Virological and Biochemical Relapse after Discontinuation of Lamivudine Monotherapy for Chronic Hepatitis B in Japan: Comparison with Breakthrough Hepatitis during Long-Term Treatment

Abstract

Objective: Comparison of virological and biochemical relapse in patients with chronic hepatitis B, based on continuation or discontinuation of lamivudine monotherapy. Methods: In Japanese genotype C-dominant hepatitis B patients, 25 patients who stopped treatment at normal levels of alanine transferase (ALT) were retrospectively compared with 75 patients who continued treatment. Both groups were matched for age, sex, and observation period after start of treatment. We investigated the relapse rates, and evaluated predictive factors for relapse and efficacy of retreatment of the discontinuous group. Results: Virological and biochemical relapse occurred significantly earlier in the discontinuous than continuous group, and the peak levels and ratios of peak to pretreatment levels of serum bilirubin and ALT after relapse were not significantly different between the two groups. Multivariate analysis identified three independent factors at discontinuation of treatment associated with early biochemical relapse: HBeAg positivity, presence of liver cirrhosis, detection of basic core promoter mutant. Normalization of ALT levels with retreatment occurred in 62.5% of patients, but 2 HBeAg-positive patients retreated after the emergence of YMDD motif mutant developed severe relapse with hyperbilirubinemia. Conclusion: Our results in Japanese patients with genotype C-dominant hepatitis B suggest that discontinuation of lamivudine monotherapy, and retreatment after the emergence of YMDD mutant should be given attention.

Clinical course of chronic hepatitis B patients who were off-treated after lamivudine treatment: analysis of 138 consecutive patients

“…Recently, cessation of antiviral agent discussed in the previous studies [12,13,19,20], but biochemical breakthrough, hepatitis flare, and retreatment outcome were not closely investigated, especially in HBeAg-negative patients. Post-treatment virologic relapse and biochemical breakthrough incidence rates in our study were low in patients who achieved undetectable serum HBV DNA level and were lower than those of previous studies [12,13,21-24]. Moreover, patients in our cohort were regularly and closely followed up after cessation of lamivudine.…”

Favorable efficacy of long‐term lamivudine therapy in patients with chronic hepatitis B: An 8‐year follow‐up study

“…Hence, our results indicate that longterm lamivudine treatment also induces long-term favorable prognosis and is safe in patients with breakthrough hepatitis if suitable additional treatments are provided, to say nothing of the favorable prognosis in patients without YMDD mutant and breakthrough hepatitis. We agree with Lok et al [2003] who provided data in support of the benefits of long-term lamivudine treatment [Akuta et al, 2004].…”

Clinical Application of Pyrosequencing in Detection of YMDD Mutations

“…It was reported that the defective replicative competency of p.M204V/I restores upon addition of lamivudine, and there is no benefit to continue lamivudine therapy after emergence of YMDD mutations. 15,16 Pyrosequencing in our experiments (Table 4) showed a high accuracy in quantifying the proportions of MUT/(MUT+WT) to identify artificially made samples with minor mutations, predominatedly mutant, and equal mixtures. Lee and colleagues demonstrated that YMDD mutations occur throughout the course of lamivudine therapy, and a 5-fold predominance of YMDD mutant to WT virus is significantly associated with viral DNA breakthrough, 17 the ability of pyrosequencing to finely quantify the proportions of MUT/(MUT+WT) may be helpful for prediction of viral DNA breakthrough.…”