Academic literature on the topic 'Daclatasvir'

Orientador : Prof. Dr. Roberto Pontarolo<br>Coorientadora : Drª. Inajara Rotta<br>Dissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências da Saúde, Programa de Pós-Graduação em Ciências Farmacêuticas. Defesa: Curitiba, 22/09/2017<br>Inclui referências : f. 83-93<br>Resumo: A hepatite viral C crônica é causada pelo vírus da hepatite C (VHC) e os indivíduos são considerados curados após atingir a resposta virológica sustentada (RVS). Porém, os elevados custos dificultam o acesso às terapias disponíveis. Dados os recursos limitados, a inserção de novas terapias deve ter sua viabilidade farmacoeconômica avaliada, para que a alocação de recursos seja eficiente. Portanto, o objetivo deste trabalho foi realizar análise de custo-efetividade das terapias preconizadas pelo Protocolo Clínico e Diretrizes Terapêuticas de 2015 no tratamento precoce de pacientes com hepatite C crônica sob a perspectiva do SUS. Esta análise utilizou um modelo de Markov para comparar o momento de inserção da terapia, comparando-se o tratamento a partir de F0, F1 ou F2 com o preconizado pelo PCDT de 2015, apenas F3 e F4. Como há diferentes genótipos (GT) do vírus e para alguns deles mais de uma terapia descrita, foram realizadas análises de subgrupos. O horizonte temporal foi a expectativa de vida do paciente, e a taxa de desconto foi determinada em 5%. A perspectiva do trabalho foi a do SUS, assim, foram mensurados apenas os custos diretos médicos. Como medida finalística foram utilizados os anos de vida ajustados por qualidade (AVAQ), estimados com base nas melhores evidências disponíveis. Os dados de eficácia foram empregados como probabilidade de transição entre os estágios de fibrose e a RVS e as demais probabilidades também foram estimadas com base na literatura. Foi assumido que apenas pacientes monoinfectados pelo VHC fariam parte do modelo, apenas os que atingissem a RVS a partir de F3 ou F4 poderiam continuar progredindo no modelo e após atingida a RVS eles não poderiam ser reinfectados. A análise demonstrou que a inserção precoce do tratamento é custo-efetiva, considerando limiar implícito sugerido para o Brasil para todas as terapias: sofosbuvir e daclatasvir para os genótipos 1, 3 e 4; sosfosbuvir e ribavirina para GT2; e sosfosbuvir, peguinterferona e ribavirina (PR) para GT3. E não é custo-efetiva para o tratamento a partir de F0, mas sim a partir de F1 ou F2 para as terapias sofosbuvir e simeprevir para GT1 e daclatasvir e PR para GT4. Porém com diferenças significativas entre as razões custo-efetividade incrementais (RCEI), variando de R$ 8.583/AVAQ a R$ 30.185/AVAQ. Para avaliar a robustez do modelo foram realizadas análises de sensibilidade. A análise determinística univariada demonstrou que as variáveis que mais afetam o modelo estão relacionadas à taxa de desconto dos resultados, ao custo dos medicamentos e aos dados de utilidade. A probabilística (PSA) permitiu quantificar as incertezas, fornecendo melhor evidência para o gestor. As 5000 iterações de cada subgrupo mantiveram-se no quadrante custo-efetivo do plano de custo-efetividade. Assim, pode-se afirmar que o tratamento precoce da hepatite C crônica é custo-efetivo, mas a alteração dos protocolos futuros depende de outras avaliações por parte dos gestores. Palavras-chave: hepatite C crônica, custo-efetividade, tratamento precoce, sofosbuvir, daclatasvir, simeprevir.<br>Abstratc: Chronic viral hepatitis C is caused by the hepatitis C virus (HCV) and is considered a curable disease, since individuals can achieve sustained virological response (SVR). However, access to the available therapies isn't universal, mainly due to high costs. As much as health resources are limited, pharmacoeconomic assessments that allow better allocation of resources are necessary. Therefore, the objective of this study is to perform a cost-effectiveness analysis of the therapies advocated by the Clinical Protocol and Therapeutic Guidelines of 2015 on early treatment of patients with chronic hepatitis C from the SUS perspective. This cost-effectiveness analysis used a Markov model to compare the moment of insertion of the therapy, comparing the treatment starts at F0, F1 or F2 with treatment according to the protocol, only F3 e F4. As there are different genotypes (GT) of the virus and for some of them more than one described therapy, subgroup analyses were performed. The model has a lifetime horizon, and the discount rate was defined in 5%. Considering the perspective of the work as the public health system, only direct medical costs were measured. As a final measure, quality adjusted life years (QALY) were estimated, based on the best available evidence. Efficacy data were used as a transition probability between the stages of fibrosis and SVR and the other probabilities were also estimated based on the literature. It was assumed that only HCV patients would be part of the model, just those who reached SVR from F3 or F4 could continue to progress in the model after reaching SVR and none of them could be reinfected. The analysis showed that the early insertion of the treatment is cost-effective, considering implicit limit suggested for Brazil for the therapies: sofosbuvir and daclatasvir for genotypes 1, 3 and 4; sosfosbuvir and ribavirina for GT2; sosfosbuvir; and peginterferon and ribavirin (PR) for GT3. And it isn't for treatment starting on F0, but it is when starting on F1 or F2 for the therapies sofosbuvir and simeprevir for GT1 and daclatasvir and PR for GT4. However, there were significant differences between the incremental cost-effectiveness ratios (ICER), ranging from R$ 8.583/AVAQ to R$ 30.185/AVAQ. To assess the robustness of the model, sensitivity analyses were performed. The univariate deterministic analyses showed that the variables that most affect the model are related to the discount rate of the results, the cost of medications and the utility data. The probabilistic (PSA) allowed to quantify the uncertainties, providing better evidence for the manager. The 5000 iterations of each subgroup remained in the cost-effective quadrant of the cost-effectiveness plan. Thus, it can be affirmed that the early treatment of chronic hepatitis C is cost-effective, but the change of future guidelines depends on other evaluations by the managers. Key-words: chronic hepatitis C, cost-effectiveness, early treatment, sofosbuvir, daclatasvir, simeprevir.

At the moment, several companies are studying the clinical potential of different all-oral combinations of direct-acting antivirals in ongoing studies. The most promising interferon-free combination therapies that are on the horizon include linear or cyclic NS3/4A protease inhibitors, nucleoside as well as non-nucleoside NS5B polymerase inhibitors , and NS5A inhibitors. DAAs that target NS3/4A (protease) and NS5B (RNA-dependent RNA polymerase) inhibit the enzymatic activity of these proteins. NS5A replication complex inhibitors will likely form a component of future interferon-free drug regimens but despite their remarkable potential to treat chronic hepatitis C, the detailed mechanism of action for this class of drug remains unclear. The goal of my work was to investigate the mechanism of action of different classes of antiviral agents believed to target the NS5A protein in the replication complex in order to improve the possibility to translate basic knowledge to a more meaningful clinical application. More specifically I focused my research on two classes of compounds, characterized by distinct resistance patterns in NS5A: a first class – with examples at the final stages of clinical development, represented by Daclatasvir (Lemm et al., 2011), and a second class - at earlier stages of development - represented by anilino-quinazolines such as A-831/AZD-2836 (Quinkert et al., 2008). I contributed to demonstrate that both of these inhibitor classes, by binding respectively to either HCV NS5A or to an NS5A-associated protein, PI4KIIIα, eventually interfere with the accumulation of PI4P 98 and cholesterol in the HCV replication membranous compartment, thus abrogating the ability of the virus form to replicate its RNA genome.

碩士<br>中山醫學大學<br>醫學研究所<br>104<br>Introduction: All-oral direct-acting agent dual therapy with Daclatasvir plus Asunaprevir (DCV+ASV) achieved high sustained virological responses (SVR) in genotype 1b (GT-1b) HCV patients in the HALLMARK-DUAL1 study and Phase 3 Japanese study2,3. DCV + ASV is approved in several countries including Taiwan in March, 2016, Japan, Korea, and Latin America, Eastern Europe. In this study, real-world experience of DCV+ASV dual therapy in HCV GT-1b patients was reported. Purpose: To evaluate the efficacy and safety of DCV+ASV therapy in GT-1b HCV infected Taiwanese patients in real-world. Method: Fifty GT-1b HCV infection patients received dual therapy were enrolled at two hospitals in central Taiwan. Five patients (10%) were excluded due to existence of baseline resistance-associated variants (RAVs). Outcomes from 27 patients, who had received 24 weeks dual therapy and been followed up for 24 weeks after end of treatment, were recorded and analyzed. Sustained virologic response at post-treatment week 12 and week 24(SVR12/SVR24) and safety profiles were evaluated. The results were compared with those from HALLMARK-DUAL study. Result: In the real-world group, the mean age was 57 years old ( male/female: 5/ 4); 63% (17/27) patients had advanced liver fibrosis or compensated cirrhosis; 56% patients were treatment-experienced. Virologic response(defined as HCV RNA < LLOQ )at week 4 was 89% (24/27) in the real-world group and74% (477/643) in phase 3 clinical trial group. SVR12 rate was higher than the phase 3 clinical trial group (93 % vs. 84%). SVR12 rates were100% (12/12), 89% (8/9) and 83% (5/6)in treatment-naive, ineligible/intolerant and non-responder patients, respectively. Patients with advanced liver disease or cirrhosis, experience of previous treatment, and higher baseline viral load (HCV RNA ≥ 800,000 IU/mL) had lower SVR 12. The results were similar to those from phase 3 study. Common adverse events included dizziness ( 3/27), pyrexia ( 1/27) and fatigue ( 1/27).There were neither SAE nor AE leading to treatment discontinuation occurred. Conclusion: Daclatasvir plus Asunaprevir were well-tolerated and resulted in a higher SVR rate in the Taiwanese real-world GT-1b HCV patients without baseline NS5A RAVs.