替诺福韦DF治疗慢性乙型肝炎和HIV感染的研究动态

1替诺福韦DF（TDF）抗病毒作用机制 替诺福韦是5’-单磷酸腺苷（脱氧腺苷）类似物,已经被美国、澳大利亚和欧洲数个国家批准用于治疗HIV感染,但是口服吸收差,替诺福韦DF（TDF）能提高口服吸收和细胞对其摄取。TDF是核苷酸逆转录酶抑制剂（NRTI）替诺福韦的酯类前体药,与其他NRTI一样,TDF为DNA的天然底物的衍生物,口服后很快就水解为替诺福韦,替诺福韦被细胞激酶磷酸化生成具有药理活性的代谢产物替诺福韦二磷酸,     

Efficacy and safety of tenofovir disoproxil fumarate in pregnancy for the prevention of vertical transmission of HBV infection

AIM:To evaluate the effects of tenofovir disoproxil fumarate(TDF)use during late pregnancy to reduce hepatitis B virus(HBV)transmission in highly viremic mothers.METHODS:This retrospective study included 45 pregnant patients with hepatitis B e antigen(+)chronic hepatitis B and HBV DNA levels>107copies/mL who received TDF 300 mg/d from week 18 to 27 of gestation(n=21).Untreated pregnant patients served as controls(n =24).All infants received 200 IU of hepatitis B immune globulin(HBIG)within 24 h postpartum and 20μg of recombinant HBV vaccine at 4,8,and 24 wk.Perinatal transmission rate was determined by hepatitis B surface antigen and HBV DNA results in infants at week 28.RESULTS:At week 28,none of the infants of TDFtreated mothers had immunoprophylaxis failure,whereas2(8.3%)of the infants of control mothers had immunoprophylaxis failure(P=0.022).There were no differences between the groups in terms of adverse events in mothers or congenital deformities,gestational age,height,or weight in infants.At postpartum week 28,significantly more TDF-treated mothers had levels of HBV DNA<250 copies/mL and normalized alanine aminotransferase compared with controls(62%vs none,P<0.001;82%vs 61%,P=0.012,respectively).CONCLUSION:TDF therapy during the second or third trimester reduced perinatal transmission rates of HBV and no adverse events were observed in mothers or infants.     

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。     

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。     

Cost-effectiveness analysis of tenofovir disoproxil fumarate for treatment of chronic hepatitis B in China

Background

Tenofovir disoproxil fumarate (TDF) is newly available for treatment of chronic hepatitis B patients in China. To date, no study has been conducted to examine the cost-effectiveness of this treatment. The aim of this study was to estimate the cost-effectiveness of TDF versus four oral nucleos(t)ide analogs [lamivudine (LAM), adefovir (ADV), telbivudine (LdT), and entecavir (ETV)] and from a pharmacoeconomic perspective to assess current drug pricing for TDF.

Methods

Based on Chinese healthcare perspectives, a Markov model was applied to simulate the lifetime (40-year time span) costs and quality-adjusted life-years (QALYs) for five different monotherapy strategies. Two kinds of rescue combination strategies (base-case: LAM + ADV then ETV + ADV; alternative: directly using ETV + ADV) were separately considered for treatment of patients refractory to monotherapy. Model parameters (including disease transition, cost, and utility) were obtained from previous Chinese population studies. Both branded and generic drugs were separately analyzed. Study model uncertainties were assessed by one-way and probabilistic sensitivity analyses. Two-way sensitivity analysis was used to explore uncertainties between efficacy and price of TDF.

Results

In the base-case analysis, the lowest lifetime cost and the best cost-effectiveness ratio were obtained by ETV, which was considered the reference treatment. LAM, ADV, and LdT treatments had significantly greater costs and lower efficacies. Compared to ETV, TDF was more effective but also more expensive. The incremental cost-effectiveness ratios of TDF versus ETV were much higher than the willing-to-pay threshold of $20,466 US dollars (USD) per QALY gained (3 × gross domestic product per capita of China, 2014). TDF would be the most cost-effective strategy if the annual cost did not exceed $2260 USD and $1600 USD for branded and generic drugs, respectively.

Conclusions

For Chinese chronic hepatitis B patients, ETV is still the most cost-effective strategy over TDF and other nucleos(t)ide analogs, with a threshold of $20,466 USD/QALY gained.

     

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.     

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.     

替诺福韦酯与替比夫定阻断乙型肝炎病毒携带孕妇病毒母婴传播的疗效和安全性比较

目的 探讨妊娠中晚期应用替诺福韦酯或替比夫定阻断乙型肝炎病毒(HBV)携带孕妇母婴垂直传播的疗效和安全性.方法 2016年5月～2019年5月在通辽市传染病医院孕检的慢性HBV携带孕妇77例,在妊娠的24～28周时,按照孕妇的意愿,43例接受替诺福韦酯治疗,34例接受替比夫定治疗,在分娩后停止治疗.所有新生儿在出生后6...     

替诺福韦酯挽救治疗HBV DNA聚合酶区204位点突变的经治慢性乙型肝炎患者疗效及安全性分析

目的 探讨应用替诺福韦酯（TDF）挽救治疗HBV DNA聚合酶区204位点突变的经治的慢性乙型肝炎（CHB）患者的疗效及安全性。方法 2013年8月~2015年12月我院诊治的CHB患者87例,纳入患者均为曾接受拉米夫定（LAM）或阿德福韦酯（ADV）治疗6个月以上,血清HBV DNA阴转后又复阳,且经检测出现rtl204v耐药者,43例接受恩替卡韦（ETV）治疗,另44例接受TDF治疗,观察疗效,并使用流式细胞仪检测外周血CD4⁺T淋巴细胞计数,常规计算内生肌酐清除率（Crcl）。结果 在治疗24 w、48 w和72 w时,TDF治疗组血清HBV DNA阴转率分别为63.6%、79.6%和95.5%,显著高于ETV治疗组【分别为35.6%、55.6%和82.2%,P<0.05】,血清ALT复常率分别为84.1%、90.9%和93.2%,而ETV 治疗组则分别为65.1%（P<0.05）、83.7%和90.7%;TDF治疗组外周血CD4⁺T细胞计数分别为（481.5±232.4）/μl、（536.5±297.5）/μl和（566.5±321.6）/μl,与ETV治疗组比,无显著性差异【分别为（475.3±229.3）/μl、（565.8±255.9）/μl和（565.1±256.5）/μl,P<0.05】;Crcl分别为（101.2±40.1）ml/min、（104.3±26.8） ml/min和（98.7±21.5） ml/min,与ETV治疗组比,无显著性差异【分别为（105.2±42.6） ml/min、（102.5±30.6） ml/min和（99.6±26.8） ml/min,P<0.05】。结论 TDF和ETV挽救治疗对核苷（酸）类治疗耐药的经治CHB患者均有良好的疗效,但似乎TDF起效更快,而ETV用量较大,不应列为首选。     

Renal safety of tenofovir disoproxil fumarate and entecavir with hepatitis B immunoglobulin in liver transplant patients

Potent nucleos(t)ide analogues and hepatitis B immunoglobulin combinations are recommended after liver transplantation to prevent the recurrence of hepatitis B virus (HBV). Despite its proven efficacy, the renal safety of tenofovir disoproxil fumarate (TDF) has not been well established in liver transplant recipients. We aimed to assess the impacts of TDF and entecavir (ETV) on tubular and glomerular functions. We analysed 206 liver transplant patients treated with TDF (n = 102) or ETV (n = 104) plus hepatitis B immunoglobulin. Serum creatinine, phosphate and uric acid levels were measured. Proximal tubular dysfunction was defined as the presence of hypophosphatemia (<2 mg/dL) and hypouricemia (<2 mg/dL). Glomerular dysfunction was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m² accompanied by a ≥25% eGFR decline from baseline. During a median follow‐up of 42.5 months, 48 patients developed proximal tubular dysfunction (30.4% and 16.3% in the TDF and ETV groups; P = .017). Serum levels of phosphate and uric acid were significantly lower in the TDF group post‐LT. TDF (OR, 2.34; 95% CI, 1.16‐4.69; P = .017) and low body mass index (OR, 2.11; 95% CI, 1.06‐4.21; P = .034) were independent risk factors for proximal tubular dysfunction. The prevalence of glomerular dysfunction was not significantly different between the two groups (TDF 51.0% and ETV 54.8%; P = .582). TDF significantly increased the risk of proximal tubular dysfunction. Although the effect of TDF on glomerular function was comparable to that of ETV, glomerular dysfunction was common after liver transplant.