Class of 2016 Abstract / Objectives: To compare the efficacy of direct acting antiviral agents for the treatment of hepatitis C virus genotype 1. Our primary null hypothesis is there will be no significant difference in efficacy among the treatment regimens for hepatitis C virus, genotype 1. Methods: This meta-analysis study will use published literature identified from Embase and PubMed for phase II or III clinical trials evaluating direct acting antiviral drug regimens to treat adults with hepatitis C virus (HCV) genotype 1 infection. The primary outcome of interest is SVR at 12 weeks after treatment initiation. Data will be analyzed both descriptively as well as using Bayesian mixed treatment comparison methods. After extracting the outcome data from individual studies, the data will be analyzed using Winbugs version 1.4.3. Moreover, a random effects model and indirect/mix-treatment comparison will be used during the analysis. The random effects model accounts for both between-study and within-study variance, and is exempted from normality assumption, possessing a wider credible interval. All pair-wise odds ratios will be generated and treatment regimens will be ranked based on the likelihood of achieving SVR. Results: Overall, combinations containing sofosbuvir and ledipasvir were significantly better than all other treatments except for simeprevir (OR 0.52, 95% CI 0.28-1.00). On the other hand, daclatasvir containing regimens were non-inferior only to simeprevir (OR 0.69, 95% CI 0.35-1.31) and grazoprevir (OR 0.66, 95% CI 0.41-1.04) while being inferior to other treatments. Sofosbuvir with ledipasvir was ranked highest in terms of obtaining a sustained viral response, followed by ABT-450, grazoprevir, simeprevir, and daclatasvir respectively. In previously treated patients, sofosbuvir with ledipasvir again demonstrated the best efficacy with only grazoprevir and ABT-450 being non-inferior (OR 0.64, 95% CI 0.3368-1.212 and OR 0.73 95% CI 0.29-1.88 respectively). Sofosbuvir with ledipasvir was followed by grazoprevir, ABT-450, simeprevir, and daclatasvir containing regimens respectively. Finally, in treatment naïve patients, simeprevir containing regimens were non-inferior to all other treatment groups, including sofosbuvir regimens (OR 1.24, 95% CI 0.28-9.93). With the exception of simeprevir, sofosbuvir with ledipasvir demonstrated superiority over all treatments. Simeprevir regimens and sofosbuvir with ledipasvir regimens were followed by ABT-450. In treatment naive patients daclatasvir was found to be non-inferior to grazoprevir (OR 1.26, 95% CI 0.75-2.10). Treatment naive patients were the only group we analyzed in which daclatasvir was not the least effective regimen, with grazoprevir claiming the last position. Conclusions: Our results reject our null hypothesis that there will be no difference between different treatment regimens in HCV genotype 1 patients. Generally, the combination of sofosbuvir and ledipasvir appears to be the most effective, while daclatasvir appears to be the least.

Orientador: Paula Rahal / Banca: João Renato Rebello Pinho / Banca: Maurício Lacerda Nogueira / Resumo: O HCV é uma das maiores causas de doença do fígado, sendo estimado que mais de 2% da população mundial está infectada. Este vírus possui um genoma de RNA (+) fita simples, que devido à falta de atividade corretiva da polimerase viral apresenta variabilidade genética em vários níveis: genótipos, subtipos e quasispecies. O genótipo 1 é o mais prevalente no Brasil e no mundo, sendo preditivo de uma baixa resposta à terapia antiviral, que atualmente é baseada na administração de PEG-IFN e ribavirina. A variabilidade genética da região viral NS5A tem sido relacionada à sensibilidade ou resistência ao IFN. Este estudo teve como objetivo investigar se a possível relação entre a composição de quasispecies da NS5A e a resposta ao tratamento. Foram selecionados 12 pacientes, sendo 4 respondedores (R), 4 não respondedores (NR) e 4 respondedores ao final do tratamento (RFT). As amostras pré-tratamento destes pacientes foram amplificadas, clonadas e seqüenciadas, resultando em 165 seqüências da NS5A completa. Estas seqüências foram alinhadas, editadas e a construção da topologia da árvore filogenética foi realizada. A NS5A e suas regiões específicas CRS, PKR-binding, ISDR, NLS e V3 foram analisadas quanto às substituições e o grau de variabilidade genético. O grupo de pacientes RFT apresentou uma maior taxa de substituições sinônimas em relação aos demais grupos. Uma maior quantidade de mutações foi observada na região downstream à ISDR, principalmente na região V3. Nenhum sítio específico de mutação foi relacionado a um tipo particular de resposta, e não houve agrupamento filogenético das quasispecies de acordo com o tipo de resposta. Estes resultados sugerem que o número de mutações não é suficiente para predizer a sensibilidade ou resistência à terapia baseada em IFN, sendo necessário avaliar se estas mutações conservaram ou não as propriedades químicas dos aminoácidos. / Abstract: Hepatitis C virus (HCV) is major causes of liver desease and about 2% of world s population are infected. This virus is a single strain RNA genome of approximately 9.6 kb. Genetics variability of HCV exists at several different levels: genotypes, subtypes and quasispecies. The high mutation rates are related to the low fidelity of viral RNA polymerase. Genotype 1 HCV is the most prevalent in Brazil, as well as worldwide. Genotypes 1a and 1b are predictive of lower sustained virological response in peginterferon (PEG-IFN) plus ribavirin combination therapy. Genetic variability of viral NS5A has been related to IFN sensibility or resistance. To evaluate whether HCV NS5A quasispecies composition are related to responsiveness to combined PEG-IFN and ribavirin therapy, this study analyzed before treatment sample of 12 treated patients (4 sustained responders - SR, 4 non responders - NR and 4 end of treatment responder - ETR). Samples were amplified, cloned and sequenced, resulting in 165 sequences of complete NS5A. Sequences were aligned, edited and phylogenetical tree was constructed. Mutations and mean of genetic distance were analyzed to NS5A and specific regions CRS, PKR-binding, ISDR, NLS and V3. The number of synonymous substitutions per synonymous sites was higher in ETR patients than in other patient groups. Mutations were more common downstream ISDR, mainly concentrated in V3 domain. No single amino acid position or motif was associated with different responses to therapy in any NS5A regions analyzed and phylogenetic analysis did not show clustering of nucleotide sequences of viral isolates from SR, NR or ETR. These results suggest that number of mutations is not sufficient to predict sensibility or resistance to IFN based therapy. Other studies are necessary to evaluate whether chemical characteristics of amino acids were altered for the mutations. / Mestre

acase@tulane.edu / Background It is estimated 3 to 5 million individuals in the U.S. are chronically infected with the Hepatitis C virus (HCV). (Durham DP, 2016) More than 12,000 deaths occur annually in the U.S. as a result of HCV-related liver disease. (Wieland A, 2015) The cost of treatment medication for an individual with HCV genotype-1 is approximately $100,000 for 12 weeks of therapy. (Reau N, 2014) The exorbitant cost of HCV treatment has led to fears that many who could benefit from treatment will not receive it considering many with HCV are uninsured or have Medicaid. Purpose The purpose of this study is to quantify the cost, cost-effectiveness, and adverse outcomes associated with denying or delaying HCV treatment among the Louisiana Medicaid (LA-Medicaid) HCV GT-1 population. Methodology This project evaluates the cost and cost-effectiveness of treating HCV compared to not treating; initiating early treatment compared to late treatment and HCV-related health outcomes. A decision tree and Markov model simulates progression through the various states of health involved in progressive HCV disease, including death (hepatic and other causes). Results Don’t Treat/Treat Comparison Treatment was generally cost-effective, exhibiting an incremental cost-effectiveness ratio (ICER) of $21,670/life-year and $37,067/QALY (Quality-Adjusted Life-Years) gained. Optimal Treatment Stage Comparison Treatment of a person at F0 was cost effective, exhibiting an ICER of $6,482/QALY and $6,194/year of life compared to not treating at all and treating at F1, F2, F3, F4 or after LT. Conclusion Treatment of HCV-infected patients without liver fibrosis or in early stages of liver fibrosis appear to be more cost-effective than treating in advance stages of liver fibrosis or denying treatment. / 1 / Dwana Green

No description available.

Made available in DSpace on 2014-06-11T19:26:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-02-26Bitstream added on 2014-06-13T20:14:38Z : No. of bitstreams: 1 jardim_acg_me_sjrp.pdf: 3983929 bytes, checksum: 587fc4359397e3ed6de6922651160d80 (MD5) / O HCV é uma das maiores causas de doença do fígado, sendo estimado que mais de 2% da população mundial está infectada. Este vírus possui um genoma de RNA (+) fita simples, que devido à falta de atividade corretiva da polimerase viral apresenta variabilidade genética em vários níveis: genótipos, subtipos e quasispecies. O genótipo 1 é o mais prevalente no Brasil e no mundo, sendo preditivo de uma baixa resposta à terapia antiviral, que atualmente é baseada na administração de PEG-IFN e ribavirina. A variabilidade genética da região viral NS5A tem sido relacionada à sensibilidade ou resistência ao IFN. Este estudo teve como objetivo investigar se a possível relação entre a composição de quasispecies da NS5A e a resposta ao tratamento. Foram selecionados 12 pacientes, sendo 4 respondedores (R), 4 não respondedores (NR) e 4 respondedores ao final do tratamento (RFT). As amostras pré-tratamento destes pacientes foram amplificadas, clonadas e seqüenciadas, resultando em 165 seqüências da NS5A completa. Estas seqüências foram alinhadas, editadas e a construção da topologia da árvore filogenética foi realizada. A NS5A e suas regiões específicas CRS, PKR-binding, ISDR, NLS e V3 foram analisadas quanto às substituições e o grau de variabilidade genético. O grupo de pacientes RFT apresentou uma maior taxa de substituições sinônimas em relação aos demais grupos. Uma maior quantidade de mutações foi observada na região downstream à ISDR, principalmente na região V3. Nenhum sítio específico de mutação foi relacionado a um tipo particular de resposta, e não houve agrupamento filogenético das quasispecies de acordo com o tipo de resposta. Estes resultados sugerem que o número de mutações não é suficiente para predizer a sensibilidade ou resistência à terapia baseada em IFN, sendo necessário avaliar se estas mutações conservaram ou não as propriedades químicas dos aminoácidos. / Hepatitis C virus (HCV) is major causes of liver desease and about 2% of world s population are infected. This virus is a single strain RNA genome of approximately 9.6 kb. Genetics variability of HCV exists at several different levels: genotypes, subtypes and quasispecies. The high mutation rates are related to the low fidelity of viral RNA polymerase. Genotype 1 HCV is the most prevalent in Brazil, as well as worldwide. Genotypes 1a and 1b are predictive of lower sustained virological response in peginterferon (PEG-IFN) plus ribavirin combination therapy. Genetic variability of viral NS5A has been related to IFN sensibility or resistance. To evaluate whether HCV NS5A quasispecies composition are related to responsiveness to combined PEG-IFN and ribavirin therapy, this study analyzed before treatment sample of 12 treated patients (4 sustained responders - SR, 4 non responders - NR and 4 end of treatment responder - ETR). Samples were amplified, cloned and sequenced, resulting in 165 sequences of complete NS5A. Sequences were aligned, edited and phylogenetical tree was constructed. Mutations and mean of genetic distance were analyzed to NS5A and specific regions CRS, PKR-binding, ISDR, NLS and V3. The number of synonymous substitutions per synonymous sites was higher in ETR patients than in other patient groups. Mutations were more common downstream ISDR, mainly concentrated in V3 domain. No single amino acid position or motif was associated with different responses to therapy in any NS5A regions analyzed and phylogenetic analysis did not show clustering of nucleotide sequences of viral isolates from SR, NR or ETR. These results suggest that number of mutations is not sufficient to predict sensibility or resistance to IFN based therapy. Other studies are necessary to evaluate whether chemical characteristics of amino acids were altered for the mutations.

No description available.