Sofosbuvir加聚乙二醇干扰素和利巴韦林治疗慢性丙型肝炎病毒

StephenW

Summary and Comment

Sofosbuvir plus Peginterferon and Ribavirin for Chronic HCV Infection

In phase II trials, a 12-week regimen resulted in high virologicresponse 24 weeks after treatment, no sofosbuvir-specific adverse effects, and no virologic breakthrough.

Sofosbuvir is a nucleotide analogue that inhibits NS5B-directed hepatitis C virus (HCV) RNA replication. In vitro studies suggest that sofosbuvir has anti-viral activity against all HCV genotypes and a high barrier to resistance. The current industry-funded, phase II companion studies evaluated the efficacy of sofosbuvir in combination with peginterferon and ribavirin in HCV-infected patients without cirrhosis.
Lawitz and colleagues randomized 122 treatment-naive patients with HCV genotype 1 in a 2:2:1 allocation to receive sofosbuvir (200 mg or 400 mg) or placebo daily in combination with peginterferon (180 µg weekly) plus ribavirin (1000–1200 mg daily) for 12 weeks. Patients with HCV genotypes 2 or 3 received open-label sofosbuvir plus peginterferon and ribavirin for 12 weeks. Some patients received an additional 12 to 36 weeksof peginterferon/ribavirin depending on viral response. In the randomized cohort, sustained virologic response (SVR) rates at 12 weeks post-treatmentwere 90%, 91%, and 58% in the 200 mg, 400 mg, and placebo groups, respectively. Although SVR rates were similar between the sofosbuvir groups, 3 patients in the 200-mg group had viral relapse versus none in the400-mg group. Among the cohort with genotypes 2 and 3, the SVR rate was 92%. The most common adverse effects were peginterferon- and ribavirin-related.
Kowdley and colleagues randomized 316 treatment-naive patients with HCV genotypes 1, 4, or 6 in a 1:2:3 allocation to receive sofosbuvir (400 mg) daily in combination with peginterferon (180 µg weekly) and ribavirin (1000–1200 mg daily) for 12 weeks, the same drug regimen for 24 weeks, or the 12-week regimen followed by either sofosbuvir monotherapy or sofosbuvir plus ribavirin for another 12 weeks. SVR rates were 89%, 89%, and 87% at 24 weeks post-treatment for the 3 groups, respectively. SVR rates were 82% for 11 patients with genotype 4 and 100% for 5 patients withgenotype 6. Baseline viral load and IL28B genotype did not affect SVR rates. As with the companion study, most adverse effects were associated with peginterferon and ribavirin and not with sofosbuvir. No evidence of HCV resistance was noted in either study.
Comment: Key observations from these trial findings include: (1) the average sustained virologic response rate was 90% for a 12-week sofosbuvir regimen in all HCV genotypes; (2) 12 weeks of therapy seems to be as effective as 24 weeks; (3) sofosbuvir should be administered at a dose of 400 mg daily; (4) sofosbuvir is well tolerated and adds no new adverse effects to the regimen; (5) resistance development does not seem tobe a concern; and (6) traditional predictors of response, such as IL28B genotype and baseline viral load, do not seem to affect response rates. The ongoing phase III studies will hopefully verify the safety and efficacy of the sofosbuvir regimen. Future studies should evaluate its efficacy in patients who are treatment-experienced or have cirrhosis.
— AtifZaman, MD, MPH
Published in JournalWatch Gastroenterology April 12, 2013

Citation(s):

  

Lawitz E   et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin  for non-cirrhotic treatment-naïve patients with genotypes 1, 2, and   3 hepatitis C infection: A randomised, double-blind, phase 2 trial.   Lancet Infect Dis    2013 Mar 15;  [e-pub ahead of print]. (http://dx.doi.org/10.1016/S1473-3099(13)70033-1)

  

Kowdley   KV et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for   treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC):   An open-label, randomised, multicentre phase 2 trial.   Lancet    2013 Mar 15;  [e-pub ahead of print]. (http://dx.doi.org/10.1016/S0140-6736(13)60247-0)

StephenW

述评
Sofosbuvir加聚乙二醇干扰素和利巴韦林治疗慢性丙型肝炎病毒感染

在II期临床试验，为期12周的治疗方案，治疗后24周高病毒学应答，没有特定sofosbuvir的不利影响，并没有病毒学突破。

sofosbuvir是一种核苷酸类似物，抑制NS5B导向的丙型肝炎病毒（HCV）RNA的复制。体外研究显示，sofosbuvir具有抗病毒活性，对所有HCV基因型和高耐药屏障。目前行业投资，第二阶段的伴侣研究的sofosbuvir结合聚乙二醇干扰素和利巴韦林在丙型肝炎病毒感染的患者无肝硬化的疗效评价。

Lawitz和他的同事们与HCV基因型1在2时02分01秒分配接收sofosbuvir（200毫克或400毫克）或安慰剂（每周180微克）与聚乙二醇干扰素联合利巴韦林（1000-1200毫克每日结合治疗初治患者随机122每天）12周。 HCV基因型2或3的患者接受开放的标签sofosbuvir加聚乙二醇干扰素和利巴韦林治疗12周。有些患者收到了额外的12至36周的聚乙二醇干扰素/利巴韦林取决于病毒应答。在随机队列，治疗后分别为90％，91％，58％，200毫克，400毫克组和安慰剂组，分别在12周持续病毒学应答（SVR）率。 ，尽管SVR率相似之间的sofosbuvir组的，在200 mg组有3例病毒复发与没有在400 mg组。基因型2和3之间的队列，SVR率为92％。最常见的副作用是聚乙二醇干扰素和利巴韦林有关。

Kowdley和同事随机316治疗初治患者的HCV基因型1，4或6 1:2:3分配接收sofosbuvir（400毫克），每日结合聚乙二醇干扰素（每周180微克）和利巴韦林（1000-1200毫克每日）为12周，24周，任sofosbuvir单一或sofosbuvir的联合利巴韦林治疗12周或12周的方案相同的药物治疗方案。 SVR率分别为89％，89％，87％为3组，分别在24周治疗后。 SVR率分别为82％，11例5例6型与基因型4和100％。基线病毒载量和IL28B基因型不影响SVR率。最不利的影响与同伴研究，均与聚乙二醇干扰素和利巴韦林，而不是与sofosbuvir。任何一项研究指出，没有证据表明抗HCV。

点评：从这些试验结果的主要意见包括：（1）所有HCV基因型12个的周sofosbuvir方案的平均持续病毒学应答率分别为90％（2）12周的治疗似乎是为24周; （3）sofosbuvir应该给药剂量为每日400毫克;（4）sofosbuvir耐受性好，没有添加新的不利影响的方案，（5）耐药性的发展似乎并没有引起人们的关注，以及（6）传统预测反应，，如IL28B基因型和基线病毒载量，似乎并没有影响响应率。正在进行的第三阶段的研究将有望验证的sofosbuvir方案的安全性和有效性。未来的研究应评价其疗效，治疗经验，或有肝硬化的患者。

- 与Atif扎曼，MD，MPH

期刊观看消化科2013年4月12日发布

引用（S）：

LawitzÉ等。 Sofosbuvir组合与非肝硬化治疗初治患者的基因型1，2，3 C型肝炎感染：采用随机，双盲，2期临床试验的聚乙二醇干扰素α-2a和利巴韦林。柳叶刀传染病杂志2013年3月15日; [E-酒馆提前打印]。 （http://dx.doi.org/10.1016/S1473-3099（13）70033-1）

kowdley KV等。 Sofosbuvir与聚乙二醇干扰素α-2a和利巴韦林治疗初治患者的丙型肝炎基因型1感染（原子）：一个开放标签，随机，多中心II期临床试验。柳叶刀“杂志2013年3月15 [E-酒馆提前打印]。 （http://dx.doi.org/10.1016/S0140-6736（13）60247-0）