Editorial: Stopping NUCs—When to Restart NUCs for the Best Outcome?

The standard treatment of chronic hepatitis B virus (HBV) infection, nucleos(t)ide analogues (NUC), is usually long-term, as HBsAg loss is rarely achieved, which signifies functional cure. Recent evidence suggests that selected HBeAg-negative individuals with prolonged viral suppression and no advanced liver fibrosis can discontinue NUC therapy before HBsAg loss [1]. Studies, including a prospective randomised trial, show a higher chance of HBsAg loss after discontinuing NUC therapy [2, 3]. However, HBsAg loss rates vary by patient origin and HBsAg levels. Caucasians have higher HBsAg loss rates (up to 41%) when levels are < 1000 IU/mL, while Asian patients achieve significant HBsAg loss when levels are < 100 IU/mL [4]. Immunological events, marked by transient ALT increases after NUC discontinuation, may trigger HBsAg loss, though the exact mechanisms are unclear [5, 6]. The appropriate time to restart NUC therapy remains debated. Premature re-treatment may inhibit beneficial flares, whereas delayed re-treatment could lead to immune exhaustion, or possibly severe hepatic flares. Studies show conflicting results regarding ALT flares and HBsAg loss [6, 7], highlighting the complexity.

Against this background, the ‘Nuc-Stop Study’ from Norway, Sweden, Denmark and Ethiopia aimed to assess two strategies for restarting NUC therapy [8]. This prospective trial involved 127 HBeAg-negative, non-cirrhotic patients with at least 24 months of viral suppression. Participants discontinued antiviral therapy and were randomly assigned to either a low-threshold or high-threshold group for restarting therapy, based on HBV DNA and ALT values (Figure 1). The primary endpoint was HBsAg loss within 36 months post-therapy. The study showed no statistically significant difference in HBsAg loss between the low-threshold (4.7%) and high-threshold (12.7%) groups. However, the study was underpowered due to the sample size calculation, which assumed HBsAg loss would occur in 20% of the high-threshold group and only 1% of the low-threshold group. The overall HBsAg loss rate was 8.7%, lower than in earlier studies [9]. Importantly, all cases of HBsAg loss occurred in patients with HBsAg < 1000 IU/mL, among whom the HBsAg loss rate was indeed higher in the high-threshold group (53.3%) than in the low-threshold group (11.5%), indicating a possible strategic benefit.

FIGURE 1

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Summary of the clinical trial ‘An open-label, randomised trial of different re-start strategies after treatment withdrawal in HBeAg negative chronic hepatitis B’.

While the optimal timing for restarting NUC therapy remains elusive, the study confirmed increased HBsAg loss rates post-NUC discontinuation in patients with HBsAg levels < 1000 IU/mL. Future research should focus on these patients and include immunologic testing to understand functional cure mechanisms. The study also found very low HBsAg loss rates in patients with genotypes B and C, more common in Asia, confirming a higher barrier for HBsAg loss after NUC discontinuation in these populations [4].

In conclusion, the concept of ‘Stop-NUC’ shows promise, especially in patients with low HBsAg levels, but many questions remain about the immunologic mechanisms involved in achieving a functional cure. However, regardless of immunologic considerations, we would recommend restarting treatment at the latest when HBV DNA levels exceed 100,000 IU/mL or consistently rise above 2000 IU/mL. Delaying restarting treatment can be dangerous, and, if incautious, can lead to severe flares, or hepatic decompensation (as was documented in a patient from London [10]), affecting the safety and efficacy of this strategy.