慢性HBV感染患者NA停用的复杂性

StephenW

The Complexities of NA Discontinuation in Patients With Chronic HBV Infection
       
         


Pietro_Lampertico


       


Pietro Lampertico, MD, PhD
Professor of Gastroenterology
Director, Division of Gastroenterology and Hepatology
IRCCS Ca Granda Policlinico Hospital
University of Milan
Milan, Italy


Part of a case-based online initiative: What I Do and Why: HBV Treatment Strategies for Diverse Patient Populations

Oral therapy with nucleos(t)ide analogues (NAs) for patients with chronic HBV infection prevents progression to cirrhosis and clinical decompensation and reduces the hepatocellular carcinoma risk by approximately 50%. It is effective, safe, and accessible to most patients. However, NA therapy requires long-term administration, and the disadvantages of continuous therapy include the risk of developing drug resistance, safety, cost, adherence, and the need for continued monitoring.

Stopping Rules for NA Therapy
The best and safest stopping rule for NA therapy, even in patients with compensated cirrhosis, is a “functional cure,” which is defined as HBsAg loss with or without seroconversion. HBsAg loss is a sign of immune control and is associated with silencing of covalently closed circular (ccc) DNA and/or a decreased number of infected liver cells. However, this endpoint is achieved in < 5% of patients over 10 years of NA therapy.

Strategies to Increase the Rate of HBsAg Loss
Strategies to foster HBsAg loss in NA-treated patients have been explored. One option would be to continue oral therapy as HBsAg levels decline. Typically, HBsAg levels decrease < 0.1 log IU/mL per year. Several studies have shown that peginterferon, either as an add-on or switch strategy, may increase functional cure rates in select patients with low HBsAg levels. Ongoing studies suggest that new antivirals targeting cccDNA, HBsAg production, or HBsAg export may contribute to accelerated HBsAg loss, even with a short-term, finite treatment course. Last but not least, stopping NA before HBsAg loss has been recently advocated as a possible alternative strategy.

Outcomes of NA Discontinuation Before HBsAg Loss
International guidelines provide recommendations on stopping NA therapy before HBsAg loss in selected HBeAg-positive and HBeAg-negative patients. HBeAg seroconversion and consolidation of response are required in HBeAg-positive patients. In HBeAg-negative patients, discontinuation of NA therapy in selected patients may be considered if no evidence of cirrhosis was present at the start of NA therapy, if the patient achieved long-term (≥ 3 years) virologic suppression, and if the patient can guarantee close posttherapy monitoring.

Recent retrospective and prospective studies demonstrated that stopping NA before HBsAg loss results in the following: a rebound in HBV DNA; an increase in ALT levels in many cases; ALT flares that can be severe and life-threatening in some cases; and loss of HBsAg in some cases. In some patients, clearance of HBsAg can follow an ALT flare. The rates of HBsAg loss in different studies vary from 1% in a cohort of Asian Canadian patients to up to 20% in a study of HBeAg-negative patients in Europe. Viral and liver parameters must be closely monitored for at least 6 months after NA withdrawal, so patients’ compliance with blood tests every 2 weeks is essential.

Reasons for NA Discontinuation Before HBsAg Loss
From my perspective, the most important question is not “if” NA can be discontinued before HBsAg loss but “why” doctors may want to pursue this strategy. If the goal is sustained long-term undetectable HBV DNA off therapy to reduce hepatocellular carcinoma risk, NA should not be discontinued. Only 30% of the patients will achieve a clinical/virologic profile of an inactive carrier, now referred to as HBeAg-negative chronic infection.

If HBsAg loss is the target, this may be achieved in some patients with discontinuation of NA therapy, but most patients will not reach this goal. In addition, approximately 40% of patients who discontinue NA therapy will have to resume antiviral therapy because of hepatitis reactivation.

In conclusion, a “one-size-fits-all” strategy cannot be used to determine if and when to discontinue NA therapy. Doctors should weigh the advantages and disadvantages of continuing or discontinuing NA therapy before HBsAg loss, and after thoughtful discussion with the patient, a recommendation can be made.

Your Thoughts?
What are your thoughts on the arguments for and against NA discontinuation in patients before HBsAg loss? Please share your insights in the comment section.

StephenW

慢性HBV感染患者NA停用的复杂性

  


Pietro_Lampertico





Pietro Lampertico，医学博士
胃肠病学教授
消化内科和肝病科主任
IRCCS Ca Granda Policlinico医院
米兰大学
意大利米兰


基于案例的在线计划的一部分：我做什么和为什么做：针对不同患者群体的HBV治疗策略

慢性乙肝病毒感染患者的核苷酸（t）核苷酸类似物（NAs）口服治疗可预防肝硬化和临床代偿失调，并将肝细胞癌风险降低约50％。它对大多数患者有效，安全且易于使用。但是，NA治疗需要长期给药，持续治疗的缺点包括产生耐药性的风险，安全性，成本，依从性以及需要持续监测的风险。

停止NA治疗的规则
即使在代偿性肝硬化患者中，NA治疗的最佳和最安全的停止规则是“功能治愈”，即定义为有或没有血清转换的HBsAg丢失。 HBsAg丢失是免疫控制的标志，并与共价闭合环状（ccc）DNA沉默和/或感染肝细胞数量减少有关。然而，在10年的NA治疗中，只有不到5％的患者达到了这一终点。

提高HBsAg丢失率的策略
已经探索出在NA治疗的患者中促进HBsAg丢失的策略。一种选择是在HBsAg水平下降时继续口服治疗。通常，HBsAg水平每年降低<0.1 log IU / mL。几项研究表明，聚乙二醇干扰素可作为一种附加或替代策略，可提高部分HBsAg水平低的患者的功能治愈率。正在进行的研究表明，针对cccDNA，HBsAg产生或HBsAg出口的新抗病毒药可能会加速HBsAg的流失，即使是短期，有限的治疗过程也是如此。最后但并非最不重要的一点是，最近有人提倡在HBsAg丢失之前停止NA作为可能的替代策略。

HBsAg丢失前NA停用的结果
国际指南为选择的HBeAg阳性和HBeAg阴性患者在HBsAg丢失之前停止NA治疗提供了建议。 HBeAg阳性患者需要HBeAg血清转化和巩固反应。在HBeAg阴性患者中，如果在开始NA治疗时没有肝硬化的迹象，如果患者获得了长期（≥3年）病毒学抑制，并且如果患者可以保证密切的治疗后监测。

最近的回顾性和前瞻性研究表明，在HBsAg丢失之前停止NA可导致以下结果：HBV DNA反弹；在许多情况下，ALT水平升高； ALT耀斑在某些情况下可能很严重并危及生命；在某些情况下会导致HBsAg丢失。在某些患者中，HBsAg清除可能会伴随着ALT爆发。在不同的研究中，HBsAg的流失率从一组加拿大亚裔患者中的1％到欧洲对HBeAg阴性患者的一项研究中的20％不等。停用NA后至少6个月内必须密切监测病毒和肝脏参数，因此患者每2周必须进行一次血液检查符合性。

HBsAg丢失前中止NA的原因
从我的角度来看，最重要的问题不是“是否”可以在HBsAg消失之前停用NA，而是“为什么”医生可能希望采用这种策略。如果目标是维持长期不可检测的HBV DNA停用疗法以降低肝细胞癌的风险，则不应停止NA。只有30％的患者会达到无活性载体的临床/病毒学特征，现在被称为HBeAg阴性慢性感染。

如果以HBsAg丢失为目标，则在某些停止NA治疗的患者中可以实现这一目标，但大多数患者将无法达到该目标。此外，由于肝炎再激活，大约40％的停止NA治疗的患者将不得不恢复抗病毒治疗。

总之，不能采用“一刀切”的策略来确定是否以及何时停止NA治疗。在HBsAg丢失之前，医生应权衡继续或终止NA治疗的利弊，并在与患者进行深入讨论之后，可以提出建议。

你的想法？
您对HBsAg丢失前患者停用NA的主张有何看法？请在评论部分分享您的见解。