替诺福韦酯治疗慢性乙型肝炎的最新进展

在众多核苷和核苷酸类药物（NAs）中,替诺福韦（TDF）以其强效、低耐药性及对多种 NAs治疗失败的慢性乙型肝炎（CHB）患者有效的特点脱颖而出,使其在临床HBV感染治疗中被广泛应用。介绍了TDF对CHB初治患者和经治患者的疗效,并分析了其对肝硬化患者治疗的效果,同时也对TDF治疗的安全性进行了评估。认为TDF耐药率低、安全性好,为目前CHB治疗的一线药物。     

Long‐term entecavir therapy results in falls in serum hepatitis B surface antigen levels and seroclearance in nucleos(t)ide‐naïve chronic hepatitis B patients

Entecavir (ETV) is reported to result in suppression of hepatitis B virus DNA (HBV DNA) replication with minimal drug resistance. However, information on the long‐term effect of such therapy on serum hepatitis B surface antigen (HBsAg) level and elimination of HBsAg is not available. ETV therapy was started in 553 nucleos(t)ide‐naïve patients with chronic hepatitis B infection (HBeAg positive: 45%) in our hospital. Serum HBsAg levels were measured serially by the Architect assay. The median baseline HBsAg was 2180 IU/mL (0.12–243 000 IU/mL), and median follow‐up period was 3.0 years, with 529, 475, 355, 247 and 163 patients followed‐up for 1, 2, 3, 4 and 5 years, respectively. At year 5, the mean log HBsAg decline from baseline was −0.48 log IU/mL, and the cumulative HBsAg clearance rate was 3.5%. Multivariate analysis identified HBV DNA level at baseline (<3.0 log copies IU/mL, odd ratio = 10.2; 95% confidence interval = 1.87–55.5, P = 0.007) and HBsAg level (<500 IU/mL, odd ratio = 29.4; 95% confidence interval = 2.80–333, P = 0.005) as independent predictors of HBsAg seroclearance. These results indicate that although serum HBsAg level declines gradually during ETV therapy, HBsAg seroclearance remains a rare event.     

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。     

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。     

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.     

富马酸替诺福韦二吡呋酯治疗慢性乙型肝炎60例

目的:观察富马酸替诺福韦二吡呋酯(TDF)治疗慢性乙型肝炎患者的临床疗效。方法:选取2018年1月至2020年6月在武汉市第七医院接受治疗的慢性乙型肝炎患者120例,随机分为2组,各60例。观察组患者服用TDF 300 mg/d,对照组患者服用恩替卡韦(ETV)0.5 mg/d,疗程均为12个月。比较两组患者治疗前后肝功能、病毒学应答变化情况以及TDF对肾功能的影响。结果:两组患者治疗后HBV DNA水平均较治疗前明显下降(P<0.05);治疗第12个月,TDF组HBV DNA水平低于ETV组(P<0.05),但两者HBV DNA转阴率差异无统计学意义(P>0.05);治疗6个月TDF组患者AST、ALT低于ETV组(P<0.05),治疗12个月尿α1-微球蛋白水平高于ETV组(P<0.05),两组血β2微球蛋白水平无明显改变(P>0.05)。结论:采用TDF治疗慢性乙型肝炎临床疗效显著,但在长期用药过程中有潜在肾损伤风险,应该积极检测肾功能。     

Relapse rates in chronic hepatitis B naïve patients after discontinuation of antiviral therapy with entecavir

Registration studies show entecavir (ETV) to be effective and safe in NUC‐naïve patients with chronic hepatitis B, but relapse rates after treatment discontinuation have not been well established. Relapse rates and predictors of relapse were evaluated in naïve HBeAg‐positive and HBeAg‐negative patients treated with ETV. Treatment duration was defined according to international guidelines. Virological relapse was defined as reappearance in serum of hepatitis B virus (HBV) DNA to >2000 IU/mL after discontinuation of treatment. A hundred and sixty‐nine consecutive patients were treated for a median 181 weeks. 61% were HBeAg positive, 23% had cirrhosis, and mean HBV DNA level was 6.88 ± 1.74 log₁₀ IU/mL. Ninety‐two per cent became HBV DNA negative; 71% of HBeAg+ve patients became HBeAg negative and 68% anti‐HBe positive; 14% became HBsAg negative and 13% anti‐HBs positive. At the end of the study, 36 patients discontinued treatment: one due to breakthrough associated with resistant variants and 35 (20%) due to sustained virological response; 33 of these patients developed HBeAg seroconversion and 18 HBsAg seroconversion. Median off‐treatment time was 69 weeks. Nine patients (26%), all HBeAg positive at baseline, developed virological relapse after a median 48 weeks off‐treatment, 3 of them showed HBeAg reversion and 4 lost anti‐HBe. No patient with HBsAg seroconversion relapsed. HBeAg clearance after week 48 of treatment was associated with an increase risk of relapse. After ETV discontinuation, HBsAg seroconversion was maintained in 100% of the patients, HBeAg seroconversion maintained in 90%, and virological relapse rate was 24%.     

Long‐term outcome and hepatocellular carcinoma development in chronic hepatitis B or cirrhosis patients after nucleoside analog treatment with entecavir or lamivudine

Aim: We conducted this prospective study to elucidate the long‐term outcome and incidence of hepatocellular carcinoma (HCC) development after nucleos(t)ide analog (NA) treatment in patients with chronic hepatitis B (CHB) or cirrhosis. Methods: CHB or cirrhosis patients without past NA treatment or HCC were started on entecavir (ETV) or lamivudine (LVD), and prospectively followed up with monthly blood tests, and with abdominal imaging every 6 months in CHB and every 3 months in cirrhosis patients. Results: A total of 256 subjects with CHB (n = 194) or cirrhosis (n = 62) received ETV (n = 129) or LVD (n = 127) for 4.25 years (range: 0.41–10.0). After NA treatment, serum HBV DNA, alanine aminotransferase and α‐fetoprotein (AFP) dropped significantly, along with significant increases in serum albumin and prothrombin time. Drug‐resistance developed in 60 cases in the LVD group and in only one case in the ETV group. HCC developed in 35 patients, and the incidence at years 1, 3, 5, 7 and 10 was significantly higher in patients with cirrhosis (8.1%, 17.5%, 43.2%, 46.7% and 53.4%, respectively) than chronic hepatitis (1.6%, 3.5%, 3.5%, 7.1% and 29.6%, respectively), with no difference between ETV and LVD. After NA treatment, the sensitivity/specificity for HCC of AFP and des‐γ‐carboxy prothrombin (DCP) was 45.7%/97.3% and 33.3%/96.2%, respectively, with the specificity of AFP being higher than at baseline (64.4%), at the cut‐off of 10 ng/mL. Conclusion: NA exerted a long‐term efficacy and improved hepatic reservation in CHB and cirrhosis. After NA treatment, AFP dropped to lower than 10 ng/mL with marked elevation of specificity, leading to an earlier detection of HCC.     

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。     

Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside‐naïve HBeAg‐positive patients with chronic hepatitis B*

Summary. This retrospective analysis was conducted to describe the characteristics of nucleoside‐naïve hepatitis B e antigen (HBeAg)‐positive patients with chronic hepatitis B, who achieved hepatitis B surface antigen (HBsAg) loss during entecavir or lamivudine therapy. HBeAg‐positive adults with chronic hepatitis B, elevated serum alanine aminotransferase, and compensated liver disease were randomized to double‐blind treatment for up to 96 weeks with entecavir 0.5 mg/day or lamivudine 100 mg/day. HBsAg and hepatitis B virus (HBV) DNA were measured at regular intervals during and off‐treatment follow‐up. Through a maximum duration of 96 weeks on‐treatment and 24 weeks off‐treatment, HBsAg loss was confirmed in 18/354 (5.1%) patients treated with entecavir and 10/355 (2.8%) patients treated with lamivudine. Among the 28 patients with confirmed HBsAg loss, 27 (96%) achieved HBV DNA <300 copies/mL, and 27 (96%) achieved confirmed HBeAg loss. All entecavir recipients with HBsAg loss had HBV DNA <300 copies/mL. Caucasian patients, and those infected with HBV genotype A or D, were significantly more likely to lose HBsAg. This retrospective analysis of data from a randomized, global phase three trial shows that confirmed loss of HBsAg occurred in 5% of nucleoside‐naïve HBeAg‐positive patients treated with entecavir, and that HBsAg loss is associated with sustained off‐treatment suppression of HBV DNA.     

Clinical course of 161 untreated and tenofovir‐treated chronic hepatitis B pregnant patients in a low hepatitis B virus endemic region

Hepatitis B immunoprophylaxis failure is linked to high maternal viraemia. There is limited North American data on hepatitis B outcomes in pregnancy. Pregnant hepatitis B carriers were enrolled January 2011–December 2014 and offered tenofovir in the 3rd trimester if hepatitis B virus (HBV)‐DNA was >7‐log IU/mL. Outcomes were determined in treated vs untreated patients. In total, 161 women with 169 pregnancies (one twin, 170 infants; median age 32 years), 18% (29/161) HBeAg+ and median HBV‐DNA 2.51 log IU/mL (IQR 1.66–3.65; range 0.8–8.1) were studied. 14.3% (23/161) received tenofovir due to high viral load (16/23, median 74 days, IQR 59–110) or due to liver disease (7/23). In 10/16 treated due to high viraemia, with confirmed adherence, follow‐up HBV‐DNA showed a 5.49 log decline (P = 0.003). In treatment naïve mothers, median alanine aminotransferase (ALT) increased from 17 IU/L (IQR 12–24) to 29 (IQR 18–36) post‐partum (P = 1.5e‐7). In seven highly viraemic mothers who declined therapy (HBV‐DNA >8‐log IU/mL); median ALT increased ~3X from baseline (P < 0.01). 26% (44/169) had Caesarean section with no difference in treated vs untreated subjects. No tenofovir‐treated mothers had renal dysfunction. Data were available on 167/170 infants; in 50.8% (85/167) who completed immunoprophylaxis, 98.8% (84/85, including 12 exposed to tenofovir in utero) were HBV immune. One infant born to an HBeAg+ mother with HBV‐DNA >8‐log IU/mL failed immunoprophylaxis. In this prospective Canadian cohort study, most untreated mothers experienced mild HBV flares. Tenofovir in pregnancy is well tolerated and reduces viral load prior to parturition.     

Hepatocellular carcinoma risk in patients with chronic hepatitis B receiving tenofovir- vs. entecavir-based regimens: Individual patient data meta-analysis

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