Different mechanism of selection of adefovir-resistant mutant viruses during adefovir monotherapy in patients with lamivudine-resistant chronic hepatitis B

• rtA181V/T and rtM250V, but not rtN236T, existed even in NA-naïve patients.
• rtA181V/T frequently coexist with rtM204V/I in LMV-resistant patients.
• In patients with rtA181T/V, rtA181V/T rapidly replaced rtM204V/I.
• In patients without rtA181V/T, rtM204V/I was slowly replaced by wild type.
• Then, above wild type was gradually replaced by rtN236T and/or rtA181V/T.

Background: Adefovir (ADV) resistance is more frequent in lamivudine (LMV)-resistant chronic hepatitis B (CHB) patients than in nucleos(t)ide analogue-naïve patients. The majority of LMV-resistant mutants harbor the rtM204V/I mutation, while a minor fraction harbor the rtA181V/T mutation. We aimed to elucidate the mechanism of the high rate of ADV resistance in LMV-resistant patients during ADV therapy. Methods: We performed a clonal analysis of HBV reverse transcriptase in treatment-naïve (n = 3) and LMV-resistant patients before ADV therapy (n = 14). Dynamic changes in the viral population (n = 9) during ADV therapy were also analyzed. Results: Before ADV therapy, rtA181V/T was observed in 30 of 680 clones (4.4%) from 7 patients with LMV resistance under dominant rt204V/I mutation and in one of 150 clones in treatment-naïve patients. The rtA181V/T mutation was more frequently found in clones from LMV-resistant patients than in treatment-naïve patients (p = 0.029). The rtN236T mutation was not observed in any clone. During ADV therapy, most rtM204V/I mutants were replaced by wild type in all 3 patients without the rtA181V/T mutation and in one patient with the rtA181V/T mutation. Subsequently, wild type was replaced by the rtN236T and/or rtA181V/T mutant. In patients with the rtA181V/T mutation (n = 6), the rtA181V/T mutant overtook the rtM204V/I mutant in 3 of 4 patients with ADV resistance. In 2 patients without ADV resistance, most of the viral population was replaced by wild type by the last follow-up. Conclusion: The high rate of ADV resistance in patients with LMV-resistance might be attributable to preexisting rtA181V/T mutant virus.