Successful treatment of chronic hepatitis C virus (HCV) leads to significant benefits in both hepatic and extrahepatic morbidity and mortality. However, treatment is costly and onerous. The purpose of this study was to evaluate the resource utilization and healthcare costs of chronic HCV patients who are treated versus those who are not treated. Patients eligible for this study were Texas Medicaid patients ≥18 and ≤63 years who had evidence of chronic HCV during the identification period (1/1/07-9/30/11) and continuous enrollment throughout the analysis period. High dimensional propensity scoring techniques were used to match treated vs. untreated patients (1:2 ratio). Unadjusted and adjusted analyses compared the healthcare costs and utilization between patient cohorts at 6 and 18 months. For those treated, adherence was measured by proportion of days covered and persistence was evaluated as a gap in medication (of one fill) as determined by refill records. There were a total of 24,032 patients identified with chronic HCV. After high dimensional propensity scoring, there were no significant differences in key clinical and demographic characteristics between treated (n=939) and untreated (n=1878) cohorts. Over 97% of patients had evidence of end stage liver disease at baseline. Based on adjusted analyses of total costs using a generalized linear regression model, the mean difference in costs between the treated vs. untreated patients was $13,960 (SE $458, p<0.001). At 18 months of follow-up, the adjusted mean all-cause costs were $20,834 higher for treated patients (n=456) compared to those untreated (n=849) (p<0.001); however, mean outpatient costs were $1,894 (SE $274) less in treated vs. untreated patients. For those treated, the average HCV medication PDC was 71%, and by the end of 24 weeks, only 42.3% of patients remained on HCV therapy. This study did not show short-term cost offsets, but the sub-analysis following patients for 18 months showed trends in downstream cost offsets. Most patients had advanced liver disease, reducing the chances of successful treatment and averting liver disease sequelae. Earlier identification and treatment could bend the cost curve before these patients reached the more advanced stages seen in this costly cohort. / text

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Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-02-26T12:31:34Z No. of bitstreams: 1 raissanevesfagundes.pdf: 1019231 bytes, checksum: 5b5446ecbb82c53b33979dbc8b0c1509 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-03-03T14:00:38Z (GMT) No. of bitstreams: 1 raissanevesfagundes.pdf: 1019231 bytes, checksum: 5b5446ecbb82c53b33979dbc8b0c1509 (MD5) / Made available in DSpace on 2016-03-03T14:00:38Z (GMT). No. of bitstreams: 1 raissanevesfagundes.pdf: 1019231 bytes, checksum: 5b5446ecbb82c53b33979dbc8b0c1509 (MD5) Previous issue date: 2015-01-15 / FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais / Introdução: No Brasil, pacientes com infecção crônica pelo VHC genótipo 1 com fibrose avançada são tratados com interferon peguilado, ribavirina e antivirais de ação direta telaprevir e boceprevir. Com o uso desses agentes taxas de Resposta Virológica Sustentada mais elevadas foram obtidas, mas também maior gravidade de eventos adversos. No Brasil, não há dados a respeito do impacto do telaprevir sobre a qualidade de vida relacionada à saúde (QVRS) em portadores de hepatite crônica C submetidos à terapia antiviral. Objetivo: Comparar os escores de QVRS em pacientes com hepatite crônica C submetidos à terapia antiviral dupla e tripla e analisar os possíveis fatores que afetam a QVRS. Casuísitca e método: Estudo do tipo observacional com inclusão prospectiva dos dados. Foram incluídos pacientes com Hepatite Crônica C submetidos a terapia antiviral com idade entre 18 e 75 anos acompanhados no HU-UFJF, no período de março de 2012 a julho de 2014. Foram excluídos coinfectados pelo HIV, VHB e portadores de doença renal crônica. Os pacientes em terapia dupla foram tratados com interferon peguilado alfa 2a ou alfa 2b (INF) associado à ribavirina (RIB) enquanto os pacientes do grupo terapia tripla receberam INF, RIB e telaprevir (TEL) nas primeiras 12 semanas seguido da terapia dupla. A classificação histológica utilizada foi a de Metavir. O Short Form 36 (SF-36) e Chronic Liver Diseases Questionnarie (CLDQ), questionários de avaliação de QVRS, foram aplicados no: pré-tratamento e nas semanas 4, 12 e 16. A comparação entre os grupos foi realizada utilizando o test-t (t). Os fatores preditivos foram calculados através da regressão linear múltipla. Valores de P < 0,05 foram considerados significantes. Resultados: Foram incluídos 32 pacientes, dos quais 17 em terapia dupla e 15 em terapia tripla. O sexo feminino foi o predominante (59%) e a média de idade observada foi 54,9 ± 15,85 anos. A maioria dos pacientes foram genótipo 1 (75,0%) e cirróticos (34%). No pré-tratamento, a média do componente físico (51,5 ± 8,40 vs. 53,8 ± 6,50; p=0,413) e mental (60,1 ± 3,80 vs. 55,1 ± 9,11; p = 0,067) resumido (CFR e CMR) foi semelhante entre o grupo terapia dupla e tripla. Após o início do tratamento (semana 4 e 12), a média do CFR e CMR foi pior na terapia tripla do que na dupla (p<0,05). Após a retirada do TEL, as médias se aproximaram, o mesmo esta ocorrendo com o escore total do CLDQ. Conclusão: Em portadores de hepatite crônica C, a terapia tripla foi associada de modo independente a redução dos escores de QVRS tanto pelo SF-36 quanto pelo CLDQ, sendo o momento mais crítico a 12ª semana de terapia. Outros fatores associados à redução dos índices de qualidade de vida foram ansiedade e depressão no prétratamento, status empregatício e raça. / Introduction: In Brazil, patients with chronic HCV genotype 1 with advanced fibrosis are treated with pegylated interferon, ribavirin and direct antiviral action telaprevir and boceprevir. With the use of these agents higher SVR rates were obtained, but also increased severity of adverse events. In Brazil, there are no data regarding the impact of telaprevir on HRQL in patients with chronic hepatitis C undergoing antiviral therapy. Objective: To compare the scores of HRQL in patients with chronic hepatitis C undergoing antiviral therapy double and triple. Casuistic and method: Study of observational with prospective inclusion of data. Patients with Chronic Hepatitis C undergoing antiviral therapy between 18 and 75 years followed at HU-UFJF, from March 2012 to July 2014. Exclusion criteria were co-infected with HIV, HBV and patients with chronic kidney disease. Patients on dual therapy were treated with pegylated interferon alpha 2a or alpha 2b (INF) in combination with ribavirin (RIB) whereas patients in the triple therapy group received INF, RIB and telaprevir (TEL) in the first 12 weeks followed by dual therapy. The histological classification was used to Metavir. The Short Form 36 (SF-36) and Chronic Liver Diseases Questionnaire (CLDQ), the evaluation of HRQL questionnaires were applied in: baseline and at weeks 4, 12 and 16. The comparison between groups was performed using the tests: test -t (t). Predictive were calculated by multiple linear regression. P values <0.05 were considered significant. Results: Were include 32 patients, 17 of whom were enrolled in dual therapy and 15 on triple therapy. The female sex was predominant (59%) and the average age was 54.9 ± 15.85 years. Most patients was genotype 1 patients (75.0%) and cirrhotic patients (34%). At baseline, the physical component (51.5 ± 8.40 vs. 53.8 ± 6.50; p = 0.413) and mental (60.1 ± 3.80 vs. 55.1 ± 9.11; p = 0.067) summarized (PCS and MCS) was similar between the dual and triple therapy group. After the initiation of treatment (Week 4 and 12) the scores of PCS and MCS, were worse in the triple therapy than double (p <0.05). After removal of the drug TEL, the HRQL improved in the two therapies. The same occurs with the total score of CLDQ. Conclusion: Patients with chronic hepatitis C, triple therapy was independently associated with reduced HRQOL scores both the SF-36 as the CLDQ, the most critical time to 12 weeks of therapy. Other factors that are associated with reduced quality of life indices are anxiety and depression at baseline, employment status and race.

Submitted by Ubirajara Cruz (ubirajara.cruz@gmail.com) on 2018-06-06T15:30:23Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) tese_debora_silva.pdf: 1913075 bytes, checksum: c12211dbca8293598c05c824e8e81e14 (MD5) / Approved for entry into archive by Aline Batista (alinehb.ufpel@gmail.com) on 2018-06-08T11:36:54Z (GMT) No. of bitstreams: 2 tese_debora_silva.pdf: 1913075 bytes, checksum: c12211dbca8293598c05c824e8e81e14 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-06-08T11:36:54Z (GMT). No. of bitstreams: 2 tese_debora_silva.pdf: 1913075 bytes, checksum: c12211dbca8293598c05c824e8e81e14 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-09-27 / O herpesvírus felino tipo 1 (FHV-1) afeta principalmente o trato respiratório superior, provocando rinite, ceratite ulcerativa e conjuntivite, mas é capaz de promover doença sistêmica, provocando pneumonia, necrose hepática, emaciação, abortos e dermatite. O tratamento é sintomático, pois não há um antiviral específico contra o FHV-1. Dessa forma, a pesquisa por compostos antivirais com atividade específica contra o FHV-1 é urgente e necessária. No entanto, pesquisas tendo o gato como modelo experimental são difíceis de serem conduzidas por envolverem questões éticas e humanitárias. O camundongo é um modelo experimental amplamente utilizado na medicina humana e veterinária, mas até o momento não há relatos sobre a infecção experimental de camundongos com o FHV-1. O presente estudo objetivou utilizar camundongos BALB/c como modelos experimentais para reproduzir a infecção pelo FHV-1 e avaliar a eficácia antiviral de diferentes compostos in vivo. Três grupos de 14 animais cada foram infectados e tratados com ganciclovir, lactoferrina e o peptídeo P34. Um grupo de 14 animais, grupo controle positivo, foi infectado com FHV-1 e não recebeu tratamento. Outro grupo de 14 animais não foi infectado nem recebeu tratamento (grupo controle negativo). Os animais foram pesados e avaliados diariamente para registrar o desenvolvimento ou não de sinais clínicos. Todos os tratamentos iniciaram 24 h pós-infecção, tiveram duração de 10 dias e foram administrados uma vez ao dia por meio de gavagem (lactoferrina e P34) e injeção intraperitoneal (ganciclovir). Após o término do tratamento foi realizada eutanásia e coleta dos órgãos (fígado, rim, baço e pulmão) para avaliação histopatológica e qPCR. Os resultados foram analisados pelo método analítico Kruskall-Wallis e não foram observadas diferenças estatisticamente significativas no ganho de peso entre os grupos de animais. Os animais infectados e não tratados desenvolveram sinais clínicos típicos de infecção pelo FHV-1, como blefarite, conjuntivite, blefaroespasmo, secreção ocular uni ou bilateral e fotofobia. Os resultados demonstraram que todos os animais foram capazes de se infectar com FHV-1, produzindo doença local e/ou sistêmica em diferentes graus de severidade. Lesões histopatológicas puderam ser observadas no pulmão (pneumonia intersticial, edema, congestão e corpúsculos de inclusão intranucleares), no fígado (congestão, vacuolização de hepatócitos, hepatite, necrose e corpúsculos de inclusão intranucleares), no baço (depleção linfoide) e no rim (nefrite intersticial e nefrose tubular). O órgão que teve maior detecção de DNA viral foi o pulmão, seguido de fígado, baço e rim. Os tratamentos utilizados neste trabalho, na dose, via e frequência de administração não foram capazes de reduzir a carga viral nos animais tratados. Por esta razão, novas pesquisas deverão ser conduzidas para avaliar essas mesmas drogas, na mesma espécie animal, porém com um diferente regime de tratamento. Os dados gerados neste trabalho sobre a patogênese do FHV-1 em camundongos são inéditos, visto que até o momento só há na literatura relatos de infecção experimental com o FHV-1 no próprio gato, o que torna o camundongo uma opção viável para estudos sobre a patogênese e avaliação de antivirais contra o FHV-1. / Feline herpesvirus type 1 (FHV-1) affects mainly the upper respiratory tract, causing rhinitis, ulcerative keratitis and conjunctivitis, but is able to induce systemic disease, causing pneumonia, hepatic necrosis, emaciation, abortion and dermatitis. Treatment is symptomatic, because there is no specific antiviral against FHV-1. This way, the search for antiviral compounds with activity particularly against FHV-1 is urgent and necessary. Notwithstanding, researches having the cat as the experimental model are difficult to be carried out because of ethical and humanitary concerns. The mouse is an experimental model used widely in human and veterinary medicine, but hitherto there are no reports about experimental infection of mice with FHV-1. The present study aimed to use BALB/c mice as experimental models to reproduce the infection with FHV-1 and evaluat the antiviral efficacy of different compounds in vivo. Three groups of 14 animals each were infected and treated with ganciclovir, lactoferrin and the peptide P34. A group of 14 animals, positive control group, was infected with FHV-1 and did not receive treatment.another group of 14 animals was not infecte dor treated (negative control group). Animals were weighed and evaluated daily to record the development of clinical signs or not. All the treatments started 24 h post-infection, had ten days of duration and were administered once a day by gavage (lactoferrin and P34) and intraperitoneal injection (ganciclovir). After the end of the treatment, euthanasia was performed and the organs (liver, kidney, spleen and lung) were collected for histopathology and qPCR. Results were analyzed by the Kruskall-Wallis analytical method and differences statistically significant wer not observed in body weight among the groups. The infected and not treated animals developed typical clinical signs of FHV-1 infection, like blepharitis, conjunctivitis, blepharoespasm, uni or bilateral ocular secretion and photophobia. The results demonstrated that all the animals were able to be infected with FHV-1, producing local and/or systemic disease in different degrees of severity. Histopathological lesions could be observed in lungs (interstitial pneumonia, edema, congestion and intranuclear inclusion bodies), in the liver (congestion, hepatocyte vacuolization, hepatitis, necrosis and e intranuclear inclusion bodies), in the spleen (lymphoid depletion) and in the kidneys (interstitial nephritis and tubular nephrose). The organ with higher viral DNA detection was the lung, followed by the liver, spleen and Kidney. The treatments used in this work, in the dose, via and frequence of administration were not able to reduce viral load in the treated animals. For that reason, new researches might be conducted to evaluate the same drugs, in the same species, however with a different regimen of treatment. Data generated in this experimental work about the pathogenesis of FHV-1 in mice are extraordinary, since until this moment there are in the literature just reports of experimental infection with FHV-1 using the cat itself, what makes the mouse a viable option to study the pathogenesis of FHV-1 and to evaluate the antiviral activity of drugs against the virus.

Les membres du genre Morbillivirus, famille Paramyxoviridae sont responsables de graves maladies chez l'homme et les animaux, comme la rougeole, la peste bovine (RP) et la peste des petits ruminants (PPR). Malgré l'existence de vaccins efficaces contre ces maladies, des traitements spécifiques sont souhaitables. L'inhibition de la réplication de ces virus peut-être acquise par interférence ARN (ARNi), un mécanisme d'inhibition post-transcriptionnel déclenché par des séquences courtes d'ARN double-brin (siARN). Le CIRAD a précédemment identifié 3 siARNs ciblant des régions conservées du gène de la nucléoprotéine virale capables d'inhiber au moins 80% de la réplication in vitro des virus de la rougeole, de la RP et de la PPR. Cependant, un problème majeur dans la stratégie d'ARNi est le risque d'apparition de virus résistants. Dans cette étude, nous avons évalué le risque d'apparition de mutants d'échappement du virus de la PPR sous pression de sélection de 3 siARNs appliqués seul ou en association après plusieurs transfections successives in vitro. Excepté pour la combinaison des 3 siARNs, le virus a échappé à l'ARNi après 3 à 20 passages consécutifs, avec des mutations simples ou multiples (synonymes ou pas) ou une délétion de 6 nucléotides dans la zone cible des siARN. Ces résultats mettent en évidence une plasticité génomique inattendue des morbillivirus surtout illustrée par cette délétion non-délétère d'une partie significative d'un gène viral essentiel, qui devrait être considérée comme un obstacle à l'utilisation de l'ARNi comme thérapie antivirale. Cependant, l'utilisation combinée de 3 siARNs peut être proposée pour diminuer le risque d'échappement aux siARNs. / Viruses in the genus Morbillivirus, within the family Paramyxoviridae are responsible for severe humans and animal diseases, including measles, rinderpest (RP) and peste des petits ruminants (PPR). In spite of the existence of efficient vaccines against these diseases, specific treatments to be applied when the infection is already present are desirable. Inhibition of morbillivirus replication can be achieved by RNA interference (RNAi), a mechanism of post-transcriptional gene silencing triggered by small double-stranded RNA (siRNA). The CIRAD previously identified three siRNAs that target conserved regions of the essential gene encoding the viral nucleoprotein and are able to prevent in vitro at least 80% of the replication of measles, RP and PPR viruses . However, a major problem in RNAi is the important risk of emergence of escape mutants. In this study, we investigated the ability of PPR virus to escape the inhibition conferred by single or multiple siRNAs after several consecutive transfections in vitro. Except with the combination of the three different siRNAs, the virus systematically escaped RNAi after 3 to 20 consecutive passages. The mutations were characterized by either single or multiple punctual nucleotide mutations (synonymous or not) or a deletion of a stretch of 6 nucleotides into the siRNA target. These results demonstrate that the genomic plasticity of morbilliviruses, illustrated maily by this significant and no-deleterious deletion in an essential viral gene, should be considered as an obstacle to the use of RNAi in antiviral therapy. However, the combined use of three siRNAs can be proposed to prevent treatment failure with siRNAs.

Although seasonal influenza epidemics represent a significant threat to public health, their treatment options remain limited. With deaths from the 1918 influenza pandemic estimated at >50,000,000 worldwide and future pandemics predicted, the need for a potent broad-spectrum influenza therapy is critical. In this thesis, I describe the use of a structurally modified zanamivir, an influenza neuraminidase inhibitor that blocks the release of nascent virus, to deliver attached therapeutic agents specifically to the surfaces of viruses and virus-infected cells, leading to simultaneous inhibition of virus release and immune-mediated destruction of both free virus and virus-infected cells. Chapter 1 describes the major characteristics of the influenza virus, the morbidity and mortality associated with annual infections by current strains of the virus, and the treatments available to reduce the disease burden associated with these infections. Chapter 2 describes the design, synthesis, and evaluation of a zanamivir-related targeting ligand and its conjugation to two orthogonal imaging agents which are then used to characterize the binding specificity and biodistribution of the targeting ligand in influenza virus-infected cells and in infected mice. Chapter 3 describes the development of an influenza virus-targeted immunotherapy, where a zanamivir-targeted hapten is exploited to redirect the immune system to destroy influenza virus and virus-infected cells. When tested in vivo, this immunotherapy is shown to be significantly superior to zanamivir in protecting mice from lethal influenza virus infections. Finally, both a zanamivir-targeted chemotherapy and a CAR-T cell therapy with different mechanisms of cytotoxicity against neuraminidase expressing cells are introduced in Chapter 4.

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MPM / Oliver Tambo Institute of Governance and Policy Studies