Background: The incidence of tuberculosis (TB) among Inuit is over 400 times that of Canadian-born non-indigenous people. To address this, more patients will need to complete preventative treatment. Methods: First, data were extracted retrospectively for all patients with a tuberculin skin test (TST) implanted in Iqaluit, Nunavut between January 2012 and March 2016 and used to identify sources of loss from the latent TB infection (LTBI) cascade of care. Associations between demographic and clinical factors and treatment non-initiation and treatment non-completion were identified using regression models. Second, using a slightly expanded version of the retrospective dataset plus other sources, a Markov model was utilized to assess the cost-effectiveness of a novel shortened regimen for LTBI (12 weeks of once weekly isoniazid and rifapentine (3HP)) compared to the current standard of care (9 months of isoniazid monotherapy (9H)). Results: Treatment non-initiation and non-completion were the largest sources of loss of TST positive patients from the cascade of care. LTBI testing via employment screening was associated with treatment non-initiation while older age was associated with both treatment noninitiation and non-completion. In cost-effectiveness analysis, 3HP was dominant over 9H: costs were lower ($835 vs $1229 per person) and health outcomes slightly improved (20.14 vs 20.13 QALYs gained per person treated), largely due to an improved treatment completion with 3HP. Conclusions: Interventions to increase LTBI treatment initiation and completion in Iqaluit are needed. This could include the use of 3HP instead of 9H for LTBI treatment which may improve treatment completion and result in cost savings and slightly improved health outcomes.

The efficacy of rifapentine, an oral antibiotic used in the treatment of tuberculosis, is reduced due to its degradation at gastric pH and low solubility at intestinal pH. We aimed to improve delivery properties in vitro by incorporating rifapentine into pH-responsive amorphous solid dispersions with cellulose derivatives including: hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate suberate (CASub), and 5-carboxypentyl hydroxypropyl cellulose (CHC). Most amorphous solid dispersions reduced rifapentine release at gastric pH, with the best performing polymer CASub showing >31-fold decrease in area under the curve compared to rifapentine alone. Lower solubility at gastric conditions was accompanied by a reduction in the acidic degradation product 3-formylrifamycin, as compared to rifapentine alone. Certain formulations also showed enhanced apparent solubility and stabilization of supersaturated solutions at intestinal pH, with the best performing polymer HPMCAS showing almost a 4-fold increase in total area under the curve compared to rifapentine alone. These in vitro results suggest that delivery of rifapentine via amorphous solid dispersion with cellulose polymers may improve bioavailability in vivo. / Master of Science in Life Sciences

Latent tuberculosis infection (LTBI) is a global health issue that affects approximately one quarter of the world’s population. It refers to a state of persistent immune response to Mycobacterium tuberculosis without clinical evidence of active tuberculosis (TB). Latent tuberculosis infected individuals are asymptomatic and not contagious to others, however 5-15% of all infected individuals are at risk of developing active tuberculosis and become contagious, severely ill, or worse, die from active TB. There are identified risk groups that are targeted for identification, diagnosis and treatment of latent tuberculosis infection. These are human immunodeficiency virus (HIV) patients, children and adolescents, household or close contacts of active TB cases, migrants, refugees, prisoners and health care workers. The standard treatment used for treating LTBI is the isoniazid monotherapy. It has a high proven efficacy rate but is linked to poor acceptance and low completion rates, basically due to its long treatment duration and poor tolerability. A newer treatment regimen is the rifapentine plus isoniazid combination therapy. It is an effective regimen against LTBI and has a shorter treatment duration. The aim of this literature study was to evaluate the efficacy of rifapentine plus isoniazid combination therapy compared with the isoniazid monotherapy as treatment of latent tuberculosis infection. This thesis was based on five randomized clinical trials collected from PubMed database. The studies should have entailed an efficacy comparison between isoniazid monotherapy and rifapentine plus isoniazid combination therapy for the treatment of patients with latent tuberculosis. The studies showed lower rates of active TB and death in the rifapentine plus isoniazid combination group in comparison with the isoniazid monotherapy. The studies also proved that rifapentine plus isoniazid combination therapy was noninferior to the standard isoniazid monotherapy. The completion rates were significantly higher in the combination therapy arm. The safety profile between the two treatment regimens was similar, but with an increased hepatotoxicity rates in the isoniazid-only arm. The rifapentine plus isoniazid combination therapy is as efficacious as the isoniazid monotherapy. This shorter regimen could be used as first hand therapy as well for latent tuberculosis patients with high-risk of developing active TB as it has shown good tolerability and higher completion rates that is important to successfully treat LTBI and help eliminate TB worldwide. / Latent tuberkulos är ett globalt hälsoproblem som drabbar ungefär en fjärdedel av världens befolkning. Den definieras som ett tillstånd av immunreaktion mot Mycobacterium tuberculosis utan kliniska tecken på aktiv tuberkulos (TB). De infekterade individerna är asymtomatiska och inte smittsamma för andra, men 5–15% av alla infekterade individer riskerar att utveckla aktiv tuberkulos och bli smittsamma, bli allvarligt sjuka, eller värre, dö av aktiv tuberkulos. Personer med latent tuberkulos som tillhör riskgrupperna prioriteras för identifiering, diagnos och behandling av latent tuberkulos. Dessa riskgrupper är humant immunbristvirus (HIV)-patienter, barn och ungdomar, nära kontakter till personer med aktiva TB-fall, migranter, flyktingar, fångar och vårdpersonal. Standardbehandlingen mot latent tuberkulos är isoniazid monoterapi. Den har en högt beprövad effektivitetsgrad men är kopplad till dålig acceptans och låga kompletteringsgrader, på grund av framförallt den långa behandlingstiden och dålig tolerans. En nyare form av behandling är rifapentin kombinerat med isoniazid. Den är en effektiv behandling mot latent tuberkulos med en kortare behandlingstid. Syftet med denna litteraturstudie var att utvärdera effekten av kombinationsterapi med rifapentin och isoniazid jämfört med isoniazid monoterapi för behandling av latent tuberkulos. Detta examensarbete baserades på fem randomiserade kliniska prövningar hämtade från PubMed-databasen. Samtliga fem studier innefattade effektivitetsjämförelse mellan isoniazid monoterapi och kombinationsterapi med rifapentin och isoniazid vid behandling av patienter med latent tuberkulos. Alla fem studier undersöktes visade lägre frekvens av aktiv TB och dödlighet i kombinationsterapi med rifapentin och isoniazid jämfört med isoniazid monoterapi. Resultatet bevisade också icke-underlägsenhet för kombinationsterapin jämfört med isoniazid monoterapin. Kompletteringsgraden var signifikant högre i kombinationsterapin. Säkerhetsprofilen mellan de två terapin var likartad, men med en ökad hepatotoxicitet i isoniazid monoterapi gruppen. Kombinationsterapi med rifapentin och isoniazid är lika effektiv som isoniazid monoterapi. Denna kortare behandling kan också användas som förstahandsbehandling för latent tuberkulos patienter med hög risk att utveckla till aktiv tuberkulos eftersom den har visat god tolerabilitet och högre kompletteringsgrad som är viktigt för att framgångsrikt behandla latent tuberkulos och hjälpa till att eliminera TB över hela världen.

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No. of bitstreams: 1 Dissertação- Rodrigo Ramos de Sena.pdf: 1144130 bytes, checksum: f450e9777d83f0777b3ca0ae1fb547e1 (MD5) Previous issue date: 2016-02-24 / Não informada / Tuberculosis is a serious public health problem and is configured as a major disease to be faced in Brazil and worldwide. To contain the epidemic around the world through prevention, diagnosis and treatment is estimated to need investments of around eight billion dollars annually. The disease comes in two forms: active and latent. The active form is manifested with classical symptoms such as persistent cough (with or without mucus and eventually blood), fever, night sweats and weight loss, being transmitted. In latently (LTBI), the individual shows no symptoms and no sign of the etiologic agent in sputum despite the PPD test is positive. By the need to prevent the latently evolve into the active form, in Brazil, the National Program for Tuberculosis Control recommends treatment with isoniazid daily for at least six months. However, this alone has brought concerns due to isoniazid-induced hepatitis and impaired adherence to treatment due to prolonged use of the drug. Alternatively, the combination of isoniazid and rifapentine in weekly doses for three months, has been the most studied pharmacotherapeutic scheme today. Equivalent effectiveness to treatment with isoniazid, the best results in terms of adhesion and therefore higher chances of therapeutic success due to the shorter period of therapy that patients undergo. The objective of this study was to estimate the budget impact of the combined use of isoniazid and rifapentine in the treatment of individuals affected by latent TB, in view of the Pharmaceutical Care General Coordination and Strategic Medicines of the Ministry of Health of Brazil, the time horizon of 2016 – 2020. To estimate the budget impact were outlined scenarios based on state and national epidemiological data of active TB, latent TB and drug costs used in the treatment of disease that are acquired and distributed by the Ministry of Health of Brazil. Accordingly, the combined use of isoniazid and rifapentine would cause impacts to the budget for the purchase of drugs for treatment of tuberculosis, the General Coordination Pharmaceutical Assistance and Strategic Medicines of the order of 21.05% in 2016, 18.54% in 2017, 16.93% in 2018, 15.50% in 2019 and 14.13% in 2020. The adoption of new treatment strategy (isoniazid and rifapentine for three months), to meet 100% of projected demand in the study, would imply spending total of R$ 35.772.400,68 in the period 2016 – 2020, requiring the need for additional funds of R$ 33.631.832,08 to spending on tuberculosis Pharmaceutical assistance General Coordination and Strategic Medicines - CGAFME, for the same period. / A tuberculose é um sério problema de saúde pública e configura-se como uma das principais doenças a serem enfrentadas no Brasil e no mundo. Para conter a epidemia em todo o planeta através de prevenção, diagnóstico e tratamento adequado é estimada a necessidade de investimentos da ordem oito bilhões de dólares anuais. A doença apresenta-se em duas formas: ativa e latente. Na forma ativa manifesta-se com sintomas clássicos como tosse persistente (com ou sem muco e eventualmente sangue), febre, sudorese noturna e emagrecimento, sendo transmissível. Na forma latente (ILTB), o indivíduo não apresenta nenhum sintoma e nenhum sinal do agente etiológico no exame de escarro, apesar do teste PPD ser positivo. Mediante a necessidade de impedir que a forma latente evolua para a forma ativa, no Brasil, o Programa Nacional de Controle da Tuberculose (PNCT) recomenda o tratamento com isoniazida diariamente durante pelo menos seis meses. Entretanto, esta monoterapia tem trazido preocupações devido à hepatite induzida por isoniazida e prejuízos na adesão ao tratamento devido ao prolongado período de uso deste fármaco. Como alternativa, a combinação de isoniazida e rifapentina em doses semanais, durante três meses, tem sido o esquema farmacoterapêutico mais estudado na atualidade. De efetividade equivalente ao tratamento com isoniazida, apresenta melhores resultados em termos de adesão e por isso, maiores chances de sucesso terapêutico, devido ao menor período de terapia a que são submetidos os pacientes. O objetivo do presente trabalho foi estimar o impacto orçamentário do uso combinado de isoniazida e rifapentina no tratamento de indivíduos acometidos por tuberculose latente, na perspectiva da Coordenação Geral de Assistência Farmacêutica e Medicamentos Estratégicos do Ministério da Saúde do Brasil, no horizonte temporal de 2016 a 2020. Para estimação do impacto orçamentário foram delineados cenários baseados em dados epidemiológicos nacionais e estaduais de tuberculose ativa, tuberculose latente e de custos com medicamentos utilizados no tratamento da doença que são adquiridos e distribuídos pelo Ministério da Saúde do Brasil. Nestas condições, o uso combinado de isoniazida e rifapentina ocasionaria impactos ao orçamento destinado à aquisição de medicamentos para tratamento de tuberculose, da Coordenação Geral Assistência Farmacêutica e Medicamentos Estratégicos da ordem de 21.05% em 2016, 18.54% em 2017, 16.93% em 2018, 15.50% em 2019 e 14.13% em 2020. A adoção de nova estratégia de tratamento (isoniazida e rifapentina por três meses), para atendimento de 100% da demanda projetada no estudo, implicaria em gastos totais de R$ 35.772.400,68 no período 2016 – 2020, requerendo a necessidade de recursos adicionais de R$ 33.631.832,08 aos gastos com tuberculose da Coordenação Geral de Assistência Farmacêutica e Medicamentos Estratégicos – CGAFME, para o mesmo período.