Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B

Elevated alanine transaminase (ALT) levels and low serum hepatitis B virus (HBV) DNA predict a higher likelihood of hepatitis B e antigen (HBeAg) loss in patients with chronic hepatitis B treated with interferon. Predictors of HBeAg loss in patients treated with lamivudine are not known. The objective of this analysis of 4 lamivudine-controlled Phase III trials was to determine patient-dependent or laboratory variables that predict HBeAg loss. Predictors of HBeAg loss in patients treated with interferon, lamivudine plus interferon, or placebo are also described. A total of 805 adults with chronic hepatitis B were treated either with lamivudine (n = 406), matching placebo (n = 196), interferon (n = 68), or the combination of lamivudine plus interferon (n = 135). Demographic and baseline disease characteristics were used in stepwise multivariate analyses to identify features that were predictive of lamivudine-induced HBeAg loss. HBeAg loss correlated with increased pretreatment ALT levels in all groups. The rate of HBeAg loss was highest among patients with pretreatment ALT levels greater than 5 times the upper limit of normal (ULN) and was most pronounced in the lamivudine group (56%). Multivariate modeling indicated that elevated baseline ALT levels (P <.001) and histologic activity index (HAI) score (P <.001) were important predictors of HBeAg loss in response to lamivudine. The effect of pretreatment ALT levels on HBeAg loss was similar for Asians and Caucasians. In conclusion, elevated pretreatment ALT levels and/or active histologic disease were the most important predictors of lamivudine-induced HBeAg loss. Asians and Caucasians had similar rates of response to lamivudine at comparable ALT levels.     

Factors related to post-treatment relapse in chronic hepatitis B patients who lost HBeAg after lamivudine therapy

BACKGROUND AND AIM: It is uncertain if a patient's lamivudine response after HBeAg loss is durable. In Korean chronic hepatitis B patients, the relapse rate is high after termination of lamivudine therapy for patients with HBeAg loss. We evaluated the factors related to relapse in chronic hepatitis B patients with HBeAg loss after lamivudine therapy. METHODS: A total of 132 chronic hepatitis B patients, who initially had HBeAg and did not have decompensated features, were analyzed in this study. These patients lost the HBeAg after lamivudine therapy and then their therapy was stopped. Post-treatment serum alanine aminotransferase (ALT), HBeAg, anti-HBe and hepatitis B virus (HBV) DNA were monitored until relapse. RESULTS: Seventy-five patients relapsed (cumulative relapse rate: 56% at 6 months). Upon univariate analysis, the factors of age, serum total bilirubin, presence of anti-HBe after HBeAg loss, and the duration of additional lamivudine therapy after HBeAg loss were associated with relapse. Upon multivariate analysis, older age, a higher serum total bilirubin and the shorter duration of additional lamivudine therapy were significant risk factors for relapse. Patterns of relapse were the re-elevation of ALT, re-emergence of HBV DNA (69 patients) and reappearance of HBeAg (55 patients). CONCLUSIONS: To prevent relapse in patients with chronic hepatitis B infection after lamivudine therapy, age and serum bilirubin level of patients as well as a prolonged duration of additional lamivudine therapy should be considered.     

Quantitative polymerase chain reaction assay for serum hepatitis B virus DNA as a predictive factor for post-treatment relapse after lamivudine induced hepatitis B e antigen loss or seroconversion

BACKGROUND AND AIMS: Lamivudine induces favourable virological and biochemical responses but post-treatment relapses are frequent, even in patients with hepatitis B e antigen (HBeAg) loss or seroconversion. The aim of this study was to determine whether extended lamivudine therapy for up to 12 months after HBeAg loss/seroconversion could decrease the risk of post-treatment virological relapse. In addition, we monitored serum hepatitis B virus (HBV) DNA levels using a quantitative polymerase chain reaction (PCR) assay during extended lamivudine therapy and analysed predictive factors for post-treatment relapse. PATIENTS AND METHODS: A total of 49 patients who exhibited HBeAg loss/seroconversion during lamivudine therapy received extended lamivudine therapy for six months (group 1, n=23) or 12 months (group 2, n=26) after HBeAg loss/seroconversion. Serum HBV DNA levels were quantified by a PCR based assay at the time of HBeAg loss/seroconversion, and at cessation of therapy. RESULTS: Post-treatment virological relapse rates at two years were 59% in group 1 and 50% in group 2. Age, time interval to HBeAg loss/seroconversion, and serum HBV DNA levels at the time of cessation of therapy were independent predictive factors for post-treatment relapse. The post-treatment relapse rate was 37% at two years in patients with serum HBV DNA levels of <200 copies/ml but 73% in those with > or =10(3) copies/ml. CONCLUSIONS: Extended lamivudine therapy for up to 12 months did not decrease the rate of post-treatment virological relapse, and monitoring of serum HBV DNA by a quantitative PCR method was helpful in predicting post-treatment relapse.     

Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pretreatment serum hepatitis B virus DNA and alanine aminotransferase

Background and aims: Interferon (IFN) induced hepatitis B e antigen (HBeAg) seroconversion is durable in 80-90% of chronic hepatitis B patients. Preliminary reports on the durability of HBeAg seroconversion following lamivudine are contradictory. We investigated the durability of response following IFN, lamivudine, or IFN-lamivudine combination therapy in a meta-analysis of individual patient data. PATIENTS AND METHODS: Twenty four centres included 130 patients in total with an HBeAg seroconversion (HBeAg negative, antibodies to hepatitis B e antigen positive) at the end of antiviral therapy: 59 with lamivudine, 49 with interferon, and 22 with combination therapy. Relapse was defined as confirmed reappearance of HBeAg. RESULTS: The three year cumulative HBeAg relapse rate by the Kaplan-Meier method was 54% for lamivudine, 32% for IFN, and 23% for combination therapy (p=0.01). Cox regression analysis identified pretreatment hepatitis B virus (HBV) DNA, alanine aminotransferase (ALT), sex, and therapy as independent predictive factors of post-treatment relapse; Asian race, previous therapy, centre, and type of study were not predictive of relapse. The relative HBeAg relapse risk of lamivudine compared with IFN therapy was 4.6 and that of combination therapy to IFN therapy 0.7 (p(overall)=0.01). CONCLUSIONS: The durability of HBeAg seroconversion following lamivudine treatment was significantly lower than that following IFN or IFN-lamivudine combination therapy. The risk of relapse after HBeAg seroconversion was also related to pretreatment levels of serum ALT and HBV DNA, but independent of Asian race.     

Efficacy of entecavir treatment for lamivudine‐resistant hepatitis B over 3 years: Histological improvement or entecavir resistance?

Background and Aims:  Long-term lamivudine therapy is required for patients with chronic hepatitis B, because hepatitis reappears frequently after it has withdrawn. However, hepatitis B virus (HBV) mutants resistant to lamivudine emerge frequently accompanied by breakthrough hepatitis.
Methods:  Effects of entecavir were evaluated in 19 patients who had developed breakthrough hepatitis during lamivudine therapy for longer than 5 years. This study is a subgroup analysis of a previously reported study. Entecavir, in either 0.5 or 1.0 mg/day doses, was given to 10 and nine patients for 52 weeks, respectively, and then all received 1.0 mg/day entecavir for an additional 68–92 weeks.
Results:  There were no differences in biochemical and virological responses in the two groups of patients with respect to the two different initial doses of entecavir. Serum levels of alanine aminotransferase were normalized in 17 (90%) patients, and hepatitis B e antigen (HBeAg) disappeared from the serum in two (14%) of the 14 patients who were HBeAg-positive before. Furthermore, a decrease in histological activity index score greater than 2 points was achieved in nine of the 11 (82%) patients in whom annual liver biopsies were performed during 3 years while they received entecavir. HBV mutants resistant to entecavir emerged in five of the 19 (26%) patients, and hepatitis flare occurred in two of them (40%).
Conclusion:  Entecavir in the long term would be useful for histological improvement of breakthrough hepatitis induced by lamivudine-resistant HBV mutants in patients with chronic hepatitis B. However, the relatively high rate of entecavir resistance is a concern, and other strategies need to be considered when available.     

拉米夫定治疗乙型肝炎病毒B、C基因型疗效比较

目的 研究乙型肝炎病毒(HBV)基因型对拉米夫定抗病毒疗效的影响。 方法 回顾调查235例拉米夫定治疗组和对照组患者的临床资料。 结果 135例患者接受拉米夫定抗病毒治疗,对照组100例。HBV优势基因型是B型和C型,拉米夫定治疗组有效率分别为92.9％和75.9％(x2=6.628,P<0.05),对照组有效率分别为9.8％和8.5％(P>0.05);YMDD变异发生率治疗组为3.6％和16.5％(x2=5.508.P<0.01)。结果发现,B基因型、丙氨酸氨基转移酶升高、HBV DNA低水平是抗病毒应答预测因素。 结论B基因氆HBV对拉米夫定的应答率优于C型,YMDD变异发生率低于C型,基因型是影响拉米夫定疗效和决定变异的重要因素之一。     

Analysis of clinical,biochemical and viral factors associated with early relapse after lamivudine treatment for hepatitis B e antigen-negative chronic hepatitis B patients in Taiwan

Summary.  The efficacy of lamivudine for HBeAg-negative chronic hepatitis B (CHB) Chinese patients has not been fully investigated. The role of the Hepatitis B virus (HBV) genotype on the treatment effect of lamivudine is controversial. Thirty-two consecutive patients with HBeAg-negative CHB were enrolled. All patients were treated with lamivudine 100 mg once daily of 7–12 months duration. The mean total period of follow-up since entry for all patients was 24 ± 3.5 months. HBV genotypes were classified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and verified by sequencing. Precore (G1896A) and basic core promoter (BCP, A1762T & G1764A) mutations were determined by PCR and direct sequencing. Twenty-one (65.6%) patients were infected by genotype B and, 11 (34.4%) by genotype C. G1896A was predominant in genotype B infected patients (95.2% vs 63.6%, P  = 0.037). At the end of treatment, 31 (96.8%) and 14 (43.8%) patients achieved biochemical and virological responses, respectively. The biochemical and virological response rates were 40.6 and 0% at 12 months after treatment. Eighteen (56.3%) patients had biochemical relapse within 12 months after withdrawal of lamivudine. By multivariate analysis, the pretreatment serum level of HBV DNA ≥12 Meq/mL was the only factor associated with early biochemical relapse (Odds ratio = 9.333, 95% CI = 1.497 ∼ 58.197, P  = 0.017). In conclusion, the virological effect of lamivudine for HBeAg-negative CHB is transient. Most patients had biochemical relapse within 12 months after lamivudine treatment regardless of HBV genotype. A high pretreatment viral load is the determinant for early biochemical relapse.     

Early response to lamivudine therapy in clinically non-cirrhotic chronic hepatitis B patients with decompensation.

This study aimed to elucidate the rate and predictors of early (6 months) therapeutic responses to lamivudine, the rate of early mortality and the use of the model for end-stage liver disease (MELD) and Index in predicting the survival in patients with a clinical diagnosis of non-cirrhotic chronic hepatitis B with decompensation. Ninety-eight patients with lamivudine therapy were enrolled and MELD and Index scores were calculated. Surviving patients were treated with lamivudine for more than 6 months. Four (4.1%) of the 98 patients died after initiation of lamivudine therapy. After a 6-month lamivudine therapy, 80 (85.1%) patients and 71 (75.5%) patients had normal alanine aminotransferase (ALT) values and negative hepatitis B virus (HBV) DNA (<200 copies/mL), respectively, and hepatitis B e antigen (HBeAg)-negative patients had a significantly higher rate of negative HBV DNA than HBeAg-positive patients (P=0.002). The rates of HBeAg seroconversion and negative HBV DNA were 28.8 and 63.5%, respectively, and patients with HBeAg seroconversion had a significantly higher rate of negative HBV DNA (P=0.004). By multivariate analyses, older age, HBV nongenotype B infection, negative HBeAg and higher ALT levels were factors associated with negative HBV DNA, and a higher ALT level was associated with HBeAg seroconversion at month 6 after lamivudine therapy. MELD score and Index score were significantly associated with death and areas under the receiver operating characteristic curve for predicting survival were 0.936 and 0.907 respectively. We concluded that after 6-month lamivudine therapy, the patients who survived achieved favourable biochemical, virological responses and rate of HBeAg seroconversion. Both MELD and Index scoring systems are good models to predict the 6-month survival.     

Optimal duration of additional therapy after biochemical and virological responses to lamivudine in patients with HBeAg-negative chronic hepatitis B: a randomized trial

Aim:  The endpoint of treatment with nucleoside analogs remains unclear for patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. We report the results of a randomized trial to determine the optimal duration of additional therapy after response to lamivudine in HBeAg-negative patients.
Methods:  Twenty-two patients with HBeAg-negative chronic hepatitis B who exhibited biochemical and virological responses to lamivudine were enrolled. When patients responded to treatment, they were randomly assigned to receive 12 more months of therapy (Group A, 11 patients) or 24 more months of therapy (Group B, 11 patients).
Results:  The baseline characteristics of the patients were similar in the two groups. Biochemical and virological responses were obtained in all patients within 6 months. Drug resistance developed in one patient in Group A during month 7 of additional therapy, and in five patients in Group B from months 13–23 of additional therapy. Ten patients in Group A and six in Group B completed the protocol and were included in analysis. Eight of the 10 patients in Group A experienced relapse between months 2 and 14 after the discontinuation of therapy, while three of the six patients in Group B experienced relapse between months 2 and 24. There was no difference in cumulative relapse rate between the groups ( P  = 0.275).
Conclusion:  Additional therapy with lamivudine for longer than 12 months after biochemical and virological responses in patients with HBeAg-negative chronic hepatitis B could increase the risk of drug resistance, but did not reduce the rate of relapse.     

Relationship of clinical and virological factors with hepatitis activity in hepatitis B e antigen-negative chronic hepatitis B virus-infected patients

To investigate the factors associated with active disease among hepatitis B surface antigen (HBsAg) positive/hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infection we studied chronic HBV infected patients who had undetectable HBeAg at the first visit. HBV DNA was determined by the cross-linking assay (NAXCOR) and polymerase chain reaction (PCR). Mutations in the core promoter and precore regions and viral genotypes were studied. Clinical outcome of these patients were followed and categorized as: (i) relapse (ALT > 200 IU/L or three times the previous levels); (ii) active hepatitis (elevated ALT < 200 IU/L with concomitant detectable HBV DNA); or (iii) remission. A total of eighty-five patients were followed up for 5.5 ± 1.0 years. At first visit, 31 (36.5%) patients had elevated ALT levels, 12 (14.1%) had measurable HBV DNA by the cross-linking assay and 26 (30.6%) by PCR. Sixteen (18.8%) patients had hepatitis relapse, 13 (15.3%) had active hepatitis, and 56 (65.9%) remained in remission. Core promoter and precore stop codon mutants were found in 27 and 12 patients, respectively. Eleven and 20 had genotype B and C HBV, respectively. Initial elevated ALT and detectable HBV DNA were associated with active liver disease. Patient demographics, viral mutants or genotypes failed to predict disease activity. Hence, serum ALT and HBV DNA levels offer the best prediction of natural course of HBeAg-negative chronic HBV infection.     

Poor durability of lamivudine effectiveness despite stringent cessation criteria: a prospective clinical study in hepatitis B e antigen-negative chronic hepatitis B patients

Background and Aims: Lamivudine, a nucleoside analog, is commonly used for treatment of chronic hepatitis B (CHB) but its durability of effectiveness after withdrawal is still uncertain. This study was designed to assess the durability of lamivudine treatment with stringent cessation criteria in hepatitis B e antigen (HBeAg)‐negative patients and to explore potential predictive factors. Methods: Sixty one HBeAg‐negative CHB patients who had received lamivudine for at least 24 months and had maintained undetectable serum hepatitis B virus (HBV) DNA plus normal alanine aminotransferase for ≥ 18 months before withdrawal were included. They were followed up monthly during the first 4 months and at 3‐month or 6‐month intervals thereafter. Relapse was defined as serum HBV DNA ≥ 10⁴ copies/mL. Results: Thirty one of 61 patients relapsed during follow‐up, over 90% occurred within 18 months after lamivudine withdrawal. Cumulative relapse rates at months 6, 12, 24, 36, 48 and 60 were 26.2%, 43.6%, 49.7%, 52.1%, 56.1% and 56.1%, respectively. Cox regression revealed that age was the only predictive factor for relapse, with lower relapse rates found in younger patients. Hepatitis B surface antigen (HBsAg) turned negative in eight patients, and none of them relapsed during follow‐up. Conclusion: Effectiveness of lamivudine treatment is not durable in HBeAg‐negative CHB patients even when stringent cessation criteria are adopted, with the exception of patients aged ≤ 20 years. The ideal end point of lamivudine treatment is clearance of serum HBsAg.     

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

BACKGROUND/AIMS: Lamivudine-induced hepatitis B e antigen (HBeAg) seroconversion in patients with chronic hepatitis B was reported to be durable by several studies but controversy still exists. The aim of this study was to evaluate the durability of the responses of lamivudine treatment. METHODS: Among 53 chronic hepatitis B patients who had acute exacerbation and had finished lamivudine therapy after at least 6 months of treatment, 31 patients achieved full HBeAg seroconversion twice at least 1 month apart, and subsequently stopped lamivudine therapy. Post-treatment monitoring was continued for up to 87 weeks. Alanine transaminase (ALT), HBeAg and hepatitis B virus (HBV) DNA were used as indicators for relapse. RESULTS: The cumulative relapse rates at 48 and 72 weeks post-treatment were 45.4% and 56.3%, respectively. During follow up, normal ALT levels precluded relapse while ALT levels over two times the upper limit of normal indicated relapse, which correlated well with HBeAg or HBV DNA reappearance. Patients older than 25 years were more likely to experience post-treatment relapse. CONCLUSIONS: Lamivudine-induced full HBeAg seroconversion was not durable in the Taiwanese population. ALT levels were useful for relapse detection. Age was the only independent predictive factor for relapse.     

A 7‐year study of lamivudine therapy for hepatitis B virus e antigen‐positive chronic hepatitis B patients in China

OBJECTIVE: To evaluate the long‐term efficacy and safety of lamivudine treatment for chronic hepatitis B and the impact of emergence of YMDD mutation of hepatitis B virus (HBV). METHODS: A total of 429 patients with serum HBsAg, HBeAg and HBV DNA positive were randomized to receive either lamivudine 100 mg daily or a placebo in a 3:1 ratio for the first 12 weeks. Thereafter, all patients were administered with lamivudine 100 mg/d for 5 years and followed up for 2 years. RESULTS: After 12 weeks of the lamivudine treatment, serum HBV DNA levels decreased rapidly and HBV DNA negativity (<1.6 pg/mL) was 92.2%, whereas it was only 14.1% (P < 0.01) in the placebo group. At the end of 5 years, serum HBV DNA continued to be substantially suppressed. The loss of HBeAg and seroconversion were significantly correlated with baseline alanine aminotransferase (ALT) levels, in patients with baseline ALT > 2 × upper limits of normal, the loss of HBeAg was 54% and seroconversion rate was 50%, respectively. YMDD mutation developed in 70.8% of the patients at years 5. In YMDD mutant patients, HBV DNA levels were increased moderately and with mild to moderate elevations of ALT. ALT flares (ALT > 5ULN) occurred in 22 patients, 16 with YMDD variants and six with non‐variants. One year durability of seroconversion after stopping lamivudine was 80%. CONCLUSION: Lamivudine is effective and tolerable for chronic hepatitis B.     

Effect of virological response on post-treatment durability of lamivudine-induced HBeAg seroconversion

Lamivudine-induced HBeAg seroconversion may not be durable in Korean patients with hepatitis B virus (HBV) infection. It is unknown whether virological response during lamivudine treatment affects the post-treatment outcome. We retrospectively analysed 124 consecutive HBeAg-positive chronic hepatitis B (CHB) patients treated with lamivudine. Lamivudine was given at a dose of 100 mg per day. HBV DNA levels in sera obtained before and during therapy were measured by the Digene Hybrid Capture II assay and Digene Ultrasensitive Hybrid Capture II assay, respectively. HBeAg seroconversion was achieved in 42 of the 124 patients (33.8%) treated with lamivudine. Mean duration of treatment in HBeAg seroconverters was 12.86 +/- 4.44 months. During the follow-up period, the cumulative relapse rates at 3 months and 6 months post-treatment in 42 patients with HBeAg seroconversion were 40.5% and 57.4%, respectively. Among 31 seroconverted patients whose sera were available at the second month of treatment, HBV DNA remained at > 4.7 x 103 genomes/mL in 15 patients and decreased to < 4.7 x 103 genomes/mL in the remaining 16 patients. HBV DNA levels at the second month of treatment was not related with relapse after discontinuation of treatment (66.7% vs. 43.8%, P= 0.2). At the time of HBeAg seroconversion, HBV DNA remained at > 4.7 x 103 genomes/mL in five patients and decreased to < 4.7 x 103 genomes/mL in the remaining 37 patients. Relapse rates were increased in patients who remained at > 4.7 x 103 genomes/mL compared with patients with HBV DNA levels < 4.7 x 103 genomes/mL (100% vs. 51.4%, P < 0.001). Thus, monitoring of serum HBV DNA at the time of HBeAg seroconversion may be helpful for predicting relapse in patients with lamivudine-induced HBeAg seroconversion.     

Intracellular levels of hepatitis B virus DNA and pregenomic RNA in peripheral blood mononuclear cells of chronically infected patients

Summary.  It remains uncertain whether hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and pregenomic RNA (pgRNA) can be detected in the serum or peripheral blood mononuclear cells (PBMC) of patients with chronic hepatitis B (CHB) infection. We examined HBV cccDNA and pgRNA in the serum and PBMC, and investigated the effect of lamivudine therapy on the viral loads in the PBMC of CHB patients. Paired serum and PBMC samples from 50 treatment-naïve CHB patients [25 hepatitis B e antigen (HBeAg) positive and 25 HBeAg negative] were quantified for total HBV DNA, cccDNA and pgRNA by real time polymerase chain reaction. HBV cccDNA and pgRNA were below the lower detection limit in all serum samples, and in 84% of PBMC. HBV DNA ( r  = 0.889, P  <   0.001) and pgRNA ( r  = 0.696, P  <   0.001) in PBMC correlated with the HBV DNA in serum. In the longitudinal study, 30 patients treated with lamivudine therapy for a median duration of 34 weeks (range 12–48 weeks) were examined. The median HBV DNA reduction in PBMC before and after treatment was 1.318 (range −0.471 to 3.846) log units, which was significantly lower than serum HBV DNA reduction [3.371 (range −0.883 to 9.454) log units, P  <   0.05]. HBV cccDNA and pgRNA were undetectable in the serum of CHB patients. HBV viral loads in PBMC correlated with serum HBV DNA. Lamivudine therapy had less effect on the HBV viral loads in PBMC compared with the serum viral loads.     

拉米夫定治疗慢性乙型肝炎患者定量检测HBeAg的意义

目的探讨拉米夫定治疗的慢性乙型肝炎患者血清HBeAg和HBV DNA载量的变化规律。方法采用免疫化学发光和荧光定量聚合酶链反应技术分别检测了64例HBeAg阳性的慢性乙型肝炎患者在接受拉米夫定治疗过程中血清HBeAg和HBV DNA水平的变化。结果治疗12个月,HBV DNA完全转阴49例(76.6%),HBeAg转阴17例(26.6%),他们的HBV DNA和HbeAg水平呈同步下降趋势;11例治疗无效的患者血清HBV DNA和HBeAg水平也呈下降趋势,但始终未转阴;4例HBV DNA短暂转阴的患者,在治疗6个月后又转为阳性,HbeAg也未阴转。结论在拉米夫定抗病毒治疗过程中动态检测HBeAg水平可用于评估抗病毒的效果。     

Effects of lamivudine on outcome after liver resection for hepatocellular carcinoma in patients with active replication of hepatitis B virus

Aim:  Patients with high serum hepatitis B virus (HBV) DNA concentrations are at high risk of tumor recurrence after liver resection for HBV-related hepatocellular carcinoma (HCC).
Methods:  Among 24 patients with high serum HBV DNA concentrations who underwent liver resection for HBV-related HCC, postoperative lamivudine therapy was chosen by 14 (lamivudine group). The other 10 patients were controls.
Results:  Clinicopathologic findings did not differ between the groups. Tumor-free survival rate after surgery was significantly higher in the lamivudine than the control group ( P  = 0.0086). By univariate analysis, multiple tumors were also a risk factor for a short tumor-free survival. By multivariate analysis, lack of lamivudine therapy and multiple tumors were independent risk factors for a short tumor-free survival. In four patients YMDD mutant viruses were detected after beginning lamivudine administration; in two of them, adefovir dipivoxil was administered because of sustained serum alanine aminotransferase elevations.
Conclusion:  Lamivudine therapy improved tumor-free survival rate after curative resection of HBV-related HCC in patients with high serum concentrations of HBV DNA, although careful follow up proved necessary for the detection of YMDD mutant viruses.     

Extended lamivudine retreatment for chronic hepatitis B: maintenance of viral suppression after discontinuation of therapy.

In patients with chronic hepatitis B, brief lamivudine therapy suppresses hepatitis B virus (HBV) DNA but results infrequently in sustained losses of virus replication posttreatment. We evaluated treatment response and its posttreatment durability during up to 18 months of lamivudine therapy (100 mg/d) in 24 patients who had hepatitis B e antigen (HBeAg) despite 1 to 3 months of prior therapy. Therapy was to be stopped after HBeAg loss or seroconversion (acquisition of antibody to HBeAg); posttreatment monitoring continued for 6 months. During therapy, which was well tolerated, HBV DNA became undetectable in all evaluable patients, accompanied by reduced alanine transaminase (ALT) activity. The cumulative 18-month confirmed loss of HBeAg during therapy was 9 of 24 (38%) and seroconversion was 5 of 24 (21%). Therapy was discontinued after HBeAg loss/seroconversion in 7 patients, and HBeAg status was maintained in all. Four of the patients with HBeAg responses lost HBsAg at least once. In 10 (43%) of 23 patients tested, we identified HBV polymerase YMDD mutations, 3 with detectable HBV DNA (2 with ALT elevations) and 7 without virological/biochemical breakthrough. In conclusion, up to 18 months of lamivudine therapy was well tolerated, suppressed HBV replication consistently, and tripled the frequency of HBeAg losses observed during brief-duration therapy; HBeAg loss/seroconversion remained durable posttreatment. The emergence of YMDD-variant HBV was relatively common but occurred typically without reappearance of detectable HBV DNA or ALT elevation. Our observations suggest that lamivudine can be stopped after confirmed HBeAg loss or seroconversion.     

End-of-treatment virologic response does not predict relapse after lamivudine treatment for chronic hepatitis B

AIM: Attaining hepatitis B e antigen (HBeAg) seroconversion during lamivudine treatment is associated with fewer relapses in HBeAg-positive patients. In HBeAg-negative patients, predictors for post-treatment relapse remain largely unknown. We therefore studied whether end-of-treatment virologic response correlated with relapse after lamivudine treatment. METHODS: We prospectively analyzed 12 HBeAg-negative patients and 14 HBeAg-positive patients with chronic hepatitis B, who received at least 9 mo of lamivudine treatment and were followed up for 12 mo post-treatment. Relapse of hepatitis B activity was defined by an elevation of serum ALT level above twice the upper limit of normal as well as reappearance of serum HBV DNA by the branched DNA assay or HBeAg during the follow-up period. The serum viral loads during and at the end of treatment were further determined by a quantitative real-time polymerase chain reaction assay. RESULTS: Relapse occurred in 6 (50.0%) HBeAg-negative patients within 12 mo post-treatment. Two relapsers had end-of-treatment serum viral load <1 000 copies/mL, the proportion was not significantly different from that in the 6 non-relapsers (33.3% vs 16.7%; P = 1.00). Hepatitis B virus (HBV) DNA levels did not correlate with post-treatment relapse in HBeAg-positive patients either. However, genotype C patients tended to have a lower relapse rate than genotype B patients (14.3% vs 57.9%, P = 0.08). CONCLUSION: Our results suggest that end-of-treatment virologic response cannot predict post-treatment relapse in patients with HBeAg-negative or -positive chronic hepatitis B. The impact of HBV genotype on the response to lamivudine treatment awaits further studies.