Efficacy and Safety of a Botanical Formula Fuzheng Huayu for Hepatic Fibrosis in Patients with CHC: Results of a Phase 2 Clinical Trial

Abstract

Background: Hepatitis C virus (HCV) is a common cause of progressive hepatic fibrosis, cirrhosis, and hepatocellular carcinoma worldwide. Despite the availability of effective direct-acting antivirals, patients often have significant hepatic fibrosis at the time of diagnosis due to delay in diagnosis and comorbidities which promote fibrogenesis. Thus, antifibrotic agents represent an attractive adjunctive therapy. Fuzheng Huayu (FZHY), a traditional Chinese medicine botanical formulation, has been used as an antifibrotic agent in chronic HBV infection. Our aim was to assess FZHY in patients with HCV infection and active viremia.

Method: We randomized 118 patients with active viremia from 8 liver centers in the U.S. to receive oral FZHY (n = 59) or placebo (n = 59) for 48 weeks. Efficacy was assessed by histopathologic changes at the end of therapy. A subset of biopsies was further analyzed using qFibrosis to detect subtle changes in fibrosis in different zones of the hepatic lobules.

Results: FZHY was well tolerated and safe. Patients with baseline Ishak fibrosis stages F3 and F4 had better response rates to FZHY than patients with baseline F0-F2 (p=0.03). qFibrosis zonal analysis showed significant improvement in fibrosis in all zones in patients with regression of the fibrosis stage.

Conclusions: FZHY produced antifibrotic effects in patients with baseline Ishak F3 and F4 fibrosis stages. Reduction in fibrosis severity was zonal and correlated with the severity of inflammation. Based on its tolerability, safety, and efficacy, FZHY should be further investigated as a therapy in chronic liver diseases because of its dual anti-inflammatory and antiibrotic properties. Lay Summary. This is the first US-based, multicenter and placebo-controlled clinical trial that shows statistically significant reduction in fibrosis in patients with active HCV using an antifibrotic botanical formula. This has important implications as there is an immediate need for effective antifibrotic agents in treating many chronic diseases including NASH that lead to scarring of the liver. With artificial intelligence-based methodology, qFibrosis, we may provide a more reliable way to assess the FZHY as a therapy in chronic liver diseases because of its dual anti-inflammatory and antifibrotic properties.

Figure 1

Schematic illustration of zones 1, 2, and 3 as applied in zonal analysis.

Figure 2

Workflow of the qFibrosis model used to assess pathologists' quantification consistency.

Figure 3

Flowchart of the patients enrolled in the FZHY clinical trial. The full-analysis set (FAS) 43/46 for patients who meet the inclusion criteria. The per-protocol set (PPS) 82 (39/43 with paired slides pretreatment and posttreatment in the FZHY and placebo groups) for primary endpoint assessment. The safety set (SS) 59/59 for all randomized patients for safety assessment.

Figure 4

Fibrosis response (progressive/regressive/no change) obtained from the consensus reading of 3 pathologists. (a) Overall fibrosis response for all patients (n = 82) with the FZHY-treated group showing a slight improvement over the placebo group, in which the progressive group (P) is defined as fibrosis stage increased by ≥1 stage after treatment, no change group (N) as no change in fibrosis stages, and regressive group (R) as fibrosis stage decreased by ≥1 stage; (b) a closer look into the fibrosis response by categorizing according to the patients' baseline fibrosis staging. For patients in the FZHY group, those with baseline Ishak fibrosis F3 and F4 were observed to be more responsive toward treatment as compared to patients with baseline F0-2 (p=0.03). The chi-squared test was performed by comparing the number of responsive patients (R) with nonresponsive patients (P) and (N) between F0-2 and F3-4 groups; (c) focusing on patients with baseline fibrosis F3 and F4, the FZHY-treated group showed a more significant improvement over the placebo group based on the consensus reading.

Figure 5

Box-whisker plots of qFibrosis component distribution relative to the Ishak scoring in the training and validation datasets. The Ishak fibrosis staging from pathologists A, B, and C is based on patients' baseline samples. For each stage, the maximum and minimum values are indicated by horizontal lines at the bottom and top of each stage, the white box in the middle represents data points in the 25% to 75% interquartile range, and the line through the middle of the central white box represents the median value. Note: r value was calculated according to the Spearman method.

Figure 6

Zonal analysis was conducted on the progressive and regressive patient subsets with baseline qFibrosis stages of F3 and F4 with statistical significance shown across zones 1, 2, and 3. FZHY-treated patients in the regressive subset showed significant fibrosis reduction as compared to the placebo group consistently across all zones. FZHY-treated patients in the progressive subset showed considerable fibrosis increment over the placebo group, particularly in zone 1.

Figure 7

Portal inflammation analysis on the progressive and regressive patient subsets with baseline qFibrosis stages of F3 and F4. No statistical significance was reported between FZHY-treated and placebo groups due to the small sample size.

Figure 8

Antifibrotic FZHY treatment-related AEs and SAEs of all grades. No significant SAEs were reported that were related to the study drug.