给编辑的一封信 评论“慢性乙型肝炎患者停用核仁（t）类似

StephenW

Letter to the Editor
Comment on “48-Week Outcome after Cessation of Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B Patient and the Associated Factors with Relapse”
Yafei Guo1 and Lingan Wang
1,2

1Department of Hematology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China
2Department of Pediatrics, Guangdong Women and Children’s Hospital, Guangzhou 511442, China

Correspondence should be addressed to Lingan Wang; [email protected]

Received 11 September 2018; Accepted 19 November 2018; Published 1 January 2019

Academic Editor: Kevork M. Peltekian

Copyright © 2019 Yafei Guo and Lingan Wang. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

We read with great interest the study conducted by Wen-xiong Xu et al. published in Canadian Journal of Gastroenterology and Hepatology [1]. The authors indicated that nucleos(t)ide analogues (NA) cessation is safe under supervision. Age and hepatitis B surface antigen (HBsAg) level can be predictive factors for virologic relapse. The data of the study demonstrated that, among 62 enrolled patients with chronic hepatitis B (CHB), a total of 23 patients (37.1%) experienced nonrelapse (Category A), while four patients (6.5%) remained with virologic relapse (Category B), 14 (22.6%) changed to nonrelapse before a transient virological relapse (Category C), and 21 (33.8%) were treated again with NAs due to clinical relapse (Category D). The study conducted by Xu et al. was elegantly designed and the results are very inspiring. However, the nonsustained response rate of up to 62.9% makes us a bit worried about long-term benefit for CHB patient after NAs cessation.

Whether and when CHB patients should be discontinued from NAs antiviral treatment after a sustained virological response is a dilemma. Although it is well established that the goal of treatment for chronic HBV infection is to improve quality of life and survival of the infected person by preventing progression of the disease to cirrhosis, decompensated cirrhosis, end-stage liver disease, hepatocellular carcinoma, and death [2], to achieve the therapeutic goals, HBV replication should be suppressed in a sustained manner, even if the patient's ALT level is within the upper limit of normal. Studies have revealed that although ALT levels are normal, liver fibrosis still exists in CHB patients and the disease is still in progress [3–5]. In the study of Xu et al. although category A was defined as no relapse, an increased HBV DNA viral load was still observed. The increasing trend of HBV DNA viral loads are more pronounced in Category B and Category C. These patients are at risk of sustained HBV replication even under long-term supervision, accompanied with re-ignition of hepatic inflammation, especially in certain specific situations such as the use of steroids. This re-ignition of liver inflammation will lead to further deterioration of liver fibrosis. Therefore, as recommended by the APASL guideline [2], the goal of CHB treatment can be achieved if HBV replication can be suppressed in a sustained manner. Then, the accompanying reduction in histological activity of CHB lessens the risk of cirrhosis and hepatocellular carcinoma, particularly in noncirrhotic patients. In CHB patients, as long as HBV DNA is positive, which means HBV continues to replicate, cessation of NAs may not be an option. Clinical guidelines have suggested that only HBsAg seroconversion is an ideal endpoint to NAs cessation [6, 7].

Another interesting result in the study is the relationship between age and HBsAg levels for sustained viral response. As confirmed by Xu et al.’s study and other similar studies [8–10], the younger the patient and the lower the serum HBsAg level, the higher the possibility of achieving a sustained virological response after NAs cessation. The reason may be the different immune status of patients. Chronic HBV is an infectious disease with a pathogenesis and course that depends on the virus-host interaction. A study has shown that the younger the patient, the higher the possibility to obtain virological response and HBsAg seroconversion after interferon treatment [11]. In particular, long-term HBV infection will significantly inhibit the immune system in CHB patients [12]. In addition, interferon as an add-on sequential regimen to tenofovir resulted in greater loss of HBsAg compared to tenofovir monotherapy [13]. Viral load reduction followed by immune modulation may be a potentially useful approach. Therefore, in Xu et al.’s study, for CHB patients with low-level HBsAg, it may be more effective to add interferon treatment as an immune modulation, rather than stop NAs, to further NAs cessation to further improve the possibility of HBsAg seroconversion and achieve a more suitable timing for NAs cessation. However, further prospective studies are required to confirm this.

Nevertheless, data from this study demonstrate that HBsAg and age are factors closely related to sustained virological response after NAs cessation. This is a valuable recommendation for real clinical practice. NAs cessation can be recommended in CHB patients with relatively younger age and relatively low serum HBsAg levels, to avoid adverse effects of long-term NAs, such as nephrotoxicity and Fanconi syndrome. CHB patients who are at a high risk of relapse after NAs cessation are not recommended to stop NAs antiviral treatment, thus avoiding patients self-discontinuing NAs treatment and the related unpredictable complications. This is especially so in the Asia-Pacific region, where NAs adherence is generally poor [14].
Conflicts of Interest

The authors declare that they have no conflicts of interest.

StephenW

给编辑的一封信
评论“慢性乙型肝炎患者停用核仁（t）类似物治疗后的48周结果及复发的相关因素”
王亚飞和王连安
1,2

1福建医科大学附属第二医院血液科，泉州362000
2广东省妇女儿童医院儿科，广东广州511442

通讯应发给王连安; [email protected]

2018年9月11日收到; 2018年11月19日接受; 2019年1月1日出版

学术编辑：Kevork M. Peltekian

版权所有©2019 Yafei Guo和Lingan Wang。这是一份根据知识共享署名许可分发的开放获取文章，允许在任何媒体中不受限制地使用，分发和复制，前提是原始作品被正确引用。

我们非常感兴趣地阅读了徐文雄等人的研究。发表于加拿大胃肠病学和肝病学杂志[1]。作者指出核苷（t）ide类似物（NA）在监督下是安全的。年龄和乙型肝炎表面抗原（HBsAg）水平可能是病毒学复发的预测因素。该研究的数据显示，在62名慢性乙型肝炎（CHB）登记患者中，共有23名患者（37.1％）经历了非复发（A类），而4名患者（6.5％）仍然存在病毒学复发（B类） ），14（22.6％）在短暂的病毒学复发（C类）之前变为非复发，21（33.8％）由于临床复发而再次用NA治疗（D类）。 Xu等人进行的研究。设计优雅，结果非常鼓舞人心。然而，非持续性反应率高达62.9％使我们有点担心在停止NAs后CHB患者的长期益处。

CHB患者是否以及何时应该在持续病毒学应答后停止NAs抗病毒治疗是一个两难选择。尽管已经确定慢性HBV感染治疗的目的是通过预防疾病进展为肝硬化，失代偿期肝硬化，终末期肝病，肝细胞癌和死亡来改善感染者的生活质量和生存[ 2]，为达到治疗目的，即使患者的ALT水平在正常上限以内，也应持续抑制HBV复制。研究表明，虽然ALT水平正常，但CHB患者仍然存在肝纤维化，并且该疾病仍在进行中[3-5]。在徐等人的研究中。虽然A类被定义为无复发，但仍观察到HBV DNA病毒载量增加。 HBV DNA病毒载量的增加趋势在B类和C类中更为明显。即使在长期监督下，这些患者也有持续HBV复制的风险，伴随着肝脏炎症的重新点燃，特别是在某些特定情况下，如使用类固醇。这种肝脏炎症的重新点燃将导致肝纤维化的进一步恶化。因此，根据APASL指南[2]的建议，如果可以持续抑制HBV复制，可以实现CHB治疗的目标。然后，伴随的CHB组织学活性的降低减少了肝硬化和肝细胞癌的风险，特别是在非肝硬化患者中。在CHB患者中，只要HBV DNA阳性，这意味着HBV继续复制，NAs的停止可能不是一种选择。临床指南表明，只有HBsAg血清学转换是NAs停止的理想终点[6,7]。

该研究的另一个有趣结果是年龄和持续病毒反应的HBsAg水平之间的关系。正如Xu等人的研究和其他类似研究[8-10]所证实的，患者年龄越小，血清HBsAg水平越低，在NAs停止后达到持续病毒学应答的可能性越高。原因可能是患者的免疫状态不同。慢性HBV是一种传染病，其发病机制和过程取决于病毒 - 宿主的相互作用。一项研究表明，患者越年轻，干扰素治疗后获得病毒学应答和HBsAg血清学转换的可能性越高[11]。特别是，长期HBV感染会显着抑制CHB患者的免疫系统[12]。此外，与替诺福韦单药治疗相比，干扰素作为替诺福韦的附加顺序方案导致更大的HBsAg损失[13]。减少病毒载量，然后进行免疫调节可能是一种潜在有用的方法。因此，在Xu等人的研究中，对于低水平HBsAg的CHB患者，加入干扰素治疗作为免疫调节而不是停止NAs，进一步减少NAs以进一步提高HBsAg的可能性可能更有效。血清转换并实现更适合NAs停止的时机。但是，需要进一步的前瞻性研究来证实这一点。

然而，该研究的数据表明，HBsAg和年龄是与NAs停止后持续病毒学应答密切相关的因素。 这对于真正的临床实践是有价值的建议。 对于年龄相对较小且血清HBsAg水平相对较低的CHB患者，可以推荐NAs戒烟，以避免长期NAs的不良反应，如肾毒性和Fanconi综合征。 在NAs停止后具有高复发风险的CHB患者不建议停止NAs抗病毒治疗，从而避免患者自行停止NAs治疗和相关的不可预测的并发症。 在亚太地区尤其如此，那里的NAs依从性普遍较差[14]。
利益冲突

作者声明他们没有利益冲突。

小牡丹

研发替代抗病毒药物的治疗手段势在必行。隔靴搔痒，劳民伤财的核苷酸类似物该淘汰了。