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There is abundant evidence that patients with chronic hepatitis B (CHB) treated with nucleoside analogues (NUC) have low HBsAg clearance, require long-term medication, and have a high risk of recurrence after discontinuation of the drug, and it is difficult to obtain HBsAg clearance after NUC discontinuation in Asian populations (related links 1, 2, and 3). Therefore, how to reduce the risk of recurrence in patients who discontinue NUC and pursue higher HBsAg clearance has been deeply explored.
Recently, the team of Professor Zhang Jiming/Zhang Wenhong/Huang Yuxian from Huashan Hospital affiliated to Fudan University, the team of Professor Li Qingxing from the First Affiliated Hospital of Wenzhou Medical University, and the team of Professor Zhang Xinxin from Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine jointly published a related study in the Journal of Hepatology, and the results showed that the cumulative virology and clinical recurrence rates of the peginterferon α (PegIFNα) treatment group were significantly lower than those in the NUC discontinuation group, and the cumulative HBsAg clearance rate was further improved. It was significantly higher than that in the NUC discontinuation group.
Research Methods:
This study is a prospective, open-label, randomized, controlled, multicenter clinical trial (NCT02594293) that included 180 patients aged 18-65 years with HBeAg-negative CHB in four centers across China from October 2015 to September 2020. The inclusion criteria were as follows: continuous treatment with adefovir disoxil, entecavir, or tenofovir for at least 2.5 years, and a sustained HBV DNA level of < 60 IU/mL for at least 1.5 years after HBV DNA inhibition and ALT normalization. The patient was HBeAg-negative and anti-HBe-positive before NUC treatment, and had a liver stiffness measurement of < 7.4 kPa.
Patients were randomized in a 1:1 ratio to NUC discontinuation group or 48-week PegIFNα monotherapy group, and were followed up to 96 weeks. The primary outcome measure was cumulative virologic recurrence (VR) rate at week 96. Secondary outcomes included HBsAg clearance and HBsAg reduction. VR is defined as two consecutive HBV DNA > 2000 IU/mL one month apart. Clinical recurrence is defined as virologic recurrence with one ALT > 2 ULN.
Patient baseline
Median HBsAg levels were 2.70 and 2.73 log10 IU/mL in the NUC discontinuation and PegIFNα treatment groups, respectively. HBV genotyping was possible in 68 patients, with types B and C being the most common.
Patient baseline
Findings:
01
The cumulative virology and clinical recurrence rates in the PegIFNα treatment group were significantly lower than those in the NUC discontinuation group
ITT analysis showed that the cumulative VR rate at week 72 in the PegIFNα treatment group was significantly lower than that in the NUC discontinuation group (13.0% vs. 46.6%, P < 0.0001). The cumulative VR rate at week 96 in the PegIFNα treatment group was significantly lower than that in the NUC discontinuation group (20.8% vs. 53.6%, P < 0.0001), and the results of PP analysis were similar.
Stratification of different HBsAg levels showed that the VR rate in the NUC discontinuation group was significantly positively correlated with the baseline HBsAg level. A similar trend was observed in the PegIFNα treatment group, but there was no statistically significant difference.
Cumulative VR rates in the PegIFNα treatment group and the NUC discontinuation group
(A) ITT analysis (B) PP analysis; Cumulative VR rates in the (C) NUC discontinuation group and (D) PegIFNα treatment group under different stratification of HBsAg levels
The cumulative clinical recurrence rate at week 96 was significantly lower in the PegIFNα treatment group than in the NUC discontinuation group (7.8% vs. 20.9%, P = 0.008). The results of PP analysis and sensitivity analysis were consistent. There was no significant difference in clinical recurrence between the two groups in patients who experienced VR.
PegIFNα treatment group and NUC discontinuation group
累积临床复发率（A）ITT分析（B）PP分析
02
The cumulative HBsAg clearance at week 96 in the PegIFNα treatment group was significantly higher than that in the NUC discontinuation group
According to ITT analysis, the cumulative HBsAg clearance rate at week 96 in the PegIFNα treatment group was 21.5%, which was significantly higher than that in the NUC discontinuation group (9.0%). The results of PP analysis and sensitivity analysis were consistent.
For patients with baseline HBsAg < 10 IU/mL, HBsAg clearance was achieved in 100% (4/4) of patients treated with PegIFNα and 50% (5/10) in the NUC discontinuation group. HBsAg clearance was not achieved in patients with HBsAg > 1000 IU/mL and in patients discontinued with NUC. The baseline HBsAg level of patients who achieved HBsAg clearance in the NUC discontinuation group was significantly lower than that in the PegIFNα treatment group (P = 0.027). The baseline HBsAg level of patients with HBsAg clearance in the two groups was significantly lower than that in patients without HBsAg clearance.
Cumulative HBsAg clearance in the PegIFNα treatment group and the NUC discontinuation group
(A) ITT analysis, (B) PP analysis, (C) HBsAg clearance in the two groups stratified according to HBsAg, and (D) baseline HBsAg levels in HBsAg-cleared and non-cleared patients in the two groups
03
The decrease in HBsAg was greater in patients treated with PegIFNα
The proportion of patients with HBsAg decrease of ≥ 1 log10 IU/mL in the PegIFNα treatment group was significantly higher than that in the NUC discontinuation group, and the HBsAg decrease was greater. In addition, patients without VR decreased significantly more in both groups than those with VR.
PegIFNα treatment group and NUC discontinuation group
（E）HBsAg下降≥ 1 log10 IU/mL的患者比例及（F）HBsAg水平动态变化；（G - H）两组有无VR患者的HBsAg水平动态变化
Liver Linjun has something to say
Most patients with chronic hepatitis B who have been treated with NUC for a long time expect to be able to safely stop the drug. However, Asian patients have low HBsAg clearance and a high risk of recurrence after NUC discontinuation (related links 1, 2, and 3). In this study, PegIFNα monotherapy significantly reduced the virology and clinical recurrence rates in NUC discontinuation patients, and further improved HBsAg clearance. It has been shown that HBsAg clearance in HBeAg-negative patients treated with PegIFNα after NUC discontinuation is 27%, and may be related to immune activation (related link). Therefore, for patients with chronic hepatitis B who have experienced NUC treatment or discontinued NUC, a PegIFNα-based treatment strategy can be adopted to pursue HBsAg clearance, and safe discontinuation is a better choice.
Bibliography:
Li F, Qu L, Liu Y, et al. PegIFN alpha-2a reduces relapse in HBeAg-negative patients after nucleo(s)tide analogue cessation: A randomized-controlled trial[J]. J Hepatol, 2024, S0168-8278(24)02426-7.
Source: Yulu Liver Lin