A viral dynamic model for treatment regimens with direct-acting antivirals for chronic hepatitis C infection.
A viral dynamic model for treatment regimens with direct-acting antivirals for chronic hepatitis C infection.
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DOI：
10.1371/journal.pcbi.1002339
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发表时间：
2012-01
影响因子：
4.3
通讯作者：
Garg V
中科院分区：
文献类型：
--
作者：
Adiwijaya BS;Kieffer TL;Henshaw J;Eisenhauer K;Kimko H;Alam JJ;Kauffman RS;Garg V
我们提出了一个整合的机制模型，该模型将体外病毒学数据、药代动力学和病毒反应整合到基因型1型慢性丙型肝炎（CHC）患者的直接作用抗病毒药物（telaprevir，HCV NS 3 -4A蛋白酶抑制剂）和聚乙二醇干扰素α-2a/利巴韦林（PR）的联合方案中。该模型采用来自初治患者早期临床研究的治疗中数据进行参数化，前瞻性预测持续病毒学应答（SVR）率，与随后在初治和经治人群中不同治疗持续时间方案的临床试验中观察到的比率相当。该模型解释了临床观察到的应答，考虑了病毒耐药变异体治疗前的IC 50、适应度和患病率以及治疗应答的患者多样性，这导致每种变异体的根除时间不同。所提出的模型提供了一个框架，以优化治疗策略，整合多方面的机制信息，并深入了解新的CHC治疗，包括直接作用的抗病毒药物。丙型肝炎病毒慢性感染全球约1.8亿人。慢性丙型肝炎患者的治疗目标是病毒根除或持续病毒应答（SVR）。HCV治疗的历史标准治疗是聚乙二醇干扰素-α和利巴韦林。最近，已批准的HCV蛋白酶抑制剂与聚乙二醇干扰素-α和利巴韦林联合使用，与单独使用聚乙二醇干扰素-α和利巴韦林相比，显示出更高的SVR率。HCV蛋白酶抑制剂作为一类直接靶向丙型肝炎病毒的新型化合物，具有不同的作用机制，并受HCV变异体的耐药性和适应性的影响。这些不同作用机制的意义，以及耐药性和病毒适应性对治疗结果的相互作用尚未阐明。在这里，我们开发并验证了一个综合的，机制模型的病毒动力学响应的组合方案，包括特拉匹韦，聚乙二醇干扰素α，利巴韦林。该模型是在478例初治患者的早期研究中开发的，其SVR率预测在随后的研究中在2380例患者中得到验证。这些结果提供了一个例子，使用的机制信息的病毒动力学模型的发展，已在最佳治疗方案的设计是有用的。
We propose an integrative, mechanistic model that integrates in vitro virology data, pharmacokinetics, and viral response to a combination regimen of a direct-acting antiviral (telaprevir, an HCV NS3-4A protease inhibitor) and peginterferon alfa-2a/ribavirin (PR) in patients with genotype 1 chronic hepatitis C (CHC). This model, which was parameterized with on-treatment data from early phase clinical studies in treatment-naïve patients, prospectively predicted sustained virologic response (SVR) rates that were comparable to observed rates in subsequent clinical trials of regimens with different treatment durations in treatment-naïve and treatment-experienced populations. The model explains the clinically-observed responses, taking into account the IC50, fitness, and prevalence prior to treatment of viral resistant variants and patient diversity in treatment responses, which result in different eradication times of each variant. The proposed model provides a framework to optimize treatment strategies and to integrate multifaceted mechanistic information and give insight into novel CHC treatments that include direct-acting antiviral agents. Hepatitis C virus chronically infects approximately 180 million people worldwide. The treatment aim for patients chronically infected with hepatitis C is viral eradication or sustained viral response (SVR). Historical standard of care for HCV treatment was peginterferon-alfa and ribavirin. Recently, approved HCV protease inhibitors, in combination with peginterferon-alfa and ribavirin, have demonstrated higher SVR rates compared to peginterferon-alfa and ribavirin alone. As members of a novel class of compounds directly targeting hepatitis C virus, HCV protease inhibitors have different mechanisms of actions and are affected by resistance and fitness of HCV variants. The significance of these different mechanisms of action, and the interplays between resistance and viral fitness to the treatment outcome has not been elucidated. Here, we developed and validated an integrative, mechanistic model of viral dynamics in response to a combination regimen including telaprevir, peginterferon-alfa, and ribavirin. The model was developed from early studies in 478 treatment-naïve patients and its SVR rate predictions were verified in 2380 patients in subsequent studies. These results provide an example of the use of mechanistic information to the development of viral dynamic model that has been useful in the design of optimal treatment regimens.
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影响因子：
13.5
作者：
Kieffer, Tara L.;Sarrazin, Christoph;Zeuzem, Stefan
通讯作者：
Zeuzem, Stefan
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Guedj, Jeremie;Perelson, Alan S.
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Perelson, Alan S.
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Dixit, NM;Layden-Almer, JE;Perelson, AS
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Perelson, AS
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158.5
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Jacobson, Ira M.;McHutchison, John G.;Zeuzem, Stefan
通讯作者：
Zeuzem, Stefan
影响因子：
13.5
作者：
Kuntzen, Thomas;Timm, Joerg;Berical, Andrew;Lennon, Niall;Berlin, Aaron M.;Young, Sarah K.;Lee, Bongshin;Heckerman, David;Carlson, Jonathan;Reyor, Laura L.;Kleyman, Marianna;McMahon, Cory M.;Birch, Christopher;Wiesch, Julian Schulze zur;Ledlie, Timothy;Koehrsen, Michael;Kodira, Chinnappa;Roberts, Andrew D.;Lauer, Georg M.;Rosen, Hugo R.;Bihl, Florian;Cerny, Andreas;Spengler, Ulrich;Liu, Zhimin;Kim, Arthr Y.;Xing, Yanming;Schneidewind, Arne;Madey, Margaret A.;Fleckenstein, Jaquelyn F.;Park, Vicki M.;Galagan, James E.;Nusbaum, Chad;Walker, Bruce D.;Lake-Bakaar, Gerond V.;Daar, Eric S.;Jacobson, Ira M.;Gomperts, Edivard D.;Edlin, Brian R.;Donfield, Sharyne M.;Chung, Raymond T.;Talal, Andrew H.;Marion, Tony;Birren, Bruce W.;Henn, Mattliew R.;Allen, Todd M.
通讯作者：
Allen, Todd M.