Effect of ABCB1 3435C>T transporter gene polymorphism on plasma efavirenz concentration in HIV-1 infected Thai adults

Objective:To investigate the influence of ABCB1 polymorphisms on the plasma level of efavirenz in Thai adult cases infected with HIV-1.Methods:A single nucleotide polymorphism of ABCB13435 C>T(rs1045642)in the gene encoding ABCB1 was genotyped using real-time PCR-based alleles in 149 HIV-infected Thai adults receiving efavirenz treatment.Plasma concentrations of efavirenz were measured by high-performance liquid chromatography 12 hr after administration.The relationship between plasma efavirenz concentrations and ABCB13435 C>T polymorphisms was analyzed.Results:Logistic regression analysis showed no significant predictors of high plasma efavirenz concentration in relation to age,gender,body weight,CD4 count and plasma HIV-1 RNA,blood biochemical parameters,antiretroviral duration or ABCB13435 C>T polymorphisms,except for height(OR=0.902,95%CI:0.835-0.973)(P<0.05).The minor allele frequency of ABCB13435 C>T was0.446.The frequency of the heterozygous mutant ABCB13435 C/T was 53.02%(n=79),ABCB13435 T/T homozygous mutant was 18.12%(n=21)and the wild type ABCB13435 C/C genotype was 28.86%(n=43).The overall median plasma concentration of efavirenz in 149 HIV-infected Thai cases was 2.41 mg/L[IQR:(1.46-4.12)mg/L].The plasma concentration of efavirenz was higher in cases with ABCB13435 T/T homozygous mutant[2.73 mg/L,IQR:(2.02-4.19)mg/L]and ABCB13435 C/T heterozygous mutant[2.29 mg/L,IQR:(1.41-4.28)mg/L]genotypes compared to the wild type ABCB13435 C/C homozygous[2.1 mg/L,IQR:(1.37-3.53)mg/L].However,there was no statistically significant difference in the efavirenz concentration between the different genotypes(P>0.05).Objective:To investigate the influence of ABCB1 polymorphisms on the plasma level of efavirenz in Thai adult cases infected with HIV-1.Methods:A single nucleotide polymorphism of ABCB13435 C>T(rs1045642)in the gene encoding ABCB1 was genotyped using real-time PCR-based alleles in 149 HIV-infected Thai adults receiving efavirenz treatment.Plasma concentrations of efavirenz were measured by high-performance liquid chromatography 12 hr after administration.The relationship between plasma efavirenz concentrations and ABCB13435 C>T polymorphisms was analyzed.Results:Logistic regression analysis showed no significant predictors of high plasma efavirenz concentration in relation to age,gender,body weight,CD4 count and plasma HIV-1 RNA,blood biochemical parameters,antiretroviral duration or ABCB13435 C>T polymorphisms,except for height(OR=0.902,95%CI:0.835-0.973)(P<0.05).The minor allele frequency of ABCB13435 C>T was 0.446.The frequency of the heterozygous mutant ABCB13435 C/T was 53.02%(n=79),ABCB13435 T/T homozygous mutant was 18.12%(n=27)and the wild type ABCB13435 C/C genotype was 28.86%(n=43).The overall median plasma concentration of efavirenz in 149 HIV-infected Thai cases was 2.41 mg/L[IQR:(1.46-4.12)mg/L].The plasma concentration of efavirenz was higher in cases with ABCB13435 T/T homozygous mutant[2.73 mg/L,IQR:(2.02-4.19)mg/L]and ABCB13435 C/T heterozygous mutant[2.29 mg/L,IQR:(1.41-4.28)mg/L]genotypes compared to the wild type ABCB13435 C/C homozygous[2.1 mg/L,IQR:(1.37-3.53)mg/L].However,there was no statistically significant difference in the efavirenz concentration between the different genotypes(P>0.05).Conclusions:There is no statistical significance for a tendency toward higher plasma efavirenz concentration in the ABCB13435 T/T and ABCB13435 C/T genotypes.No parameters of physiological characteristics in this study except for height were found to be predictors of high plasma efavirenz concentration in Thai HIV-1 infected cases.

Immunological responses of HIV/AIDS patients treated with Nevirapine versus Efavirenz based highly active anti-retroviral therapy in Addis Ababa, Ethiopia: A retrospective cohort study

Background: There are two approved non-nucleoside reverse transcriptase inhibitor antiretroviral drugs;namely Nevirapine (NVP) and Efavirenz (EFV). Nevirapine and EFV have comparable clinical efficacy when administered in combination regimens. But there is a lack of recent evidence showing the effect of NVP and EFV-based ARTs on immunological responses in HIV infected individuals in Ethiopia in general and Addis Ababa in particular. Methods: Retrospective cohort study design was used to compare immunological response rate of NVP and EFV based HAART regimen in Addis Ababa. Four hundred ninety two HIV infected patients who started HAART in ten selected health facilities were included in the study. Rate of immunologic response was examined at the 6th, 12th, 18th, and 24th months of follow-up period. The time required to get immunological response was analyzed by Kaplan-Meier survival curve. Adjusted hazard ratio was calculated with a 95% confidence interval by Cox proportional hazards model to determine the rate of immunological response. To ascertain the association, bivariate and multi variable Cox proportional hazard model was used. Statistical significance was considered with two sides P-value of 0.05. Results: The mean CD4 count ranged between 132.2 cell/μl at baseline and 302.3 cell/μl at the end of the follow-up period. This change was significant at 95% of CI but did not show significant differences among the comparison group. The median time to get immunological response was 18 (75% percental 12) months. At the end of the follow-up period, 73.2% (76.6% for NVP and 69.8% for EVF P-value 0.13) of the study population had immunological response. Conclusion: As a conclusion, there was a robust and sustained CD4 response and the effect of NVP and EFV based ART on change of mean CD4 count and immunological response was comparable and effective. Initiation of ART with high baseline CD4 count, in combination of IPT and with either NVP or EFV based NNTI was recommended.

Influence of CYP2B6 516G > T and Long Term HAART on Population Pharmacokinetics of Efavirenz in Rwandan Adults on HIV and Tuberculosis Cotreatment

Aim: To describe the pharmacokinetic parameters of efavirenz and estimate its clearance (CL/F) accounting simultaneously for drug-drug interactions and CYP2B6 genetic polymorphism. Methods: Genotyping of 516G > T single nucleotide polymorphism of CYP2B6 was performed using a PCR-based technology and plasma efavirenz concentrations were measured by high performance liquid chromatography on blood samples from 76 HIV adults co-infected with tuberculosis who had received an efavirenz-based regimen. Data were analyzed using population modeling with NONMEM. Results: The absorption rate constant and the apparent volume of distribution in the final model were 1.9 h-1 and 580 L/70kg, respectively. The CL/F at baseline was 11.8 L/h/70kg, 8.8 L/h/70kg and 3.9 L/h/70kg for patients carrying the G/G, G/T and T/T genotypes of CYP2B6 516G > T, respectively, in patients who were administered tuberculosis (TB) treatment prior to HIV treatment (Group A);and 16.7 L/h/70kg, 10.6 L/h/70kg and 1.8 L/h/70kg for G/G, G/T and T/T genotype patients respectively, in patients with previous exposure to HIV treatment (Group B). The CL/F at baseline and steady state was always higher in Group B compared to Group A patients. Expectedly, carriers of CYP2B6 516G/G and T/T genotypes exhibited higher and lower CL/F, respectively. Conclusion: Our results indicated that the CL/F of efavirenz in the population studied was predictably different due to whether the patients were mono-treated for TB with HAART deferred or for HIV before initiation of TB therapy, and to CYP2B6 516G > T variant, implying that both CYP2B6 genetic polymorphisms and previous efavirenz-based HAART should be taken into account when adjusting efavirenz dose.

Efavirenz联合用药效果优

据2005年7月在巴西召开的第三次世界艾滋病学会HIV发病机理及治疗大会上发表的一项公开标签研究结果，作为一线治疗方案，efavirenz（Ⅰ）加拉米夫定（lamivudine）（Ⅱ）／abacavir（Ⅲ）联合用药配方的疗效优于tenofovir disoproxil富马酸盐（Ⅳ）加（Ⅱ）／（Ⅲ）联合用药配方。

Efavirenz疗法对HIV感染儿童安全可行

对于婴儿和年龄较小的儿童来说,基于利托那韦辅助洛匹那韦的（ritonavirboosted lopinavir）治疗方法是推荐使用的一线抗逆转录病毒治疗方法。而对于成年人以及年龄稍大的儿童来说,依法韦仑（efavirenz）则是推荐使用的一线抗逆转录病毒治疗药物之一。但对于暴露于奈韦拉平（一种用于预防病毒通过母婴传播的药物）的儿童来说,依法韦仑的作用效果仍然存疑。

每日一次efavirenz有效

第43届美国感染病学会年会上发表的Ⅲb期DART（Daily Antiretroviral Therapy）Ⅱ研究结果显示，每日一次应用Merck公司的efavirenz[Sustiva，Stocrin]的抗逆转录病毒方案对于尚未进行治疗的HIV感染患者有效。这一开放标签的研究共纳入了70位HIV-1RNA病毒载量≥1000拷贝／mL的患者，他们每日服用一次efavirenz、司他夫定缓释剂和拉米夫定，为期96周。基线的平均病毒载量是4．5log10拷贝／mL，平均CD4＋细胞计数为351／mm^3.

依非韦伦、奈韦拉平或洛匹那韦/利托那韦方案对艾滋病病毒/艾滋病病人血脂代谢的长期影响

目的观察依非韦伦(EFV)、奈韦拉平(NVP)或洛匹那韦/利托那韦(LPV/r)方案对艾滋病病毒(HIV)感染者/艾滋病(AIDS)病人(简称HIV/AIDS病人)血脂代谢的长期影响。方法采用回顾性队列研究的方法,以南京市第二医院2013年3月至2018年12月启动抗逆转录病毒治疗(ART)的成年HIV/AIDS病人为研究对象,收集其人口学、临床基线和治疗随访数据,分析纳入对象在随访期间三酰甘油(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、空腹血糖(FPG)以及TC/HDL-C的检测水平及异常率的变化情况。结果与EFV相比,NVP组在具体随访期间有较高TG异常率和较低的HDL-C、FPG和TC/HDL-C异常率,两组总的血脂异常率随时间增加有明显变化;相较EFV,LPV/r组在具体随访期间有较低的FPG异常率和较高的TG、TC以及TC/HDL-C异常率,两组异常TG、TC、HDL-C、FPG和TC/HDL-C百分率随时间增加有明显变化。结论与EFV相比,NVP可能与有利的脂质谱相关但LPV/r可能对血脂危害更大,另外,EFV对血糖的影响高于其他两药,糖尿病病人应谨慎选择并做好监测。临床医生需要高度警惕HIV/AIDS病人启动ART治疗相关高脂血症所带来的潜在风险。

Switching from efavirenz to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide reduces central nervous system symptoms in people living with HIV

Background:Central nervous system(CNS)symptoms after efavirenz(EFV)treatment in people living with human immunodeficiency virus(HIV)could persist and impact their quality of life.We assessed the impact of EFV-based regimen replacement with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide(E/C/F/TAF),which is considered an alternative option for subjects who do not tolerate EFV.Most specifically,we assessed the safety and the efficacy of E/C/F/TAF and its effects on the participants’neuropsychiatric toxicity symptoms in a real-life setting.Methods:A prospective cohort study was conducted among virologic suppressed HIV-positive participants receiving EFV-based regimens with ongoing CNS toxicity≥grade 2.The participants were switched to single-pill combination regimens E/C/F/TAF and followed up for 48 weeks.The neuropsychiatric toxicity symptoms were measured using a CNS side effects questionnaire,as well as the Hospital Anxiety and Depression Scale and the Pittsburgh Sleep Quality Index.The primary outcome measure was the proportion of participants experiencing grade 2 or higher CNS toxicity after EFV switch off at weeks 12,24,and 48.Secondary endpoints included virologic and immunological responses and the effect on fasting lipids at week 48 after switch.Results:One hundred ninety-six participants(96.9%men,median age:37.5 years,median:3.7 years on prior EFV-containing regimens)were included in the study.Significant improvements in anxiety and sleep disturbance symptoms were observed at 12,24,and 48 weeks after switching to E/C/F/TAF(P<0.05).No significant change in depression symptom scores was observed.At 48 weeks after switch,HIV viral load<50 copies/mL was maintained in all of the participants,median fasting lipid levels were moderately increased(total cholesterol[TC]:8.2 mg/dL,low-density lipoprotein cholesterol[LDL-C]:8.5 mg/dL,high-density lipoprotein cholesterol[HDL-C]:2.9 mg/dL,and triglyceride(TG):1.6 mg/dL,and the TC:HDL-C ratio remained stable.Conclusions:The single-pill combination regimens E/C/F/TAF is safe and well tolerated.This study reveals that switching from EFV to E/C/F/TAF significantly reduces neuropsychiatric toxicity symptoms in people living with HIV with grade 2 or higher CNS complaints.

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。

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。

含多替拉韦与含依非韦伦方案抗逆转录治疗对人类免疫缺陷病毒感染母婴影响的荟萃分析

目的:分析含多替拉韦方案对比含依非韦伦方案抗逆转录治疗对人类免疫缺陷病毒(HIV)感染母婴影响情况。方法:检索建库至2023年6月在PubMed、EMBase、the Cochrane Library、Medline、中国知网、万方、维普、中国生物医学文献数据库公开发表的中英文研究,采用纽卡斯尔-渥太华量表(NOS)评分方法,纳入符合条件的文献,提取相关数据资料,利用RevMan 5.4软件进行荟萃分析。结果:最终共纳入文献6篇,其中多替拉韦组2769例患者,依非韦伦组6006例患者。两组孕产妇抗逆转录治疗后病毒应答率比较差异有统计学意义(RR=1.25,95%CI 1.06~1.46,Z=2.73,P<0.05)。胎儿及新生儿情况分析中,两组新生儿出生体质量比较差异有统计学意义(MD=0.14,95%CI 0.05~0.22,Z=3.03,P<0.05),而在胎儿及新生儿严重不良事件胎儿宫内死亡(OR=1.08,95%CI 0.78~1.49,Z=0.47,P>0.05)、早产(RR=0.95,95%CI 0.85~1.07,Z=0.82,P>0.05)、新生儿死亡(OR=0.71,95%CI 0.25~2.00,Z=0.65,P>0.05)比较差异无统计学意义。结论:孕期使用含多替拉韦抗逆转录治疗方案的病毒应答率高于含依非韦伦治疗组,同时依非韦伦治疗组新生儿体质量低于含多替拉韦组。

不同剂量的依非韦伦对体重<55 kg的HIV成人感染者的疗效对比研究

目的:探讨不同剂量的依非韦伦(Efavirenz,EFV)对体重<55 kg的人类免疫缺陷病毒(human immunodeficiency virus,HIV)成人感染者的疗效。方法:选取2020年1月—2021年1月丰城市人民医院收治的体重<55 kg的60例HIV成人感染者为研究对象,将其按随机数字表法分为对照组和试验组,各30例。两组均采用以EFV为基础的三联方案治疗,其中对照组EFV剂量为400 mg/d,试验组EFV剂量为300 mg/d。比较两组治疗效果、HIV病毒载量抑制情况、CD4^(+)T淋巴细胞计数变化情况和不良反应发生情况。结果:治疗48周后,两组免疫学指标有效率均为90.00%,病毒学指标有效率对照组为93.33%,试验组为90.00%;治疗96周后,两组病毒学指标有效率均为96.67%,免疫学指标有效率对照组为96.67%,试验组为93.33%。治疗48周后,两组HIV病毒载量抑制率均为90.00%;治疗96周后,两组HIV病毒载量抑制率均为93.33%。两组以上指标比较,差异均无统计学意义(P>0.05)。治疗16、48、96周后,两组CD4+T淋巴细胞计数均较治疗前显著升高(P<0.05),但各时间节点下两组比较,差异均无统计学意义(P>0.05)。治疗96周后,试验组血脂异常率显著低于对照组(P<0.05)。试验组肝功能损害率、不良反应总发生率均显著低于对照组(P<0.05)。结论:不同剂量的EFV治疗体重<55 kg的HIV成年感染者的效果相当,在抑制HIV病毒载量和重建免疫功能上效果相似,且EFV每日剂量调整至300 mg后,不良反应显著减少。

使用含依非韦伦方案艾滋病患者基线HIV RNA水平与免疫功能重建相关性分析

目的通过观察使用含依非韦伦(efavirenz,EFV)方案进行治疗的不同基线人免疫缺陷病毒核糖核酸(human immunode?ciency virus ribonucleic acid,HIV RNA)水平的艾滋病(acquired immune deficiency syndrome,AIDS)患者在抗病毒治疗过程中CD4^(+)T淋巴细胞计数的变化,探讨基线病毒载量(viral load,VL)与免疫功能重建的相关性。方法研究对象为2010年1月31日—2020年12月31日在柳州市人民医院关爱门诊随访管理的初治成年AIDS患者,所有患者均接受含EFV的抗病毒治疗方案,观察期为120个月。利用受试者工作特征曲线确定基线VL预测免疫功能重建的最佳界值,根据最佳界值将患者分为低基线VL组和高基线VL组,用广义估计方程(generalized estimating equations,GEE)分析基线VL的高低与免疫功能重建的关系。结果基线VL预测免疫功能重建的最佳界值为5.533×10^(4)copies/mL。低基线VL组免疫重建成功率(87.58%)高于高基线VL组(70.93%)(P<0.05)。广义估计方程模型效应检验显示,CD4^(+)T淋巴细胞计数在低基线VL组和高基线VL组之间相比,差异有统计学意义(Waldχ^(2)=24.789,P=0.000),不同随访时间点差异也有统计学意义(Waldχ^(2)=911.501,P=0.000)。结论当AIDS患者的基线VL<5.533×10^(4)copies/mL时,使用含EFV方案进行抗病毒治疗后,其免疫功能的恢复和重建效果较好。

依非韦伦致男性乳房发育1例分析

目的 探讨非核苷类反转录酶抑制剂依非韦伦致男性乳房发育病例,为临床预防及处理其不良反应提供参考。方法 分析1例感染人类免疫缺陷病毒(HIV)男性患者服用依非韦伦导致乳房发育的治疗过程,探讨依非韦伦致乳腺增生的机理并排除其他药物的可能性。结果 患者服用依非韦伦后单侧乳房发育,停用该药并予以手术治疗2个月后,乳房不适减轻。结论 依非韦伦致男性乳房发育或与影响雌激素/雄激素的作用有关,用药期间应定期做乳房检查,做到早识别、早处理。

高效液相色谱法测定依法韦仑异构体含量

目的建立测定依法韦仑异构体含量的高效液相色谱法。方法色谱柱为Agilent Zorbax SB-Phenyl苯基柱(250 mm×4.6 mm,5µm)和Chiralpak OD-H手性柱(250 mm×4.6 mm,5µm),流动相为正己烷-乙醇(97∶3,V/V),流速为1.0 mL/min,检测波长为250 nm,柱温为35℃,进样量为20µL。结果依法韦仑异构体的质量浓度在0.05~20.52µg/mL范围内与峰面积线性关系良好(r=0.9997,n=6);检测限为0.015µg/mL,定量限为0.050µg/mL;中间精密度试验和重复性试验结果的RSD均为5.22%(n=6);平均加样回收率为96.73%,RSD为1.50%(n=9)。3批样品中依法韦仑异构体的含量分别为0.11%,0.12%,0.11%。结论该方法可用于依法韦仑异构体的含量测定。