Durability of lamivudine-induced HBeAg seroconversion for chronic hepatitis B patients with acute exacerbation

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.

Section: Discussionmentioning

confidence: 71%

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

Akuta

Suzuki²,

Kobayashi³

et al. 2005

“…Of our 96 seroconverters who were taken off lamivudine therapy, 45% developed HBeAg reversion with hepatitis flares and 13% developed HBeAg-negative but HBV DNA-positive hepatitis flares (86% within 6 months) [23] and age [24] have been postulated as possible factors. Obviously, long-term lamivudine therapy is usually required in patients with chronic HBV infection.…”

Section: Discussionmentioning

confidence: 99%

Short-Term Lamivudine Therapy in Patients with Chronic Hepatitis B

Chien¹,

Liaw²

2003

Lamivudine is a nucleoside analogue with potent inhibitory effects on hepatitis B virus (HBV) polymerase/reverse transcriptase activity. The rate of hepatitis B e antigen (HBeAg) seroconversion in a large series of Asian patients treated with lamivudine 100 mg daily for 1 year was only 16% and the incidence of YMDD mutants was 14%. Further analysis of this Asian trial has shown that patients with a pretreatment alanine aminotransferase (ALT) level higher than 5-fold the upper limit of normal (ULN) have a much higher HBeAg seroconversion rate as compared with patients with a pretreatment ALT level <2 × upper limit of normal (64 vs. 5%; p < 0.001). In order to avoid the development of YMDD mutants, we selected 186 patients with acute exacerbation for treatment with lamivudine during 9 months, if possible, and not more than 15 months. They were all seropositive for both hepatitis B surface antigen and HBeAg for more than 6 months and also had serum HBV DNA; 138 (74%) of them were male. HBV genotypes were A in 2 (1%), B in 115 (62%), C in 65 (35%), D in 2 (1%) and F in the remaining 2 (1%). Four patients (2%) had liver cirrhosis. They had mean pretreatment levels of ALT at 608 IU/l (range: 184–2,400 IU/l), total bilirubin at 1.5 mg/dl (0.3–14.8 mg/dl), and HBV DNA at 2,246 pg/ml (0.5–25,903 pg/ml). After a median of 8.2 months (3–15 months) on lamivudine, 96 patients (51%) achieved HBeAg seroconversion, while the other 90 (48%) patients did not. Genotype B was detected comparably frequently in seroconverters and nonconverters (63 vs. 61%). During 1-year follow-up after withdrawal of lamivudine, 56 (58%) of the 96 seroconverters experienced flare-ups with ALT levels elevated higher than 5 × ULN in 50 (89%). Of 90 patients who remained HBeAg-positive, in contrast, 80 (86%) experienced ALT flares (with ALT >5 × ULN in 84%) within 1 year. YMDD mutants did not develop in any of these 186 patients during the course of lamivudine therapy. In conclusion, short-term lamivudine therapy in patients with chronic active hepatitis B can reduce the incidence of YMDD mutants and achieve an acceptable HBeAg seroconversion rate. However, the relapse rate was high (60% during 1-year follow-up). Further study is needed to establish how to improve a sustained HBeAg response.

“…The standard lamivudine treatment is given for up to 6 months, which has been recommended to avoid the development of YMDD mutants [5]. The lack of durability of HBeAg seroconversion accomplished by lamivudine, especially in Asian patients [7,12], casts doubt on the overall effect of lamivudine and restricted its use over a long period of time. Some doctors in Hong Kong and the United States, however, have put patients on lamivudine for longer than 3 years [13,14].…”

Section: Discussionmentioning

confidence: 99%

“…HBeAg seroconversion induced by lamivudine is reported to be more durable in Caucasians [19] than Asians [7,12], in whom the ethnicity and the time of infection play a role leading to differences. Most studies, however, examined the reversion to HBeAg in patients who were taken off lamivudine after they had received it for a limited time.…”

Section: Discussionmentioning

confidence: 99%

Continued Lamivudine Therapy in Patients with Chronic Hepatitis B

Kumada¹

2003

From September 1995 through April 2002, 286 patients with chronic hepatitis B were started on lamivudine at the Toranomon Hospital in Tokyo, Japan, and most of them continued with it. At present, 16 patients received lamivudine for 5 years, 7 of whom for 7 years or longer. YMDD mutants increased gradually and developed in 69% of them during the 7 years on lamivudine. Biochemical and virological responses were achieved in 9 of the 16 patients (56%) at 5 years, and in 4 of the 7 patients (57%) at 7 years. Histological assessments were performed at 3 years in the 16 patients and further at 4 and 7 years in the 7 patients. Necroinflammatory changes improved remarkably with a decrease in the total histological activity score from 11.3 ± 3.0 to 4.1 ± 1.7 (p < 0.0001) at 3 years in the 16 patients. Histological improvements continued in 4 of the 7 patients (57%) at 7 years on lamivudine, while the pathology was unchanged in 2 patients (29%) and aggravated in the remaining 1 patient (14%). Severe acute exacerbation of hepatitis developed in 1 patient, who received additional interferon-α therapy to cope with it. Based on my experience, the continuation of lamivudine in patients with chronic hepatitis B benefits approximately two thirds of them with persistent virological and biochemical responses accompanied by histological improvements. Breakthrough hepatitis induced by YMDD mutants along the way in a small number of patients needs to be diagnosed promptly by regular monitoring for transaminases and, if it develops, it can be treated with interferon or other antiviral agents.