VR can be achieved in most patients undergoing therapy with potent NAs. However, some patients show persistent or intermittent episodes of detectable, but low levels of serum HBV DNA (<2,000 IU/mL), referred to as low-level viremia (LLV) or suboptimal VR [5]. When using low genetic barrier NAs such as lamivudine, LLV signals emerging resistance and virologic breakthrough, and continued use can lead to treatment failure [6]. Hence, detecting LLV indicated a time for a change: switch from low genetic barrier NAs to high genetic barrier NAs [6]. The situation is different when using high genetic barrier NAs, such as entecavir and tenofovir. Continued use of high genetic barrier NAs in patients with LLV can further induce VR with very low risk of resistance and virologic breakthrough [7]. Thus, it is unclear whether LLV in patients under high genetic barrier NAs means a time for a change as in patients under low genetic barrier NAs. In this issue, Lee et al. [8] analyzed the association between LLV and long-term outcomes in 894 patients with CHB who were treated with entecavir, a high genetic barrier NA, to address this issue.

The goal of NA treatment is to achieve persistent undetectable serum HBV DNA levels, known as maintained virologic response (MVR) [1]. However, virologic tools used to measure HBV DNA have improved over the past years. MVR that would have been previously defined using old assays could now be classified as LLV with the use of more sensitive assays. Patients reaching LLV, rather than having undetectable HBV DNA levels, may be sufficient for improving patient prognosis [9]. The study by Lee et al. [8] supports that continued treatment with high genetic barrier NAs is sufficient in adherent patients with LLV. In this study, LLV was associated with HCC in the entire cohort, indicating that LLV is an alarming sign of poor prognosis. However, there was no association between LLV and poor prognosis when the analysis was limited to 617 adherent patients. Thus, poor prognosis in patients with LLV was mostly driven by poor adherence. Hence, the study suggested that LLV means time to check adherence but is not a time for a change in treatment when using a high genetic barrier NA. This study provides evidences on how to manage patients with LLV when using high genetic barrier NA.

However, the study design was an observational cohort study with inherent limitations. Lee et al. [8] provide excellent discussion on the potential limitations and implications of their findings. In addition, some points need to be further discussed. LLV usually refers to a subgroup of patients that exhibit persistent or intermittent episodes of detectable, but low serum HBV DNA levels (<2,000 IU/mL) without virologic breakthrough. However, patients with virologic breakthrough were included in this study. Out of the 240 patients with LLV, 56 (23.3%) switched to tenofovir and were censored when entecavir treatment was switched to tenofovir. In contrast to findings from Lee et al. [8], some studies suggest that changing instead of continuing with the current treatment may be better approach. In an analysis of 239 patients with paired liver biopsy, LLV was more frequently observed for patients with fibrosis progression (50%) than in patients with fibrosis regression (19%) or indeterminate fibrosis (26%) (P=0.015), suggesting that LLV may still promote fibrosis progression [10]. In our previous study, we observed a higher risk of HCC in cirrhotic patients with LLV than with MVR [5]. In a randomized trial conducted in Korea, patients with CHB with detectable HBV DNA (>60 IU/mL) treated with 0.5 mg of entecavir for >12 months showed higher VR (HBV DNA <20 IU/mL) after switched to tenofovir (55%) than in patients that continued with entecavir (20%, P=0.022) [11].

Therefore, here is the question: Is LLV during high genetic barrier NA therapy a meaningful sign to change therapy? In this study, Lee et al. [8] showed similar risks of liver-related death, transplantation, HCC, and hepatic decompensation between MVR and LLV groups in good adherent patients. However, the ultimate question is whether a change in therapy (switch to another NA or adding an additional NA) can decrease the risk of liver‐related mortality or HCC among patients showing LLV. To our knowledge, no information is available on whether changing NA therapy can decrease the risk of liver‐related mortality or HCC compared to continuing same treatment. In the recently revised guidelines of the Korean Association for the Study of the Liver, either continued treatment or switching to another NA has been suggested as a treatment option [1]. The findings from Lee et al. [8] provide another clue for the answer, yet, are imperfect to direct one approach. Until more robust data are available, the decision to continue, switch, or add another NA should be made based on available evidence, precise follow-up, and careful assessment of risks and benefits.