富马酸替诺福韦与恩替卡韦挽救治疗拉米夫定耐药的HBeAg阴性慢性乙型肝炎患者疗效分析

目的探讨应用富马酸替诺福韦(TDF)与恩替卡韦(ETV)挽救治疗拉米夫定耐药的血清HBeAg阴性的慢性乙型肝炎(CHB)患者的临床疗效,并分析影响临床疗效的因素。方法2017年1月~2021年12月我院收治的拉米夫定治疗耐药的血清HBeAg阴性的CHB患者50例,被随机分为TDF治疗组25例和ETV治疗组25例,前者常规剂量应用,后者加倍应用。两组均治疗48周,监测疗效。应用二分类变量的Logistic回归分析影响病毒学应答的因素。结果在治疗4周、12周、24周、36周和48周时,TDF治疗组血清HBV DNA累积转阴率分别为32%、60%、72%、80%和92%,显著高于ETV治疗组(分别为4%、24%、32%、40%和44%,均P<0.05);TDF治疗组血清ALT复常率分别为56%、68%、80%、84%和96%,与显著高于ETV治疗组(分别为16%、32%、52%、56%和72%,均P<0.05);在治疗48周时,TDF治疗组血清肌酐水平显著高于治疗前(85.4±13.9μmol/L对76.2±17.5μmol/L,P=0.0001),而ETV治疗组治疗前后血清肌酐水平无显著变化(76.6±12.9μmol/L对77.3±11.2μmol/L,P=0.769);Logistic回归分析显示,应用TDF治疗和血清HBV DNA载量为影响血清HBV DNA转阴的独立预测因素。结论TDF挽救治疗拉米夫定耐药的CHB患者可能获得更好的疗效,但需要密切监测肾功能的变化。

人类免疫缺陷病毒感染/艾滋病经治患者转换为多替拉韦/拉米夫定复方单片制剂的真实世界研究

目的评估真实世界中达到病毒抑制的人类免疫缺陷病毒(human immunodeficiency virus,HIV)感染/艾滋病(acquired immunodeficiency syndrome,AIDS)患者转换为多替拉韦/拉米夫定(dolutegravir/lamivudine,DTG/3TC)复方单片制剂的疗效及安全性。方法纳入2021年6月1日至2022年6月1日在郑州市第六人民医院门诊长期随访的HIV得到有效抑制并在研究期间抗病毒方案转换为DTG/3TC方案的HIV/AIDS患者79例,收集转换治疗方案前及治疗期间T淋巴细胞亚群、HIV RNA、血脂水平以及肾功能等检测指标,记录不良事件的发生情况。结果79例转换治疗方案患者以中年男性为主,有30.4%的患者合并非艾滋病定义性疾病。前3位转换治疗方案原因分别是:简化方案,改善耐受性、药物不良反应、合并非艾滋病定义性疾病。48周病毒持续抑制率为100%,CD4~+T淋巴细胞计数较基线变化差异无统计学意义(P>0.05);转换治疗方案48周后高密度脂蛋白、血肌酐、血糖、体质量升高,肾小球滤过率和尿微量白蛋白水平下降,差异均有统计学意义(P均<0.05)。有5例患者因血脂异常转换为DTG/3TC方案,转换治疗方案48周后总胆固醇明显下降(P<0.05)。有13例患者因肾毒性转换为DTG/3TC方案,转换治疗方案48周后血肌酐、肾小球滤过率、尿微量白蛋白的变化差异无统计学意义(P均>0.05)。结论达到病毒抑制的患者转换为DTG/3TC方案后能持续抑制病毒、安全性及耐受性好,特别是对于合并非艾滋病定义性疾病、出现肾毒性及血脂异常的患者,DTG/3TC方案是很好的优化治疗方案选择之一。

Lamivudine的治疗进展

本文就近年来核苷类似物Lamivudine治疗慢性乙型肝炎和HIV感染的初步疗效及副反应作一初步综述。该药似有替代干扰素治疗的倾向。

嘎狗噜醇提物抗鸭乙型肝炎病毒感染的短期疗效分析

目的探究嘎狗噜醇提物体内抗鸭乙肝病毒(DHBV)及保肝作用。方法建立鸭乙型肝炎病毒感染动物模型,随机分成6组(每组10只):嘎狗噜醇提物高剂量组、中剂量组、低剂量组,安慰剂组,拉米夫定组,非感染组,每日灌胃给药1次,持续28天;在给药前(T_(0))及给药后7 d(T_(7))、14 d(T_(14))、21 d(T_(21))、28 d(T_(28))和停药后5 d(P_(5)),取各组麻鸭静脉血,实时荧光定量PCR法检测鸭血清样本中鸭乙肝病毒(DHBV DNA)水平、酶联免疫吸附法(ELISA)测定鸭乙肝表面抗原(DHBsAg)和鸭乙肝e抗原(DHBeAg),检测ALT和AST水平,停药后6天(P_(6))处死麻鸭并解剖取肝,观察麻鸭肝脏病理切片。结果给药前(T_(0)),基线指标差异无统计学意义(P>0.05)。嘎狗噜醇提物各剂量组均未发现DHBV DNA载量下降,DHBsAg OD值也未见降低(P>0.05),对AST作用不明显;嘎狗噜醇提物各剂量组DHBeAg OD值、ALT均降低(P<0.05);肝脏病理结果显示,嘎狗噜醇提物高剂量组病变程度低于其他剂量组(P<0.05)。结论未发现嘎狗噜醇提物有抑制DHBV、DHBsAg的作用,对AST作用不明显;嘎狗噜醇提物各剂量组均能抑制DHBeAg、降低ALT水平,高剂量组能够改善肝脏病理损伤,对肝脏有一定保护作用。

基于单盲前瞻性随机试验探讨艾考恩丙替片单药与TDF+3TC+EFV方案治疗AIDS的效果比较

目的探讨并比较艾考恩丙替片单药与替诺福韦(TDF)^(+)拉米夫定(3TC)^(+)依非韦伦(EFV)方案在获得性免疫缺陷综合征(AIDS)患者治疗中的效果。方法选取2022年1-10月就诊于该院AIDS患者100例,根据随机数字表法分为A组和B组,每组50例,A组采取艾考恩丙替片单药治疗,B组采取TDF^(+)3TC^(+)EFV方案治疗,观察两组治疗前后人类免疫缺陷病毒(HIV)载量,机体免疫指标(CD4^(+)、CD8^(+)、CD4^(+)CD38^(+)细胞比值、CD8^(+)CD38^(+)细胞比值),脂代谢指标[总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)],糖代谢指标[空腹血糖(FPG)、糖化血红蛋白(HbA1c)],糖蛋白130(gp130),白细胞介素(IL)-35及其受体IL-12Rβ2水平,并分析两组药物安全性。结果治疗3个月后,两组HIV载量、CD8^(+)、CD4^(+)CD38^(+)细胞比值、CD8^(+)CD38^(+)细胞比值均低于治疗前,CD4^(+)均高于治疗前(P<0.05),但A、B两组比较差异均无统计学意义(P>0.05);治疗3个月后,两组IL-12Rβ2、gp130、IL-35、TC、TG、LDL-C水平均高于治疗前,HDL-C水平均低于治疗前,且B组变化幅度大于A组(P<0.05);治疗1、3个月后B组FPG、HbA1c水平均升高,且高于A组(P<0.05);药物安全性分析结果显示,A组不良反应发生率为12.00%(6/50),B组为26.00%(13/50),两组不良反应发生率比较差异无统计学意义(P>0.05);A组肝肾损伤发生率为10.00%(5/50),B组12.00%(6/50),A、B两组比较差异无统计学意义(P>0.05)。结论艾考恩丙替片单药方案与TDF^(+)3TC^(+)EFV方案均可明显降低AIDS患者HIV载量,改善机体免疫水平,但前者对患者糖脂代谢及炎症因子的影响更小,基于安全性及疗效综合考虑,单药方案较优。

典型抗病毒药物拉米夫定的降解研究进展

近年来,抗病毒药物拉米夫定逐渐成为热点,也引出了关于该药物在环境中环境行为的社会和学术关注。本文针对拉米夫定药物,从其来源、理化性质及危害开始,再总结归纳降解研究进展,探讨拉米夫定在不同条件下的降解去除率,并深入挖掘拉米夫定的降解机理和途径,总结了其降解反应产物。同时,也对未来拉米夫定的降解研究进行了展望。

De novo combined lamivudine and adefovir dipivoxil therapy vs entecavir monotherapy for hepatitis B virus-related decompensated cirrhosis

AIM:To compare efficacy of combined lamivudine(LAM)and adefovir dipivoxil(ADV)therapy with that of entecavir(ETV)monotherapy for hepatitis B virus(HBV)-related decompensated liver cirrhosis.METHODS:A total of 120 na ve patients with HBVrelated decompensated cirrhosis participated in this study.Sixty patients were treated with combined LAM and ADV therapy(LAM+ADV group),while the other60 were treated with ETV monotherapy(ETV group)for two years.Tests for liver and kidney function,alpha-fetoprotein,HBV serum markers,HBV DNA load,prothrombin time(PT),and ultrasonography or computed tomography scan of the liver were performed every1 to 3 mo.Repeated measure ANOVA and theχ2test were performed to compare the efficacy,side effects,and the cumulative survival rates at 48 and 96 wk.RESULTS:Forty-five patients in each group were observed for 96 wk.No significant differences in HBV DNA negative rates and alanine aminotransferase(ALT)normalization rates at weeks 48(χ2=2.12 and 2.88)and96(χ2=3.21 and 3.24)between the two groups were observed.Hepatitis B e antigen seroconversion rate in the LAM+ADV group at week 96 was significantly higher in the ETV group(43.5%vs 36.4%,χ2=4.09,P<0.05).Viral breakthrough occurred in 2 cases(4.4%)by week 48 and in 3 cases(6.7%)by week 96 in the LAM+ADV group,and no viral mutation was detected.In the ETV group,viral breakthrough occurred in 1 case(2.2%)at the end of week 96.An increase in albumin(F=18.9 and 17.3),decrease in total bilirubin and in ALT(F=16.5,17.1 and 23.7,24.8),reduced PT(F=22.7 and 24.5),and improved Child-Turcotte-Pugh and the model for end-stage liver disease scores(F=18.5,17.8,and 24.2,23.8)were observed in both groups.The cumulative rates of mortality and liver transplantation were 16.7%(10/60)and 18.3%(11/60)in the LAM+ADV and ETV groups,respectively.CONCLUSION:Both LAM+ADV combination therapy and ETV monotherapy can effectively inhibit HBV replication,improve liver function,and decrease mortality.

化妆品中阿昔洛韦等6种抗病毒类药物的检测

建立了化妆品中阿昔洛韦、更昔洛韦、喷昔洛韦、阿糖腺苷、利巴韦林和拉米夫定6种抗病毒类药物的高效液相色谱(HPLC)检测方法。采用十八烷基硅烷键合硅胶色谱柱,以甲醇-水为流动相,柱温:35℃,流速:1.0 mL·min^(-1),进样量:10μL,检测波长为207和273 nm进行梯度洗脱。阿昔洛韦等6种组分在0.2~50.0μg·mL^(-1)质量浓度范围内的线性关系良好,相关系数R^(2)均大于0.999,各加标水平浓度的平均回收率为86.128%~118.850%,相对偏差小于10%,日内精密度在0.090%~2.283%,日间精密度在0.058%~2.367%,方法的重复性与稳定性良好。该方法灵敏、准确、快速,阿昔洛韦等6种组分的检验参数均能满足方法需要,适合日后方法的推广与应用。

A meta-analysis of lamivudine for interruption of mother-to-child transmission of hepatitis B virus

AIM： To determine the therapeutic effect of lamivu- dine in late pregnancy for the interruption of motherto-child transmission （MTCT） of hepatitis B virus （HBV）. METHODS： Studies were identified by searching available databases up to January 2011. Inclusive criteria were HBV-carrier mothers who had been involved in randomized controlled clinical trials （RCTs） with lamivudine treatment in late pregnancy, and newborns or infants whose serum hepatitis B surface antigen （HBsAg）, hepatitis B e antigen （HBeAg） or HBV DNA had been documented. The relative risks （RRs） for inerruption of MTCT as indicated by HBsAg, HBV DNA or HBeAg of newborns or infants were calculated with 95% confidence interval （CI） to estimate the efficacy of lamivudine treatment. RESULTS： Fifteen RCTs including 1693 HBV-carrier mothers were included in this meta-analysis. The overall RR was 0.43 （95% CI, 0.25-0.76; 8 RCTs; Phet- erogeneity= 0.04） and 0.33 （95% CI, 0.23-0.47; 6 RCTs; Pheterogeneity = 0.93） indicated by newborn HBsAg or HBV DNA. The RR was 0.33 （95% CI, 0.21-0.50; 6 RCTs; Pheterogeneity = 0.46） and 0.32 （95% CI, 0.20-0.50; 4 RCTs; Pheterogeneity = 0.33） indicated by serum HBsAg or HBV DNA of infants 6-12 mo after birth. The RR （lamivudine vs hepatitis B immunoglobulin） was 0.27 （95% CI, 0.16-0.46; 5 RCTs; Pheterogeneity = 0.94） and 0.24 （95% CI, 0.07-0.79; 3 RCTs; Pheterogeneity = 0.60） indicated by newborn HBsAg or HBV DNA, respectively. In the mothers with viral load 〈 106 copies/mL after lamivudine treatment, the efficacy （RR, 95% CI） was 0.33, 0.21-0.53 （5 RCTs; Pheterogeneity = 0.82） for the interruption of MTCT, however, this value was not significant if maternal viral load was 〉 106 copies/mL after lamivudine treatment （P = 0.45, 2 RCTs）, as indicated by newborn serum HBsAg. The RR （lamivudine initiated from 28 wk of gestation vs control） was 0.34 （95% CI, 0.22-0.52; 7 RCTs; Pheterogeneity = 0.92） and 0.33 （95% CI, 0.22-0.50; 5 RCTs; Pheterogeneity = 0.86） indicated by newborn HBsAg or HBV DNA. The incidence of adverse effects of lamivudine was not higher in the mothers than in controls （P = 0.97）. Only one study reported side effects of lamivudine in newborns. CONCLUSION： Lamivudine treatment in HBV carrier- mothers from 28 wk of gestation may interrupt MTCT of HBV efficiently. Lamivudine is safe and more efficient than hepatitis B immunoglobulin in interrupting MTCT. HBV MTCT might be interrupted efficiently if maternal viral load is reduced to 〈 106 copies/mL by lamivudine treatment.

超高效液相色谱-串联质谱法同时测定5种抗逆转录病毒药物血药浓度

目的建立超高效液相色谱-串联质谱(UPLC-MS/MS)法同时测定人血浆中多替拉韦、拉替拉韦、依非韦伦、拉米夫定和替诺福韦浓度,并应用于治疗药物监测。方法分别以多替拉韦-D5、拉替拉韦-D4、依非韦伦-D5、拉米夫定-^(13)C-^(15)N_(2)、替诺福韦-D7作为内标,样本经乙腈沉淀蛋白法处理后稀释进样分析。色谱柱为Shim-pack XR-ODSⅢ(2.0 mm×50 mm,1.6μm),流动相为0.1%甲酸-0.1%甲酸乙腈,梯度洗脱,流速为0.3 mL·min^(-1),柱温40℃。采用电喷雾离子源,正离子-多反应监测模式扫描分析,待方法学验证后用于人类免疫缺陷病毒(HIV)感染患者治疗药物监测。结果多替拉韦、拉替拉韦、依非韦伦、拉米夫定、替诺福韦血药浓度分别在62.5~3000、10~500、125~6000、10~500、10~500 ng·mL^(-1)范围内线性关系良好,线性相关系数(R^(2))均>0.998;四水平质控样品的日内和日间精密度RSD<7%,准确度为94.0%~109.3%;提取回收率为98.7%~104.5%、不同类型血浆基质效应为95.7%~106.0%,且血浆样本在一定的储存环境中稳定性良好。临床样本检测结果显示接受多替拉韦、依非韦伦、拉米夫定、替诺福韦的HIV患者血药谷浓度分别为107.7~2366.0、740.0~3410.0、38.5~1229.3、31.6~224.4 ng·mL^(-1)。结论该方法准确度高、操作简便、成本低,适用于HIV患者多替拉韦、拉替拉韦、依非韦伦、拉米夫定、替诺福韦的治疗药物监测。

Effects of entecavir and lamivudine for hepatitis B decompensated cirrhosis: Meta-analysis

AIM:To compare the effects of entecavir(ETV)and lamivudine(LAM)for the treatment of hepatitis B decompensated cirrhosis using a meta-analysis.METHODS:We conducted a literature search for all eligible studies published prior to May 30,2013 using PUBMED,MEDLINE,EMBASE,the China National Knowledge Infrastructure(CNKI),the VIP database,the Wanfang database and the Cochrane Controlled Trial Register.Randomized controlled trials(RCTs)comparing ETV with LAM for the treatment of hepatitis B decompensated cirrhosis were included.The data were analyzed with Review Manager Software 5.0.2.We used RR as an effect measure,and reported its95%CI.The meta-analysis was performed using either a fixed-effect or random-effect model,based on the absence or presence of significant heterogeneity.Two reviewers assessed the risk of bias and extracted data independently and in duplicate.The analysis was executed using the main outcome parameters including hepatitis B virus(HBV)DNA undetectability,HBV DNA level,hepatitis B e antigen(HBeAg)seroconversion,alanine aminotransferase(ALT)level,albumin level,total bilirubin(TBIL)level,prothrombin time activity(PTA)level,Child-Turcotte-Pugh(CTP)score,mortality,drugresistance,and adverse reactions.Meta-analysis of the included trials and subgroup analyses were conducted to examine the association between pre-specified characteristics and the therapeutic effects of the two agents.RESULTS:Thirteen eligible trials(873 patients in total)were included and evaluated for methodological quality and heterogeneity.Of these studies,all had baseline comparability,12 of them reported baseline values of the two treatment groups in detail.Following various treatment durations(12,24,36,48 and>48 wk),both ETV and LAM significantly reduced HBV DNA level,however,reductions were greater in the ETV group(MD=-0.66,95%CI:-0.83-0.50,P<0.00001),(MD=-0.93,95%CI:-1.36-0.51,P<0.0001),(MD=-1.4,95%CI:-1.78-1.01,P<0.00001),(MD=-1.18,95%CI:-1.90-0.46,P=0.001),(MD=-0.14,95%CI:-0.17-0.11,P<0.00001,respectively).At 12,24 and48 wk of treatment,ETV had a significant effect on the rate of HBV DNA undetectability(RR=1.55,95%CI:1.22-1.99,P=0.0004),(RR=1.25,95%CI:1.13-1.38,P<0.0001),(RR=1.2,95%CI:1.10-1.32,P<0.0001,respectively).Although HBeAg seroconversion in the ETV group was more pronounced than that in the LAM group at 24 wk(27.90%vs 26.19%)and 48 wk(31.52%vs 25.00%)of treatment,there was no statistically significant difference between them(RR=1.49,95%CI:0.98-2.28,P=0.07),(RR=1.27,95%CI:0.98-1.65,P=0.07,respectively).Following various treatment durations,both the ETV group and the LAM group showed significantly improved liver function(ALT,AIB,TBIL,PTA and CTP levels)and reduced mortality(ETV 6.37%,LAM 7.89%).The effects in the ETV group(0.33%)were statistically lower than those in the LAM group(14.33%)regarding the rate of drug-resistance(RR=0.1,95%CI:0.04-0.24,P≤0.00001).In addition,no severe adverse reactions were observed in the two treatment groups.CONCLUSION:ETV and LAM significantly improved liver function and reduced mortality.Both drugs produced similar serological responses,and were safe and well tolerated.However,ETV resulted in a better virological response and lower drug-resistance,but is more expensive.

Entecavir vs lamivudine therapy for na?ve patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure

AIM:To investigate the short-term and long-term efficacy of entecavir versus lamivudine in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure(ACLF).METHODS:This was a single center,prospective cohort study.Eligible,consecutive hospitalized patients received either entecavir 0.5 mg/d or lamivudine 100mg/d.All patients were given standard comprehensive internal medicine.The primary endpoint was survival rate at day 60,and secondary endpoints were reduction in hepatitis B virus(HBV)DNA and alanine aminotransferase(ALT)levels,and improvement in Child-Turcotte-Pugh(CTP)and model for end-stage liver disease(MELD)scores at day 60 and survival rate at week 52.RESULTS:One hundred and nineteen eligible subjects were recruited from 176 patients with severe acute exacerbation of chronic hepatitis B:65 were included in the entecavir group and 54 in the lamivudine group(full analysis set).No significant differences were found in patient baseline clinical parameters.At day 60,entecavir did not improve the probability of survival(P=0.066),despite resulting in faster virological suppression(P<0.001),higher rates of virological response(P<0.05)and greater reductions in the CTP and MELD scores(all P<0.05)than lamivudine.Intriguingly,at week 52,the probability of survival was higher in the entecavir group than in the lamivudine group[42/65(64.6%)vs 26/54(48.1%),respectively;P=0.038].The pretreatment MELD score(B,1.357;95%Cl:2.138-7.062;P=0.000)and virological response at day30(B,1.556;95%Cl:1.811-12.411;P=0.002),were found to be good predictors for 52-wk survival.CONCLUSION:Entecavir significantly reduced HBV DNA levels,decreased the CTP and MELD scores,and thereby improved the long-term survival rate in patients with spontaneous reactivation of hepatitis B presenting as ACLF.

Baseline HBV DNA level is the most important factor associated with virologic breakthrough in chronic hepatitis B treated with lamivudine

AIM: To identify the factors associated with virologic breakthrough and to select a subgroup of patients who respond well to lamivudine without developing virologic breakthrough (VBT). METHODS: Of 79 patients who had received lamivudine therapy for 9-57 mo, 34 were HBeAg-positive and 45 were HBeAg-negative, 24 developed virologic breakthrough and 55 did not. Clinical and virologic factors were compared between the two groups. RESULTS: The median duration of therapy was 25 (9-57) mo. Virologic breakthrough was defined as a > 1 log HBV DNA increase following initial suppression. When several factors, including gender, duration of infection, baseline HBV DNA, and baseline ALT in HBeAg-positive chronic hepatitis patients were analyzed by logistic regression, the most important predictor of virologic breakthrough was the baseline HBV DNA (r2 = 0.12, P < 0.05). When HBeAg-postitive chronic hepatitis patients were divided into two groups by a point of 6.6 log HBV DNA, the incidence of virologic breakthough between two groups was significantly different. CONCLUSION: Lamivudine may remain an effective first line therapy for those HBeAg-positive patients with a baseline HBV DNA < 6.6 log10 copies/mL.

Tenofovir vs lamivudine plus adefovir in chronic hepatitis B:TENOSIMP-B study

AIM To demonstrate the non-inferiority(15% non-inferiority limit) of monotherapy with tenofovir disoproxil fumarate(TDF) vs the combination of lamivudine(LAM) plus adefovir dipivoxil(ADV) in the maintenance of virologic response in patients with chronic hepatitis B(CHB) and prior failure with LAM.METHODS This study was a Phase IV prospective, randomized, open, controlled study with 2 parallel groups(TDF and LAM+ADV) of adult patients with hepatitis B e antigen(HBe Ag)-negative CHB, prior failure with LAM, on treatment with LAM+ADV for at least 6 mo, without prior resistance to ADV and with an undetectable viral load at the start of the study, in 14 Spanish hospitals. The follow-up time for each patient was 48 wk after randomization, with quarterly visits in which the viral load, biochemical and serological parameters, adverse effects, adherence to treatment and consumption of hospital resources were analysed.RESULTS Forty-six patients were evaluated [median age: 55.4 years(30.2-75.2); 84.8% male], including 22 patients with TDF and 24 with LAM+ADV. During study development, hepatitis B virus DNA(HBV-DNA) remained undetectable, all patients remained HBe Ag negative, and hepatitis B surface antigen(HBs Ag) positive. Alanine aminotransferase(ALT) values at the end of the study were similar in the 2 groups(25.1± 7.65, TDF vs 24.22 ± 8.38, LAM+ADV, P = 0.646). No significant changes were observed in creatinine or serum phosphorus values in either group. No significant differences between the 2 groups were noted in the identification of adverse effects(AEs)(53.8%, TDF vs 37.5%, LAM+ADV, P = 0.170), and none of the AEs which occurred were serious. Treatment adherence was 95.5% and 83.3% in the TDF and the LAM+ADV groups, respectively(P = 0.488). The costs associated with hospital resource consumption were significantly lower with the TDF treatment than the LAM+ADV treatment(€4943 ± 1059 vs €5811 ± 1538, respectively, P < 0.001).CONCLUSION TDF monotherapy proved to be safe and not inferior to the LAM+ADV combination therapy in maintaining virologic response in patients with CHB and previous LAM failure. In addition, the use of TDF generated a significant savings in hospital costs.

Interferon and lamivudine combination therapy versus lamivudine monotherapy for hepatitis B e antigen-negative hepatitis B treatment:a meta-analysis of randomized controlled trials

BACKGROUND: It has been demonstrated that only a minority of patients with hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) obtain a sustained response after either interferon (IFN) or nucleos (t)ide analogue monotherapy. Therefore, combination therapy of drugs with synergistic antiviral effects was proposed to have a sustained response in these patients. We compared the effect and safety of lamivudine monotherapy and its combination with IFN including conventional interferon (CON-IFN) and pegylated interferon (PEG-IFN) for HBeAg-negative CHB patients. DATA SOURCES: A group of three independent reviewers identified 9 eligible randomized controlled trials through electronic searches (MEDLINE, OVID, EMBASE, the Cochrane Library Clinical Trials Registry, and the Chinese Medical Database), manual searches, and contact with experts. Sustained virological and biochemical responses were defined as primary efficacy measures. We performed quantitative meta-analyses to assess differences between CON-IFN plus lamivudine combination and lamivudine monotherapy groups. RESULTS: No greater sustained virological and biochemical rates were found in patients receiving CON-IFN/lamivudine combination therapy [29.1% vs. 26.7%, odds ratio (OR)=0.98, 95% confidence interval (CI) 0.65-1.50, P=0.94, and 41.8% vs. 40.3%, OR=1.13, 95% CI 0.78-1.65, P=0.51, respectively],though a reduced YMDD mutation rate was achieved in the combination group [8.39% vs. 30.0%, OR=0.16, 95% CI 0.076-0.33, P<0.001]. However, data from one PEG-IFN trial showed greater sustained virological and biochemical rates in patients receiving combination therapy [response rate 19.5% vs. 6.6%, OR=3.42, 95% CI 1.71-6.84, P<0.001 and 60.0% vs. 44.2%, OR=1.88, 95% CI 1.23-2.85, P=0.003, respectively]. CONCLUSIONS: Addition of CON-IFN to lamivudine did not improve treatment efficacy but suppressed YMDD mutation by lamivudine. Combination of PEG-IFN and lamivudine might increase the sustained response, and further clinical trials are needed for confirmation.

Tenofovir disoproxil fumarate is superior to lamivudine plus adefovir in lamivudine-resistant chronic hepatitis B patients

AIM:To assess the efficacy of tenofovir disoproxil fumarate(TDF) in lamivudine(LAM)-resistant patients with a suboptimal response to LAM plus adefovir(ADV).METHODS:We retrospectively analyzed the efficacy of switching to tenofovir disoproxil fumarate in suboptimal responders to lamivudine plus adefovir.Charts were reviewed for LAM-resistant chronic hepatitis B(CHB) patients who visited the Zhejiang Province People's Hospital and The First Affiliated Hospital,College of Medicine,Zhejiang University,from June 2009 to May 2013.Patients whose serum hepatitis B virus(HBV) DNA remained detectable despite at least 6 mo of LAM plus ADV combination therapy were included.Patients with a suboptimal response to LAM plus ADV were randomized to switch to TDF monotherapy(300 mg/d orally; TDF group) or to continuation with LAM(100 mg/d orally) plus ADV(10 mg/d orally; LAM plus ADV group) and were followed for 48 wk.Serum HBV DNA was determined at baseline and weeks 4,12,24,36,and 48.HBV serological markers and biochemistry were assessed at baseline and weeks 12,24,and 48.Resistance surveillance and side effects were monitored during therapy.RESULTS:Fifty-nine patient were randomized to switch to TDF(n =28) or continuation with LAM plus ADV(n =31).No significant differences were found between the groups at baseline.Prior to TDF therapy,all patients had been exposed to LAM plus ADV for a median of 11 mo(range:6-24 mo).No difference was seen in baseline serum HBV DNA between the two groups [5.13 ± 1.08 log10 copies/m L(TDF) vs 5.04 ± 31.16 log10 copies/m L(LAM +ADV),P =0.639].There was no significant difference in the rates of achieving complete virological response(CVR) at week 4 between the TDF and LAM +ADV groups(17.86% vs 6.45%,P =0.24).The rate of achieving CVR in the TDF and LAM plus ADV groups was 75% vs 16.13% at week 12,82.14% vs 22.58% at week 24,89.29% vs 25.81% at week 36,and 96.43% vs 29.03% at week 48,respectively(P < 0.001).The rate of alanine aminotransferase normalization was significantly higher in the TDF than in the LAM plus ADV group at week 12(75% vs17.86%,P < 0.001),but not at week 24(78.57% vs 54.84%,P =0.097) or 48(89.26% vs 67.74%,P =0.062).Patients were hepatitis B e antigen(HBe Ag) positive at baseline.There was no significant difference in HBe Ag negativity between the TDF and LAM plus ADV groups at week 48(4% vs 0%,P =0.481).There were no drug-related adverse effects at week 48 in either group.CONCLUSION:Switching to TDF monotherapy was superior to continuous add-on therapy in patients with LAM-resistant CHB with a suboptimal response to LAM plus ADV.

Surgical treatment of HCC in a patient with lamivudine-resistant hepatitis B cirrhosis with adefovir dipivoxil

We describe a 77-year-old woman with chronic hepatitis B who became resistant to lamivudine.She was started on adefovir(10 mg daily)while still continuing lamivudine therapy.Four mo later her liver function improved and serum Hepatitis B virus(HBV)-DNA level became undetectable.Three years after the start of additional adefovir treatment,hepatocellular carcinoma (HCC)was detected and the patient underwent a successful hepa-tectomy.Our findings suggest tha-t the addition of adefovir to ongoing lamivudine therapy cannot completely suppress hepatocarcinogenesis,but is useful for improving liver function in patients with lamivudine-resistant HBV-related cirrhosis,allowing HCC surgery.

Long-term alpha interferon and lamivudine combination therapy in non-responder patients with anti-HBe-positive chronic hepatitis B:Results of an open,controlled trial

AIM: To investigate the safety and efficacy of long-term combination therapy with alpha interferon and lamivudine in non-responsive patients with anti-HBe-positive chronic hepatitis B.METHODS: 34 patients received combination treatment (1 month lamivudine, 12 month lamivudine+interferon, 6month lamivudine), 24 received lamivudine (12 months),24 received interferon (12 months). Interferon was administered at 6 MU tiw and lamivudine at 100 mg orally once daily. Patients were followed up for 6 months after treatment.RESULTS: At the end of treatment, HBV DNA negativity rates were 88 % with lamivudine+interferon, 99 % with lamivudine and 55 % with interferon, (P=0.004, combination therapy vs. interferon, and P=0.001 lamivudine vs.interferon), and serum transaminase normalization rates were 84 %, 91% and 53 % (P=0.01 combination therapy vs. interferon, and P=0.012 lamivudine vs. interferon). Six months later, HBV DNA negativity rates were 44 % with lamivudine+interferon, 33 % with lamivudine and 25 % with interferon, and serum transaminase normalization rates were 61%, 42 % and 45 %, respectively, without statistical significance. No YMDD variants were observed with lamivudine+interferon (vs. 12 % with lamivudine). The combination therapy appeared to be safe. CONCLUSION: Although viral clearance and transaminase normalization are slower with long-term lamivudine+interferon than that with lamivudine alone, the combination regimen seems to provide more lasting benefits and to protect against the appearance of YMDD variants. Studies with other regimens regarding sequence and duration are needed.

Fatal liver failure due to reactivation of lamivudine-resistant HBV mutant

We report a case of fatal liver failure due to reactivation of lamivudine-resistant HBV. A 53-year-old man was followed since 1998 for HBV-related chronic hepatitis. Serum HBV-DNA was 150 MEq/mL (branched DNA signal amplification assay) and ALT levels fluctuated between 50-200 IU/L with no clinical signs of liver cirrhosis. Lamivudine (100 mg/d) was started in May 2001 and serum HBV-DNA subsequently decreased below undetectable levels. In May 2002, serum HBV-DNA had increased to 410 MEq/mL, along with ALT flare (226 IU/L). The YMDD motif in the DNA polymerase gene had been replaced by YIDD. Lamivudine was continued and ALT spontaneously decreased to the former levels. On Oct 3 the patient presenting with general fatigue, nausea and jaundice was admitted to our hospital. The laboratory data revealed HBV reactivation and liver failure (ALT: 1828 IU/L, total bilirubin: 10 mg/dL, and prothrombin INR: 3.24). For religious reasons, the patient and his family refused blood transfusion, plasma exchange and liver transplantation. The patient died 10 d after admission. The autopsy revealed remarkable liver atrophy.

Hepatitis B virus genotypes and lamivudine resistance mutations in Jordan

AIM:To investigate and identify prevalent hepatitis B virus(HBV) genotypes and to explore lamivudine-resistant mutations among treated and untreated patients in Jordan.METHODS:A total of 107 cases with chronic hepatitis B were recruited from different medical centers in Jordan.Serological tests were preformed for all cases using a microparticle enzyme immunoassay.HBV Genotyping was performed for 70 cases using Line probe genotyping assay.The YMDD mutations were explored for 20 cases(4 were lamivudine naive) using the INNO-LiPA HBV DR assay.RESULTS:Genotype D was the only detected genotype.A total of 6 YMDD mutations were detected in 5 treated patients(31%) while one mutation was detected in the naive patients.Seventeen percent of cases were positive for HBeAg and had statistically significant higher levels of serum aminotransferases.CONCLUSION:HBV genotype D appears to be the only circulating type in Jordanian patients.The YMDD mutations were detected in 31% of lamivudine-treated cases with similar patterns to those found in the literature.We also found a relatively low prevalence of HBeAg expression among examined cases(17%).Awareness of these serologic,genotypic and resistance patterns might help in the formulation of management plans and for predicting clinical outcomes.Further larger scale studies are needed to confirm our results and to examine possible associations among clinical,serologic,and genetic patterns of HBV infections in Jordan.