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.

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.

Pre-Formulation Development of Lamivudine 300 mg and Tenofovir Disoproxil Fumarate (TDF) 300 mg Fixed Dose Combination Tablets

Introduction: In this study, physical and chemical characteristics of Lamivudine, Tenofovir Disoproxil Fumarate (TDF) and potential excipients were systematically followed and documented [1]. Objective: The objective of this scientific work was to carry out pre-formulation studies including compatibility studies on Lamivudine and Tenofovir Disoproxil Fumarate with their potential excipients prior a direct compression process [2]. Methodology: The interaction was studied in three set of environments namely uncontrolled room conditions for Zone VI b (30°C ± 2°C), oven conditions in which the oven was set at 50°C and accelerated climatic conditions in which a climatic chamber was set at 40°C ± 2°C/75% ± 5% Relative Humidity (RH %). Sample preparation was done by mixing the amount of formulation excipients to active substances at a ratio of 1:10, whereas active substance to another active substance at a ratio of 1:1, active substance to coating materials at 1:4, coating materials to the whole set of excipients 1:4. The whole set of samples was geometrically mixed and triturated by mortar and pestle to very fine uniform powder to ensure homogeneity of the mixture. HPLC analytical method was used for simultaneous quantitative determination of lamivudine and tenofovir disoproxil fumarate. Transmittance of the mixture was determined by Near Infra-Red (NIR) technique. Results: The amount of Lamivudine as on day 0 was comparable to day 90 for in all tested conditions (Room, Oven and Climatic Chamber), whereas for Tenofovir Disoproxil Fumarate only the amount of the drug at Room (30°C ± 2°C) was comparable to results on day 90. A significant drop of amount of Tenofovir Disoproxil Fumarate (TDF) exposed to moisture (Climatic chamber at 40°C ± 2°C/75% ± 5% Relative Humidity (RH %)) and temperature of 50°C was observed. Colour change was observed for samples subjected to moisture (Climatic chamber at 40°C ± 2°C/75% ± 5% Relative Humidity (RH %)) and as well picked up in the NIR region 400 to 1500 cm-1 (Finger print region) by a significant shift in Transmittance. Conclusion: It can be concluded that microcrystalline cellulose, cross linked sodium carboxymethyl cellulose, magnesium stearate and sodium carbxymethyl cellulose can be compressed together with Lamivudine and Tenofovir Disoproxil Fumarate (TDF) to produce a pharmaceutically acceptable solid dosage form, tablet. The produced tablets should be packed in moisture and light protective containers as Tenofovir Disoproxil Fumarate (TDF) has diester linkages which can be hydrolysed into the active drug Tenofovir in the presence of moisture.

Simultaneous quantitation of lamivudine,zidovudine and nevirapine in human plasma by liquid chromatography-tandem mass spectrometry and application to a pharmacokinetic study

A rapid and sensitive LC-MS/MS method for the simultaneous quantitation of lamivudine,zidovudine and nevirapine in human plasma using abacavir as internal standard has been developed and validated.The analytes and IS were extracted from plasma by solid phase extraction using Oasis HLB cartridges and separated on a Hypurity Advance C18 column using a mixture of acetonitrile:0.1% formic acid(76:24,v/v)at a flow rate of 0.8 mL/min.Detection involved an API-4000 LC MS/MS with electrospray ionization in the positive ion mode and multiple-reaction monitoring for analysis.The method was validated according to FDA guidelines and shown to provide intra-and inter-day precision and accuracy within acceptable limits in a run time of only 3.5 min.The method was sucessfully applied to a pharmacokinetic study involving a single oral administration of a combination tablet to human male volunteers.

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。

Comparing the Efficacy and Safety of Treating Chronic Hepatitis B Infection during Pregnancy with Lamivudine,Telbivudine,and Tenofovir:A Meta-analysis

Background and Aims:The perinatal transmission of hepatitis B virus(HBV)remains an important global health problem.Here,a systematic review and meta-analysis were conducted to evaluate the evidence regarding the efficacy and maternal/fetal safety of treating pregnant women with lamivudine,telbivudine(LdT),and tenofovir(TDF).Methods:A PubMed and Scopus search resulted in 1,076 records,which were reduced to 36,containing 7,717 pregnant women with chronic HBV infection and 7467 infants meeting the inclusion criteria.The latest search was in August 2019.Results:Treatment with LdT,but not lamivudine and TDF,could significantly reduce the hepatitis B virus surface antigen-positive rate(odds ratio(OR)=0.37)in infants;it also led to higher rates of hepatitis B e antigen loss(OR=12.14),hepatitis B e antigen seroconversion(OR=8.93),and alanine aminotransferase normalization in mothers(OR=1.49).Each of these treatments was able to significantly reduce HBV DNA positivity at birth(total OR=0.19)and mother-to-child-transmission of HBV(total OR=0.15),and to cause higher rates of HBV DNA suppression in mothers(total OR=25.53).However,nucleos(t)ide analogues might also be involved in creatine kinase elevation(total OR=7.48).In contrast,no significant association was found between nucleos(t)ide analogue therapy and preterm/premature births,congenital malformation,low birth weight,and abortion or fetal/infant death.The results suggested LdT's high capability of preventing mother-to-childtransmission.However,TDF failed to show significant associations to a reduced risk of mother-to-child-transmission,probably due to the low number of patients included.Conclusions:Although using either lamivudine,LdT,orTDF could lead to more favorable maternal/fetal outcomes,LdT seemed to show more potential in resolving certain infant-and maternal-related outcomes.More studies on the safety profile of such treatments are required.

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。

拉米夫定、替诺福韦、洛匹那韦利托那韦联合治疗对HIV/AIDS患者细胞免疫及病毒载量变化分析

目的分析拉米夫定、替诺福韦、洛匹那韦利托那韦联合对人类免疫缺陷病毒/获得性免疫缺陷综合征(HIV/AIDS)患者细胞免疫及病毒载量变化。方法选取2020年1月至2023年3月期间在乐平市人民医院诊断为HIV/AIDS的84例患者作为此次试验的研究对象,按照治疗方法将其分为对照组(n=35)和观察组(n=49),其中对照组采用拉米夫定、替诺福韦、依非韦伦联合治疗,观察组采用拉米夫定、替诺福韦、洛匹那韦利托那韦联合治疗。比较两组治疗前后细胞免疫(CD3^(+)、CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+))水平,生化指标[谷丙氨酸转移酶(ALT)、谷草氨酸转移酶(AST)、血肌酐(Cr)、胆固醇(TC)、甘油三酯(TG)]水平,病毒载量,不良反应发生率。结果治疗1个月时,两组CD3^(+)和CD8^(+)均较治疗前下降(P<0.05),且观察组低于对照组(P<0.05),两组CD4^(+)和CD4^(+)/CD8^(+)均治疗前上升(P<0.05),且观察组高于对照组(P<0.05);治疗3个月时,两组CD3^(+)和CD8^(+)均较1个月时下降(P<0.05),且观察组低于对照组(P<0.05),两组CD4^(+)和CD4^(+)/CD8^(+)均较1个月时上升(P<0.05),且观察组高于对照组(P<0.05)。治疗前,两组ALT、AST、Cr、TC、TG等均差异无统计学意义(P>0.05),治疗后,ALT、AST、Cr、TC、TG均较治疗前上升,观察组高于对照组(P<0.05),且ALT、AST、Cr、TC均在正常范围内,治疗3个月时,TG已高于正常范围。治疗1个月时,两组的病毒载量较治疗前下降,但差异无统计学意义(P>0.05),治疗3个月时,两组的病毒载量均较治疗1个月时下降(P<0.05),且观察组低于对照组(P<0.05)。治疗期间,两组腹泻、恶心呕吐、胸闷、皮疹的发生率均差异无统计学意义(P>0.05),且总发生率差异无统计学意义(P>0.05)。结论HIV/AIDS患者采用拉米夫定、替诺福韦、洛匹那韦利托那韦联合治疗后,可改善患者的细胞免疫水平,并有效降低细胞载量,且具有一定安全性,对临床治疗AIDS具有重要的参考价值。

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。

恩替卡韦联合替诺福韦与恩替卡韦联合阿德福韦治疗拉米夫定耐药性慢性乙型肝炎患者疗效比较

目的：探讨恩替卡韦（ETV）联合替诺福韦（TDF）与ETV联合阿德福韦（ADV）治疗拉米夫定（LMD）耐药性慢性乙型肝炎患者疗效，并对主要预后影响因素进行分析。方法选取在本院治疗的拉米夫定耐药的成年慢性乙型肝炎患者103例作为研究对象，其中ETV联合ADV组51例，ETV联合 TDF组52例。回顾性分析患者的病历资料，包括年龄、性别、身高、体质量、体质量指数（BMI）、血小板、丙氨酸氨基转移酶（ALT）、总胆红素、清蛋白、国际标准化比值INR（IQR）、Child‐Pugh评分、乙型肝炎e抗原（HBeAg）阳性数、乙肝病毒（HBV）的DNA水平、HBV的ADV耐药突变数、rtA181V／T变异、rtA181V／T＋ rtN236T变异、HBV的ETV耐药突变数、rtS202G变异、rtT184I／L／S变异、rtM250V／L变异及 HBV的LAM、ADV及ETV耐药突变数、3～12个月患者 HBV的DNA减少量及病毒学反应等信息，并进行统计分析。结果 ETV联合 TDF组患者9个月 HBV 的DNA减少量（3．14±1．58）log10 IU／mL高于ETV联合ADV组（2．31±1．84）log10 IU／mL ，差异具有统计学意义（P＜0．05）；ETV联合TDF组患者12个月HBV的DNA减少量（3．28±1．62）log10 IU／mL高于ETV联合ADV组（2．85±1．73）log10 IU／mL ，差异具有统计学意义（P＜0．05）。ETV联合TDF组患者6个月、9个月及12个月病毒学反应正常数均高于ETV联合ADV组患者，差异具有统计学意义（P＜0．05）。ETV联合TDF患者HBV的ADV耐药突变及rtA181V／T变异均低于ETV联合ADV组患者，差异具有统计学意义（均 P＜0．05）；而ETV联合TDF患者HBV的ETV耐药突变及rtS202G变异均高于ETV联合ADV组患者，差异具有统计学意义（P＜0．05）。ETV联合TDF组男性12个月HBV的DNA减少量高于女性（P＜0．05）；男性患者6个月及9个月病毒学反应高于女性（P＜0．05）。根据多因素 Logistic回归分析结果，HBV的 DNA 水平（OR＝0．26，95％ CI：0．03～0．64，P＝0．015）是拉米夫定耐药性慢性乙型肝炎患者预后的危险因素，ETV 联合 TDF治疗（OR＝98．54，95％ CI：75．77～323．55，P＝0．001）是拉米夫定耐药性慢性乙型肝炎患者预后的保护性因素。结论在慢性乙肝患者抗病毒疗效方面， TDF较ADV具有更强的抑制病毒活性。在对LAM和ADV应答下降的HBV感染者，TDF可能是高度有效的替代治疗药物。

高效液相色谱-串联质谱法同时测定奈韦拉平、拉米夫定、司他夫定、齐多夫定和依非韦伦的血药浓度

目的建立高效液相色谱串联质谱技术(HPLC-MS/MS)同时检测奈韦拉平、拉米夫定、司他夫定、齐多夫定和依非韦伦(均为抗艾滋病药)的血药浓度方法。方法用蛋白沉淀法提取,色谱柱为EclipseXDB-C18(4.6mm×150mm,5μm),流动相为(甲醇+0.3%甲酸)-(水+0.3%甲酸)=80∶20,流量为0.5mL·min-1,用质谱多反应监测方法(MRM)检测。结果齐多夫定与拉米夫定的线性范围为25～3200μg.L-1,奈韦拉定与依非韦伦的线性范围为50～6400μg.L-1,最低检测限均为1μg.L-1;司他夫定的线性范围为100～3200μg.L-1,最低检测限为5μg.L-1,γ均大于0.99。高、中、低3个浓度的日内精密度小于10%,日间精密度小于15%,绝对回收率均大于50%。结论用HPLC-MS/MS法能同时快速、准确测定血浆中这5种药物。

人血浆中拉米夫定、齐多夫定、奈韦拉平的LC-MS／MS法测定

建立了LC-MS/MS法同时测定人血浆中拉米夫定、齐多夫定、奈韦拉平。以克来夫定为内标,血浆样品用甲醇沉淀蛋白处理,采用ESI源正离子模式、多反应监测进行定量分析。三组分的线性范围均为20～5000ng/ml,方法回收率为96.45%～101.5%,批内、批间RSD分别小于6.4%和6.7%。已用于健康志愿者同时服用3种药物的药动学研究。

拉米夫定和阿德福韦酯初始联合与替诺福韦酯单药治疗慢性乙型肝炎48周疗效和安全性比较

目的比较拉米夫定和阿德福韦酯初始联合与替诺福韦酯单药初治慢乙肝患者48周的临床治疗效果及安全性。方法将80例未曾使用抗病毒药物,且符合抗病毒治疗指征的初治慢性乙型肝炎患者随机分为联合组40例和单药组40例。联合组给予拉米夫定(100mg/d)联合阿德福韦酯(10mg/d)治疗;单药组使用替诺福韦酯(300mg/d)治疗,所有患者均治疗48周。治疗基线、12、24和48周分别进行病毒学、生化学、血清学检测。回顾性分析,比较两组患者上述治疗时间点的HBV DNA转阴率、ALT复常率、病毒学突破率、HBe Ag血清学转换率及观察药物不良反应。结果联合组患者治疗48周后HBV DNA转阴率、ALT复常率分别为85.0%(34/40)、80.0%(32/40),单药组分别为87.5%(35/40)、80.0%(32/40),两组比较差异无统计学意义(P均>0.05)。而48周后,联合组与单药组的HBe Ag血清学转换率分别为34.6%(9/26)和14.3%(4/28),两组比较差异均有统计学意义(P<0.05)。联合用药组累计发生病毒学突破2例(2/40,5.0%),单药组未发生病毒学突破,比较差异具有统计学意义(P<0.05)。两组患者耐受性均良好,无1例出现严重不良反应而导致停药。结论拉米夫定和阿德福韦酯初始联合在HBV DNA转阴率、ALT复常率及安全性方面与替诺福韦酯单药治疗相似;HBe Ag血清转换率方面优于替诺福韦酯单药治疗;然而病毒学突破率高于替诺福韦酯单药治疗。

抗病毒药物阻断乙型肝炎母婴传播的研究进展

乙型肝炎病毒感染是一个世界性的公共卫生问题。在亚洲地区,母婴垂直传播是发生慢性感染的主要原因。对于体内高病毒载量的孕妇分娩的新生儿即使在产后进行适当的联合免疫接种,仍有10%~15%的母婴垂直传播率。因此,如何在孕期有效地阻断母婴垂直传播,以及应用抗病毒治疗的安全性问题是孕期管理乙型病毒性肝炎患者所面临的挑战。大量研究显示,体内高病毒载量的孕妇在孕晚期应用抗病毒药物（包括拉米夫定、替比夫定、替诺福韦）能够有效地降低母婴垂直传播率。本文就抗病毒药物阻断乙型肝炎母婴传播的相关研究进展进行综述。

齐多夫定与拉米夫定联用预防艾滋病病毒母婴传播效果的系统评价

目的系统评价齐多夫定(zidovudine,ZDV)与拉米夫定(lamivudine,3TC)联用阻断HIV母婴传播的有效性和安全性。方法计算机检索Cochrane图书馆(2007第2期)、PubMed、EMbase、CINAHL、AIDSearch、AIDSLINE、AIDSTRIALS、AIDSDRUGS、AIDSinfo、CRD(center of review and dissemination)、CBMdisc,VIP和CNKI等数据库,以及全球或地区性AIDS相关的会议论文集、政府或非政府组织的相关文件等,全面收集ZDV+3TC联用预防HIV母婴传播的随机对照试验。检索日期从1980年1月1日到2007年5月31日。由两名评价员独立筛查文献、评价质量和提取资料,然后交叉核对,若遇分歧则征求第三方意见讨论解决。Meta分析采用RevMan软件。结果共纳入4篇全文和7篇摘要,涉及3个RCT。1个大样本RCT(PETRA,1797例)比较了母乳喂养人群ZDV+3TC长疗程(从孕36周到产后1周)、短疗程(产时到产后1周)和超短疗程(仅产时)与安慰剂预防HIV母婴传播的效果,结果显示:在15个月内,长程和短程ZDV+3TC预防效果均优于安慰剂,能降低HIV母婴传播风险的35%～65%;但超短疗程与安慰剂比较,差异无统计学意义。在6周到3月内,长程和短程ZDV+3TC均优于超短程,能降低HIV母婴传播风险的41%～63%。各组死产、婴儿6周和18个月内死亡、出生缺陷和不良反应发生率均相似(P>0.05)。1个大样本RCT(SAINT,1317例)比较了短程ZDV+3TC(产时到产后1周)与奈韦拉平(NVP,母婴均单剂)预防HIV母婴传播的效果,结果显示:两组婴儿8周时HIV感染率和死产率、母婴死亡率、母婴不良反应发生率差异均无统计学意义(P>0.05)。1个小样本RCT(Moodley,20例)显示:3TC单用和ZDV+3TC联用(均从孕38周开始治疗至产后1周),在产后1～2周两组婴儿均无HIV感染,12个月时仅1例感染,且两组药物耐受性均较好。结论与安慰剂比较,在母乳喂养人群中长程(孕36周至产后1周)和短程(产时至产后1周)ZDV+3TC预防HIV母婴传播更有效,而且安全性相似。短程ZDV+3TC预防效果和安全性与母婴单剂NVP相似。长程ZDV+3TC预防效果与3TC相似。

拉米夫定联合替诺福韦治疗艾滋病合并慢性病毒性乙型肝炎的临床和实验研究

目的探讨拉米夫定（3TC）联合替诺福韦（TDF）治疗重症艾滋病（AIDS）合并慢性病毒性乙型肝炎（CHB）患者的疗效。方法收集患者住院治疗及随访阶段的实验室检查数据。高效抗反转录病毒（HAART）治疗前及治疗后24周、28周留取患者血标本，用巢式PCR扩增HBVP基因区，反转录．巢式PCR扩增HIV pol基因区，分析HBV及HIV是否发生耐药。结果患者随访1年身体状况佳，主要实验室检查基本正常，未发现HBV相关耐药，HIVRNA扩增结果为阴性。结论联合3TC与TDF两种药物的HAART方案能在短期内达到对HIV和HBV两种病毒的抑制，临床疗效显著。

替诺福韦酯与拉米夫定在老年慢性乙型肝炎患者中的疗效比较

目的比较替诺福韦酯与拉米夫定在老年慢性乙型肝炎患者中的疗效。方法将75例慢性乙型肝炎老年患者随机分为观察组40例与对照组35例。观察组给予富马酸替诺福韦二吡呋酯片口服,对照组给予拉米夫定口服,两组均治疗48周。比较两组患者治疗前、治疗4周、12周、24周和48周ALT及HBV-DNA水平,以及治疗48周后的ALT复常率和HBV-DNA转阴率。结果观察组ALT及HBV-DNA水平随治疗时间延长而下降的趋势较对照组更明显(均P <0. 05)。治疗48周后,观察组ALT复常率与HBV-DNA转阴率均高于对照组(均P <0. 05)。结论相比于拉米夫定,替诺福韦酯能更有效地降低老年慢性乙型肝炎患者ALT及HBV-DNA水平,提高ALT复常率和HBV-DNA转阴率。

LAM和ADV长期联合后转换为替诺夫韦治疗乙型肝炎肝硬化患者疗效及其对肾功能的影响

目的探讨长期联合应用拉米夫定(LAM)和阿德福韦酯(ADV)后转换为替诺夫韦治疗乙型肝炎肝硬化患者疗效及其对肾功能的影响。方法2015年2月~2018年2月我院收治的乙型肝炎肝硬化患者130例,纳入患者均经过LAM联合ADV治疗至少5年以上(5~8年)。采用随机数字表法将患者分成观察组(n=65)和对照组(n=65)。在对照组,继续应用LAM联合ADV治疗,而在观察组,改用替诺夫韦治疗,观察12个月。采用电化学发光免疫法检测血清25-羟维生素[25-(OH)D 3]水平,使用流式细胞仪检测外周血辅助性T细胞17(Th17)和调节性T细胞(Treg)百分比,并计算Th17/Treg细胞比值。检测血清肌酐(Cr)和尿素(Urea),并计算估算的肾小球滤过率(eGFR)。结果在治疗12个月末,观察组血清HBV DNA水平为(2.3±0.7)lg IU/mL,显著低于对照组[(3.1±0.9)lg IU/mL,P<0.05],Child评分为(6.3±1.4),显著低于对照组【(8.2±1.3),P<0.05】;观察组血清25-(OH)D 3水平为(26.8±2.1)ng/ml,显著高于对照组[(22.6±1.7)ng/ml,P<0.05],外周血Treg细胞百分比为(3.4±0.6)%,显著高于对照组[(3.1±0.4)%,P<0.05],Th17细胞百分比为(2.1±0.3)%,显著高于对照组[(1.5±0.1)%,P<0.05],而Th17/Treg细胞比值为(0.3±0.1),显著低于对照组[0.4±0.1),P<0.05];观察组血清Cr水平为(0.80±0.07)mg/dl,显著低于对照组[(0.89±0.06)mg/dl,P<0.05],Urea水平为(11.27±4.36)mmol/L,显著低于对照组[(15.85±4.77)mmol/L,P<0.05],而eGFR为(103.72±11.74)m L/(mi n·1.73m^2),显著高于对照组[(90.63±13.75)mL/(min·1.73m^2),P<0.05]。结论对早期应用了LAM联合ADV治疗的乙型肝炎肝硬化患者及时转换为替诺夫韦治疗,能进一步提高血清HBV DNA转阴率,改善免疫功能,对肾功能具有保护作用,其长期疗效还需要进一步观察。

核苷(酸)类似物在妊娠期乙型肝炎患者中的安全性研究进展

慢性乙型肝炎病毒(hepatitis B virus,HBV)感染是严重危害人类健康的世界性公共卫生问题。母婴传播是HBV感染的主要途径之一,妊娠女性高病毒载量是HBV母婴传播的高危因素,因此,有必要在妊娠期通过有效、安全的抗病毒治疗来降低高病毒载量母体血清HBV DNA水平,降低胎儿感染HBV的风险。本文通过检索国内外文献资料,从临床前的动物试验和人类妊娠期的使用经验两个方面对核苷(酸)类似物(nucleoside/nucleotide analogues,NAs)在妊娠期乙型肝炎患者中的安全性研究进展进行了归纳和总结。目前而言,所有NAs在妊娠期使用仍然存在潜在的风险,基于现有数据,替诺福韦酯、替比夫定和拉米夫定是妊娠期相对风险较低的NAs,但NAs暴露对婴儿发育是否存在远期风险仍需更多临床数据进行评估。

替诺福韦酯治疗慢性乙型肝炎20例短期疗效观察

目的:观察富马酸替诺福韦二吡呋酯(TDF)治疗慢性乙型肝炎(CHB)的短期疗效。方法:回顾性分析20例CHB患者病历资料,均给予TDF 300 mg/d口服治疗。检测TDF治疗前后乙肝病毒耐药突变、血清ALT、HBeAg定量、HBVDNA定量,以及肾功能、血常规和甲胎蛋白等指标。结果:治疗第8周时HBVDNA不可测比率,ALT<2倍正常值上限(ULN)患者较ALT≥2倍ULN的患者高(P=0.022),HBeAg阴性患者比HBeAg阳性患者高(P=0.004),拉米夫定(LAM)非耐药患者比LAM耐药的患者高(P=0.029),治疗第24周时,上述病毒学应答率的差异均消失,所有患者达到HBVDNA不可测的比率为85.0%,ALT正常率为100%,HBeAg阳性患者均未出现HBe血清学转换。患者治疗初始与治疗24周时相比,甲胎蛋白、血尿素氮、血肌酐水平及白细胞、血小板计数的水平无差异(P>0.05)。结论:替诺福韦酯治疗CHB应答迅速,治疗24周HBVDNA检测不到的比率高(85.0%),达到HBe血清学转换比率低(0%),未出现明显副作用。