Yakoot Mostafa, Abdo Alaa M, Yousry Ahmed, Helmy Sherine
Green Clinical Research Center; Abbas Helmy Clinics.
Tropical Medicine and Hepatology Department, Alexandria Faculty of Medicine.
Drug Des Devel Ther. 2016 Aug 25;10:2659-67. doi: 10.2147/DDDT.S111496. eCollection 2016.
This is the second and final report for our study designed to compare two generic sofosbuvir products for the degree and speed of virologic response to a dual anti-hepatitis C virus (HCV) treatment protocol. We aimed to test the applicability of the early virus response kinetics and the very rapid virologic response (vRVR) rate as quick outcome measures for accelerated comparative efficacy studies and as a foundation for a personalized response-guided therapy.
Fifty eligible chronic HCV patients were randomized to either one of two generic sofosbuvir products (Gratisovir or Grateziano) at a daily dose of one 400 mg tablet plus a weight-based ribavirin dose. Data were compared between the groups for early virus response kinetics and vRVR rates in relation to the rates of final sustained virologic response at week 12 posttreatment (SVR12).
The Log10 transformed virus load (Log polymerase chain reaction) curves showed fairly similar rapid decline during the first 2 weeks, with no significant difference between the groups at four analysis points throughout the study by repeated-measures factorial analysis of variance test (P=0.48). The SVR12 rates were 96% (95% confidence interval, 79.6%-99.9%) in Gratisovir group (24/25) and 95.7% (95% confidence interval, 78%-99.9%) in Grateziano group (22/23). There was no statistically significant difference found by exact test (P>0.999). There was a significant association between the vRVR and the SVR12, with 100% positive predictive value (38/38 of those who had vRVR, achieved a final SVR12) and 82.6% sensitivity (among the total 46 with SVR12, 38 were having vRVR).
We can conclude from our study that the early HCV response kinetics and the vRVR rates could be used as sensitive quick markers for efficacy (with a very high positive predictive value for SVR12), based on our accelerated comparative efficacy research model. This might open the way for new models of accelerated equivalence efficacy studies along with the bioequivalence kinetics studies to test a generic drug against a reference. Also, the early response kinetics and the vRVR might be used as qualifiers for a personalized course of treatment. This could shorten unnecessarily long treatment courses in rapid responders and might help to avoid relapses in slow responders.
这是我们研究的第二篇也是最后一篇报告，该研究旨在比较两种索磷布韦仿制药产品对双重抗丙型肝炎病毒（HCV）治疗方案的病毒学应答程度和速度。我们旨在测试早期病毒应答动力学和极快速病毒学应答（vRVR）率作为加速比较疗效研究的快速结局指标以及个性化应答指导治疗基础的适用性。
50例符合条件的慢性HCV患者被随机分配至两种索磷布韦仿制药产品（Gratisovir或Grateziano）中的一种，每日剂量为1片400mg片剂加基于体重的利巴韦林剂量。比较两组之间早期病毒应答动力学和vRVR率与治疗后第12周最终持续病毒学应答（SVR12）率的关系。
Log10转换的病毒载量（Log聚合酶链反应）曲线在前2周显示出相当相似且快速的下降，通过重复测量方差分析在整个研究的四个分析点上两组之间无显著差异（P = 0.48）。Gratisovir组的SVR12率为96%（95%置信区间，79.6% - 99.9%）（24/25），Grateziano组为95.7%（95%置信区间，78% - 99.9%）（22/23）。精确检验未发现统计学显著差异（P>0.999）。vRVR与SVR12之间存在显著关联，阳性预测值为100%（38例有vRVR者中有38例最终实现SVR12），敏感性为82.6%（在46例有SVR12者中，38例有vRVR）。
基于我们的加速比较疗效研究模型，我们可以从研究中得出结论，早期HCV应答动力学和vRVR率可作为疗效的敏感快速标志物（对SVR1来说阳性预测值非常高）。这可能为加速等效性疗效研究的新模型以及生物等效性动力学研究开辟道路，以测试仿制药与参比制剂。此外，早期应答动力学和vRVR可能用作个性化治疗疗程的限定指标。这可以缩短快速应答者不必要的长疗程，并可能有助于避免缓慢应答者复发。
