Rapidly decreased HBV RNA predicts responses of pegylated interferons in HBeAg-positive patients: a longitudinal cohort study

Min Zhang,Wenzhou Fan,Guozhong Gong,Kaizhong Luo,Vidaurre Diego,Minxiang Zhang,Guangdi Li,Yongfang Jiang,Hai Ding,Mahmoud Reza Pourkarim,Yue Peng ,Qing Mao,Yun Xu,Guiqiang Wang,Qing Xie,Jia Shang,Chen Pan,Zhang Yin ,Xuewen Xiao ,Erik De Clercq

doi:10.1007/s12072-020-10015-3

Abstract

BackgroundAs an important anti-HBV drug, pegylated interferon α (PegIFNα) offers promising clinical efficacy, but biomarkers that accurately forecast treatment responses are yet to be elucidated. Here, we evaluated whether HBV RNA could act as an early monitor of pegylated interferon responses.MethodsWe analyzed a phase 3, multicenter, randomized cohort of 727 HBeAg-positive non-cirrhotic patients receiving a 48-week treatment of PegIFNα-2a or PegIFNα-2b and a 24-week treatment-free follow-up. Serum levels of HBV RNA, HBV DNA, HBeAg, and HBsAg were measured at weeks 0, 12, 24, 48, and 72.ResultsHBeAg seroconversion and HBsAg loss at week 72 were observed in 217 (29.8%) and 21 (2.9%) patients, respectively. During the 48-week treatment, HBV RNA decreased more rapidly than HBV DNA and HBsAg, but HBV RNA and HBeAg shared similar dynamics with positive correlations. Multivariate regression analyses consistently revealed the significance of HBV RNA at weeks 0, 12, 24, and 48 to monitor HBeAg seroconversion but not HBsAg loss. Although baseline HBV RNA only showed a modest AUC performance, HBV RNA with a significant increase of AUC at week 12 outperformed other HBV biomarkers to forecast HBeAg seroconversion (p value < 0.05). HBV RNA ≤ 1000 copies/mL was an optimized cutoff at week 12 that offered better prediction than other HBV biomarkers. This optimized cutoff plus patient age, HBV genotype B, and HBeAg offered a strong estimation of HBeAg seroconversion (accuracy 95.2%, true negative rate 99.8%).ConclusionHBV RNA at week 12 is an effective monitor of HBeAg seroconversion in HBeAg-positive patients treated with pegylated interferons.

Highlights

Materials and methodsTo offer effective treatment responses towards hepatitis B virus (HBV) infections, eight FDA-approved drugs belonging to two classes are currently available, including two interferon alfa drugs and six nucleos(t)ide analogs [1]
In a responder-enriched subpopulation of 76 patients treated with pegylated interferon α (PegIFNα)-2a, HBV RNA was recognized as a sound predictor of HBeAg seroconversion by univariate analyses alone [13], whereas its strength was unclear in large cohorts with non-responders
Our entire cohort consisted of 523 males and 204 females predominately infected with HBV genotype C (n = 427, 58.7%), followed by genotypes B (n = 292, 40.2%), D (n = 7, 1%), and B/C recombinant (n = 1, 0.1%)

Summary

Materials and methods

To offer effective treatment responses towards hepatitis B virus (HBV) infections, eight FDA-approved drugs belonging to two classes are currently available, including two interferon alfa drugs and six nucleos(t)ide analogs [1]. Dynamic changes of HBV RNA in large-scale cohorts of interferon-treated patients remain poorly understood, since previous studies focused mostly on nucleos(t)ide analogs. To address the above questions, we assessed HBV RNA in a longitudinal cohort of 727 HBeAg-positive patients who randomly received PegIFNα-2a or PegIFNα-2b Based on this large-scale cohort, our findings support the hypothesis that even at the early interferon treatments, HBV RNA is a strong monitor of HBeAg seroconversion, despite its modest role in the prediction of HBsAg loss. This study was performed using the cohort of 727 patients who completed the full course of the randomized trial and had serum samples at week 72 to measure treatment responses.

Results

Discussion

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