Pregenomic HBV RNA and Hepatitis B Core-Related Antigen Predict Outcomes in Hepatitis B e Antigen-Negative Chronic Hepatitis B Patients Suppressed on Nucleos(T)ide Analogue Therapy
Pregenomic HBV RNA and Hepatitis B Core-Related Antigen Predict Outcomes in Hepatitis B e Antigen-Negative Chronic Hepatitis B Patients Suppressed on Nucleos(T)ide Analogue Therapy
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DOI：
10.1002/hep.31026
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发表时间：
2020-07-01
期刊：
影响因子：
13.5
通讯作者：
Agarwal, Kosh
中科院分区：
文献类型：
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作者：
Carey, Ivana;Gersch, Jeffrey;Agarwal, Kosh
背景和目的在慢性B型肝炎的自然病程和治疗过程中，存在B型肝炎病毒DNA和B型肝炎表面抗原（HBsAg）浓度的二分分离。我们评估了B型肝炎病毒（HBV）RNA和B型肝炎核心相关抗原（HBcrAg）作为共价闭合环状DNA（cccDNA）沉默替代物的能力，以表征这种解离和病毒学结果。方法和结果研究了三个队列的B e抗原（HBeAg）阴性患者：队列A：66例长期接受核苷（酸）类似物（NA）治疗的HBeAg阴性患者;队列B：23例抗B e抗原抗体阳性患者停止治疗的（抗-HBe）阳性患者;和队列C：19例抗-HBe阳性患者接受长期NA治疗，达到HBsAg丢失，并停止治疗。在治疗开始/结束的不同时间点，测量连续样本中HBV血清学/病毒学生物标志物（HBV DNA、HBsAg、HBcrAg和HBV RNA）的浓度。队列A：经过3年的抗病毒治疗，33%和30%分别检测到HBcrAg和HBV RNA，尽管所有人都是HBV-DNA阴性。NA治疗5年后，HBcrAg和HBVRNA的检出率分别为27%和14%。仅在发生重度转氨酶发作的患者中观察到停药时可检测到HBcrAg和HBV RNA。在队列C中，只有那些HBV再激活的患者在停药时可检测到HBV RNA，但未检测到HBcrAg和HBV DNA。结论HBcrAg和HBVRNA是HBeAg阴性患者中cccDNA持续转录的敏感生物标志物，尽管NA显著抑制HBV-DNA。这些标志物是治疗停药后严重丙氨酸转氨酶发作和HBV-DNA再激活的预测因子。在B型肝炎的自然病程期间以及在用当前和新药物治疗时测量它们，可以表征来自cccDNA的残留HBV-RNA转录，并有助于药物开发和疾病管理。
Background and Aims A dichotomous separation of hepatitis B viral DNA and hepatitis B surface antigen (HBsAg) concentrations occurs during the natural history and treatment of chronic hepatitis B. We have evaluated the ability of hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg) as surrogates of silencing of covalently closed circular DNA (cccDNA), to characterize this dissociation, and virological outcomes. Approach and Results Three cohorts of hepatitis B e antigen (HBeAg)-negative patients were studied: cohort A: 66 HBeAg-negative patients on long-term nucleos(t)ide analogue (NA) therapy; cohort B: 23 antibodies against hepatitis B e antigen (anti-HBe)-positive patients who stopped treatment; and Cohort C: 19 anti-HBe-positive patients on long-term NA treatment who achieved HBsAg loss and in whom treatment was withdrawn. Concentrations of HBV serological/virological biomarkers (HBV DNA, HBsAg, HBcrAg, and HBV RNA) were measured in sequential samples at different time points on/off therapy. Cohort A: After 3 years of antiviral therapy, 33% and 30% had detectable HBcrAg and HBV RNA, respectively, despite all being HBV-DNA negative. After 5 years' therapy with NA, 27% and 14% had detectable HBcrAg and HBV RNA. Detectable HBcrAg and HBV RNA at the time of treatment withdrawal was only observed in those patients who developed a severe aminotransferase flare. Only those patients with HBV reactivation in cohort C had detectable HBV RNA at treatment withdrawal, but HBcrAg and HBV DNA were not detected. Conclusions HBcrAg and HBV RNA are sensitive biomarkers of continued transcription of cccDNA in HBeAg-negative patients despite marked HBV-DNA suppression by NA. These markers were predictors of severe alanine transaminase flares, after treatment withdrawal, and HBV-DNA reactivation. Their measurement during the natural history of hepatitis B, and on treatment with current and new agents, could characterize residual HBV-RNA transcription from cccDNA and assist drug development and disease management.