Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, Doherty Institute Melbourne, Royal Melbourne Hospital, Melbourne, Vic., Australia.
Department of Gastroenterology, St. Vincent's Hospital, Fitzroy, Vic., Australia.
Liver Int. 2018 Oct;38(10):1760-1769. doi: 10.1111/liv.13716. Epub 2018 Mar 6.
Alanine aminotransferase (ALT) flares during NA therapy are uncommon but occur. Evaluation of ALT flares during nucleos(t)ide analogue (NA) therapy is important as new immunomodulatory therapies for hepatitis B virus (HBV) are developed. We evaluated the association between ALT flares and HBsAg loss during long-term therapy for genotype A CHB.
This analysis included genotype A subjects from a phase III study of tenofovir vs adefovir in HBeAg-positive HBV. ALT flare was defined as (i) a rise in ALT >2x ULN from normal ALT levels; or (ii) a rise in ALT >2x baseline ALT level. HBsAg response at week 384 was recorded as one of HBsAg loss vs HBsAg decline (≥1 log IU/mL decline) vs non-response. The primary analysis evaluated the association between ALT flare and HBsAg response.
54 subjects were included. 23/54 (43%) subjects experienced an on-treatment ALT flare. 45% achieved an HBsAg reduction ≥1 log IU/mL, and of these 67% achieved HBsAg loss at a median of 102 weeks [IQR: 64-156]. Flare was associated with HBsAg decline vs non-response (67% vs 23%, P = .002), and were more common in subjects who achieved HBsAg loss vs non-response (56% vs 23%), P = .049). There was a median delay of 56 weeks [IQR: 40-80] between a flare and HBsAg loss.
In genotype A subjects undergoing long-term NA therapy, ALT flares predict for HBsAg response. The delay between ALT flare and HBsAg loss has implications for clinical trial design for early phase development of immunomodulatory strategies aiming for HBsAg loss.
NA 治疗期间丙氨酸氨基转移酶（ALT）升高并不常见，但确实会发生。评估核苷（酸）类似物（NA）治疗期间的 ALT 升高很重要，因为新的乙型肝炎病毒（HBV）免疫调节治疗正在开发中。我们评估了 ALT 升高与长期治疗 A 基因型 CHB 期间 HBsAg 丢失之间的关联。
本分析包括 III 期替诺福韦与阿德福韦酯治疗 HBeAg 阳性 HBV 的研究中的 A 基因型受试者。ALT 升高定义为：（i）ALT 从正常 ALT 水平升高>2xULN；或（ii）ALT 升高>2x基线 ALT 水平。在第 384 周记录 HBsAg 应答为 HBsAg 丢失与 HBsAg 下降（≥1 log IU/mL 下降）与无应答之一。主要分析评估了 ALT 升高与 HBsAg 应答之间的关联。
纳入了 54 名受试者。54 名受试者中有 23 名（43%）经历了治疗期间的 ALT 升高。45%的受试者实现了 HBsAg 下降≥1 log IU/mL，其中 67%的受试者在中位数为 102 周[IQR：64-156]时实现了 HBsAg 丢失。与无应答相比，升高与 HBsAg 下降相关（67%比 23%，P=0.002），在实现 HBsAg 丢失的受试者中更为常见（56%比 23%，P=0.049）。与 HBsAg 丢失相关的 ALT 升高与 HBsAg 丢失之间的中位延迟为 56 周[IQR：40-80]。
在接受长期 NA 治疗的 A 基因型受试者中，ALT 升高预测 HBsAg 应答。ALT 升高与 HBsAg 丢失之间的延迟对旨在实现 HBsAg 丢失的免疫调节策略早期阶段开发的临床试验设计具有影响。
