抗病毒联合标准疗法在 HBV 中达到“受控生物学状态”

StephenW

抗病毒联合标准疗法在 HBV 中达到“受控生物学状态”
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伦敦 — 据国际肝病大会的一位发言人称，与标准疗法相比，结合小干扰 RNA、衣壳组装调节剂和核苷酸类似物的疗法在 24 周内降低了 HBsAg 水平。
科什·阿加瓦尔

伦敦国王学院医院肝脏研究所的医学博士 Kosh Agarwal 对与会者说：“重要的是我们要考虑公共卫生和全球病毒以及肝病，而乙型肝炎是一种全球相关的病毒。” “我相信最新的估计表明，全世界有近 3 亿人受到乙型肝炎的影响，几乎每 30 秒，世界某个地方就有一人死于乙型肝炎。”
史蒂夫·福雷斯特/EASL
“我们没有治愈，但在随访结束时，很大一部分患者处于‘受控生物学状态’——这是否足够好？”医学博士 Kosh Agarwal 向与会者提问。 “当我们报告 48 周时，这是否会被执行？”资料来源：史蒂夫福雷斯特/EASL

他补充说：“我们有可以控制乙型肝炎的良好治疗方法，但我们没有治愈乙型肝炎的治疗方法。在丙型肝炎取得惊人成功的背景下，该领域存在着一种尝试并实现治愈乙型肝炎的愿望。乙型肝炎，我们通过失去表面抗原（乙型肝炎的标志物）来表征这一点。”

在 REEF-2 2b 期研究中，Agarwal 及其同事选择了 130 名 HBsAg 大于 100 IU/mL 并接受核苷酸类似物治疗至少 2 年的非肝硬化 HBeAg 阴性慢性乙型肝炎患者，并将他们随机分配到一个研究性小干扰 RNA（siRNA；JNJ-3989，Arrowhead Pharmaceuticals）加上衣壳组装调节剂（JNJ-6379，Janssen Pharmaceuticals）或安慰剂。

该研究的主要终点是在没有重新开始核苷酸类似物治疗的情况下，在随访第 24 周时达到 HBsAg 水平低于 0.05 IU/mL 的患者比例。

“这项研究的独特之处在于，48 周后，所有治疗都停止了，”Agarwal 说。 “如果你想治愈，你必须考虑有限的治疗时间，而目前，我们没有。”

据研究人员称，在基线时，联合治疗组 80% 的患者 HBsAg 水平至少为 1,​​000 IU/mL，之前使用核苷酸类似物的平均持续时间为 8.4 年，而标准治疗组中 76% 的 HBsAg 水平为至少 1,000 IU/mL，之前平均核苷酸类似物使用时间为 8.1 年。

治疗结束后，HBsAg 与基线的平均降低在联合组中为 –1.89 (0.060) log10 IU/mL，在对照组中为 –0.06 (0.012) log10 IU/mL。在联合组中，71.1%的患者HBsAg低于100 IU/mL，19.7%低于10 IU/mL，2.6%低于1 IU/mL。在对照组中，仅有 2.4% 的患者 HBsAg 低于 100 IU/mL；然而，两组中都没有患者达到 HBsAg 血清学清除。

“经过 24 周的随访，在这项研究中，无论是活动臂还是对照组，都没有患者失去其表面抗原——即治愈了乙型肝炎，”Agarwal 说。 “然而，有证据表明，这些药物的组合，以及 siRNA 的一个特定方面，显示出我们对乙型肝炎感兴趣的一些标志物显着减少，这是在 24 周。”

他补充说：“所以我们没有治愈，但在随访结束时，很大一部分患者处于‘受控生物学状态’——这是否足够好？当我们报告 48 周时，这是否会被执行？这将使我们重新考虑是否需要更好的抗病毒治疗，是否需要考虑不同的组合以及停止所有治疗是否是正确的策略。”

StephenW

Antiviral combination plus standard therapy achieves ‘controlled biological state’ in HBV
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LONDON — Therapy combining small interfering RNA, capsid assembly modulator and nucleotide analogue reduced HBsAg levels over 24 weeks compared with standard therapy, according to a presenter at the International Liver Congress.
Kosh Agarwal

“It’s important that we think about public health and global viruses and liver disease, and hepatitis B is a globally relevant virus,” Kosh Agarwal, MD, from the Institute of Liver Studies at King’s College Hospital in London, told attendees. “I believe the latest estimates suggest that almost 300 million people in the world are affected with hepatitis B, and almost every 30 seconds, someone dies of hepatitis B somewhere in the world.”
Steve Forrest/EASL
“We didn't achieve a cure, but at the end of follow-up, a significant proportion of patients were in a ‘controlled biological state’ — is that good enough?” Kosh Agarwal, MD, asked attendees. “Is that going to be followed through when we report 48 weeks?” Source: Steve Forrest/EASL

He added: “We have good treatments that can control hepatitis B, but we do not have treatments that cure hepatitis B. On the back of the stunning success of hepatitis C, there is within the field, a wish to try and achieve cure of hepatitis B, and we characterize that by losing surface antigen, a marker of hepatitis B.”

In the phase 2b REEF-2 study, Agarwal and colleagues selected 130 non-cirrhotic HBeAg-negative chronic hepatitis B patients with HBsAg greater than 100 IU/mL and nucleotide analogue treatment for at least 2 years, and randomly assigned them to add on an investigational small interfering RNA (siRNA; JNJ-3989, Arrowhead Pharmaceuticals) plus a capsid assembly modulator (JNJ-6379, Janssen Pharmaceuticals) or placebo.

The primary endpoint for the study was the proportion of patients who achieved HBsAg levels less than 0.05 IU/mL at follow-up week 24 without restarting nucleotide analogue therapy.

“The unique aspect of this study is that after 48 weeks, all treatment was stopped,” Agarwal said. “If you want to get to a cure, you have to think about a finite duration of therapy, and currently, we don’t have that.”

According to researchers, at baseline, 80% patients in the combination therapy group had HBsAg levels of at least 1,000 IU/mL and a mean duration of previous nucleotide analogue use of 8.4 years, while 76% of the standard therapy group exhibited HBsAg levels of at least 1,000 IU/mL with prior mean nucleotide analogue use of 8.1 years.

Following the end of treatment, mean reductions in HBsAg from baseline were –1.89 (0.060) log10 IU/mL in the combination group and –0.06 (0.012) log10 IU/mL in the control group. In the combination group, 71.1% of patients achieved HBsAg of less than 100 IU/mL, 19.7% less than 10 IU/mL and 2.6% less than 1 IU/mL. In the control group, only 2.4% of patients achieved HBsAg of less than 100 IU/mL; however, no patient in either group achieved HBsAg seroclearance.

“After 24 weeks of follow up, no patients in this study lost their surface antigen — ie, were cured of hepatitis B — in either the active arm or the control arm,” Agarwal said. “However, there is evidence to show that the combination of these drugs, and one particular aspect of siRNA, shows a significant decrease in some of the markers that we are interested in for hepatitis B, and this is at 24 weeks.”

He added: “So we didn't achieve a cure, but at the end of follow-up, a significant proportion of patients were in a ‘controlled biological state’ — is that good enough? Is that going to be followed through when we report 48 weeks? This will take us back to the drawing board to think about whether we need better antiviral treatments, whether we need to think about different combinations and whether stopping all treatment is the right strategy to take.”