ABSTRACT
Objective To analyze the clinical occurrence and phenotypic characteristics of rtA181S-related novel multidrug-resistance mutation in reverse transcription region of hepatitis B virus (HBV). Methods The clinical data and sequence information of 16 443 patients with chronic HBV infection who received nucleos(t)ide analogues (NAs)-resistance testing at the original PLA 302 Hospital from 2012 to 2017 were retrospectively analyzed. rtA181S-related mutation patterns were analyzed and cloning-sequencing (≥20 clones/sample) was performed on the mutation samples of rtA181S+T184I+M204I with the highest detection rate. Phenotypic analysis was performed to evaluate the viral replication capacity and drug susceptibility. Results The rtA181S mutation was detected in 0.75% (124/16 443) of the patients. Among them, 21 patients were detected with coexistence of lamivudine (LAM)-resistance mutation and 74 patients were detected with coexistence of entecavir-resistance (ETVr) mutation. The rtA181S+T184I+M204I novel mutation accounted for 77.0% (57/74) of the rtA181S+ETVr mutation. Dynamic clinical data analysis showed that the rtA181S+T184I+M204I mutation emerged after adefovir dipivoxil (ADV), ETV, and LAM/telbivudine (LdT) treatment, accompanied by virological breakthrough or inadequate virological response. Compared to wild-type strain, rtA181S+T184I+M204I mutant had 53.7% decreased replication capacity, over 1000-, 3.9-, and 383.3-fold increased LAM, ADV, and ETV resistance, respectively, and remained sensitive to tenofovir (TDF). Conclusions rtA181S+T184I+M204I mutation is a novel multidrug-resistance mutation, which is related to the ADV, ETV or LAM/LdT sequential or combined treatment. TDF-based rescue therapy should be considered for patients harboring this mutation in clinical practice.