替诺福韦酯治疗核苷和核苷酸类药物耐药慢性乙型肝炎患者的研究进展

替诺福韦酯为目前治疗慢性乙型肝炎的一线药物,叙述了其对拉米夫定、阿德福韦酯耐药患者及恩替卡韦治疗不佳和多重耐药患者治疗效果的研究进展,介绍了关于替诺福韦酯单药治疗和联合治疗效果的对比研究结果。认为替诺福韦酯安全性好,对包括孕妇在内的耐药患者有较好治疗效果,但在单药治疗和联合治疗效果对比方面,各项研究结果均无明显差异。     

替诺福韦酯治疗慢性乙型肝炎的最新进展

1995年Dienstag等发现拉米夫定可抑制HBV DNA复制以来,以拉米夫定为代表的核苷（酸）类似物抗乙型肝炎病毒（HBV）的临床应用成为慢性乙型病毒性肝炎（CHB）治疗史上的里程碑,其问世推动了CHB治疗的进程。迄今为止,已有4种核苷（酸）类似物即拉米夫定（LMV）、阿德福韦酯（ADV）、恩替卡韦（ETV）和替比夫定（LdT）获得美国食品与药品管理局（FDA）批准用于慢性乙型病毒性肝炎的治疗。     

治疗慢性乙型肝炎新药-替诺福韦酯

替诺福韦酯(TDF)是一种新型的无环核苷(酸)类似物,于2001年被美国FDA批准治疗人免疫缺陷病毒(HIV)的感染.目前TDF已经是广泛使用的治疗HIV的核苷(酸)类逆转录酶抑制剂之一.替诺福韦酯在临床实践中的效果,良好的适用性和合适的剂量均使其成为一线治疗的最流行药物之一.已有临床研究显示,TDF对合并感染HIV及乙型肝炎病毒(HBV)的患者具有较好的疗效.本文主要对TDF的研发背景、作用机制、药理学特点、不良反应、在CHB相关疾病方面的临床应用以及在治疗CHB的费用效能分析等方面的研究作一简要述评.     

替诺福韦酯治疗34例慢性乙型肝炎核苷(酸)类似物经治患者的临床分析

目的观察替诺福韦酯(TDF)对慢性乙型肝炎(CHB)核苷(酸)类似物经治患者的临床疗效。方法回顾性分析TDF治疗34例CHB核苷(酸)类似物经治患者48周的临床资料,其中原发治疗失败患者18例、抗病毒耐药患者16例。分析第12、24、48周时HBV DNA阴转率、ALT复常率和48周的HBeAg血清转换率以及不良事件发生率。两组间比较采用t检验,多组间比较采用单因素方差分析。结果第12、24、48周的HBV DNA阴转率分别为35.3%、67.6%和94.1%。治疗前及治疗第12、24、48周的ALT分别为(63.9±18.9)、(49.8±11.9)、(42.7±7.3)和(35.1±3.9)U/L,治疗前后比较,差异有统计学意义(F=36.3,P0.05),48周时ALT复常率为91.1%。第48周时HBeAg阴转率为25%,HBeAg血清转换率为20%。治疗期间,随访各时间点病毒学突破率为0,肌酸激酶(CK)超过正常上限(ULN)2倍发生率0。血肌酐(Scr)治疗前为(75.1±11.1)μmol/L,治疗48周时为(76.8±10.8)μmol/L,差异无统计学意义(t=0.578,P=0.565)。Scr超过ULN发生率0。骨密度变化发生率0,血磷低于ULN发生率0。结论对于核苷(酸)类药物应答不佳和耐药的CHB患者,TDF单药治疗能有效抑制病毒,且ALT复常率高,不良事件发生率低。     

替诺福韦酯治疗慢性乙型肝炎的最新进展

核苷(酸)类似物抗病毒药物已广泛应用于慢性乙型肝炎的治疗,其中替诺福韦酯作为一种新型药物,以其良好的抗病毒作用及低耐药性成为目前研究的热点.本文概述了近年来替诺福韦酯的体内外研究进展及其在临床应用的前景.     

替诺福韦酯与恩替卡韦对慢性乙型肝炎初治疗患者的疗效

目的评估替诺福韦酯与恩替卡韦在治疗慢性乙型肝炎的疗效。 方法纳入2010年6月至2015年6月入住济南军区总医院的慢性乙型肝炎的初治患者100例,采用随机数字表法分为观察组(替诺福韦酯)50例、对照组(恩替卡韦)50例,随访时间12、24个月,比较二者在HBV-DNA转阴率、HBeAg血清学转换率、丙氨酸转氨酶复常率、耐药率、安全性方面是否存在差异。 结果与治疗前比较,观察组与对照组在随访观察12、24个月后各项指标较前明显改善,但二者在HBV-DNA转阴率(32/50 vs.28/50、46/50 vs.42/50)、HBeAg血清学转换率(4/28 vs.6/30、8/28 vs.12/30)、丙氨酸转氨酶复常率(42/50 vs.40/50、49/50 vs.46/50)、耐药率方面未见明显差异;但长期口服恩替卡韦对肾脏影响高于替诺福韦酯组,差异有统计学意义(P<0.05)。 结论替诺福韦酯与恩替卡韦比较,二者在治疗慢性乙型肝炎效果相当,但长期口服药物安全性方面有优势,因此建议长期治疗慢性乙型肝炎临床运用替诺福韦酯作为首选方案。     

富马酸替诺福韦二吡呋酯和恩替卡韦初治慢性HBV感染者的效果比较

目的比较富马酸替诺福韦二吡呋酯(TDF)、恩替卡韦(ETV组)治疗初治慢性HBV感染者的抗病毒疗效。方法收集2014年7月-2015年7月周口市中心医院和南京中医药大学附属八一医院接受TDF或ETV抗病毒治疗且定期随诊的420例初治慢性HBV感染或肝硬化患者,其中接受TDF治疗者184例(TDF组),接受ETV治疗者236例(ETV组)。监测患者的基线值以及治疗后4、8、12、24、48周的实验室指标:肝肾功能指标、血钙、血磷、肌酸激酶、HBV DNA水平、肝炎标志物(HBs Ag、HBeAg、抗-HBe等),以及药物的不良反应。计量资料组间比较采用t检验,计数资料组间比较采用χ2检验或Fisher确切概率法。结果治疗48周时,TDF组与ETV组的HBeAg阳性患者、HBeAg阳性且HBV DNA>6 lg IU/ml患者的HBeAg阴转率比较差异均无统计学意义(P值均>0.05);TDF组与ETV组的HBeAg阴性患者、HBeAg阳性患者、HBeAg阳性且HBV DNA>6 lg IU/ml患者的ALT复常率比较差异均无统计学意义(P值均>0.05)。给予抗病毒治疗后,2组患者HBV DNA水平逐渐下降。治疗48周时,TDF组与ETV组的HBeAg阳性患者中的HBV DNA水平低于检测值下限率分别为75.5%、60.8%,差异有统计学意义(χ2=5.857,P=0.016);TDF组与ETV组HBeAg阳性且HBV DNA>6 lg IU/ml患者中HBV DNA水平低于检测值下限率分别为75.7%、60.5%,差异有统计学意义(χ2=5.722,P=0.017)。96周时,不管是整体还是在亚组(HBeAg阳性、HBeAg阳性且HBV DNA>6 lg IU/ml)间比较,TDF组HBV DNA低于检测值下限率均高于ETV组(93.5%vs 86.9%,χ2=4.921,P=0.027;89.1%vs 76.2%,χ2=6.781,P=0.009;88.3%vs 73.7%,χ2=7.456,P=0.006)。结论在HBeAg阳性慢性HBV感染者中,TDF抑制HBV DNA的能力明显优于ETV,尤其对HBV DNA>6 lg IU/ml的患者。     

恩替卡韦治疗慢性乙型肝炎的疗效观察

目的评价恩替卡韦治疗慢性乙型肝炎(CHB)患者96周的疗效。方法收集2011年7月-2014年7月在江苏省泰兴市人民医院门诊和住院的62例CHB患者,给予恩替卡韦0.5 mg/d抗病毒治疗96周。所有病例分为两组,HBe Ag阳性组患者43例,HBe Ag阴性组患者19例。其中HBV DNA106拷贝/ml患者38例,HBV DNA106拷贝/ml患者24例。比较两组治疗24、48及96周的疗效。计数资料组间比较采用χ2检验。结果在治疗24、48、96周时,HBe Ag阳性组患者HBV DNA阴转率分别为34.88%、65.12%、74.42%,明显低于HBe Ag阴性组的78.95%、89.47%、100%,差异均有统计学意义(P值分别为0.003、0.047、0.038)。两组患者的ALT复常率差异均无统计学意义(P值分别为0.102、0.779、0.638)。在38例HBV DNA载量106拷贝/ml和24例HBV DNA载量106拷贝/ml的两组中,治疗24、48、96周时,两组患者HBV DNA阴转率差异均有统计学意义(34.21%vs70.83%、57.89%vs 95.83%、76.32%vs 95.83%,P值分别为0.005、0.001、0.002);两组患者ALT复常率差异均无统计学意义(P值分别为0.940、0.150、0.280)。结论恩替卡韦治疗CHB有很好的抗病毒活性,在抑制病毒复制的同时能改善肝功能。     

艾米替诺福韦治疗慢性乙型肝炎患者疗效初步研究

目的 分析应用艾米替诺福韦治疗慢性乙型肝炎(CHB)患者的疗效。方法 2021年8月～2022年2月我院诊治的62例CHB患者,被随机分为A组和B组,每组31例,分别给予艾米替诺福韦或富马酸替诺福韦治疗,治疗观察48 w。采用实时荧光定量PCR法检测血清HBV DNA载量,采用化学发光免疫分析法检测血清HBsAg和HBeAg水平,使用肝脏瞬时弹性成像仪行肝脏硬度检测(LSM),常规检测血液和血清指标,计算肝纤维化4因子指数(FIB-4)和估算的肾小球滤过率(eGFR)。结果 在治疗24 w时,A组血清ALT、AST水平和HBV DNA载量分别为(64.3±13.6)IU/L、(61.5±4.0)IU/L和(1.2±0.2)Ig IU/mL,在治疗48 w时,分别为(40.1±3.8)IU/L、(39.4±3.3)IU/L和(0.9±0.2)In IU/mL,与B组比,均无显著性差异【分别为(67.2±3.8)IU/L、(65.3±4.2)IU/L和(1.2±0.3)Ig IU/mL及(38.4±4.1)IU/L、(42.8±3.9)IU/L和(0.9±0.2)Ig IU/mL,P<...     

PEG-IFNα-2a治疗HBeAg阳性慢性乙型肝炎48周应答不佳患者序贯替诺福韦酯24周疗效分析

目的观察PEG-IFNα-2a单药治疗HBeAg阳性慢性乙型肝炎(CHB)患者48周血清学应答不佳序贯应用替诺福韦酯(TDF)治疗24周的疗效。方法纳入2015年6月-2016年2月就诊于上海市公共卫生临床中心,经PEG-IFNα-2a 180μg/周治疗48周HBeAg未发生血清学转换的CHB患者共21例。其中11例患者加用TDF 300 mg/d,12周后停用PEG-IFNα-2a,继续予TDF单药治疗12周;10例患者序贯阿德福韦酯(ADV)10 mg/d单药治疗24周。治疗12、24周时检测HBV DNA,肝、肾功能,HBV血清学标志物等指标,对比两组疗效。两组计量资料比较,满足正态分布的组间比较采用独立样本t检验,组内比较采用配对t检验;不满足正态分布的采用Mann-Whithey U检验。计数资料比较采用Fisher确切概率法。结果治疗12、24周时,两组患者的HBs Ag、HBeAg水平差异无统计学意义(P值均0.05)。治疗24周时,TDF组患者HBeAg转换率(18.2%,2/11)与ADV组(10.0%,1/10)比较差异无统计学意义(P0.05);TDF组患者治疗12、24周时HBeAg分别为(1.75±0.59)log10S/CO、(1.61±0.70)log10S/CO,较基线[(1.86±0.58)log10S/CO]明显下降,差异均有统计学意义(P值分别为0.017、0.027);治疗24周时TDF组患者ALT水平低于ADV组,差异有统计学意义[21.0(15.0~27.0)U/L vs 33.0(21.5~63.5)U/L;U=-2.616,P=0.046]。两组患者e GFR水平在治疗12、24周差异均无统计学意义(P值均0.05)。结论对于PEG-IFNα-2a单药治疗48周HBeAg血清学应答不佳的CHB患者,加用TDF 12周后再单用TDF 12周较直接序贯ADV治疗,短期内更有助于降低血清ALT和HBeAg水平。     

No detectable resistance to tenofovir disoproxil fumarate in HBeAg+ and HBeAg− patients with chronic hepatitis B after 8 years of treatment

A major hurdle in the long‐term treatment of chronic hepatitis B (CHB) patients is to maintain viral suppression in the absence of drug resistance. To date, no evidence of resistance to tenofovir disoproxil fumarate (TDF) has been observed. A cumulative evaluation of CHB patients who qualified for resistance surveillance over 8 years of TDF treatment was conducted. Patients in studies GS‐US‐174‐0102 (HBeAg?) and GS‐US‐174‐0103 (HBeAg+) were randomized 2:1 to receive TDF or adefovir dipivoxil (ADV) for 48 weeks followed by open‐label TDF through year 8. Population sequencing of HBV pol/RT was attempted for all TDF‐treated patients at baseline and, annually if viremic, at discontinuation, or with addition of emtricitabine. Overall, 88/641 (13.7%) patients qualified for sequence analysis at one or more time points. The percentage of patients qualifying for sequence analysis declined over time, from 9 to 11% in years 1‐2 to <4% over years 3‐8. Forty‐one episodes of virologic breakthrough (VB) occurred throughout the study, with most (n=29, 70%) associated with nonadherence to study medication. Fifty‐nine per cent of VB patients with an opportunity to resuppress HBV achieved HBV DNA resuppression. A minority of patients who qualified for sequencing had polymorphic (41/165, 24.8%) or conserved (17/165, 10.3%) site changes in pol/RT, with six patients developing lamivudine and/or ADV resistance‐associated mutations. No accumulation of conserved site changes was detected. The long‐term treatment of CHB with TDF monotherapy maintains effective suppression of HBV DNA through 8 years, with no evidence of TDF resistance or accumulation of conserved site changes.     

Maintained virological suppression and renal function with reduced dose tenofovir disoproxil fumarate in renally impaired chronic hepatitis B patients

Tenofovir disoproxil fumarate (TDF) effectively suppresses viral replication in chronic hepatitis B (CHB), but occasionally leads to renal impairment. We evaluated the prevalence of viral and biochemical breakthrough and renal function kinetics in renally impaired patients with CHB on reduced and on full‐dose TDF. This clinic‐based longitudinal cohort study included patients receiving full and reduced dose TDF (due to eGFR [Cockcroft‐Gault] <60 mL/min/1.73 m²). Viral and biochemical breakthroughs were assessed 1 month after starting full and reduced TDF dose until the end‐of‐follow‐up. Breakthroughs were studied in full and reduced dose TDF, and renal function (MDRD) longitudinally before and after dose reduction within patients starting on full‐dose TDF. Of 750 patients on TDF, 78 (10%) had reduced dose and 672 (90%) full dose. At the time of dose reduction, 36 (46%) patients had chronic kidney disease stage G3B. A viral breakthrough occurred in one cirrhotic dialysis‐dependent patient (dosed 300 mg weekly) which resolved without signs of decompensation, and in one patient on full dose which resolved spontaneously. One biochemical breakthrough occurred during dose reduction and resolved naturally without viral breakthrough. The MDRD improved within the first year of dose reduction (+3.0 [2.5] mL/min per year; P < .005) and remained stable thereafter. Fifty‐three (79%) patients reached an MDRD >50 mL/min during dose reduction. Low dose TDF maintains renal function and viral suppression in most renally impaired patients with CHB, even in those with advanced liver disease. This useful, yet simple strategy could be particularly viable in resource‐constrained settings.     

Long‐term entecavir or tenofovir disoproxil fumarate therapy in treatment‐naïve chronic hepatitis B patients in the real‐world setting

The aim of this study was to determine the long‐term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) on the natural course of disease in chronic hepatitis B patients (CHB) with/without cirrhosis in clinical practice. A total of 355 treatment‐naïve CHB patients were enrolled into the study. The primary outcome measure was viral suppression as defined by serum HBV DNA level <20 IU/mL. A secondary outcome measure was to determine the development of Hepatocellular carcinoma (HCC). Virological and biochemical responses were similar between the two treatment groups over time. The presence of cirrhosis and hepatitis B e antigen (HBeAg) positivity did not appear to impact viral suppression. The cumulative probability of HBeAg loss was 41% at 4 years of therapy. Hepatitis B surface antigen (HBsAg) loss occurred in four patients. Model for End‐Stage Liver Disease score was significantly improved from baseline to week 48 and 96 under antiviral therapy (P = 0.013, P = 0.01). HCC was diagnosed in 17 patients (4.8%). The cumulative probability of the development of HCC was 3.3% at 1 year and 7.3% at 4 years of therapy. The development of HCC was independently associated with older age (P = 0.031) and the presence of cirrhosis (P = 0.004). Serum creatinine levels and creatinine clearance remained stable over time. ETV and TDF effectively maintained virological and biochemical responses in long‐term follow‐up of CHB patients with/without cirrhosis. HCC may still develop, although at a lower rate, and is more likely to develop in patients with cirrhosis, especially in older patients.     

Improvement of bone mineral density and markers of proximal renal tubular function in chronic hepatitis B patients switched from tenofovir disoproxil fumarate to tenofovir alafenamide

Tenofovir alafenamide (TAF) is a novel prodrug that reduces tenofovir plasma levels by 90% compared to tenofovir disoproxil fumarate (TDF), resulting in decreased bone mineral density (BMD) loss and renal toxicity. We aimed to study changes in BMD and markers of renal function of chronic hepatitis B (CHB) patients previously treated with TDF who were switched to TAF in as early as 12 weeks. This was a prospective single‐arm open‐label study of 75 CHB patients treated with TDF 300 mg daily who were switched to TAF 25 mg daily and followed for 24 weeks. All patients had been treated with TDF for at least 12 months and had HBV DNA <21 IU/mL at the time of switch. BMD and markers of renal function were taken on the day of switch and repeated after 12 and 24 weeks of TAF treatment. Hip and spine bone mineral density significantly increased from baseline to week 12 (+12.9% and +2.4%, respectively, P < 0.01). There were significant decreases in urinary beta‐2‐microglobulin to creatinine and retinol‐binding protein to creatinine ratios by week 12 (P < 0.01 for both). Mean estimated glomerular filtration rate (GFR) did not change. Tubular reabsorption of phosphate was decreased at week 24 (P < 0.05). In conclusion, CHB patients previously treated with TDF experienced significant improvement in bone density and some markers of renal tubular function and as early as 12 weeks after switching to TAF. Bone density changes associated with TDF may not be entirely related to renal handling of phosphate.     

替诺福韦酯对阿德福韦酯应答不佳患者的挽救治疗研究进展

阿德福韦酯(adefovir dipivoxil,ADV)作为常用抗HBV治疗药物,与拉米夫定(lamivudine,LAM)、替比夫定和恩替卡韦无交叉耐药,且价格相对低廉,长期以来用于初治患者和LAM耐药患者的挽救治疗。然而由于ADV耐药基因屏障较低且临床用药剂量较低,临床长期应用累积了较多ADV应答不佳患者。替诺福韦酯(tenofovir disoproxil fumarate,TDF)作为ADV应答不佳患者的挽救治疗方案之一,对ADV初治应答不佳患者和LAM耐药的ADV应答不佳患者的临床疗效略有差异。然而多项体外研究显示TDF对ADV耐药病毒株抑制作用减弱。ADV应答不佳的患者换用TDF是否会引起或加重肾损害值得临床关注。本文就TDF对ADV应答不佳患者挽救治疗的国内外研究进展作综述,为提高耐药HBV感染防治的管理提供帮助。     

Tenofovir disoproxil fumarate vs adefovir dipivoxil in Chinese patients with chronic hepatitis B after 48 weeks: a randomized controlled trial

Tenofovir disoproxil fumarate (TDF) has demonstrated long‐term efficacy and a high barrier to resistance in multiple chronic hepatitis B (CHB) populations outside of China. This study aimed to evaluate the efficacy and safety of TDF compared with adefovir dipivoxil (ADV) in Chinese patients with CHB during 48 weeks of treatment (ClinicalTrial.gov number, NCT01300234). A Phase 3, multicentred, randomized, double‐blind, controlled trial compared the efficacy and safety of TDF with ADV in Chinese patients with CHB. The primary endpoint was the proportion of patients with HBV DNA <400 copies/mL in each treatment group at Week 48, using an unpooled Z‐test for superiority. Secondary endpoints included viral suppression, serologic response, histological improvement, normalization of alanine aminotransferase (ALT) levels and the emergence of resistance mutations. A total of 509 patients, 202 hepatitis B e antigen (HBeAg)‐positive and 307 HBeAg‐negative, with HBV DNA ≥10⁵ copies/mL received either TDF 300 mg od or ADV 10 mg od. At Week 48, TDF demonstrated superior viral suppression compared with ADV in both HBeAg‐positive (76.7% vs 18.2%, P < 0.0001) and HBeAg‐negative (96.8% vs 71.2%, P < 0.0001) patients. The majority of patients in both treatment arms achieved ALT normalization (>85%). No resistance to TDF was observed. The frequency of adverse events was comparable between treatment arms (TDF 3.9% vs ADV 4.8%). In this double‐blind, randomized, clinical trial, TDF demonstrated superiority over ADV with respect to viral suppression in Chinese patients with CHB at 48 weeks of treatment and without the development of resistance.