不含干扰素方案100%治愈难治性丙肝患者

亚特兰大——在今年的逆转录病毒和机会性感染大会(CROI)上，新西兰奥克兰临床研究中心Edward Gane博士报告的ELECTRON试验表明，在初治以及既往无应答的慢性丙肝基因1型患者中，sofosbuvir和利巴韦林联合ledipasvir治疗使所有患者在治疗后12周获得了持续病毒学应答。

在全球约1.7亿丙肝病毒(HCV)感染者中，基因1型占到了3/4，而且是最难治疗的一种亚型。现有治疗包括蛋白酶抑制剂(PI)加聚乙二醇化干扰素和利巴韦林三联治疗24~48周，但由于给药方案复杂、潜在耐药以及既往无应答者的应答率低等因素，以PI为基础的治疗比较局限。

研究者猜测联用2种作用机制不同的直接抗病毒药物可以提高治疗应答率。

在去年的CROI大会上，Gane博士报告称核苷酸NS5B抑制剂sofosbuvir(曾用名GS-7977)加利巴韦林治疗可产生抑制早期病毒载量的效果，但停止治疗后4周内出现的复发导致初治患者的治疗后12周持续病毒学应答率(SVR12)只有84%，既往对干扰素治疗无应答者的SVR12仅10%。

在本次报告的这项试验中，25例未经治疗的非肝硬化患者和9例既往无应答者(定义为聚乙二醇化干扰素和利巴韦林治疗12周后HCV RNA下降不足2个对数级)在sofosbuvir和基于体重的干扰素治疗基础上还加用了NS5A抑制剂ledipasvir(曾用名GS-5885)，所有药物均连续使用12周。

大部分初治患者和既往无应答者都是基因1a型(80%和89%)，并且基线HCV RNA载量较高(平均5.9 log₁₀ IU/ml和 6.9 log₁₀ IU/ml)。预后较好的IL28B基因型CC基因型见于36%的初治患者，但未见于所有既往无应答者。患者的中位年龄为48岁，白人占94%。

Gane博士称，治疗早期病毒抑制非常快，所有初治患者以及除1例外的所有既往无应答者在第4周都已检测不到病毒载量。例外的那名患者其病毒载量在第4周处于阈值水平，到了第5周即检测不到，因此两组患者的SVR12率都达到了100%。

试验没有观察到病毒学突破，所有患者都获得了治疗结束时应答。与去年报告的试验不同，两组患者在治疗后4周和12周都仍然检测不到HCV病毒载量。Gane博士说：“显然，加用第二种直接抗病毒药物ledipasvir进一步增强了sofosbuvir加利巴韦林治疗的疗效。”

而且这种三联疗法的耐受性和安全性良好。共出现了3例严重不良事件，但均与治疗无关。1例患者因不良事件不得不在第8周停止治疗，但之后仍然达到了SVR24。最常见的不良事件包括贫血(20%)、抑郁(8%)和头痛 (4%)，这些不良事件均出现在未经治疗的患者中。52%的未经治疗的患者和22%的既往无应答者出现了3级实验室异常，没有患者出现任何4级实验室异常。

Gane博士表示，ledipasvir和sofosbuvir现已制成单片固定剂量复方片剂，目前正在肝硬化患者中开展Ⅲ期试验以确定是否还需要与利巴韦林联用。此外，还在开展其他研究以探讨是否可以缩短治疗的持续时间。

ELECTRON试验由吉利德科学公司(Gilead Sciences)资助。Gane博士声明与吉利德、杨森-齐拉格、诺华、Pharmasset、罗氏和Vertex公司之间存在利益关系。

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By: PATRICE WENDLING, Internal Medicine News Digital Network

ATLANTA – Adding ledipasvir to sofosbuvir and ribavirin produced sustained virological responses 12 weeks after therapy in 100% of treatment-naive and prior nonresponder patients with chronic hepatitis C genotype 1 in the ELECTRON trial.

"Certainly adding a second direct-acting antiviral agent, ledipasvir, increases the efficacy of sofosbuvir plus ribavirin," Dr. Edward Gane said at the Conference on Retroviruses and Opportunistic Infections.

Three-quarters of the roughly 170 million people infected with hepatitis C virus (HCV) worldwide have genotype 1, the most difficult strain to treat.

Current treatment includes triple therapy with a protease inhibitor plus peginterferon and ribavirin for 24-48 weeks, but PI-based therapy is limited by complex dosing regimens, the potential for resistance, and lower responses in prior nonresponders, explained Dr. Gane of Auckland Clinical Studies in New Zealand.

The investigators hypothesized that combining two direct-acting antivirals with a different mechanism would enhance response.

At last year’s CROI meeting, Dr. Gane reported that treatment with the nucleotide NS5B inhibitor sofosbuvir (formerly known as GS-7977) and ribavirin alone led to early viral load suppression, but relapses within 4 weeks of stopping treatment resulted in 12-week posttreatment sustained virological response (SVR12) rates of 84% among treatment-naive patients and only 10% among previous interferon-based therapy null responders.

In the current arm of the trial, the NS5A inhibitor ledipasvir (formerly known as GS-5885) was added to sofosbuvir and weight-based ribavirin, all for 12 weeks, in 25 noncirrhotic treatment-naive and 9 null responders, defined by less than a 2-log reduction in HCV RNA after 12 weeks of peginterferon and ribavirin.

The majority of treatment-naive and null responders were genotype 1a (80% and 89%) and had high baseline HCV RNA loads (mean 5.9 log10 IU/mL and 6.9 log10 IU/mL). The more favorable IL28B genotype CC genotype was present in 36% of treatment-naive patients, but in no null responders. The patients median age was 48; 94% were white.

Early on–treatment viral suppression was very rapid, with all treatment-naive patients and all but one prior null responder having an undetectable viral load at week 4, Dr. Gane said. This patient’s load was on the threshold at week 4 and became undetectable by week 5, resulting in SVR12 rates of 100% in both groups.

No viral breakthroughs were observed, and all patients achieved an end-of-treatment response.

Unlike the earlier arm of the trial, however, both groups maintained undetectable HCV viral loads at 4 and 12 weeks after therapy, he said.

The triple combination was well tolerated and safe. Three serious adverse events occurred, but none were treatment related. One patient had to stop therapy at week 8 due to the event, but subsequently achieved SVR24. The most common adverse events were anemia (20%), depression (8%), and headache (4%), and all were in treatment-naive patients.

Grade 3 laboratory abnormalities occurred in 52% of the treatment-naive and 22% of null responders. No grade 4 abnormalities were seen, Dr. Gane said.

Ledipasvir and sofosbuvir have been combined into a single fixed-dose tablet and is being evaluated in phase III studies in patients with cirrhosis and to determine whether there is a need for ribavirin, he said. Additional studies are also underway to explore shorter durations of therapy.

ELECTRON was sponsored by Gilead Sciences. Dr. Gane reported ties with Gilead, Janssen-Cilag, Novartis, Pharmasset, Roche and Vertex.