新型抗纤维化改善慢性乙型肝炎的纤维化 — 来自中国的 II

StephenW

新型抗纤维化改善慢性乙型肝炎的纤维化
— 来自中国的 II 期试验表明附加疗法的益处

作者：Zaina Hamza，MedPage Today 特约撰稿人 2022 年 7 月 15 日

在中国进行的一项 II 期试验发现，研究性氢尼酮与恩替卡韦 (Baraclude) 联合使用可减少慢性乙型肝炎患者的肝纤维化。

据报道，在对 168 名此类患者进行的意向治疗分析中，46.4% 的跨剂量组患者在 6 点 Ishak 量表中将纤维化改善至少 1 分，而安慰剂组为 26%。中国武汉华中科技大学的 Ping Yin 博士及其同事，撰写临床胃肠病学和肝病学。

仅中间剂量组的获益显着，在第 52 周时，使用 270 mg/天的氢尼酮比安慰剂组纤维化至少改善 1 点的可能性是安慰剂组的 2.14 倍（55% 对 26%，P=0.030） .其他氢尼酮剂量显示出类似的数值优势，但未达到显着性：

    每天 180 毫克：改善 41%，RR 1.58 (95% CI 0.86-2.99)
    每天 360 毫克：改善 44%，RR 1.72 (95% CI 0.94-3.21)

研究人员指出：“接受氢尼酮治疗的 CHB [慢性乙型肝炎] 患者表现出肝纤维化的显着组织学改善，口服 270 mg 显示出纤维化消退的最佳效果。 “我们的研究结果进一步表明，氢尼酮可能对轻度或中度纤维化阶段有效，而不仅仅是显着的纤维化。”

研究人员指出，乙型肝炎感染通常会导致肝纤维化，进而导致肝硬化甚至肝细胞癌。目前尚无针对伴有肝纤维化的慢性乙型肝炎患者的特定治疗选择，这是第一个评估氢尼酮用于这些适应症的试验。

Hydronidone 在结构上与 pirfenidone (Esbriet) 相似，用于治疗特发性肺纤维化，因此 Yin 的团队将其视为肝毒性的新治疗选择。

他们招募了 168 名慢性乙型肝炎患者，并以 1:1:1:1 的比例随机分配他们在中国的 8 个中心以双盲方式接受每天 180 毫克、270 毫克或 360 毫克的口服氢尼酮或安慰剂，为期 52 周，直至2019 年 9 月 5 日。所有患者还每天接受 0.5 毫克恩替卡韦。

参与者年龄在 18 至 65 岁之间，经活检证实为肝纤维化（Ishak 评分至少为六分之三）。纳入还要求丙氨酸转氨酶 (ALT) 水平低于正常和阳性乙型肝炎表面抗原上限的八倍至少 6 个月。不包括失代偿期肝硬化、肝癌、严重上消化道出血、精神障碍或其他形式的严重疾病。

各组患者和临床特征相似，平均年龄为 39 至 41 岁，男性占 66-77%，平均 BMI 为 24。平均 ALT 水平为 54-67 IU/L，天冬氨酸氨基转移酶 (AST) 水平为 42 -48 国际单位/升。

各组的总体安全性和严重不良事件 (SAE) 的发生率相似。在发生的 7 例 SAE 中，5 例发生在氢尼酮患者身上，主要由转氨酶水平升高组成，导致 3 例患者停止治疗。另外两人因中度虚弱或眩晕而停药。

与治疗相关的不良事件大多为轻度或中度，最不常见的是每天 270 mg 组 (4%)，其次是每天 360 mg (6%)，但每天 180 mg 氢尼酮组的不良事件略高 (17 %) 与安慰剂 (10%)。到研究结束时，总共有 18 名患者停止了治疗。

与安慰剂相比，联合氢尼酮组的纤维化消退与纤维化进展的比率显着更高（比率 3.62 对 1.22，P=0.03）。

与持续检测的患者相比，检测不到乙型肝炎病毒 DNA 的患者更有可能实现纤维化消退（47% 对 12%，P=0.001）。

作者承认数据的局限性。很少有 Ishak 评分低于 3 的患者被纳入。此外，肝活检由三位血液病理学专家进行分析，他们之间和读者之间的一致性不令人满意。

    Zaina Hamza 是今日 MedPage 的特约撰稿人，报道胃肠病学和传染病。她常驻芝加哥。
披露
本研究得到北京大洲药业、GNI集团、上海基因组学和国家基本药物研发项目的支持。

尹和合著者披露没有利益冲突。
主要资源
临床胃肠病学和肝病学
来源参考：Cai X, et al “Hydronidone for treatment ofliver fibrosis related tochronic BHBV: a Phase 2 randomised controlled trial” Clin Gastroenterol Hepatol 2022； DOI：10.1016/j.cgh.2022.05.056。

StephenW

Novel Antifibrotic Improved Fibrosis in Chronic Hepatitis B
— Phase II trial from China suggests benefit of add-on therapy

by Zaina Hamza, Staff Writer, MedPage Today July 15, 2022

Investigational hydronidone, when added to entecavir (Baraclude), reduced liver fibrosis for chronic hepatitis B patients, a phase II trial in China found.

In an intention-to-treat analysis of 168 such patients, the direct-acting antifibrotic agent improved fibrosis by at least 1 point on the 6-point Ishak scale for 46.4% of patients across dose arms, compared with 26% on placebo, reported Ping Yin, PhD, of Huazhong University of Science and Technology in Wuhan, China, and colleagues, writing in Clinical Gastroenterology and Hepatology.

The benefit was significant only for the intermediate dose group, with at least a 1-point improvement in fibrosis 2.14-fold more likely on 270 mg/day of hydronidone than with placebo at week 52 (55% vs 26%, P=0.030). Other hydronidone doses showed a similar numerical advantage that did not reach significance:

    At 180 mg per day: 41% improvement, RR 1.58 (95% CI 0.86-2.99)
    At 360 mg per day: 44% improvement, RR 1.72 (95% CI 0.94-3.21)

"Patients with CHB [chronic hepatitis B] who were treated with hydronidone showed significant histological improvement of liver fibrosis and 270 mg orally showed best efficacy of fibrosis regression," the researchers noted. "Our results further demonstrated that hydronidone may be effective for mild or moderate stages of fibrosis, while not only significant fibrosis."

Hepatitis B infection often results in liver fibrosis, which further causes cirrhosis and even hepatocellular carcinoma, the researchers noted. No specific treatment option currently exists for chronic hepatitis B patients with associated liver fibrosis, and this is the first trial to assess the use of hydronidone for these indications.

Hydronidone is structurally similar to pirfenidone (Esbriet), used to treat idiopathic pulmonary fibrosis, so Yin's group looked at it as a novel therapeutic option to hepatotoxicity.

They enrolled 168 chronic hepatitis B patients and randomized them 1:1:1:1 to receive 180 mg, 270 mg, or 360 mg per day of oral hydronidone or placebo in a double-blind manner across eight centers in China for 52 weeks through Sept. 5, 2019. All patients also received 0.5 mg per day of entecavir.

Participants were ages 18 to 65 with biopsy-confirmed liver fibrosis (Ishak score of at least three out of six). Inclusion also required alanine transaminase (ALT) levels less than eight times the upper limit of normal and positive hepatitis B surface antigens for at least 6 months. Excluded were those with decompensated liver cirrhosis, liver cancer, severe upper gastrointestinal hemorrhage, mental disorders, or other forms of serious disease.

Similar patient and clinical characteristics were seen across groups, with a mean age of 39 to 41, 66-77% men, and mean BMI of 24. Average ALT levels were 54-67 IU/L and aspartate aminotransferase (AST) levels were 42-48 IU/L.

Overall safety and incidence of serious adverse events (SAEs) were similar across groups. Of the seven SAEs that occurred, five were in hydronidone patients, mainly consisting of elevated levels of transaminases, which led to three patients discontinuing treatment. Two others discontinued because of moderate asthenia or vertigo.

Treatment-related adverse events were mostly mild or moderate and least common for the 270 mg per day group (4%), followed by 360 mg per day (6%), but slightly higher for the 180 mg per day of hydronidone group (17%) versus placebo (10%). Eighteen patients overall discontinued treatment by the end of the study.

The ratio of regression of fibrosis to progression of fibrosis was significantly greater among the combined hydronidone group, compared to placebo (ratio 3.62 vs 1.22, P=0.03).

Patients who achieved undetectable hepatitis B virus DNA were more likely to achieve fibrosis regression, compared to those with persistent detection (47% vs 12%, P=0.001).

The authors acknowledged limitations to the data. Few patients who had an Ishak score below 3 were included. Furthermore, liver biopsies were analyzed by three expert hematopathologists, with unsatisfactory inter- and intra-reader consistency among them.

    Zaina Hamza is a staff writer for MedPage Today, covering Gastroenterology and Infectious disease. She is based in Chicago.
Disclosures
This study was supported by Beijing Continent Pharmaceuticals, GNI Group, Shanghai Genomics, and the State Project for Essential Drug Research and Development of China.

Yin and co-authors disclosed no conflicts of interest.
Primary Source
Clinical Gastroenterology and Hepatology
Source Reference: Cai X, et al "Hydronidone for the treatment of liver fibrosis related to chronic hepatitis B: a phase 2 randomized controlled trial" Clin Gastroenterol Hepatol 2022; DOI: 10.1016/j.cgh.2022.05.056.

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