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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 .

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.

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