富马酸替诺福韦二吡呋酯片处方开发研究

目的：对富马酸替诺福韦二吡呋酯片的处方进行筛选,提取出最佳的处方配伍方案。方法参照国外上市片“VIREAD？”的处方工艺,对其稀释剂、崩解剂、粘合剂、润滑剂以及包衣工艺进行实验,并将自制样品与参比制剂在高温、高湿及光照条件下进行稳定性考察,筛选出合理的处方工艺。结果最终确定处方工艺为：富马酸替诺福韦二吡呋酯300mg;乳糖60mg;微晶纤维素165mg;预胶化淀粉100mg;交联羧甲基纤维素钠35mg;硬脂酸镁5mg;欧巴代薄膜包衣预混剂20mg;以纯化水为粘合剂。结论确定的处方工艺稳定,生产过程不苛刻,适合放大生产,稳定性研究结果与市售品性质相似,体外溶出行为相近,处方设计合理。     

One year of hepatitis B immunoglobulin plus tenofovir therapy is safe and effective in preventing recurrent hepatitis B infection post-liver transplantation

BACKGROUND:

Hepatitis B immunoglobulin (HBIG) given in combination with a nucleos(t)ide analogue has reduced the rate of recurrent hepatitis B virus (HBV) infection following liver transplantation (LT); however, the most effective protocol remains unclear.

OBJECTIVE:

To evaluate the use of tenofovir disoproxil fumarate (TDF) in combination with one year of low-dose HBIG.

METHODS:

Twenty-four adults who underwent LT for HBV-related liver disease at the University Health Network (Toronto, Ontario) and received TDF (± lamivudine) and one year of HBIG to prevent recurrent HBV infection from June 2005 to June 2011 were evaluated.

RESULTS:

The median length of follow-up post-LT was 29.1 months. Three patients died during the follow-up period. Patient survival was 100% and 84.1% at one and five years, respectively. None of the patients developed recurrent HBV infection. No significant adverse event was observed due to TDF administration; renal function pre- and post-LT were also acceptably preserved.

CONCLUSION:

The present study demonstrated that a short, finite course of low-dose HBIG combined with maintenance of long-term TDF staring before LT is cost-effective and safe. However, further prospective study involving a larger patient cohort with a longer followup period is required to confirm the results.     

肝康宁片联合替诺福韦治疗病毒性肝炎的临床研究

目的探讨肝康宁联合替诺福韦治疗病毒性肝炎的临床疗效。方法选取2017年5月—2018年5月在荆州市第二人民医院治疗的病毒性肝炎患者84例,根据就诊号分为对照组(42例)和治疗组(42例)。对照组口服富马酸替诺福韦二吡呋酯片,300 mg/次,1次/d;治疗组在对照组基础上口服肝康宁片,5 g/次,3次/d。两组患者均连续治疗12周。观察两组患者临床疗效,同时比较治疗前后两组患者肝功能、肝纤维化和细胞因子水平。结果治疗后,对照组和治疗组临床有效率分别为80.95%和97.62%,两组比较差异具有统计学意义(P0.05)。治疗后,两组丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、总胆红素(TBIL)、总胆汁酸(TBA)、白细胞介素-18(IL-18)、降钙素原(PCT)、巨噬细胞移动抑制因子(MIF)、肿瘤坏死因子-α(TNF-α)、基质金属蛋白酶-13(MMP-13)、透明质酸(HA)、Ⅲ型前胶原N端肽(PC-Ⅲ)、Ⅳ型胶原(Ⅳ-C)、层黏连蛋白(LN)水平明显降低,同组比较差异具有统计学意义(P0.05),且治疗组患者上述指标水平明显低于对照组,两组比较差异具有统计学意义(P0.05)。结论肝康宁联合替诺福韦治疗病毒性肝炎不仅可以改善患者肝功能和肝纤维化,还可以降低机体炎性反应、增加机体免疫力。     

替诺福韦联合干扰素-α治疗HBeAg阳性慢性乙型肝炎患者疗效及其血清细胞因子水平变化

目的 探讨应用替诺福韦联合干扰素-α(IFN-α)治疗血清HbeAg阳性的慢性乙型肝炎(CHB)患者疗效及其血清肿瘤坏死因子(TNF-α)、白细胞介素-6(IL-6)和IL-10水平的变化。方法 2017年1月～2018年8月我院肝病科诊治的血清HBeAg阳性的CHB患者89例被随机分为对照组(n=43例)和联合组(n=46例),分别给予替诺福韦口服治疗和替诺福韦联合国产IFN-α2b治疗,两组连续治疗观察48周。采用ELISA法检测血清TNF-α、IL-6和IL-10水平,采用ELISA法检测血清HBV标记物,采用ABI7300荧光定量PCR分析仪检测血清HBV DNA水平。结果 在观察结束时,联合组血清ALT和AST水平分别为(39.2±10.8)U/L和(36.4±8.2)U/L,显著低于对照组【分别为(75.2±15.7)U/L和(56.6±12.3)U/L,P<0.05】;联合组血清TNF-α水平为(26.6±6.8)mg/L,显著低于对照组【(35.5±6.8)mg/L,P<0.05】,血清IL-6水平为(15.5±3.3)pg/mL,显著低于对照组【(22.4±4.1)pg/mL,P<0.05】,血清IL-10水平为(21.4±5.7)pg/mL,显著低于对照组【(29.4±6.5)pg/mL,P<0.05】;两组血清HBV DNA均转阴,血清ALT复常率无显著性差异(P>0.05),但联合组血清HBeAg转阴率(44.2%对11.6%,P<0.05)和血清HBsAg转阴率(13.0%对0.0%,P<0.05)显著高于对照组。另外,联合组分别有19例(44.2%)和2例(4.3%)患者发生HbeAg和HBsAg血清转换。结论 应用替诺福韦短期联合IFN-α治疗HBeAg阳性的CHB患者能提高血清HBeAg阴转率,并在短期内促进一些患者发生HbeAg和HBsAg血清转换,可能与联合治疗抑制了细胞免疫反应有关,但其长期疗效还需要观察。     

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,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)D₃水平为(26.8±2.1)ng/ml,显著高于对照组,外周血Treg细胞百分比为(3.4±0.6)%,显著高于对照组,Th17细胞百分比为(2.1±0.3)%,显著高于对照组,而Th17/Treg细胞比值为(0.3±0.1),显著低于对照组;观察组血清Cr水平为(0.80±0.07)mg/dl,显著低于对照组,Urea水平为(11.27±4.36)mmol/L,显著低于对照组,而eGFR为(103.72±11.74)mL/(min·1.73m²),显著高于对照组。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。     

应用替比夫定和替诺福韦治疗阻断血清HBV DNA高载量孕妇母婴传播的效果分析*

目的 比较应用替比夫定(LdT)和替诺福韦(TDF)治疗血清乙型肝炎病毒(HBV)脱氧核糖核酸(DNA)高载量孕妇,阻断病毒母婴传播的疗效。方法 2017年7月~2019年6月我科诊治的血清HBV DNA高载量(＞1×10⁶ IU/mL)孕妇85例,随机分为两组,分别在孕28周时接受LdT治疗(n=43)或TDF治疗(n=42)至分娩结束。新生儿出生时规范接受乙肝疫苗和人乙型肝炎病毒免疫球蛋白接种,新生儿或婴儿血清HBV DNA＞5×10² copies/mL或HBsAg阳性,视为HBV感染。结果 在分娩结束时,LdT治疗组妇女血清HBV DNA和HBeAg水平分别为(2.9±0.6)lg IU/mL和(939.5±286.6)S/CO,与TDF治疗组的【(3.1±0.7)lg IU/mL和(940.7±285.6)S/CO,P>0.05】比,无显著差异,两组血清HBsAg、ALT和AST水平均无显著变化; LdT治疗组妇女所生新生儿出生胎龄为(39.4±1.2)w,身长为(50.9±2.8)cm,头围为(33.8±1.3)cm,体质量为(3087.9±471.5)g,Apgar评分为(9.5±0.4)分,与TDF治疗组比,差异无统计学意义【分别为(39.6±1.1)w、(51.2±3.1)cm、(33.9±1.5)cm、(3112.9±464.9)g和(9.6±0.6)分,P>0.05】;随访婴儿至12个月,两组分别有1例(2.3%对2.4%)幼儿发生HBV感染。结论 应用LdT或TDF治疗孕晚期血清高HBV DNA载量的乙型肝炎病毒携带孕妇均可阻断HBV母婴传播,效果肯定,值得临床开展大规模研究。     

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。     

Comparison of tenofovir plus lamivudine versus tenofovir monotherapy in patients with lamivudine-resistant chronic hepatitis B

Background/Aims:

Tenofovir disoproxil fumarate (TDF) exhibits similar antiviral efficacy against treatment-naïve and lamivudine (LAM)-resistant chronic hepatitis B (CHB). However, there are few clinical reports on the antiviral effects of TDF–LAM combination therapy compared to TDF monotherapy in patients with LAM-resistant CHB.

Methods:

We investigated the antiviral efficacy of TDF monotherapy vs. TDF–LAM combination therapy in 103 patients with LAM-resistant CHB.

Results:

The study subjects were treated with TDF alone (n=40) or TDF–LAM combination therapy (n=63) for ≥6 months. The patients had previously been treated with TDF-based rescue therapy for a median of 30.0 months (range, 8–36 months). A virologic response (VR) was achieved in 99 patients (96.1%): 95.0% (38/40) of patients in the TDF monotherapy group and 96.8% (61/63) of patients in the TDF–LAM combination therapy group. The VR rates were not significantly different between the TDF monotherapy and TDF–LAM combination therapy groups (88.9 vs. 87.3% at month 12, and 94.4 vs. 93.7% at month 24, log-rank p=0.652). Univariate and multivariate analyses revealed that none of the pretreatment factors were significantly associated with VR.

Conclusions:

TDF monotherapy was as effective as TDF–LAM combination therapy for maintaining viral suppression in the vast majority of patients with LAM-resistant CHB, which suggests that TDF add-on therapy with LAM is unnecessary.     

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of tenofovir and emtricitabine in human plasma and its application to a bioequivalence study

A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for simultaneous quantification of Tenofovir (TEN) and Emtricitabine (EMT) in human plasma using Chromolith Speed Rod RP18. The mass transition ion-pair has been followed as m/z 288.10-->176.10 for TEN, m/z 248.20-->130.20 for EMT and m/z 230.10-->112.10 for Lamivudine (LAM). The method involves solid phase extraction from plasma, simple isocratic chromatographic conditions and mass spectrometric detection using an API 5000 instrument that enables detection at nanogram levels. Lamivudine was used as the internal standard. The proposed method has been validated with a linear range of 10-600 ng/ml for TEN and 25-2,500 ng/ml for EMT. The intrarun and interrun precision values are within 12.0% for TEN and 15.6% for EMT at their respective LOQ levels. The overall recoveries for TEN and EMT were 84.3% and 68.5%, respectively. Total elution time was as low as 2 min.