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.     

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.     

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.     

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     

Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy.

Lamivudine is a potent inhibitor of hepatitis B virus (HBV) replication, but its long-term use may be associated with HBV tyrosine-methionine-aspartate-aspartate (YMDD) motif mutation. To examine the clinical features and course after emergence of YMDD mutants, 55 patients who received lamivudine therapy over 104 weeks at our unit were assayed for YMDD mutation(s). Thirty-two of them were found to have the YMDD mutation. They continued lamivudine therapy and were followed up weekly or biweekly if clinically indicated. Thirty (93.7%) of them showed elevation of alanine transaminase (ALT), and 13 (40.6%) experienced acute exacerbation at 4 to 94 weeks (median, 24 weeks) after emergence of the YMDD mutant. The incidence of exacerbation is much higher than 4.3% in patients without the YMDD mutation (P =.003). Compared with patients without exacerbation, patients with exacerbation had a significantly higher serum HBV-DNA level after emergence of the YMDD mutant (P <.005). Before exacerbation, serum HBV-DNA level was rising to its peak, followed by the peaking of ALT (247-2,010 U/L) 1 to 4 weeks later. Three patients developed hepatic decompensation, but then in association with hepatitis B e antigen (HBeAg) seroconversion, recovered. Of the 12 evaluable patients, 8 (75%) showed HBeAg seroconversion, and 3 showed mutant clearance within 1 to 5 months after exacerbation. In contrast, none of the patients without exacerbation showed HBeAg seroconversion (P <.001). These results indicate that acute exacerbations may occur after emergence of the YMDD mutation. The incidence, clinicopathological features, and subsequent course, and possibly the underlying immune mechanisms, are similar to those of wild-type HBV chronic infection. Because severe hepatitis may occur, patients should be followed carefully once the YMDD mutant emerges.     

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.     

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.     

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.     

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.