Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy

A study in Chinese patients with chronic hepatitis B showed that treatment with lamivudine for 1 year significantly improves liver histology and enhances hepatitis B e antigen (HBeAg) seroconversion compared with placebo. Fifty-eight patients from this 1-year study have received long-term treatment with lamivudine 100 mg; the outcome of 3 years of lamivudine is reported here. Before treatment, all patients had detectable HBeAg. HBeAg seroconversion (HBeAg-negative, anti-HBe-positive), hepatitis B virus (HBV)-DNA suppression, alanine transaminase (ALT) normalization, emergence of YMDD variant HBV, liver histology, and long-term safety were assessed. After 3 years of continuous treatment with lamivudine 100 mg daily, 40% (23 of 58) of patients achieved HBeAg seroconversion. In patients with baseline serum ALT >2 x upper limit of normal (ULN), the rate of HBeAg seroconversion was 65% (17 of 26). Median serum HBV-DNA concentrations were below the level of detection, and median ALT concentrations were within the normal range throughout 3 years of treatment. YMDD variant HBV emerged in 33 of 58 (57%) patients during the 3 years, of whom 9 (27%) achieved HBeAg seroconversion (6 after emergence of YMDD variant HBV). ALT levels and histologic scores after emergence of YMDD variant HBV did not show major deterioration. Lamivudine was well tolerated during 3 years of therapy. In conclusion, these data in Chinese patients with chronic hepatitis B show enhanced seroconversion rates with extended lamivudine treatment. Up to two thirds of patients with moderately elevated pretreatment ALT achieved HBeAg seroconversion after 3 years of therapy.     

拉米夫定治疗慢性乙型肝炎三年疗效观察

目的　评估拉米夫定治疗慢性乙型肝炎 3年的长期疗效和安全性 ,以及病毒变异的发生率和影响。方法　采用多中心双盲、随机、安慰剂、对照临床试验及开放试验。 4 2 9例HBsAg、HBeAg阳性的慢性乙型肝炎病人 ,先按 3∶1随机分成拉米夫定组和安慰剂组 ,治疗 12周 ,以后所有病人均服拉米夫定 10 0mg/d ,共 3年。结果　治疗 12周 ,拉米夫定组HBVDNA累计阴转率 (<1 6pg/ml)为 92 2 % ,安慰剂组仅为 14 1% (P <0 0 1)。服药 3年后 ,血清HBVDNA仍持续降低 ,非变异组病人其中位值 ,低于可检测水平 ,变异组则可有轻度或中度回升 ,中位值为 86mEq/ml (bDNA法 ,相当于液相杂交法的 10pg/ml)。第 3年结束时 ,HBeAg阴转率为 2 0 3% ,HBeAg/抗 HBe血清转换率为17 3%。此与治疗前ALT水平有显著关系。治疗前ALT基础值 >2倍正常值上限 (2ULN)和 >5ULN者 ,3年时HBeAg阴转率分别为 4 2 2 %和 6 6 7% ,血清转换率分别为 34 4 %和 6 1 1%。治疗前ALT增高的病人 ,3年治疗后 ,ALT的复常率为 5 8 8%。第 1、2和 3年的YMDD变异率分别为 12 1%、4 9 7%和 70 5 %。发生变异后 ,继续服药 ,HBVDNA大多仍抑制 ,少数可回升 ,中位值为 86mEq/ml,仍继续有HBeAg阴转和血清转换 ,分别为 2 0 0 %和 15 1% ,低于非变异组病人。ALT增     

拉米夫定与α干扰素联合治疗慢性乙型肝炎

目的 观察拉米夫定(LAM)联合干扰素α1b(IFNα1b)治疗慢性乙型肝炎的近期疗效和安全性。方法 HBV DNA和HBeAg均阳性的90例慢性乙型肝炎患者，按1：1：1的比例进入三个不同的治疗组。联合治疗组：用IFNα1b 5MU，隔日肌肉注射，及口服LAM 100mg／d，共6个月，随后单用口服LAM 100mg／d6个月；LAM组：口服LAM 100mg／d共12月：IFN组：IFN α1b 5MU，隔日肌肉注射，共6个月。结果 治疗结束时，HBV DNA转阴率，联合治疗组为90．0％，LAM组为80％，IFN组为46．7％。丙氨酸氨基转移酶(ALT)复常率，联合治疗组为90．0％，LAM组为80．0％，IFN组为53．3％。HBeAg／抗HBe血清转换率，联合治疗组为46．7％，LAM组为13．3％，IFN组为33．3％。联合治疗组患者治疗结束时无一例检测到YMDD变异。结论 联合治疗组对HBV DNA抑制作用及ALT复常率高于单用干扰素组，与单用拉米夫定组接近。HBeAg／抗HBe血清转换率高于拉米夫定组，与单用干扰素组相近。初步显示联合治疗组发生YMDD变异较少。     

Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group

BACKGROUND & AIMS: One-year lamivudine therapy significantly suppressed hepatitis B virus (HBV) replication, improved hepatic necroinflammatory activity, and prevented progression of fibrosis. However, the effects of prolonged therapy are unknown. METHODS: A total of 334 Asian patients with chronic hepatitis B from a previously reported 1-year study were randomized to receive either lamivudine (100 or 25 mg) or placebo for another year. The effects of treatment on serum HBV-DNA suppression, alanine transaminase (ALT) normalization, and hepatitis B e antigen (HBeAg) seroconversion were measured. The presence of YMDD variant HBV and its effect were also determined. RESULTS: A significantly greater proportion of patients achieved sustained HBV-DNA suppression and ALT normalization with 100 mg lamivudine daily for 2 years compared with lamivudine for 1 year followed by placebo for the second year (P<0.001). Daily lamivudine therapy for 2 years was safe and resulted in incremental HBeAg seroconversion from 17% at week 52 to 27% at week 104. HBeAg seroconversion during continued lamivudine therapy increased linearly with increasing pretherapy ALT levels (P< 0.001). Despite the emergence of YMDD mutant in 38% of the patients, they continued to clear serum HBeAg and maintain lower median serum HBV-DNA and ALT levels than baseline values. In contrast, ALT levels increased 8-12 weeks after switching from lamivudine to placebo, but returned to normal once lamivudine treatment was resumed. CONCLUSIONS: Treatment with lamivudine for 2 years is both well tolerated and efficacious in patients with chronic hepatitis B.     

拉米夫定相关性HBV变异对乙型肝炎预后的影响

目的 进一步探讨拉米夫定相关性ＨＢＶ变异对患者临床经过的影响。方法 将接受拉米夫定治疗１００ｍｇ／ｄ的８２例患者在第１０４周按其发生变异程序分为完全变异、部分变异和无变异３组,分别进行肝功能和血清学指标比较。结果 在第１０４周,Ｆ和Ｍ组无１例ＨＢｃＡｇ阴国专,而Ｎ组有１８例ＨＢｅＡｇ阴转 ,１１例ｃＡｇ／抗－ＨＢｅ血清转换;拉米夫定相关性ＨＢＶ变异发生后ＡＬＴ可增高,完全变异组Ｈ ＢＶＤＮＡ水平明     

拉米夫定治疗HBeAg阳性慢性乙型肝炎患者血清转换持久性的研究

目的观察拉米夫定长期治疗慢性乙型肝炎(CHB)3年以上患者的血清转换率和停药后持久率,及影响疗效的有关因素.方法167例CHB患者,每天服用拉米夫定100mg,持续3年以上,连续2次以上出现血清转换(间隔3个月),即HBeAg转阴和抗HBe转阳,继续服药6～12个月后,停药并随访1年以上.服药第1年每月,以后第3个月观察临床症状和血清病毒学标志、丙氨酸转氨酶(ALT)、HBV DNA定量及YMDD变异等项目.HBV基因分型应用型特异性PCR方法.结果共有45例患者出现血清转换(27.0%),继续服药6～12个月后停药并随访1年以上,9例出现血清学重新激活,血清转换持久率为80.0%.经单因素统计和Logistic多元回归分析,得出血清转换率和停药后持久率与基线ALT水平呈正相关,与基线HBV DNA水平和治疗后YMDD变异呈负相关.结论CHB患者出现血清转换后继续应用拉米夫定治疗6个月以上,大多数患者可达到持续转换.对血清转换率和持久率有显著影响意义的因子为基线ALT、治疗后YMDD变异.     

Dynamics of hepatitis B e antigen index ratio correlate with treatment response in chronic hepatitis B patients.

BACKGROUND/AIM: Hepatitis B e antigen (HBeAg) seroconversion is an important event in the natural history of chronic hepatitis B virus (HBV) infection. Whether early dynamics of HBeAg index ratio could predict therapeutic endpoint of HBeAg seroconversion in patients receiving lamivudine remains unclear and thus deserves investigation. METHODS: A total of 52 patients (males/females, 40/12; mean age, 31.1+/-7.5 years) with HBeAg-positive chronic hepatitis B and serum alanine aminotransferase (ALT) level > or = 5 x upper limit of normal were enrolled. They received daily 100 mg lamivudine for at least 1 year. Pretreatment HBeAg index ratio and the dynamics during treatment [early serologic response (ESR) and serologic breakthrough (SB)] between responders and non-responders were compared. RESULTS: Of these 52 patients, mean pretreatment serum ALT level was 580 IU/l and baseline HBeAg index ratio (S/N) was 37.9. The overall 1-year on-treatment combined response rate was 50%. By using linear regression analysis, HBeAg index ratio was positively correlated with serum HBV DNA level (Pearson's correlation coefficient: 0.62, P<0.0001). By using multivariate logistic regression analysis, ESR could predict the success of treatment response (P=0.0302), and SB had a 90% positive predictive value of treatment failure. CONCLUSIONS: HBeAg index ratio is closely correlated with serum HBV DNA level, and the dynamics of HBeAg index ratio may predict 1-year on-treatment combined response to lamivudine in HBeAg-positive chronic hepatitis B patients.     

Four years of lamivudine treatment in Chinese patients with chronic hepatitis B

BACKGROUND AND AIMS: This study assessed the efficacy and safety of up to 4 years of lamivudine treatment and the clinical relevance of the emergence of YMDD-variant hepatitis B virus (HBV). METHODS: Fifty-eight Chinese adult patients with chronic hepatitis B (CHB) were randomized to lamivudine 100 mg/day for up to 5 years and were monitored for YMDD-variant HBV, hepatitis B e antigen (HBeAg) seroconversion (loss of HBeAg and detectable antibody to HBeAg) and serum alanine aminotransferase (ALT) concentrations. Four-year data are reported here. RESULTS: The rate of HBeAg seroconversion increased with extended therapy and also with higher baseline ALT concentrations. YMDD-variant HBV was detected in 67% (39/58) of patients at some point during treatment. After 4 years, a total of 47% (27/58) of patients achieved HBeAg seroconversion. Thirty-three per cent (13/39) of patients with YMDD-variant HBV achieved HBeAg seroconversion; this increased to 57% (8/14) in patients with moderately elevated (>2-5 x upper limit of normal) pre-treatment ALT concentrations. The proportion of patients that achieved normal serum ALT increased from 29% (17/58) at baseline to 69% (31/45) following 4 years of treatment. That included 68% (23/34) of patients with YMDD-variant HBV and 73% (8/11) of those without the variant. All patients receiving lamivudine had reduced serum concentrations of HBV-DNA compared with baseline, despite the emergence of YMDD-variant HBV in 39 patients. Lamivudine was generally well tolerated; there was little change in the number or type of drug-related adverse events in the fourth year of the study. CONCLUSIONS: Despite the emergence of YMDD-variant HBV, Chinese patients showed increased HBeAg seroconversion and improvement in ALT levels with an increased duration of treatment with lamivudine.     

拉米夫定治疗慢性乙型肝炎病人的长期疗效

通过多中心,承机,双盲,安慰剂对照的临床试验,研究拉米夫定（ｌａｍｉｖｕｄｉｎｅ）对慢性乙型肝炎（乙肝）病人的疗效和安全性。方法随机选择３２２例慢性乙肝病拉米夫定治疗（１００ｍｇ／ｄ）,１０７例病人服用安慰剂作对照,共治疗１２周,在１２周治疗结束后,拉米夫定组和安慰剂组病人均继续服用拉米夫定１００ｍｇ治疗至５２周。疗效评估包括临床症状和体征,肝功能和ＨＢＶ复制指标。结果治疗１２周,拉米夫定组ＨＢＶ     

拉米夫定治疗慢性乙型肝炎患者的疗效观察

目的探讨拉米夫定治疗慢性乙型肝炎患者的疗效与安全性。方法60例患者给予拉米夫定0．1口服，1次／日，疗程一年；其中13例患者进行治疗前后的肝组织病理学检查。结果治疗一年后肝组织学纤维化和炎症程度改善率为69．23％；36．3％的患者ALT复常；85％的患者HBV DNA水平由阳性转变为检测线以下，而HBeAg／抗-HBe血清转换率只有7．1％。结论拉米夫定可明显降低患者血清HBV DNA水平，并能改善肝组织学的炎症和纤维化程度，且用药安全，但HBeAg／抗-HBe血清转换率低。     

A higher alanine aminotransferase level correlates with earlier hepatitis B e antigen seroconversion in lamivudine‐treated chronic hepatitis B patients

Background/Aims: A pretherapy serum alanine aminotransferase (ALT) level above five times the upper limit of normal (ULN) is known to predict hepatitis B e antigen (HBeAg) seroconversion during lamivudine therapy for chronic hepatitis B patients. However, whether an even higher pretherapy serum ALT value or other viral factors could affect treatment responses remains unclear. Patients and methods: A total of 253 HBeAg‐positive chronic hepatitis B patients who had a pretherapy serum ALT level over five times ULN and received lamivudine for 12–18 months were retrospectively collected. Among these patients, 38% had received prior lamivudine treatment. HBeAg seroconversion was the primary endpoint of treatment. Baseline clinical and viral features were compared between responders and non‐responders at the end of treatment and 6 months post‐treatment. Results: At the end of therapy, the overall HBeAg seroconversion rate was 33.6%. For lamivudine‐naïve patients, the HBeAg seroconversion rate was 37.8%. Subgroup analysis showed that patients with pretherapy ALT levels over 10 times ULN had a significantly higher HBeAg seroconversion rate than those with a pretherapy ALT level between five and 10 times ULN at 3 months (P=0.045) and 6 months (P=0.037) of lamivudine treatment. No significant difference was found in terms of pretherapy serum ALT values, viral load and genotypes between seroconverters and non‐seroconverters. Conclusions: For lamivudine‐treated HBeAg‐positive patients with pretherapy ALT levels over five times ULN, an even higher ALT level could predict earlier HBeAg seroconversion; however, neither ALT levels nor viral factors correlate with higher response rates after 12–18 months of treatment.     

Lamivudine for the treatment of chronic hepatitis B

Lamivudine (Zeffix) is the first of a new class of antiviral agents to become available for the treatment of chronic hepatitis B. The results of controlled clinical trials indicate that in most patients, lamivudine improves necro-inflammatory liver disease, reduces the progression of hepatic fibrosis, normalises serum alanine aminotransferase, and enhances hepatitis B e antigen (HBeAg) seroconversion. For patients with HBeAg-positive chronic hepatitis B, one year of lamivudine therapy results in HBeAg seroconversion rates similar to those obtained with a standard course of interferon-alpha. Moreover, results from two and three years of lamivudine therapy show that the cumulative HBeAg seroconversion rate continues to increase with extended lamivudine therapy. Even in the absence of HBeAg seroconversion, lamivudine therapy leads to improvements in liver disease in many patients. HBV strains (YMDD variants) with reduced in vitro sensitivity to lamivudine were detected in some patients after at least 9 months therapy. Although the clinical benefits to lamivudine were greatest for those patients who remained free of YMDD variants, one year of lamivudine therapy led to improvements in most response parameters compared with placebo, regardless of whether YMDD variants were detected. Controlled and open-label studies show that lamivudine may provide similar benefits to other important groups of patients with chronic hepatitis B, including those with pre-core mutant disease and those with hepatic decompensation. Lamivudine was well tolerated in all patient groups studied. The incidence of adverse events was consistently similar in patients who received lamivudine compared with those given placebo. In conclusion, extensive clinical data provide evidence that lamivudine is a well-tolerated, effective, and convenient medicine for patients with chronic hepatitis B.     

Lamivudine therapy for children with chronic hepatitis B

AIM: To assess the effectiveness and side-effects of lamivudine therapy for children with chronic hepatitis B (CHB) who fail to respond to or have contraindications to interferon-α(IFN-α) therapy. METHODS: Fifty-nine children with CHB were treated with 100 mg lamivudine tablets given orally once daily for 12 mo. Alanine aminotransferase (ALT) activity was evaluated monthly during the therapy and every 3 months after its discontinuation. HBe antigen, anti-HBe antibodies, HBV DNA level in serum were evaluated at baseline and every six months during and after the lamivudine therapy. Sustained viral response (SVR) to lamivudine therapy was defined as permanent (not shorter than 6 mo after the end of the therapy), namely ALT activity normalization, seroconversion of HBeAg to anti-HBe antibodies, and undetectable viral HBV-DNA in serum (lower than 200 copies per mL). The analysis of the side-effects of the lamivudine treatment was based upon interviews with the patients and their parents using a questionnaire concerning subjective and objective symptoms, clinical examinations, and laboratory tests performed during clinical visits monthly during the therapy, and every 3 mo after the therapy. RESULTS: ALT normalisation occurred in 47 (79.7%) patients between the first and 11th mo of treatment (mean 4.4±2.95 mo, median 4.0 mo), and in 18 (30.5%) of them after 2 mo of the therapy. There was no correlation between the time of ALT normalization and the children's age, the age of HBV infection, the duration of HBV infection, inflammation activity score (grading), staging, ALT activity before treatment, serum HBV DNA level, and lamivudnie dose per kg of body weight. HBeAg/anti HBe seroconversion was achieved in 27.1% of cases. The higher rate of seroconversion was connected with lower serum HBV DNA level and longer duration of HBV infection. There was no connection between HBeAg/ anti HBeAb seroconversion and the children's age, age of HBV infection, grading, staging, ALT activity before treatment, and lamivudnie dose per kg of body weight. No complaints or clinical symptoms were observed during lamivudine therapy. Impairment of renal function or myelotoxic effect was noted in none of the patients. CONCLUSION: One year lamivudine therapy for children with chronic hepatitis B is effective and well tolerated. Seroconversion of HBeAg/HBeAb and SVR are connected with lower pre-treatment serum HBV DNA level.     

拉米夫定治疗慢性乙型肝炎出现血清转换的持续性研究

目的观察拉米夫定治疗慢性乙型肝炎患者5年的血清转换率和持续血清转换率及多元因素对两者的影响。方法81例慢性乙型肝炎患者,每天服用拉米夫定100 mg,持续5年。出现血清转换后, 继续服拉米夫定6个月以上(每3个月随访1次,至少2次以上),仍为乙型肝炎e抗原(-)和抗-HBe( ), 则停药并继续随访6-12个月。所需观察项目有丙氨酸氨基转移酶、血清病毒学标志物、乙型肝炎病毒DNA 载量及基因分型、YMDD变异等。结果(1)共有26例患者出现血清转换。总血清转换率为32.10% (26/81)。第1-5年,每年累积的血清转换率为16.05%、19.75%、27.16%、28.40%和32.10%。(2)停药后4例出现复发,持续血清转换率为84.62%(22/26)。(3)经Logistic多元回归分析,得出近期血清转换率和持续血清转换率与治疗前丙氨酸氨基转移酶水平呈正相关,与治疗前乙型肝炎病毒DNA水平呈负相关。持续血清转换与血清转换后继续服药时间有相关性。结论慢性乙型肝炎患者出现血清转换后继续应用拉米夫定治疗6个月以上,大多数患者可达到持续转换。对持续血清转换的影响因素为治疗前丙氨酸氨基转移酶和乙型肝炎病毒DNA水平(P<0.05)。     

Correlation of YMDD mutation and breakthrough hepatitis with hepatitis B virus DNA and serum ALT during lamivudine treatment

Aim: Continuous lamivudine treatment is associated with high frequency of drug resistance. We analyzed the incidence of tyrosine‐methionine‐aspartate‐aspartate (YMDD) motif mutant and breakthrough hepatitis (BTH) in hepatitis B virus (HBV) DNA positive patients receiving lamivudine for > 1 year and correlated it with HBV DNA and alanine aminotransferase (ALT) levels to evaluate if these measurements can provide a practical option for monitoring patients in clinical practice and define early switch from lamivudine therapy. Methods: Of the 929 patients receiving lamivudine for > 1 year, 359 patients who maintained an ALT level of ≤ 40 IU/L during the course of lamivudine treatment were stratified into two groups based on the duration of lamivudine treatment – one receiving lamivudine for < 3 years and the other for ≥ 3 years. Results: The incidence of YMDD motif in patients receiving lamivudine for < 3 years was 27% in patients with ALT ≤ 20 IU/L, 58% with ALT ≤ 30 IU/L, and 63% with ALT ≤ 40 IU/L, (P = 0.002). The corresponding incidence of BTH was 2%, 7%, and 48% (P < 0.001). The incidence of YMDD motif and BTH in these patients was 7% and 2% with HBV DNA < 2.6 (log copies/mL) and ALT ≤ 20 IU/L, while with ALT at 21–30, the YMDD motif mutant was 16% and BTH was 0%. Conclusion: Correlation of ALT and HBV DNA levels with YMDD motif mutant and BTH indicates that these measurements can be used in clinical practice for deciding early switch from lamivudine to other suitable antiviral therapies.     

Treatment of chronic hepatitis B: case selection and duration of therapy

Hepatitis B viral (HBV) infection is a major health burden in the Asia-Pacific region. The seriousness of chronic hepatitis B (CHB) is often realized at a late stage. The resultant morbidity and mortality from cirrhosis complications is considerable, with a high human cost. The most affected patients are men aged 40 years or older. Two decades ago, the prognosis for the 300 million "Australia antigen"-positive people (people with chronic HBV infection) was gloomy, with no effective intervention. Twenty years on, research and development have changed their outlook. Chronic hepatitis should now be diagnosed early, at the asymptomatic stage. Proper assessment and judicial introduction of therapy can suppress replication of HBV and resolve liver inflammation, thereby preventing the silent progression of chronic liver disease to end-stage cirrhosis. Interferon (IFN) monotherapy has been available for nearly 20 years, but various limitations restrict its general application. Injection-based therapies are inconvenient, the response rate is low (33% hepatitis B e antigen (HBeAg) seroconversion rate among optimal cases), side-effects are many, and some serious, and the cost is unaffordable for most people. However, in non-cirrhotic patients with mild to moderate disease activity, IFN is still a worthwhile option because the treatment course is shorter, mutation seems less of a problem and most responses are permanent and reduce or abolish late complications. Lamivudine, an oral nucleoside analog with potent antiviral effects, has been approved in many countries. Daily dosing of 100 mg reduces serum HBV-DNA to below detectable levels within 6 weeks. In HBeAg-positive patients, approximately 16% of treated patients seroconverted with the first year. This was associated with significant improvement in liver histology. Long-term treatment induces further HBeAg seroconversion, but overall clinical benefit is undermined by continuous emergence of drug-resistant YMDD mutants. In an Asian multicentre study, 58 patients on 5 years lamivudine therapy showed annual cumulative HBeAg seroconversion rates at 1, 2, 3, 4 and 5 years of 22, 29, 40, 47 and 50%, respectively. The best predictor of response is pretreatment alanine aminotransferase (ALT). Among patients with ALT > 2x the upper limit of normal (ULN), annual HBeAg seroconversion is increased to 38, 42, 65, 73 and 77%, respectively. However, emergence of YMDD mutants occurred at a cumulative rate of 15, 38, 55, 67 and 69%, respectively. The impact of this emergence on disease activity is unpredictable. Thus, while continued disease suppression, or even HBeAg seroconversion, still occurred in some patients, in others hepatitis may relapse and liver failure has been reported despite continuation of lamivudine. While the duration of lamivudine therapy is difficult to define, the best strategy may be to define only active CHB with major ALT elevation (par-ticularly ALT > 5x ULN) for a duration of 1 year or less. Lamivudine can be stopped in responders. The response is durable in approximately 80% of responders. Non-responders should be monitored closely for rebound off treatment. Therapy can be re-instituted if ALT is over 5x ULN. Management of patients with YMDD mutants can be challenging, but there is no clear evidence to recommend stopping or continuing lamivudine, or to add other possible effective agents, such as adefovir dipivoxil. More data are required to help draw up guidelines. Hepatitis B e antigen-negative CHB has been less well studied. Both IFN and lamivudine can suppress disease activity, but permanent responses are few. Without a distinct marker as an end-point for response, the duration of treatment is even more difficult to define. Quantitative polymerase chain reaction for low viral levels may give a clue, but definitive studies are required. Monotherapy is clearly not the answer for the majority of CHB patients with active disease. Combination therapy has the theoretical advantage of additional or synergistic efficacy. Preliminary results on IFN and lamivudine are promising and further clinical trials are ongoing. Emtricitabine (FTC), adefovir dipivoxil, entecavir, BL-thymidine (L-dT), DAPD, clevudine (l-FMAU), thymosin, therapeutic vaccines and various herbal medicines are potential candidates. Antiviral action in conjunction with immune modulation may have a better chance of eradicating HBV and its cccDNA in the hepatocytes as the basis for an eventual successful outcome. The key points are: (i) approved therapeutic agents for chronic hepatitis B (CHB) are IFN, lamivudine and thymosin (in a few countries only); (ii) indications for IFN therapy are viremia in compensated CHB patients with moderately raised ALT; (iii) lamivudine has broader therapeutic indications: it is effective in subgroups of CHB patients with compensated or decompensated liver diseases, but generally works better if patients have raised ALT; (iv) lamivudine has a potent suppressive action on HBV replication, including HBeAg-negative variants, but cannot eliminate cccDNA; this is the reason for the relapse of disease after discontinuing treatment, unless HBeAg seroconversion is obtained; (v) successful use of lamivudine aims at HBeAg seroconversion or profound suppression of HBV-DNA to serum levels of less than 100 000 viral copies/mL, in order to prevent emergence of drug-resistant YMDD mutants (which commences from 6 months onward); (vi) YMDD mutants may cause a flare of hepatitis, resulting in deterioration of liver histology and, occasionally, liver failure; (vii) combination therapy of lamivudine with IFN (standard or pegylated) or other nucleoside analogs should be the next advance. Preliminary data from IFN and lamivudine combination therapy show some promise, but there are conflicting results.     

A case-control study of response to lamivudine therapy for 2 years in Japanese and Chinese patients chronically infected with hepatitis B virus of genotypes Bj, Ba and C.

BACKGROUND/AIMS: In eastern Asian countries, hepatitis B virus (HBV) genotype Ba (HBV/Ba), HBV/Bj and HBV/C are prevalent. The aim was to investigate the response or resistance to lamivudine therapy among patients with different HBV genotypes. METHODS: Of 67 Japanese and Chinese patients with chronic hepatitis B, 18 patients with HBV/Bj, 15 with HBV/Ba and 34 with HBV/C were selected for a case-control study matched according to gender and age. All the patients were treated with lamivudine for 2 years and evaluated the response or emergence of the YMDD mutation at year 2 during the treatment. HBV genotypes were detected by the restriction fragment length polymorphism. The YMDD mutation was detected by the direct sequencing after amplification by PCR. RESULTS: At year 2 during therapy, 44.8% of the patients showed normalization of ALT and undetectable HBV DNA (favorable response), 35.8% developed the YMDD mutation. There was no significant difference of response to the therapy among the three genotype groups. The emergence of the YMDD mutation was associated with HBV/C. By the multiple logistic regression analysis, however, the significant factor of a favorable response was a higher pretreatment ALT level and negative HBeAg status and the significant factor of the emergence of the YMDD mutation was HBV/C. CONCLUSIONS: Higher pretreatment ALT level, HBeAg status or HBV genotype may affect the response or resistance to lamivudine therapy.     

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.     

Management of patients with chronic hepatitis B

Better understanding of hepatitis B virus (HBV) replication and the natural history and immunopathogenesis of chronic hepatitis B, together with the introduction of effective agents with different mechanisms of action, is the basis for better therapeutic strategies against chronic hepatitis B. Substantial experience has now been accumulated in the use of some of these drugs, and an Asia-Pacific Consensus has been reached on indications for their use. The goals of therapy and aspects of general management will be reviewed here. Among currently available drugs, alpha-interferon therapy gives a response rate (hepatitis B e antigen (HBeAg) seroconversion) of 30-40% compared with 10-20% in matched controls, but patients with lower alanine aminotransferase (ALT), higher HBV-DNA, and immunosuppressed patients have a poorer response, and alpha-interferon can be dangerous in cirrhosis. Meta-analysis of four controlled trials also suggests that thymosin-alpha1 is effective, but more studies are needed. Lamivudine has been most extensively studied. It is effective in terms of HBV-DNA loss, ALT normalization, HBeAg seroconversion, and improvement in histology, as well as being well tolerated. After 1 year of treatment, HBeAg seroconversion rate increased with higher pretherapy ALT levels, suggesting that patients with stronger endogenous antiviral defenses to kill hepatocytes harboring covalently closed circular DNA have a better response to direct antiviral effects. Lamivudine is also beneficial in HBeAg negative chronic hepatitis B, and patients with decompensated cirrhosis and HBV replication. However, genotypic-resistant tyrosine-methionine-aspartate-aspartate (YMDD) mutations start to emerge after 9-10 months of lamivudine therapy, and their incidence increases more quickly than the HBeAg seroconversion rate durating prolonged therapy. Thus the benefits of long-term lamivudine must be balanced against concern about YMDD mutations, and the durability of treatment response. There are encouraging preliminary results for adefovir dipivoxil, entecavir, emtricitabine, clevudine and other nucleoside/nucleotide analogs in the early stages of appraisal; entecavir and adefovir dipivoxil appear effective in patients with YMDD mutants. Further development of new drugs and new strategies, such as combination or sequential therapy, may help to better achieve the goals of treatment for chronic hepatitis B in the new century.     

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.