慢性丙型肝炎病毒感染的无干扰素治疗方案：越来越近

StephenW

Interferon-Free Regimens for Chronic HCV Infection: Getting Closer

Several regimens with polymerase or protease inhibitors plus ribavirin achieved high sustained virologic response rates without interferon.

A major drawback of current therapies for chronic hepatitis C virus (HCV) infection is poor tolerability of adverse effects, mainly caused by peginterferon. Previous studies of interferon-free HCV regimens were early phase trials (JW Gastroenterol Jan 18 2012 and JW Gastroenterol Sep 30 2011); now results are available from two industry-sponsored, open-label, phase 2a trials in patients with HCV genotypes 1, 2, and 3.

In the first study, investigators randomized 40 treatment-naive patients with genotype 2 or 3 in a 1:1:1:1 ratio to four groups, all of which received sofosbuvir — an oral nucleotide HCV polymerase inhibitor — (400 mg daily) and ribavirin (1000–1200 mg daily) for 12 weeks. Three groups also received peginterferon (180 µg weekly) for 4, 8, and 12 weeks, respectively. Subsequently added study groups included the following: 10 patients with genotypes 2 or 3 who received sofosbuvir monotherapy for 12 weeks; 10 patients with genotypes 2 or 3 who received sofosbuvir, ribavirin, and peginterferon for 8 weeks; and 25 genotype 1, treatment-naive patients and 10 genotype 1 null responders to previous peginterferon/ribavirin treatment who received sofosbuvir and ribavirin for 12 weeks. The primary end point of sustained virologic response at 24 weeks post-therapy was achieved by all 40 patients who received sofosbuvir plus ribavirin with or without peginterfero n, 6 of the 10 patients who received sofosbuvir monotherapy, 21 of the 25 genotype 1, treatment-naive patients who received sofosbuvir and ribavirin, and only 1 of the 10 genotype 1, treatment-experienced patients who received sofosbuvir and ribavirin. No mutations were observed in the other 9 patients. Adverse effects were mild.

In the second study, investigators sequentially enrolled patients with HCV genotype 1. All patients received ABT-333 — a nonnucleoside NS5B polymerase inhibitor — (400 mg twice daily), ribavirin (1000–1200 mg daily), and one of two daily doses of ABT-450/r (ABT-450, an NS3 protease inhibitor, combined with 100 mg of ritonavir daily) for 12 weeks. Groups of 19 and 14 treatment-naive patients received 250 mg and 150 mg of ABT-450/r, respectively, and a third group of 17 treatment-experienced patients received 150 mg of ABT-450/r. The primary end point was extended rapid virologic response (undetectable HCV RNA from weeks 4 through 12), which was achieved in 89%, 79%, and 59% of the three groups, respectively. Sustained virologic response was achieved in 95%, 93%, and 47%, respectively. Resistant variants in NS3 and NS5B were observed in 8 of the 9 patients who had virologic failure in group three. Side effects were mild.

Comment: These findings suggest that we are close to realizing the ideal HCV treatment — an interferon-free, simple regimen of short duration with minimal adverse effects and low resistance rates. Patients with genotypes 2 or 3 and treatment-naive patients with genotype 1 will be the first to benefit. Ribavirin seems to be here to stay, at least for now. Unfortunately, difficult-to-treat patients such as genotype 1, treatment-experienced patients will likely continue to require interferon as part of their regimens.

— Atif Zaman, MD, MPH

Published in Journal Watch Gastroenterology January 2, 2013

Citation(s):

Gane EJ et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013 Jan 3; 368:34.

Poordad F. Exploratory study of oral combination antiviral therapy for hepatitis. N Engl J Med 2013 Jan 3; 368:45.

StephenW

慢性丙型肝炎病毒感染的无干扰素治疗方案：越来越近了

几个聚合酶和蛋白酶抑制剂联合利巴韦林的治疗方案实现持续病毒学应答率，无干扰素。

目前的治疗慢性丙型肝炎病毒（HCV）感染的主要缺点是耐受性差的不利影响，主要是由于聚乙二醇干扰素。以往的研究中无干扰素-HCV治疗方案的早期阶段试验（JW胃肠病学杂志2012年1月18日和JW胃肠病学杂志2011年9月30日日）;结果可以从两个行业赞助的，开放标签，第2A期试验中患者HCV基因型1， 2，和3。

在第一项研究中，研究人员随机40基因型2或3 1:1:1:1的比例分为四组，所有这一切都sofosbuvir  - 口服核苷酸丙型肝炎病毒聚合酶抑制剂 - （每天400毫克）和治疗初治患者利巴韦林（每日1000-1200毫克）治疗12周。三组聚乙二醇干扰素（每周180微克）为4，8，和12周，分别。随后研究组包括如下：10患者的基因型2或3谁收到sofosbuvir的单药治疗12周，10例2或3收到sofosbuvir的基因型，利巴韦林和聚乙二醇干扰素8周和25治疗初治基因1型，患者和10例基因1型空应答以前的聚乙二醇干扰素/利巴韦林治疗，收到sofosbuvir和利巴韦林12周。在24周治疗后的持续病毒学应答的主要终点是通过所有40例患者的25个基因1型，治疗谁收到sofosbuvir的联合利巴韦林带或无peginterfero N，6接受sofosbuvir单药治疗的10例患者中，21天真的患者谁收到sofosbuvir和利巴韦林的10个基因型，收到sofosbuvir和利巴韦林的治疗经验的患者，只有1。在其他9例患者中，无突变观察。不良反应轻微。

在第二项研究中，研究人员依次参加试验的患者与HCV基因型1。所有患者均接受ABT-333  - 非核苷NS5B聚合酶抑制剂 - （400毫克，每天两次），利巴韦林（每日1000-1200毫克），每天服用ABT-450 / R（ABT-450，NS3蛋白酶抑制剂，结合与利托那韦每日100毫克）12周。 19日和14组治疗过的患者接受了ABT-450 / R 250毫克和150毫克，分别和ABT-450 / R，第三组为17例治疗经验的患者接受150毫克。研究的主要终点是快速病毒学应答（从4到12周检测不到HCV RNA），达到89％，79％和59％的三组，分别延长。 95％，93％和47％，分别取得了持续的病毒学应答。 8病毒学失败的三组9例患者中耐药变异的NS3和NS5B观察。副作用是轻微的。

评论：这些结果表明，我们正在接近实现理想的丙型肝炎病毒治疗 - 无干扰素的，简单的方案用最少的不利影响和低电阻率的持续时间短。患者的基因型2或3，治疗初治基因1型患者将首先受益。利巴韦林似乎是在这里留下来，至少现在是。不幸的是，很难治疗基因1型的患者，如治疗经验的患者可能会继续要求干扰素作为其方案的一部分。

-  ATIF扎曼，MD，MPH

在中国手表胃肠病学2013年1月2日发布

参考文献（S）：

盖恩EJ等。核苷酸聚合酶抑制剂sofosbuvir加利巴韦林治疗丙型肝炎的新英格兰医学杂志2013年1月3日，368:34。

Poordad F.口头组合型肝炎的抗病毒治疗的探索性研究。治疗Ĵ医学2013年3 368:45。

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