Continued lamivudine therapy in patients with chronic hepatitis B

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-alpha 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.     

慢性乙型肝炎患者拉米夫定耐药后的后续抗病毒治疗

目的探讨慢性乙型肝炎患者拉米夫定耐药后采用α-干扰素或（和）α1胸腺肽进行后续抗病毒的治疗效果.方法66例拉米夫定耐药患者,分治疗组和对照组.治疗组36例,用α-干扰素或（和）α1胸腺肽治疗1个月后停用拉米夫定,然后继续用α-干扰素或（和）α1胸腺肽治疗,共6个月.对照组30例,直接停用拉米夫定,不用其他抗病毒药.定期进行血清肝功能和病毒学指标检测.结果治疗组肝功能复常率、HBV DNA阴转率和HBeAg/抗-HBe转换率均明显高于对照组,治疗组HBVDNA阴转率最高为27.8%,HBeAg/抗-HBe转换率最高为25.0%.结论慢性乙型肝炎患者拉米夫定耐药后采用α-干扰素或（和）α1胸腺肽进行后续抗病毒治疗是有益的.     

Effect of long-term lamivudine in chronic hepatitis B virus-infected children

OBJECTIVE: To evaluate, retrospectively, biochemical, serological and histological responses in chronic hepatitis B (CHB)-infected children who received combination therapy and continued with prolonged treatment with lamivudine (3TC). PATIENTS AND METHODS: CHB infection was defined as the presence of hepatitis B surface antigen (HBsAg), hepatitis Be antigen (HBeAg) and hepatitis B virus (HBV) DNA in serum screened at 3-month intervals for at least 1 year, serum alanine aminotransferase (ALT) levels >1.5 times the normal limit and CHB with histological activity index (HAI) >5 by liver biopsy. A total of 99 children with CHB infection were treated with IFN-alpha (three times a week, 5 MU/m2) and 3TC (4 mg/kg/d) orally for 6 months. End of therapy response (CR) was defined as ALT normalization, HBV-DNA clearance and e seroconversion. Partial responders (PR) were defined as patients who had ALT normalization and HBV-DNA clearance, but who had not had e seroconversion. Forty-five children with PR at the end of the sixth month continued to receive 3TC alone thereafter. Breakthrough infection was determined as re-emergence of HBV DNA in serum after its clearance. The response rate, side effects and the breakthrough infection rate were examined on prolonged 3TC treatment. Liver biopsy was held in 29 patients at median 32 (14-66) months of 3TC; pre- and post-treatment liver histology was compared. RESULTS: Pre- and post-treatment evaluation was carried out in 45 children [mean age: 11+/-4.2 years, 31 males (69%), 14 females (31%)] with PR at the end of the sixth month of combination therapy. The initial mean ALT values and HAI scores were 75.6+/-60 IU/l and 8+/-3.3, respectively. 3TC was continued for median 33 (14-66) months and CR was achieved in 15.6% (7/45) and 5.6% (2/36) at the end of first and second year, and 0% (none) at the end of third and fourth year, respectively. Breakthrough incidence was detected in six (13.3%) cases at 12 months and increased to 69.4% (n=25) and 82.4% (n=14) at the end of the second and third years, respectively. Patients with breakthrough continued to receive 3TC. Seroconversion and CR of the mutant virus was achieved in one patient (2.9%) at month 46 of treatment with 3TC. Liver biopsy was held in 29 cases at median 32 (14-66) months of 3TC. Pre- and post-treatment mean HAI scores were 8+/-3.3 and 3.9+/-2.1, respectively (P=0.000). Mean necrosing scores were not different at the beginning and end of therapy (P=1.0). Inflammation, bridging and fibrosis scores decreased to 0.8+/-0.6, 1.3+/-1.2 and 0.6+/-0.8, respectively (P=0.000, P=0.002, P=0.000). CONCLUSION: The long-term 3TC usage in children with PR does not induce complete response and is associated with high breakthrough incidence. However, histological improvement is achieved and/or sustained even in children with HBV DNA breakthrough.     

Polymerase domain B mutation is associated with hepatitis relapse during long-term lamivudine therapy for chronic hepatitis B

Breakthrough hepatitis remains the major issue in long-term lamivudine therapy for chronic hepatitis B. However, the emergence of drug-resistant hepatitis B virus (HBV) is not always accompanied by a relapse of hepatitis. To elucidate factors predictive of breakthrough hepatitis, 53 patients with genotype C of HBV on long-term lamivudine therapy were analyzed. HBV reappeared during therapy in 19 patients with a cumulative incidence of 15% at 1 year, 34% at 2 years, and 60% at 3 years. Within this group, breakthrough hepatitis developed in 12 patients (63%). A polymerase gene domain B mutation (rt180M) emerged in 13 patients, and domain C mutations (rt204I, rt204V) were found in 19 patients. The rt180M mutation was associated with breakthrough hepatitis (p < 0.05) with a positive predictive value of 85% and a negative predictive value of 83%. Patients with the rt180M mutation had higher HBV-DNA levels during viral breakthrough compared to patients with rt180wt (p < 0.05). The mutational pattern of rt204 was not associated with breakthrough hepatitis. In conclusion, genotypic assays for the rt180M mutation after viral breakthrough may be useful in predicting the risk of breakthrough hepatitis and in deciding when to initiate alternative or additive nucleoside analogue therapy.     

Hepatitis B genotypes in chronic hepatitis B and lamivudine therapy

The influence of hepatitis B virus (HBV) genotypes on the natural history and the response to treatment of patients with chronic hepatitis B are of potential interest. Compared to the patients with HBV genotype C, those with genotype B were of a younger age and had a higher cumulative rate of hepatitis B e antigen (HBeAg) seroconversion during the initial 6 years of follow-up. The earlier HBeAg seroconversion in the patients with genotype B, however, did not provide them with a benefit in terms of a reduced risk of developing long-term complications. The response to lamivudine therapy was evaluated in 21 patients infected with HBV genotype B (all of subtype Ba) and 61 with genotype C. There were no differences in the virological response to lamivudine therapy, based on the reduction in median logarithmic HBV DNA titer as well as alanine aminotransferase (ALT) levels, normalization of ALT and the rate of HBeAg seroconversion between the patients with genotypes B and C. No differences were noted either, in the frequency of YMDD mutants at week 52 or the cumulative risk of HBV DNA breakthroughs with YMDD mutations during long-term lamivudine therapy (median 37.5 months). In conclusion, there is no influence of HBV genotypes on the development of long-term complications and lamivudine therapy in Hong Kong.     

Impact of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B

Lamivudine is a nucleoside analogue with potent inhibitory effects on hepatitis B virus (HBV) replication. Prolonged therapy is required for sustained suppression. However, HBV species with mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV RNA-dependent DNA polymerase conferring resistance to lamivudine may emerge after 9-10 months therapy with an incidence of 38 and 67% after 2 and 4 years of lamivudine therapy, respectively. During continued lamivudine therapy, patients with YMDD mutant HBV usually show serum alanine aminotransferase (ALT) and HBV DNA elevations at lower median levels than their baseline. Marked flare of serum ALT or acute exacerbation may occur as the result of CLT-mediated hepatocytolysis directed against YMDD mutants. Although viral clearance with or without emergence of distinct lamivudine-resistant mutants may occur after such exacerbations, 20% of the exacerbations are complicated with decompensation or even fatality. The exacerbations appear to be more severe than those that occur during the natural course of wild-type HBV chronic infection. In addition, some mutations may generate S gene truncation near 'transactivity-on-region'. Thus, the benefit of prolonged lamivudine therapy must be balanced against concern about YMDD mutants. Currently, the most cost-effective strategy is to select patients with stronger endogenous anti-HBV immunity, thereby increasing efficacy and shortening the duration of lamivudine therapy. New drugs and new strategies are needed to better achieve the goals of therapy and minimize the problem of YMDD mutants.     

Serum cytokine levels in patients with chronic hepatitis B according to lamivudine therapy

Background: Cytokines are known to play critical roles in the pathogenesis of chronic hepatitis B (CHB). However, the relationship between cytokines and treatment responses to drugs for CHB is not clearly defined yet. We measured the serum cytokine levels of interleukin (IL)‐1α, IL‐1β, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, vascular endothelial growth factor, interferon‐γ, tumor necrosis factor‐ (TNF‐α), macrophage/monocyte chemotactic protein 1, and epidermal growth factor to elucidate the cytokine expression pattern according to the patients' responses to lamivudine. Methods: Fifty‐eight specimens from 27 CHB patients and 98 specimens from healthy individuals were tested for 12 kinds of cytokines. The patients were grouped as: before treatment, ongoing treatment, duringmaintaining remission, and patients with viral breakthrough owing to resistance against lamivudine. The Evidence Investigator (Randox, Antrim, UK), a protein chip analyzer, was used to quantify serum cytokines. Results: Among 12 cytokines, IL‐6, IL‐8, IL‐10, and TNF‐α were significantly elevated in patients with resistance against lamivudine compared with patients maintaining response. IL‐8, IL‐10, and TNF‐α levels also weak to moderate correlated with ALT and HBV‐DNA concentrations. Conclusions: Serum cytokine levels would reflect the pathological differences of the individual treatment phases and may become useful indices in monitoring the treatment response of CHB. J. Clin. Lab. Anal. 25:414–421, 2011. © 2011 Wiley Periodicals, Inc.     

Viral breakthrough during lamivudine therapy for chronic hepatitis B

The mainstay of therapy for patients with chronic hepatitis B is inhibition of the replicative cycle of hepatitis B virus (HBV) in hepatocytes. Antiviral agents have different potencies. The measurement of HBV DNA in serum can monitor the potency of these therapeutic agents. Viral breakthrough may occur during therapy, which is defined as an abrupt increase in serum HBV DNA levels after a period of persistent suppression. The accuracy of HBV DNA detection depends on the sensitivity of assays. The third-generation quantitative assays have a lower limit of detection in ranges similar to those of quantitative PCR reaching 2 log10 copies/ml. The sensitive assays also give insight into the pathophysiology of chronic hepatitis B. Monotherapy usually suppresses the viral replication inadequately. It only brings about a reduction of serum HBV DNA levels from 8 to 4 log10 copies/ml. In other words, HBV is not completely eliminated. Viral breakthrough occurs with noncompliance to therapy and, also, when drug-resistant mutants emerge. Mutations in the YMDD motif of HBV polymerase lead to resistance to antivirals, such as lamivudine and famciclovir. In clinical practice, the diagnosis and management of viral breakthroughs are problematic and controversial. Due to advances in therapy, more potent agents are available such as adefovir dipivoxil that seldom induce viral breakthroughs for up to 134 weeks of therapy. Potent antiviral agents also lead to the decline of cccDNA in hepatocytes. Combination therapies may further improve efficacy and avoid viral breakthroughs.     

Short-term lamivudine therapy in HBeAg-negative chronic active hepatitis B in Taiwan

Lamivudine treatment in hepatitis B e antigen (HBeAg)-negative and hepatitis B virus (HBV) DNA-positive chronic hepatitis B (CHB) patients is associated with poor sustained response. A previous study has shown that short-term lamivudine therapy in HBeAg-positive patients with alanine aminotransferase (ALT) > 5x upper limit of normal (ULN) could achieve a high HBeAg response rate and low lamivudine resistance rate. We, therefore, prospectively treated 85 HBeAg-negative CHB patients with ALT > 5x ULN by lamivudine for 6-12 months. The mean pretreatment levels were as follows: ALT (normal < 36 U/I) 533 U/I (range: 180-2,418 U/I); total bilirubin (normal < 1.3 mg/dl) 2.0 mg/dl (range: 0.2-29.6 mg/dl), HBV DNA (normal, undetectable) 1.6 x 10(8) copies/ml (range: 1.4 x 10(5)-1.7 x 10(9) copies/ml). After a mean of 7.4 months (6-12 months) treatment, 69 (81%) patients achieved complete response. In a follow-up, 12 months after stopping lamivudine therapy, 33 (39%) patients showed sustained complete response. Patients with sustained response were younger than the relapsed patients (39.7 +/- 11.9 years versus 47.0 +/- 10.3 years; P = 0.005). The emergence of lamivudine-resistant variant HBV was documented in two patients (2%). It is concluded that in HBeAg-negative chronic hepatitis B patients with ALT levels above 5x ULN, a 6-12 month course of lamivudine therapy may achieve sustained an off-treatment response in approximately one-third of patients.     

拉米夫定治疗慢性乙型肝炎患者乙型肝炎病毒YMDD变异的研究

目的探讨拉米夫定治疗1年后慢性乙型肝炎（CHB）患者发生YMDD基序变异的状况及其检测方法。方法采用荧光定量PCR法检测血清HBV DNA含量，荧光PCR法和变性高效液相色谱法检测HBV YMDD基序变异。结果61例CHB患者经过拉米夫定治疗1年后，40例（65．6％）HBV DNA阴转；在21例HBV DNA阳性患者中，10例为YMDD野生型，11例出现YMDD基序变异，变异率达18．0％（11／61）。在11例基序变异中，完全变异7例（63．6％），部分变异4例（36．4％）。在完全变异型中，YIDD变异型5例，YVDD变异型2例；在部分变异型中，YIDD变异型3例，YVDD变异型1例。结论CHB患者拉米夫定治疗1年后，出现较高的YMDD基序变异率。利用荧光PCR法结合变性高效液相色谱法检测基序变异，经济便捷，可作为CHB患者YMDD基序变异的常规监测。     

Role of lamivudine in the treatment of chronic hepatitis B virus infection.

OBJECTIVE: To examine the evidence regarding the therapeutic effectiveness of lamivudine in the treatment of chronic hepatitis B virus (HBV) infection in immunocompetent patients. DATA SOURCES: Using chronic hepatitis B and lamivudine as MeSH headings, MEDLINE was searched from 1966 to September 1998 for all published randomized controlled trials evaluating lamivudine in chronic HBV infection. Relevant articles from selected bibliographies were also retrieved. STUDY SELECTION: Only randomized, single- and double-blind trials in human HBV carriers published in the English language were included. DATA SYNTHESIS: Evidence from the controlled trials suggests that lamivudine has a therapeutic effect in suppressing HBV replication in immunocompetent patients. Lamivudine 100 mg/d appears to suppress HBV replication in as many as 97% of patients within two weeks after the initiation of therapy and is capable of suppressing histologic damages. However, viral suppression is effective only during the therapy; on discontinuation of lamivudine therapy, most patients return to the pretreatment condition. Viral resistance to lamivudine has been observed. Most patients with chronic HBV infection appear to tolerate 100 mg/d of lamivudine therapy. CONCLUSIONS: Evidence has shown that oral lamivudine 100 mg/d will produce rapid and significant suppression of viral replication in immunocompetent patients with chronic HBV infections. Treatment periods up to one year have been effective and well tolerated. The suppression of viral replication may not be sustained after cessation of lamivudine therapy, and very few patients have complete elimination of HBV during therapy. Therefore, long treatment periods may be necessary. Efficacy and tolerability of treatment beyond one year need to be investigated. Resistance to lamivudine has been reported in patients receiving therapy. A combination anti-HBV regimen using lamivudine and other agents with different mechanisms of action should be investigated to maximize the elimination of the viral infection while minimizing or preventing damage to the liver cells and tissues and the development of viral resistance.     

Additive antiviral effects of lamivudine and alpha-interferon in chronic hepatitis B infection

alpha-Interferon has limited efficacy against chronic hepatitis B virus (HBV) infection. Nucleoside analogues may confer greater benefits, however, it is likely that combination therapies will be required for effective control of this infection. We investigated the antiviral effect of lamivudine and interferon therapy in eight patients with high HBV-DNA levels. Six patients received lamivudine/interferon combination therapy followed, after a 6-month drug-free period, with lamivudine monotherapy. Mean HBV viral load (copies/ml) reduction was significantly greater after 4 months of combination therapy (4.3 x 10(3)) compared to an equivalent period of lamivudine monotherapy (2.9 x 10(2)) (P=0.03). Two patients were given 6 months of lamivudine/interferon combination therapy followed immediately by lamivudine monotherapy. Cessation of interferon in these patients led to a rapid 1-2 log10 increase in HBV viral load. These findings suggest that alpha-interferon has a direct antiviral effect on chronic HBV infection, which may be additive to, or synergistic with lamivudine.     

The clinical impact of early detection of the YMDD mutant on the outcomes of long-term lamivudine therapy in patients with chronic hepatitis B

The early emergence of lamivudine (3TC)-resistant tyrosine-methionine-aspartate-aspartate (YMDD) mutants has been reported during 3TC therapy in patients with chronic hepatitis B (CHB) in hepatitis B virus (HBV)-endemic areas; however, its clinical impact during long-term 3TC therapy is unknown. This study was performed to investigate the impact of the early emergence of YMDD mutants 3 months after the initiation of treatment on the outcomes of long-term 3TC therapy in HBV e antigen (HBeAg)-positive CHB. We analysed YMDD genotypes in consecutive samples from 30 patients with HBeAg positive CHB throughout 3TC treatment using both restriction fragment length polymorphism and mass spectrometric assays. Long-term outcome was compared between patients who had YMDD mutations detected at 3 months and those who had no mutations. YMDD mutation was detected in 16 (53.3%) out of 30 patients at 3 months and only the rtM2041 mutation was found. Cumulative HBeAg loss rates at 3 years was 12.5% and 57.4% in patients who had the rtM2041 mutant and wild-type virus at 3 months, respectively (P=0.010). Cumulative viral breakthrough rates at 3 years was 75.0% and 14.3% in patients who had the rtM204I mutant and wild-type virus at 3 months, respectively (P=0.002). Logistic regression revealed that YMDD mutation at 3 months was significantly related to viral breakthrough within 24 months (P=0.003). In conclusion, early detection for HBV YMDD mutation at 3 months may be useful to predict the long-term outcomes of 3TC therapy in patients with HBeAg-positive CHB in HBV-endemic areas.     

Efficacy of alpha interferon therapy for lamivudine resistance in chronic hepatitis B

OBJECTIVES: The occurrence of lamivudine resistance is often associated with the clinical breakthrough, which is characterised by the reappearance of hepatitis B virus (HBV) DNA in serum and the elevation of aminotransferases. We evaluated the efficacy of alpha interferon for clinical breakthrough in patients receiving lamivudine therapy. PATIENTS: Six chronic hepatitis B patients receiving lamivudine were enrolled in the study. RESULTS: Under lamivudine therapy, clinical breakthroughs occurred in between fifteenth and thirty-fourth month of lamivudine therapy. HBV DNA reappeared, and alanine aminotransferase was elevated. Genotypic analysis showed M552V, M552I and L528M mutations. After determining the clinical breakthrough, standard alpha interferon-2b was given for 6 months. Lamivudine was also maintained. In only one patient, HBV DNA became negative by polymerase chain reaction, and serum alanine transaminase level was normal at the end of therapy. CONCLUSION: Alpha interferon added to lamivudine is generally ineffective in the treatment of lamivudine resistance.     

Long-term follow-up of lamivudine treatment in patients with severe acute exacerbation of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B

BACKGROUND: The long-term efficacy of lamivudine treatment for patients suffering from severe acute exacerbation of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B is unknown. METHODS: Consecutive patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B were prospectively recruited from 1999 to 2004 and treated with lamivudine. All patients had alanine aminotransferase (ALT) and serum bilirubin levels 10x and 3x above the upper limit of normal, respectively. HBeAg-positive patients without severe acute exacerbation served as controls. RESULTS: Forty-five patients with severe acute exacerbation and 31 controls were treated with lamivudine for a median of 2.8 (range 1.0-7.1) years and 3.8 (range 3.5-8.4) years, respectively. Compared with controls, patients with severe acute exacerbation had higher HBeAg seroconversion rates (78% versus 52%; P=0.02) and lower risk of virological breakthrough. However, 33% of patients with severe acute exacerbation still developed lamivudine resistance and virological breakthrough by year 5. HBV DNA levels at week 4 and prolonged baseline prothrombin time were independent factors associated with virological breakthrough. All patients with week 4 HBV DNA <3 log10 copies/ml had maintained virological response. Among 15 patients who stopped lamivudine after sustained HBeAg seroconversion for > or =6 months, 11 (73%) had virological relapse at a median of 1.4 (0.2-3.9) years. ALT increased beyond 10x the upper limit of normal in six (38%) patients who stopped lamivudine and two (7%) patients on maintained lamivudine treatment (P=0.02). CONCLUSION: Among patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B treated with lamivudine, virological breakthrough and post-treatment relapse are common despite a high rate of HBeAg seroconversion. Severe hepatitis flare is also common particularly among patients developing virological relapse after discontinuation of lamivudine.     

Efficacy of lamivudine in HBeAg-negative chronic hepatitis B

The necessity of the search for new drugs to treat chronic hepatitis B (CHB) is explained by the necessity to prevent hepatic cirrhosis (HC) and hepatocellular carcinoma. Treatment of HBeAg-negative CHB rests on the same principles as of HBeAg-positive one. Efficacy of nucleoside analogue lamivudin is well studied in HBeAg-positive CHB. The aim of this study was to evaluate lamivudine efficacy in therapy of HBeAg-negative CHB. Lamivudine (epivir--150 mg/day or zeffix--100 mg/day) was given for 1 year to 10 patients (5 males, 5 females, mean age 49.5 +/- 13.5). Their blood serum contained no HBeAg but contained HBeAb and HBVDNA. Chronic hepatitis was verified morphologically in 9 patients of whom 2 had HC and 2 developing HC. Moderate activity of the disease was in 4 patients, low--in 5. All the patients had a high ALT level (150 +/- 140 U/l, 60-528 U/l, high normal value 40 U/l). ALT and HBV DNA in the serum were examined by polymerase chain reaction in the course of treatment and for 6 months after its end. To the end of the treatment a complete response (absence of HBVDNA and normalization of ALT) was achieved in 8 (80%) patients. 5 (63%) of them 2-4 months after the end of the treatment had the exacerbation with appearance of HBVDNA in the serum and elevation of ALT level. A persistent response (6 months after lamivudin treatment) was in 3 (30%) patients, in 2 of them HBsAg was not detected. Lamivudin therapy is effective in HBeAg-negative CHB. In this study a high baseline level of ALT was the factor predisposing to a lasting response to treatment.     

Efficacy of lamivudine therapy and factors associated with emergence of resistance in chronic hepatitis B virus infection in Japan

OBJECTIVE: Several reports have examined the efficacy of long-term lamivudine therapy and the risk factors involved in emergence of viral resistance in Japanese patients with hepatitis B virus (HBV) infection. However, the patient cohorts in such studies are relatively small. METHODS: We analyzed 234 chronically HBV-infected Japanese patients who were treated with lamivudine for more than 12 months. They comprised patients with HBV genotype A (n = 8), genotype B (n = 21), genotype C (n = 203) and other HBV genotypes (n = 2). RESULTS: In most patients, lamivudine resulted in normalization of alanine transaminase (ALT) levels at 6 and 12 months, and suppression of serum HBV DNA to undetectable levels by the branched chain DNA probe assay (bDNA). Rates of ALT normalization and non-detection of HBV DNA were higher among patients with genotype B than genotype C disease. The proportions of patients who achieved HBeAg loss were 27, 42 and 45% after 6 months, 1 year and 2 years, respectively. The emergence of mutations was not different among genotypes A, B and C by the Kaplan-Meier method. Multivariate analyses identified high HBV DNA level (bDNA >or=100 MEq/ml) as an independent factor associated with emergence of the YMDD motif mutation in all patients. Among patients with genotype C disease, which is the predominant HBV genotype in Japan, multivariate analysis also identified high HBV DNA level and HBeAg positivity as factors associated with emergence of resistance. CONCLUSION: Patients exhibiting these factors at the commencement of lamivudine treatment must be monitored carefully at regular intervals for emergence of viral resistance.