Sulkowski Mark S, Flamm Steve, Kayali Zeid, Lawitz Eric J, Kwo Paul, McPhee Fiona, Torbeyns Anne, Hughes Eric A, Swenson Eugene S, Yin Philip D, Linaberry Misti
Viral Hepatitis Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Feinberg School of Medicine Northwestern University, Chicago, IL, USA.
Liver Int. 2017 Jun;37(6):836-842. doi: 10.1111/liv.13335. Epub 2017 Feb 2.
BACKGROUND & AIMS: The phase 2, FOURward study (NCT02175966) investigated short-duration therapy (4/6 weeks) with four direct-acting antivirals (DAAs) with distinct mechanisms of action in patients infected with hepatitis C virus (HCV) genotype-1.
Non-cirrhotic patients were randomized 1:1 to DCV-TRIO (fixed-dose daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg) twice-daily + sofosbuvir 400 mg once-daily for 4 or 6 weeks. The primary endpoint was sustained virological response at post-treatment Week 12 (SVR12). Patients without SVR12 were offered retreatment based on the DAA resistance profile at failure; patients with resistance to ≤1 DCV-TRIO component received DCV-TRIO + RBV for 12 weeks.
Twenty-eight patients with HCV genotype-1 were enrolled; 79% had genotype-1a infection and median baseline HCV-RNA levels were high (9 × 10 IU/mL). Most patients had undetectable HCV-RNA at end of treatment (96% [n=27/28]); however, relapse occurred in 77% (n=10/13) and 43% (n=6/14) treated for 4 and 6 weeks, leading to SVR12 rates of 29% (n=4/14) and 57% (n=8/14) respectively. SVR12 was higher in patients with lower baseline HCV-RNA (<2 million IU/mL, 71% [n=5/7]; ≥2 million IU/mL, 33% [n=7/21]). None of the 16 non-SVR12 patients had NS3 or NS5B resistance-associated substitutions (RAS) detected at failure. All 15 patients retreated with DCV-TRIO + RBV for 12 weeks achieved SVR12. All regimens were well tolerated.
Short-duration treatment with four DAAs with distinct mechanisms of action was insufficient for most patients with genotype-1 infection and high baseline viraemia. Non-SVR12 was not associated with emergence of NS3 or NS5B RAS and retreatment with DCV-TRIO + RBV for 12 weeks led to SVR in all patients.
2期FOURward研究（NCT02175966）调查了对丙型肝炎病毒（HCV）基因型1感染患者使用四种作用机制不同的直接抗病毒药物（DAA）进行短期治疗（4/6周）的效果。
将非肝硬化患者按1:1随机分组，分别接受DCV-TRIO（固定剂量的30毫克达卡他韦、200毫克阿舒瑞韦和75毫克贝克洛维）每日两次+400毫克索磷布韦每日一次，持续4周或6周。主要终点是治疗后第12周的持续病毒学应答（SVR12）。未达到SVR12的患者根据失败时的DAA耐药情况接受再次治疗；对≤1种DCV-TRIO成分耐药的患者接受DCV-TRIO+利巴韦林治疗12周。
纳入了28例HCV基因型1感染患者；79%为1a基因型感染，基线HCV-RNA水平中位数较高（9×10⁶IU/mL）。大多数患者在治疗结束时HCV-RNA检测不到（96%[n=27/28]）；然而，接受4周和6周治疗的患者分别有77%（n=10/13）和43%（n=6/14）复发，导致SVR12率分别为29%（n=4/14）和57%（n=8/14）。基线HCV-RNA较低（<200万IU/mL，71%[n=5/7]；≥200万IU/mL，33%[n=7/21]）的患者SVR12率更高。16例未达到SVR12的患者在失败时均未检测到NS3或NS5B耐药相关替代（RAS）。所有15例接受DCV-TRIO+利巴韦林再次治疗12周的患者均实现了SVR12。所有治疗方案耐受性良好。
对大多数基因型1感染且基线病毒血症较高的患者而言，使用四种作用机制不同的DAA进行短期治疗是不够的。未达到SVR12与NS3或NS5B RAS的出现无关，使用DCV-TRIO+利巴韦林再次治疗12周可使所有患者实现SVR。
