对于既往无应答的慢性丙型肝炎基因1型感染患者，使用美利他滨联合博赛泼维或特拉泼维，与聚乙二醇干扰素α-2a加利巴韦林联合治疗：随机DYNAMO 1和DYNAMO 2研究
Mericitabine and Either Boceprevir or Telaprevir in Combination with Peginterferon Alfa-2a plus Ribavirin for Patients with Chronic Hepatitis C Genotype 1 Infection and Prior Null Response: The Randomized DYNAMO 1 and DYNAMO 2 Studies.
作者信息
Wedemeyer Heiner, Forns Xavier, Hézode Christophe, Lee Samuel S, Scalori Astrid, Voulgari Athina, Le Pogam Sophie, Nájera Isabel, Thommes James A
机构信息
Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical School, Hannover, Germany.
Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain.
出版信息
PLoS One. 2016 Jan 11;11(1):e0145409. doi: 10.1371/journal.pone.0145409. eCollection 2016.
UNLABELLED
Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a previous null response (<2-log10 reduction in HCV RNA by treatment week 12) to peginterferon/ribavirin (PegIFN/RBV) do not achieve a sustained virological response (SVR) when re-treated with a first-generation HCV protease inhibitor (PI) administered in combination with PegIFN/RBV. We studied the incremental benefits associated with adding mericitabine (nucleoside analog inhibitor of HCV polymerase) to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials (with boceprevir in DYNAMO 1, and with telaprevir in DYNAMO 2). The primary endpoint in both trials was SVR, defined as HCV RNA <25 IU/mL 12 weeks after the end of treatment (SVR12). Overall, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60-70% in DYNAMO 1 and of 71-96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-generation PI.
TRIAL REGISTRATION
ClinicalTrials.gov NCT01482403 and ClinicalTrials.gov NCT01482390.
未标注
大多数慢性丙型肝炎病毒（HCV）1型感染患者，既往对聚乙二醇干扰素/利巴韦林（PegIFN/RBV）治疗无反应（治疗第12周时HCV RNA下降幅度<2 log10），再次接受第一代HCV蛋白酶抑制剂（PI）联合PegIFN/RBV治疗时，未实现持续病毒学应答（SVR）。在两项双盲随机多中心2期试验中（DYNAMO 1中使用博赛匹韦，DYNAMO 2中使用特拉匹韦），我们研究了在基于PI加聚乙二醇干扰素α-2a/利巴韦林的治疗方案中添加美利他滨（HCV聚合酶的核苷类似物抑制剂）的额外益处。两项试验的主要终点均为SVR，定义为治疗结束后12周时HCV RNA<25 IU/mL（SVR12）。总体而言，在DYNAMO 1中，在PI加聚乙二醇干扰素α-2a/利巴韦林治疗方案中添加美利他滨导致SVR12率为60% - 70%，在DYNAMO 2中为71% - 96%。在两项试验中，HCV 1a和1b基因型感染患者的SVR12率相似。两项研究中的安慰剂对照臂均因病毒学失败率高而停止。在数值上，较低的复发率与美利他滨较长疗程（24周与12周）、含特拉匹韦的方案以及包括48周聚乙二醇干扰素α-2a/利巴韦林治疗的方案相关。在任何一项试验的任何患者中均未鉴定出美利他滨耐药突变。添加美利他滨并未增加与基于特拉匹韦或博赛匹韦方案相关的安全负担。这些研究表明，当将具有中等抗病毒效力的核苷聚合酶抑制剂添加到含第一代PI的方案中时，难治性患者的SVR率增加且复发率降低。
试验注册
ClinicalTrials.gov NCT01482403和ClinicalTrials.gov NCT01482390。
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