWID in making small behavioral changes that could reduce their risks of injection-related harms, irrespective of whether or not they are in a position to stop injecting. In conclusion, at a time when many countries have embarked onto a global effort to eliminate HCV, efforts are needed to ensure that well-evidenced harm-reduction programs are optimised to reduce transmission of HCV, treatment for HCV infection is scaled-up among those who are infected ,and efforts do not overlook the basic needs and concerns of affected communities. This thesis provided data to help inform (i) optimisation of OAT provision for the prevention of HCV transmission, (ii) expanded access to HCV treatment, and (iii) access to stable housing and income to reduce the risk of injection-related harms among PWID. Ultimately, findings could contribute to reducing the HCV burden among PWID, helping move towards HCV elimination and, more broadly, improving the overall health of this marginalised group.

The prevalence of Hepatitis C Virus (HCV) in the US is estimated at 3.5 million with 18,153 deaths in 2016. It is the most common bloodborne infection, with a higher age-adjusted mortality rate than Hepatitis B Virus or Human Immunodeficiency Virus. Without treatment, nearly 1.1 million people will die from HCV by 2060. About 41,200 new cases of HCV were reported in 41 states in the US in 2016. The reported cases of acute HCV in 2016 is 2.3 per 100,000 in Tennessee, which is more than twice the national goal set by Healthy People 2020. This is a descriptive study to ascertain the HCV prevalence and usefulness of screening in medical outreach settings (MO) compared to indigent healthcare clinics (IHC) in northeast Tennessee. This study period was from April 2017 – February 2019. Participants (n=250), were adults, who engaged in routine, opt-out HCV testing at 4 IHC and 3 MO sites in the Tri-Cities, TN region. During the screening, demographic information- age, gender, race- were collected and the de-identified data were analyzed using Statistical Analysis System (SAS 9.3) to perform a descriptive analysis. Also, several discrete Chi-Square tests of independence between the demographic variables, screening locations, and HCV antibody prevalence was conducted. A total of 250 clients were screened for HCV. The majority of clients screened were non-Hispanic whites 228 (91.20%); females 136 (54.40%); young adults 131 (52.40%) and at IHC clinics 187 (74.80%). Screening showed HCV antibody prevalence of 14.8%. The majority of positive cases were non-Hispanic whites 36 (97.30%; P=0.1561); females 19 (51.35%; P=0.6867) and young adults 23 (62.16%; P=0.286). The prevalence at the IHC clinics and MO settings were 36 (97.30%; P=0.0006) and 1(2.70%) respectively. This analysis shows the higher yield of targeted HCV screening at IHC clinics. Focused HCV screening is critical in the era of opioid epidemic, particularly when direct-acting antiviral agents (DAAs) which offer a Sustained Virologic Response (SVR) rate of more than 90% are available. The use of case control or cohort study designs to establish causality is recommended for improving focused HCV screening.