对聚乙二醇干扰素联合利巴韦林治疗没有反应的慢性丙型肝炎的患者，可能从增加多个直接作用的抗病毒药物治疗方案中受益。这种开放式模式，第2a期研究包括探索对以前治疗没有反应的1型慢性HCV的21例患者（即，应用聚乙二醇干扰素和利巴韦林联合治疗≥12周后HCV RNA下降小于2log （10） 的患者）。我们随机分配患者接受NS5A复制复合体抑制剂daclatasvir（60毫克，每天一次）和NS3蛋白酶抑制剂asunaprevir的（600毫克，每天两次）单独组（A组，11例）或联合聚乙二醇干扰素α-2a和利巴韦林（B组，10例），用药持续24周。主要终点是患者的治疗期结束后12周持续病毒学应答的百分比。A组中一共有4名患者（36％;9名HCV基因型为1a中的2人及基因型为1b的2人）分别在12周及24周治疗后有持续病毒学应答。6例（均属于HCV基因型1a）在接受治疗的同时有病毒学突破，并发现在所有情况下对这两种抗病毒药有耐药性，其中一名患者在治疗结束后有病毒学应答，但在治疗期间有病毒复发。B组中全部10例患者治疗12周后有持续病毒学应答；9例治疗24周后仍有持续病毒学应答。腹泻在这两个群体中是最常见的不良事件。6例患者出现一过性谷丙转氨酶水平升高超过正常上限的3倍以上。这个初步研究，涉及到常规治疗没有应答的基因1型HCV感染者，提示只有通过应用两个直接的抗病毒药物才能达到持续病毒学应答。此外，当两个直接作用抗病毒药物联合聚乙二醇干扰素α-2a和利巴韦林治疗时，持续病毒学应答率很高。（由Bristol-Myers公司的ClinicalTrials.gov提供数据，NCT01012895）。
吉林大学第一医院肝胆胰内科 徐鹤 摘译
本文首次发表于[N Engl J Med. 2012 Jan 19;366(3):216-224]
Preliminary study of two antiviral agents for hepatitis C genotype 1
BACKGROUND:Patients with chronic hepatitis C virus (HCV) infection who have not had a response to therapy with peginterferon and ribavirin may benefit from the addition of multiple direct-acting antiviral agents to their treatment regimen.METHODS:This open-label, phase 2a study included an exploratory cohort of 21 patients with chronic HCV genotype 1infection who had not had a response to previous therapy (i.e. had not had ≥2 log(10) decline in HCV RNA after ≥12 weeks of treatment with peginterferon and ribavirin).We randomly assigned patients to receive the NS5A replication complex inhibitor daclatasvir daclatasvir(60 mg once daily) and the NS3 protease inhibitor asunaprevir (600 mg twice daily) alone (group A, 11 patients) or in combination with peginterferon alfa-2a and ribavirin (group B, 10 patients) for 24 weeks. The primary end point was the percentage of patients with a sustained virologic response 12 weeks after the end of the treatment period.RESULTS:A total of 4 patients in group A (36%; 2 of 9 with HCV genotype 1a and 2 of 2 with genotype 1b) had a sustained virologic response at 12 weeks after treatment and also at 24 weeks after treatment. Six patients (all with HCV genotype 1a) had viral breakthrough while receiving therapy, and resistance mutations to both antiviral agents were found in all cases; 1patient had a viral response at the end of treatment but had a relapse after the treatment period.All 10 patients in group B had a sustained virologic response at 12 weeks after treatment, and 9 had a sustained virologic response at 24 weeks after treatment. Diarrhea was the most common adverse event in both groups. Six patients had transient elevations of alanine aminotransferase levels to more than 3 times the upper limit of the normal range.Conclusions:This preliminary study involving patients with HCV genotype 1 infection who had not had a response to prior therapy showed that a sustained virologic response can be achieved with two direct-acting antiviral agents only.In addition, a high rate of sustained virologic response was achieved when the two direct-acting antiviral agents were combined with peginterferon alfa-2a and ribavirin. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01012895.)
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