Letter: No Biochemical Relapse Is Associated With the Highest Off-Therapy HBsAg Loss Rate

Abstract

The results of the large study of Tsai YN et al. [1] analysed the association of ALT elevation and HBsAg loss after cessation of Nucleos(t)ide analogue Nuc and concluded that ALT was not a factor for HBsAg loss. Several points in their discussion require clarification and further discussion:

First, it has already been well documented that “ALT elevation after Nuc cessation is not associated with higher HBsAg loss” [2, 3]. For example, a large study reported in 2018 [2] showed that the annual incidence of HBsAg loss was highest in those with normal ALT (sustained response 6.3%, virological relapse alone 2.4%), followed by clinical relapse (ALT> 2× ULN) without retreatment (1.7%) and lowest in those with relapse and retreatment (0.18%). Clearly, off-therapy HBsAg loss is highly associated with normal ALT.

Second, the cumulative HBsAg loss rate in the current study was 10-year 12.4%, which seems lower than 5-year 8.8% in their own previous prospective study [4] and apparently lower than 3-year 19% in a Caucasian cohort [5] and 13%–20.8% by year 6 in Asian cohorts [2-4]. One plausible explanation is that 17% of their patients were pretreatment HBeAg-positive, who are usually younger and likely have higher end-of-treatment (EOT) HBsAg levels, which were not reported in this study. The higher EOT HBsAg levels are only associated with a higher probability of relapse but not associated with relapse severity nor timing [5]. Naturally, higher EOT HBsAg levels would require a longer duration to achieve HBsAg seroclearance, thereby lowering the observed loss rate.

Third, our finding that off-therapy retreatment is inversely associated with HBsAg clearance [2] has been supported by other recent off-Nuc cohort studies [3, 4, 6, 7]. Importantly, the predictive value of combined HBsAg/ALT kinetics has been validated in a large study that no retreatment in patients with host-dominating flare is associated with a 3-yr HBsAg loss rate of 21%, in contrast to 0% in retreated counterparts [8]. With ‘safety first’ in mind, off-therapy monitoring of viral kinetics and tracking HBsAg levels throughout ALT elevations are vital for virus-dominating flare when prompt retreatment is necessary—especially for patients at risk of severe flare or hepatic decompensation [9].

Finally, the authors have misunderstood that selecting candidates for finite therapy relied on distinguishing ALT flares. The most important consideration in the strategy of finite Nuc therapy is a thorough discussion and evaluation right before the joint decision of the physician and patient. While accelerating HBsAg clearance—along with achieving optimal prognosis and reducing the risks of hepatocellular carcinoma or other adverse hepatic events [10]—is a shared ultimate therapeutic goal, vigilant follow-up and timely intervention are crucial. A stringent monitoring plan and timely retreatment are necessary strategies to enhance safety and ensure effective outcomes, especially for patients at elevated risk of severe flare or hepatic decompensation [9].

Wen-Juei Jeng: conceptualization, investigation, writing – original draft, writing – review and editing, methodology, data curation, funding acquisition, visualization, formal analysis, resources. Yun-Fan Liaw: conceptualization, investigation, writing – review and editing, validation, project administration, supervision.

This article is linked to Tsai et al papers. To view these articles, visit https://doi.org/10.1111/apt.18515 and https://doi.org/10.1111/apt.70083.