Is it possible to predict the development of an entecavir resistance mutation in patients with chronic hepatitis B in clinical practice?

Potent nucleos(t)ide analogs (NAs) with a high genetic barrier, such as entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate, are strongly recommended as a front-line treatment for chronic hepatitis B (CHB) by current international practice guidelines. Among the potent NAs, there has been no detectable resistance to TDF after 6 years of therapy in CHB patients. However, clinical resistance to ETV has been reported in NA-naïve patients, although the incidence was as low as 1.2% at year 3. Since this study reported a low resistance rate for ETV, excluding the non-response groups at 48 and 96 weeks, the ETV-resistance rate might have been underestimated, as compared with that seen in real-world clinical practice. Hepatitis B virus (HBV) exists in the form of quasispecies in patients with CHB. During ETV treatment in patients who experienced low-potency NAs, lamivudine (LAM)-resistant strains that might not be detected in a baseline mutation test if the proportion of LAM-resistant strains were relatively small could become the predominant strains because of positive selection by ETV, as they are less susceptible to ETV. According to the two-hit mechanism of ETV resistance, the positive selection of LAM-resistant strains by ETV acts like the first hit, and the second hit of an additional variant in these selected strains could easily lead to the development of ETV resistance. Of course, there may be another pathway for the development of entecavir resistance besides this stepwise manner. A simultaneous genetic mutation against ETV can also occur without a predeveloped LAM resistance, although a requirement to simultaneously develop multiple resistances contributes to the high genetic barrier to ETV. However, the clinical characteristics of patients with potential ETV resistance have not yet been completely elucidated in real-world practice. In this issue of Clinical and Molecular Hepatology, a Korean real-world study by Kim et al. indicates that a higher viral load 6 months after antiviral therapy and failure to achieve a complete virologic response (CVR) during treatment with ETV were independently associated with ETV resistance. In this study, patients were excluded if they were confirmed to have any genotypic resistance to NAs at baseline. Eight (3.1%) out of 258 patients See Article on Page 323 Is it possible to predict the development of an entecavir resistance mutation in patients with chronic hepatitis B in clinical practice?