阿德福韦酯单药挽救治疗对拉米夫定耐药的慢性乙型肝炎患者3年疗效观察

目的总结阿德福韦酯(ADV)单药挽救治疗拉米夫定(LAM)耐药慢性乙型肝炎患者效果,分析疗效影响因素,探讨单药挽救LAM耐药的可行性。方法 60例慢性乙型肝炎应用LAM耐药后入组挽救治疗。收集患者的基本特征:如年龄、性别、肝生化指标、HBV DNA及HBV M。纪录治疗持续时间及应答,并进行分组对照。结果 60例中,HBV DNA定量反弹≥1log10拷贝/ml 20例,HBV DNA测序rtM204I/V、rtL180M位点变异40例。生化学突破的LAM耐药患者,给予ADV单药治疗。完成156周治疗者42例。HBV DNA低复制组(基线水平HBV DNA 103～105拷贝/ml)治疗后第12至156周HBV DNA转阴率均为80.0%,高复制组(基线水平HBV DNA≥106拷贝/ml)转阴率为40.7%～44.7%,两组相比差异有统计学意义(P<0.01)。HBV DNA转阴率随治疗时间延长渐增加。治疗156周时,HBeAg阳性血清学转换率24.1%。4例因检测出rtA181V/I/S位点变异改用恩替卡韦(ETV)。结论 ADV单药挽救治疗LAM耐药慢性乙型肝炎,具有一定的疗效,且更适合于低病毒载量患者。     

Lamivudine treatment of decompensated hepatitis B virus-related cirrhosis

BACKGROUND: Patients with decompensated hepatitis B vires (HBV)-related cirrhosis tend to have low or undetectable HBV replication. However, some patients continue to have high levels of HBV replication and effective suppression of HBV replication with antiviral agents may potentially decrease hepatic necroinflammation and improve or stabilize liver function. This review was to under stand the efficacy and safety of lamivudine in the treatment of decompensated HBV cirrhosis. DATA SOURCES: An English-language literature search (MEDLINE January 1988-July 2005) was performed, and a total of 52 articles/abstracts relevant to the issue were selected. After review of the selected papers, the meaningful results and conclusions were extracted using scientific crite ria. The papers reviewed pertained mainly to the efficacy and safety profiles of lamivudine treatment for decompensated HBV cirrhosis. RESULTS: The ultimate treatment of decompensated HBV cirrhosis is liver transplantation, but lamivudine treatment may lead to rapid suppression of viral replication and improvement of biochemical and clinical parameters, reduced morbidity and hospitalization for complications of liver disease, increased pre-transplant survival as well as reduced need for transplantation. However, viral resistance can develop after prolonged treatment with lamivudine, and breakthrough hepatitis may be fatal in few patients. Adefovir is effective for lamivudine-resistant HBV mutants. CONCLUSIONS: Antiviral therapy with lamivudine for decompensated HBV cirrhosis can be effective. However, some patients may experience a hepatitis flare with the emergence of YMDD mutants resulting in progressive worsening of liver disease, and should be referred for "rescue" therapy with other nucleoside/nucleotide analogues such as adefovir dipivoxil.     

拉米夫定耐药慢性乙型肝炎患者改用或加用阿德福韦酯治疗48周疗效比较

目的观察拉米夫定(LAM)与阿德福韦酯(ADV)联合应用和单用ADV治疗LAM耐药HBeAg阳性慢性乙型肝炎患者的疗效及安全性。方法收集2006年1月至2011年12月在本院就诊的LAM耐药HBeAg阳性慢性乙型肝炎患者40例,单药组与联合组各20例,分别以ADV与LAM联合或单用ADV进行治疗。观察治疗24周、48周时的血清HBV DNA水平及转阴率、HBeAg转阴率、ALT复常率以及治疗过程中药物的不良反应和耐药性。组间比较计量资料采用t检验,计数资料采用卡方检验。结果两组患者在性别、年龄、治疗前的HBV DNA及ALT水平上差异均无统计学意义(P0.05);治疗结束时联合组的血清HBV DNA转阴率和ALT复常率分别为90%及95%,而单药组的血清HBV DNA转阴率和ALT复常率分别为60%及65%,两组比较差异有统计学意义(P0.05);治疗结束时联合组血清HBeAg转阴率为45%,单药组为35%,两组比较差异无统计学意义(χ2=0.417,P=0.519)。结论 ADV联合LAM或ADV单药治疗LAM耐药HBeAg阳性慢性乙型肝炎患者均有较好的临床疗效,但ADV与LAM联合治疗可提高HBV DNA转阴率及ALT复常率,其安全性良好,值得借鉴。     

Tenofovir plus lamivudine as rescue therapy for adefovir‐resistant chronic hepatitis B in hepatitis B e antigen‐positive patients with liver cirrhosis

Background/Aims: There is no consensus on the management of patients with adefovir (ADV)‐resistant hepatitis B virus (HBV) infection. The aim of this study was to investigate whether tenofovir disoproxil fumarate (TDF) combined with lamivudine (LMV) is effective and safe in patients with resistance to or non‐response to ADV. Methods: Six patients with HBV‐related cirrhosis, viral breakthrough during LMV therapy and viral breakthrough or non‐response during ADV therapy were treated daily with TDF plus LMV for at least 6 months. The HBV DNA level, alanine aminotransferase (ALT), the Child–Pugh score and serum creatinine were monitored. Genotypic LMV‐ or ADV‐resistant mutations were measured in stored samples. Results: In five of six patients, ADV‐resistant mutations at rt181 or rt236 were detected during ADV therapy. At 6 months of starting TDF/LMV combination, HBV DNA levels became undetectable (detection limit, 400 copies/ml) in four of six patients. Within 12 months, HBV DNA levels became undetectable in all patients, and ALT levels were normalized in four of six patients. These responses persisted up to the end of the observation period (median duration 16.5 months, range 6–21 months). The Child–Pugh scores improved in two of three patients with hepatic decompensation. No significant changes in serum creatinine were observed. Conclusion: Our data demonstrated that TDF plus LMV safely and markedly suppressed HBV replication in patients with resistance to or non‐response to ADV. This study suggests that this combination may be a promising rescue therapy for these patients, particularly those with liver cirrhosis or pre‐existing LMV resistance.     

Long-term efficacy of entecavir in adefovir-refractory chronic hepatitis B patients with prior lamivudine resistance

This study aimed to evaluate the long-term efficacy of entecavir (ETV) in adefovir (ADV)-refractory chronic hepatitis B (CHB) patients with prior lamivudine (LMV) resistance. A total of 55 ADV-refractory CHB patients with prior LMV resistance, who received rescue therapy with ETV 1 mg daily for at least 12 months, were consecutively enrolled and analysed. Forty-four patients were men, and their median age was 47 (25-69). Ten patients had liver cirrhosis and 46 patients were positive for hepatitis B e antigen (HBeAg). Median hepatitis B virus DNA levels were 6.6 (4.3-8.0) log(10) copies/mL, and the median duration of ETV therapy was 24 (12-47) months. Cumulative virologic response rates at 6, 12, 24 and 36 months were 18%, 29%, 58% and 75%, respectively. HBeAg loss occurred in 10 (21.7%) of 46 HBeAg-positive patients. In multivariate analysis, only initial virologic response at 3 months remained as an independent predictor for virologic response (RR 3.143; 95% CI 1.387-7.120; P = 0.006). The patients with a virological response at 3 months had not only a significantly higher probability of achieving a virologic response (P < 0.001) but also lower probability of experiencing a virologic breakthrough (P = 0.043) than the patients without an early response. Viral breakthrough was observed in 29 patients during the follow-up period. Cumulative breakthrough rates at 6, 12, 24 and 36 months were 0%, 15%, 45% and 73%, respectively. ETV monotherapy may be considerably efficacious in cases with an initial virological response but its efficacy is attenuated by frequent emergence of ETV resistance in ADV-refractory CHB patients with prior LMV resistance.     

Adefovir plus lamivudine are more effective than adefovir alone in lamivudine-resistant HBeAg- chronic hepatitis B patients: A 4-year study

Background and Aim:  Adefovir dipivoxil (ADV) is effective in lamivudine (LAM)-resistant hepatitis B e antigen-negative (HBeAg^-) chronic hepatitis B (CHB). However, it is unclear whether LAM treatment should be continued in these patients. We aimed to compare the long-term efficacy of adding ADV to ongoing LAM treatment versus switching to ADV monotherapy in LAM-resistant HBeAg^- CHB.
Methods:  Sixty LAM-resistant patients with HBeAg^- CHB were randomly assigned (3:1) to combination therapy (10 mg ADV once daily plus ongoing LAM at 100 mg once daily [ n  = 45]) or 10 mg ADV monotherapy once daily ( n  = 15). Virological and biochemical responses were defined as hepatitis B virus (HBV)–DNA <400 copies/mL and as normalization of alanine aminotransferase levels, respectively.
Results:  The median follow-up time was 53 months (range 20–60 months). A virological response was observed in 38/45 (84.4%) and 11/15 (73.3%) patients in the ADV/LAM and ADV monotherapy groups, respectively ( P  = 0.56). Biochemical response rates were higher in the ADV/LAM group than in the ADV monotherapy group (90.9% vs 57.1%, respectively; P  = 0.01). In the ADV/LAM group, serum HBV–DNA remained undetectable in all patients who achieved a virological response ( n  = 38). In the ADV monotherapy group, virological breakthrough occurred in four of the 11 patients who achieved a virological response (36.4%; P  < 0.001 vs the ADV/LAM group, log–rank test). In addition, two patients in each group who did not achieve a virological response eventually developed ADV resistance.
Conclusions:  Adding ADV to LAM is more effective than switching to ADV monotherapy in LAM-resistant patients with HBeAg^- CHB.     

乙型肝炎核心相关抗原对慢性乙型肝炎患者拉米夫定耐药的预测作用

目的评价乙型肝炎核心相关抗原（HBcrAg）对慢性乙型肝炎患者拉米夫定（LAM）耐药的预测作用。方法收集2009年1月至2011年12月期间住院和门诊收治的43例慢性乙型肝炎初治患者,拉米夫定治疗≥6个月,随访≥6个月,根据随访期间HBV DNA测序结果分为耐药组2l例,非耐药组22例。分别检测各研究节点ALT、HBsAg、HBeAg、HBcrAg、HBV DNA水平。计量资料两组问比较采用独立样本t检验,方差不齐采用Mann—Whitney U检验;计数资料采用卡方检验。相关性分析采用Spearman分析。影响因素采用Logistic回归分析。结果LAM抗病毒前HBcrAg与HBV DNA水平有较好的一致性,Spearman相关系数为0．863（P〈0．001）。LAM抗病毒治疗后,外周血HBcrAg与HBV DNA水平均有所下降,但HBcrAg下降速度与幅度均低于HBV DNA。Logistic回归分析显示,随访结束时HBcrAg水平可能为LAM耐药的影响因素（P〈0．01）。HBcrAg对LAM耐药预测价值较高,ROC曲线下面积为0．872（P〈0．001）。结论LAM抗病毒前外周血HBcrAg与HBV DNA有较好的一致性,随访结束时HB—crAg水平可较好的预测LAM耐药。     

Overlap lamivudine treatment in patients with chronic hepatitis B receiving adefovir for lamivudine-resistant viral mutants

Adefovir dipivoxil is effective against lamivudine-resistant hepatitis B virus (HBV) strains. Whether short-term overlap lamivudine is beneficial remains unknown, particularly in patients with decompensated chronic hepatitis B. We enrolled 30 patients who underwent 48-week adefovir treatment (10 mg daily) for exacerbation of hepatitis B, associated with lamivudine-resistant mutants. Nineteen (63.3%) patients had baseline evidence of hepatic decompensation. Lamivudine was combined for or=6 months in 12 (group III). We analysed their serial alanine aninotransferase (ALT) levels, Child-Pugh (CP) score, serum viral load and lamivudine-resistant strains. We found that serum ALT became normalized in 20 (66.7%) and HBV-DNA decreased to or=2 months might lead to better virological but not biochemical outcomes in patients receiving adefovir for lamivudine-resistance HBV. As our sample size was small and the study was not randomly controlled, further studies are needed.     

Long-term efficacy of entecavir therapy in chronic hepatitis B patients with antiviral resistance to lamivudine and adefovir

No studies have reported the long-term effects of entecavir switching in patients with multidrug resistance who developed resistance after lamivudine/adefovir sequential therapy. We evaluated the efficacy of 96 weeks of entecavir therapy in patients with resistance to lamivudine/adefovir sequential therapy. In total, 33 patients with chronic hepatitis B virus (HBV) infection with evidence of active viral replication (HBV DNA levels ≥ 10(5) copies/mL) or a history of treatment failure to lamivudine/adefovir sequential therapy between April 2007 and July 2009 were treated with entecavir (1.0 mg daily) for at least 48 weeks. The rates of alanine transaminase (ALT) normalization and HBV DNA negativity were 66.7% (14/21) and 24.2% (8/33) at 48 weeks, respectively. The initial HBV DNA level was the only factor that was inversely associated with serum HBV DNA negativity after 48 weeks of entecavir therapy (P < 0.023). At 96 weeks, the rates of ALT normalization and HBV DNA negativity were 77.8% (7/9) and 16.7% (3/18), respectively. Viral breakthrough occurred in 21.2% (7/33) and 78.9% (15/19) of patients at 48 and 96 weeks, respectively. Patients who achieved a HBV DNA level of <4 log(10) copies/mL at 48 weeks maintained a similar HBV DNA level and a normal ALT level until 96 weeks. Entecavir monotherapy for 96 weeks was not efficacious for patients with lamivudine/adefovir-resistant HBV. The initial HBV DNA level was the only predictive factor for antiviral efficacy. However, patients who achieved a HBV DNA level of <4 log(10) copies/mL with a normal ALT level at 48 weeks should maintain, rather than stop, entecavir therapy.     

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.     

Low efficacy of entecavir therapy in adefovir‐refractory hepatitis B patients with prior lamivudine resistance

Summary. We determined the virologic response, incidence of entecavir resistance, and evolution of lamivudine and adefovir‐resistant mutants during entecavir (ETV) therapy in adefovir‐refractory patients with prior lamivudine resistance. Forty adefovir‐refractory chronic hepatitis B patients with prior lamivudine resistance who had received entecavir for ≥6 months were included and monitored for virologic response and entecavir resistance. Ten per cent of patients achieved HBV DNA < 50 copies/mL by PCR after 24 weeks of ETV therapy, and an initial virologic response was observed in 12 of 40 patients (30%). Higher pretreatment ALT (P = 0.039) and the presence of the rtL180M mutation (P = 0.038) were associated with an initial virologic response. During a mean follow‐up of 11.4 months, four patients (10%) experienced virologic breakthrough, while ETV‐resistant mutants were detected in six patients (15%). YMDD and adefovir‐resistant mutants were detected in 57 and 35% of patients at baseline, respectively. At 48 weeks of therapy, 96 and 4% of patients had YMDD and adefovir‐resistant mutants, respectively. These data suggest an early development of ETV resistance and low antiviral response during ETV therapy in adefovir‐refractory patients with prior lamivudine resistance.     

拉米夫定联合阿德福韦酯治疗HBeAg阳性慢性乙型肝炎患者48周临床观察

我国现有慢性乙型肝炎（CHB）患者约2000万例,其中HBeAg阳性CHB患者近60%,常常表现为ALT持续或间歇升高,HBV复制活跃,肝组织重度炎症坏死,与HBeAg阴性患者相比,有较高的肝硬化比率[1]及较快速的病情进展[2]。而持续的高病毒载量又与肝细胞癌（HCC）直接相关[3],那么最大限度地长期抑制HBV,减轻肝细胞炎症坏死及纤维化,延缓和减少肝脏失代偿、肝硬化、HCC及其并发症的发生,从而改善生存质量和延长生存时间[4]成为CHB治疗的总体目标。核苷和核苷     

Development of HCC in patients receiving adefovir dipivoxil for lamivudine‐resistant hepatitis B virus mutants

Aim: To identify factors for the development of hepatocellular carcinoma (HCC) in the patients who receive adefovir add‐on lamivudine for treatment of lamivudine‐resistant hepatitis B virus (HBV) mutants. Methods: A total of 247 patients who developed lamivudine‐resistant HBV mutants, with an increase of HBV DNA ≥ 1 log copies/mL, received adefovir dipivoxil 10 mg add‐on lamivudine 100 mg daily during a median of 115 weeks (range: 25–282 weeks). They were followed for the development of HCC by imaging modalities every 3?6 months. Results: HCC developed in 18 of the 247 (7.3%) patients. Eight factors were in significant association with the development of HCC by the univariate analysis. They included age, cirrhosis, platelet counts, levels of bilirubin, aspartate aminotransferase (AST), alanine aminotransferase and α‐fetoprotein, as well as YMDD mutants at the start of adefovir dipivoxil. By the multivariate analysis, AST levels, YIDD mutants, cirrhosis and age were independent factors for the development of HCC. By the Kaplan‐Meier analysis, AST levels ≥ 70 IU/L, YIDD mutants, cirrhosis and age ≥ 50 years increased the risk of HCC (P = 0.018, P = 0.035, P = 0.002 and P = 0.014, respectively). HCC developed more frequently in the patients with than without cirrhosis at the start of adefovir (10/59 [16.9%] vs. 8/188 [4.3%], P = 0.002). Conclusion: HCC can develop in cirrhotic patients receiving adefovir add‐on lamivudine. Hence, the patients with baseline AST ≥ 70 IU/L and YIDD mutants would need to be monitored closely for HCC.     

Pharmacology,clinical efficacy and safety of lamivudine in hepatitis B virus infection

Lamivudine was the first nucleoside analog for the treatment of chronic hepatitis B (CHB). It is well-tolerated and induces a decrease in serum HBV DNA levels associated with normalization of serum alanine aminotransferase levels. However, a sustained response with hepatitis B ‘e’ antigen to anti-hepatitis B e seroconversion is obtained in a smaller proportion of patients and hepatitis B surface antigen loss is exceptional. The response is maintained during therapy, and needs to be continued indefinitely in the majority of patients since withdrawal of treatment is generally followed by a rapid reappearance of the virus. However, mutations can be induced in long-term treatment.     

Antiviral efficacy of lamivudine versus entecavir in patients with hepatitis B virus-related advanced hepatocellular carcinoma

Background and Aim: Little information is available about the antiviral efficacy of lamivudine (LAM) and entecavir (ETV) in patients with hepatitis B virus (HBV)‐related advanced hepatocellular carcinoma (HCC). Thus, we compared the antiviral efficacy of LAM and ETV in these patients. Methods: The medical records of 134 antiviral therapy‐naïve patients with HBV‐related advanced HCC (modified Union for International Cancer Control [UICC] Tumor, Nodes, and Metastases [TNM] stages III–IV) treated between January 2005 and September 2009 were reviewed. After HCC diagnosis, 87 (64.9%) and 47 (35.1%) patients received LAM and ETV, respectively. Results: The mean age of patients (115 men, 19 women) was 53 years. Sixty‐five (48.5%) and 69 (51.5%) patients had TNM stages III and IV HCC, respectively. Treatment outcomes during follow‐up, including virologic, biochemical, and serologic responses and appearance of antiviral resistance, were similar in the LAM and ETV groups (all P > 0.05). Multivariate analysis identified Child–Pugh class, α‐fetoprotein, and TNM stage as independent predictors of overall survival (all P < 0.05). Antiviral agent type (LAM vs ETV) did not influence overall survival (median 9.6 months in LAM vs 13.6 months in ETV group; P = 0.493). HCC treatment was not interrupted due to HBV flare up in any patient. Conclusions: The antiviral efficacy of LAM and ETV was similar and the type of antiviral agent did not influence overall survival in patients with HBV‐related advanced HCC. Thus, LAM, which is less expensive than ETV in Korea, might be sufficient to control HBV in these patients.     

拉米夫定耐药后联合阿德福韦酯治疗发生再耐药的慢性乙型肝炎患者的基因型及耐药位点分析

目的研究拉米夫定(LAM)耐药后联合阿德福韦酯(ADV)抗病毒治疗中发生病毒学突破的慢性乙型肝炎(CHB)患者的耐药位点和基因分型。方法收集2010年6月-2013年6月河南省人民医院收治的89例单用LAM耐药后,联合ADV抗病毒治疗的CHB患者的血清,应用实时定量PCR进行HBV拷贝检测,通过测序进行基因分型,并对rt N236T、rt A181V、rt M204V、rt L180M耐药位点进行检测。计量资料组间比较采用t检验,计数资料组间比较采用χ2检验。结果 89例患者单用LAM治疗后均发生LAM rt M204V位点突变,联合ADV治疗后,9例发生ADV rt N236T单位点突变,5例发生ADV rt A181V单位点突变,8例发生rt A181V+rt N236T双位点联合突变,累计ADV耐药率为24.7%(22/89)。89例患者的HBV基因分型中,C基因型82例,其中8例发生rt A181V+rt N236T双位点联合突变;B基因型7例。结论与B基因型相比,C基因型CHB患者单用LAM耐药后,联合ADV治疗中更易发生rt A181V+rt N236T双位点联合突变。     

Efficacy of adefovir dipivoxil in the treatment of lamivudine-resistant hepatitis B virus genotype C infection.

BACKGROUND AND AIMS: Adefovir dipivoxil (ADV) is a nucleotide analogue that is known to be effective for lamivudine-resistant hepatitis B virus (HBV) mutants as well as wild-type HBV. The aim of this study is to assess the efficacy of ADV against lamivudine-resistant genotype C HBV mutants. METHODS: Thirty-five patients with breakthrough hepatitis due to lamivudine-resistant HBV received ADV 10 mg daily with discontinuation of lamivudine. Quantitative HBV DNA, HBeAg, liver function test including alanine aminotransferase (ALT) was checked every 4-12 weeks to evaluate the efficacy of ADV. RESULTS: ADV was administered for a median of 48 weeks (range: 24-120 weeks). The rate of serum HBV DNA loss was 68.6%, 80.0%, 84.0%, and 88.2% at weeks 12, 24, 36, and 48, respectively. The rate of serum HBeAg seroconversion was 8.3% and 14.3% at weeks 24 and 48, respectively. The rate of serum ALT normalization at week 48 was 70.6%. Within 32 weeks after stopping ADV therapy, serum HBV DNA levels increased to a median of 378.9 pg/ml in 88.9% of patients, who were treated for a median of 40 weeks. Moreover, in some patients, the ALT level increased to more than five times the upper limit of normal. CONCLUSIONS: Administration of ADV is an effective option for the treatment of patients with lamivudine-resistant genotype C HBV infection.     

膦甲酸钠联合阿德福韦酯治疗拉米夫定耐药慢性乙型肝炎的临床研究

目的 观察膦甲酸钠联合阿德福韦酯治疗拉米夫定耐药的慢性乙型肝炎患者的疗效和安全性.方法 选择拉米夫定耐药的慢性乙型肝炎患者70例,随机分为联合组(膦甲酸钠和阿德福韦酯组)36例,对照组(阿德福韦酯组)34例,完成4周和12周治疗时,分别检测血清HBV DNA水平和肝功能变化.结果 在治疗4周和12周时,联合组肝功能恢复及病毒应答率,均显著高于对照组.两组均未发生与研究药物相关的严重不良反应.两组不良事件发生率无统计学差异.结论 膦甲酸钠联合阿德福韦酯治疗拉米夫定耐药的慢性乙型肝炎,可在生物化学及病毒学方面取得较好疗效,且安全性好.     

Adefovir dipivoxil is effective for the treatment of cirrhotic patients with lamivudine failure

Background/Aims: Data on the efficacy of adefovir dipivoxil (ADV) in elderly and cirrhotic patients with lamivudine‐resistant (LAM‐R) chronic hepatitis B are scarce. This retrospective cohort study evaluated the safety and efficacy of ADV in this specific patient population. Methods: Sixty‐eight cirrhotic LAM‐R patients, of whom 19 (27.9%) were elderly (≥65 years of age) and nine had severe disease (two post‐orthotopic liver transplantation, four pre‐orthotopic liver transplantation and three decompensated), with hepatitis B virus (HBV) infection received ADV. Virological and biochemical responses to the addition of ADV were analysed. Results: At inclusion, all patients were receiving LAM; ADV was added. 75.4% of patients received a combination of LAM and ADV throughout this study for a median treatment duration of 12.6 months; the remainder received ADV with an overlap with LAM treatment for a median duration of 7.9 months. At the end of follow‐up, 41.2% of patients had undetectable HBV DNA (≤2000 copies/ml) with a median reduction of 3.4 log₁₀ copies/ml. Time to reach undetectable HBV DNA was dependent on baseline alanine aminotransferase (ALT) levels and HBeAg status. Normalization of serum ALT levels was observed in 55.2% (32/58) of patients. In patients who were HBeAg positive at baseline, HBeAg loss and seroconversion occurred in 23% (9/39) and 10% (4/39) respectively. No resistance mutations and no significant side effects were observed during the study period. Conclusion: Adefovir dipivoxil provides effective and safe treatment in cirrhotic and elderly patients who failed LAM therapy.     

Hepatitis B surface antigen seroconversion is associated with favourable long-term clinical outcomes during lamivudine treatment in HBeAg-negative chronic hepatitis B patients

The aims of this study were to assess hepatitis B surface antigen (HBsAg) seroconversion and to determine its impact on the natural course of the disease in patients with HBeAg-negative chronic hepatitis B (CHB) during lamivudine (LMV) treatment. A total of 183 consecutive patients with HBeAg-negative CHB who were treated with LMV were included in the study. Data were retrospectively collected from outpatient visit charts. The primary endpoint was HBsAg seroconversion to anti-HBs. The secondary endpoint was to determine the development of cirrhosis. Loss of HBsAg was confirmed in 10 patients and seroconversion to anti-HBs in nine patients during LMV treatment or after its discontinuation. HBsAg seroconversion was achieved on-treatment in four patients after a median treatment duration of 30 months and off-treatment in the remaining five patients in a median 61 months after LMV discontinuation. The cumulative probability of HBsAg seroconversion increased from 0.6% at 1 year and 1.9% at 5 years to 21.5% at 10 years of LMV during and after LMV treatment. HBsAg clearance was preceded by undetectable serum hepatitis B virus (HBV) DNA. The majority of the patients responding to treatment had undetectable HBV DNA levels at 24 weeks of treatment. The cumulative probability of LMV resistance increased from 2.2% at 1 year to 37.3% at 5 years. No baseline parameter predicting either HBsAg seroconversion or the emergence of LMV resistance was identified. None of the patients with HBsAg seroconversion experienced virological breakthrough or disease progression during the follow-up period. These results indicate that HBsAg seroclearance can occur in patients with HBeAg-negative CHB under LMV therapy and predicts better clinical outcome.