Association of core promoter mutations with viral breakthrough in chronic hepatitis B patients on long-term lamivudine therapy

Background and Aim: Virologic breakthrough (VBTH) during long‐term lamivudine therapy is believed to be due to the emergence of rtYM204I/VDD mutants. We observed VBTH in 17 of 67 patients receiving long‐term lamivudine therapy. The YMDD mutant at the onset of VBTH and/or subsequently was seen in eight (47%) of 17 such patients. We investigated other potential loci in the viral genome contributing to VBTH. Methods: Chronic hepatitis B (CHB) patients (n = 17) on long‐term (≥12 months) lamivudine therapy who had at least one episode of VBTH were selected (group I). Age, sex, serology and baseline viral load matched patients on long‐term lamivudine without VBTH (n = 12) served as controls (group II). Hepatitis B virus (HBV) DNA sequences were analyzed for pre‐S, surface, polymerase, core promoter, precore and core regions and were compared with sequences of respective genotypes. Results: Group I patients with VBTH (n = 17) either had rtYM204I/VDD mutations (n = 8, group Ia YMDD) or no rtYM204I/VDD mutations (n = 9, group Ib non‐YMDD). Group Ia patients had median baseline HBV DNA of 2794 pg/mL (range 3–9166 pg/mL) and a mean alanine aminotransferase (ALT) level of 86 ± 33 IU/L. In group Ib, the median baseline viral DNA was 916 pg/mL (range 8.3–5787 pg/mL) and the mean ALT was 61 ± 38 IU/L. The first VBTH in group Ia and Ib patients was noted at 21 ± 9 months and 15.2 ± 5.9 months, respectively, with a rise in HBV DNA levels from undetectable limits to 952 pg/mL (range 4.3–4875 pg/mL) and 571 pg/mL (range 1.2–1970 pg/mL), respectively. Core promoter mutations were seen in five of eight (62.5%) and in six of nine (66.6%); classic double mutations (A1762T/G1764A) of core promoter region were detected in two and three patients and novel double mutations of core promoter (G1764T/C1766G) in one patient each of group Ia and Ib patients, respectively. Compared to 11 (68%) of 17 group I patients, only three (25%) of 12 patients in group II had core promoter mutations (P