LAg-Avidity EIA用于中国HIV-1新发感染率估算的适用性研究
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摘要
研究背景
利用实验室检测技术从横断而样本中发现HIV-1新近感染样本,从而估算HIV-1新发感染率的实验室方法越来越受到重视。目前,普遍使用的BED方法存在影响因素多,假近期感染率较高等问题；为了解决这些问题,最近国际上研发出了一种新的亲和力方法——限制性抗原亲和力酶联免疫方法(Limiting antigen avidity enzyme immunoassay, LAg-Avidity EIA),经初步评价该方法受影响因素较少,误判率大大降低,可以明显提高估算的HIV-1新发感染率的准确性。
研究目的
一、评价LAg-Avidity试剂盒的重复性和准确度,探讨其在中国推广应用的可行性；
二、获得LAg-Avidity方法应用于中国HIV-1新发感染率计算所必需的窗口期参数；
三、研究LAg-Avidity方法应用于中国HIV-1新发感染率计算所必需的假近期感染率参数,初步探讨CD4+T淋巴细胞计数对LAg-Avidity方法的影响；
四、研究抗病毒治疗对LAg-Avidity方法准确性的影响。
研究方法
一、采用试剂盒自带的质控品和校准品通过检测精密度和孔问精密度指标,评价LAg-Avidity试剂的重复性,通过四位实验员之间刘BOCA101盘检测结果的一致性,四位实验员对该标准盘检测结果的平均值与该标准盘期望值结果的一致性,进一步评价试剂盒的重复性；同时,BOCA101盘的判读结果用于评价LAg-Avidity试剂的准确度。
二、通过检测531份血清学阳转队列样本(151个血清学阳转感染者),利用SPSS17.0软件对检测结果进行统计学分析,研究LAg-Avidity方法的窗口期。
三、通过检测513份已知长期感染(诊断时间大于方法学两倍窗口期)并且未进行抗病毒治疗的感染者样本,研究LAg-Avidity方法的假近期感染率参数。
四、通过对720份抗病毒治疗不同时间的病人样本的检测,计算误判比例,研究抗病毒治疗时间以及治疗后病毒载量值与LAg-Avidity方法误判的关系。
研究结果
一、检测精密度结果显示,经过校准品校准以后,试剂盒低阳对照和高阳对照的ODn值的CV小于10%；不同实验员实验结果的一致性较好,四个实验员实验结果的平均值与美国疾病预防控制中心提供的实验结果的相关性较高,R2为0.9849；孔间精密度结果显示,大批量生产的试剂盒可能存在酶联板包被量不均匀的情况。准确性检验中,试剂盒对BOCA101盘评判结果与预期值完全一致。
二、LAg-Avidity方法的假近期感染率参数为0.39%(2/513,95%CI0.00%-0.93%),不受CD4+T细胞计数影响(0/52)。
三、当方法学的临界值取1.0时,LAg-Avidity方法的窗口期参数为126天。
四、抗病毒治疗对LAg-Avidity方法影响较大,误判率为10.00%(72/720,95%CI7.81%-12.19%),误判率和治疗时间没有相关性,治疗以后病毒载量值越低(小于等于1000copies/ml)越容易造成误判。
研究结论
一、大规模生产的LAg-Avidity试剂盒重复性较好,试剂盒准确度较高,可以在中国推广应用；但试剂盒质量仍有提高的空间。
二、初步获得了LAg-Avidity方法用于中国HIV-1新发感染率估算的核心参数,窗口期为126天,假近期感染率为0.39%；与BED方法相比假近期感染率更低,可以使估算的新发感染率更接近真实水平。
三、LAg-Avidity方法不受CD4+T淋巴细胞计数的影响,但易受抗病毒治疗的影响,在横断面调查时,应删除已经进行抗病毒治疗的病人样本。
Background
Differentiating the recent and long-term HIV-1infection by using the laboratory method in cross-sectional investigation, then calculating the HIV-1incidence by a formula became more and more important. Now, the BED-CEIA used in China had some problems, its accuracy can be affected by antiretroviral therapy, HIV-1subtype, CD4+T cells count et al. and the false recent rate of BED assay is higher. To address those problems of BED assay, a new avidity method, limiting-antigen avidity enzyme immunoassay (LAg-Avidity EIA), was developed in these years, the pilot study showed that less factors can affect this new assay and the false recent rate of this assay was much lower than BED assay, which could result in the HIV-1incidence calculated by this LAg-Avidity assay was much closer to the true value.
Objectives
1. To evaluate the repeatability and accuracy of LAg-Avidity EIA kits, to find out if it can be applied in China HIV network laboratories;
2. To obtain the mean duration of recent HIV-1infection of LAg-Avidity assay used in China for incidence calculation;
3. To abtain the false recent rate of LAg-Avidity assay used in China for incidence calculation, to find out if the CD4+T cell count is one of the factors which could affect the accuracy of the assay;
4. To find out if the antiretroviral therapy could affect the accuracy of the LAg-Avidity assay.
Methods
1. Evaluate repeatability of the LAg-Avidity kit by testing the controls and calibrator in it and calculating precision of different runs and wells, examining the correlation of ODn values of BOCA101of four technicians, and the correlation of the average ODn values of BOCA101tested by foure technicians with the expected results of this panel; at the same time, evaluating the accuracy of the kit by interpretating the BOCA101panel.
2. By testing531seroconversional specimens from two cohort studies (151seroconvertors), analyzing the data by SPSS17.0to obtain the mean duration of recency of the LAg-Avidity assay.
3. By testing513long-term infection (diagnosed time longer than two mean duration of recency of LAg-Avidity assay), antiretroviral therapy naive specimens to analyzing the false recent rate of the LAg-Avidity assay.
4. By testing720specimens collected from patients under antiretroviral therapy for different years, to find out the influence of the therapy years and the viral load after therapy to the LAg-Avidity assay.
Results
1. After calibration, the Coefficient of Variation (CV) of high positive control and low positive control were less than10%; the correlation of4technicians was high, and the correlation of the ODn average values of the4technicians with the ODn valuses presented by US CDC was0.9849; the precision of different wells was not so good, which showed the amounts of antigen coated in the wells maybe heterogeneous in lot production. The BOCA101panel had the same interpretation results with the USA CDC expected.
2. The false recent rate of LAg-Avidity assay used in China was0.39%(2/513,95%CI0.00%-0.93%), and CD4+T cell counts could not affect this assay (0/52).
3. When the cutoff value of LAg-Avidity assay was1.0. the mean duration of recency of this assay used in China was126days.
4. Antiretroviral therapy could affect the accuracy of the LAg-Avidity assay, the false recent rate was10.00%(72/720,95%C17.81%-12.19%), there was no evidence showed that the false recent rate correlated with the therapy time, but low viral load (less than1000copies/ml) after therapy could resulted in high false recent rate.
Conclusions
1. The repeatability and accuracy of the LAg-Avidity kit were better, and this assay can be used in network HIV laboratories all over the China; but the quality of the kits in batch production still needed to be improved.
2. Obtained the mean duration of recency and false recent rate of LAg-Avidity assay used in China, the false recent rate was much lower than BED assay's false recent rate, which could improve the accuracy of HIV-1incidence calculated by the new assay.
3. CD4+T cell counts could not affect the LAg-Avidity assay; the antiretrivoral therapy was an important influence factor of the assay, and the specimens collected from patients under antiretroviral therapy should be excluded from cross-sectional survey.
利用实验室检测技术从横断而样本中发现HIV-1新近感染样本,从而估算HIV-1新发感染率的实验室方法越来越受到重视。目前,普遍使用的BED方法存在影响因素多,假近期感染率较高等问题；为了解决这些问题,最近国际上研发出了一种新的亲和力方法——限制性抗原亲和力酶联免疫方法(Limiting antigen avidity enzyme immunoassay, LAg-Avidity EIA),经初步评价该方法受影响因素较少,误判率大大降低,可以明显提高估算的HIV-1新发感染率的准确性。
研究目的
一、评价LAg-Avidity试剂盒的重复性和准确度,探讨其在中国推广应用的可行性；
二、获得LAg-Avidity方法应用于中国HIV-1新发感染率计算所必需的窗口期参数；
三、研究LAg-Avidity方法应用于中国HIV-1新发感染率计算所必需的假近期感染率参数,初步探讨CD4+T淋巴细胞计数对LAg-Avidity方法的影响；
四、研究抗病毒治疗对LAg-Avidity方法准确性的影响。
研究方法
一、采用试剂盒自带的质控品和校准品通过检测精密度和孔问精密度指标,评价LAg-Avidity试剂的重复性,通过四位实验员之间刘BOCA101盘检测结果的一致性,四位实验员对该标准盘检测结果的平均值与该标准盘期望值结果的一致性,进一步评价试剂盒的重复性；同时,BOCA101盘的判读结果用于评价LAg-Avidity试剂的准确度。
二、通过检测531份血清学阳转队列样本(151个血清学阳转感染者),利用SPSS17.0软件对检测结果进行统计学分析,研究LAg-Avidity方法的窗口期。
三、通过检测513份已知长期感染(诊断时间大于方法学两倍窗口期)并且未进行抗病毒治疗的感染者样本,研究LAg-Avidity方法的假近期感染率参数。
四、通过对720份抗病毒治疗不同时间的病人样本的检测,计算误判比例,研究抗病毒治疗时间以及治疗后病毒载量值与LAg-Avidity方法误判的关系。
研究结果
一、检测精密度结果显示,经过校准品校准以后,试剂盒低阳对照和高阳对照的ODn值的CV小于10%；不同实验员实验结果的一致性较好,四个实验员实验结果的平均值与美国疾病预防控制中心提供的实验结果的相关性较高,R2为0.9849；孔间精密度结果显示,大批量生产的试剂盒可能存在酶联板包被量不均匀的情况。准确性检验中,试剂盒对BOCA101盘评判结果与预期值完全一致。
二、LAg-Avidity方法的假近期感染率参数为0.39%(2/513,95%CI0.00%-0.93%),不受CD4+T细胞计数影响(0/52)。
三、当方法学的临界值取1.0时,LAg-Avidity方法的窗口期参数为126天。
四、抗病毒治疗对LAg-Avidity方法影响较大,误判率为10.00%(72/720,95%CI7.81%-12.19%),误判率和治疗时间没有相关性,治疗以后病毒载量值越低(小于等于1000copies/ml)越容易造成误判。
研究结论
一、大规模生产的LAg-Avidity试剂盒重复性较好,试剂盒准确度较高,可以在中国推广应用；但试剂盒质量仍有提高的空间。
二、初步获得了LAg-Avidity方法用于中国HIV-1新发感染率估算的核心参数,窗口期为126天,假近期感染率为0.39%；与BED方法相比假近期感染率更低,可以使估算的新发感染率更接近真实水平。
三、LAg-Avidity方法不受CD4+T淋巴细胞计数的影响,但易受抗病毒治疗的影响,在横断面调查时,应删除已经进行抗病毒治疗的病人样本。
Background
Differentiating the recent and long-term HIV-1infection by using the laboratory method in cross-sectional investigation, then calculating the HIV-1incidence by a formula became more and more important. Now, the BED-CEIA used in China had some problems, its accuracy can be affected by antiretroviral therapy, HIV-1subtype, CD4+T cells count et al. and the false recent rate of BED assay is higher. To address those problems of BED assay, a new avidity method, limiting-antigen avidity enzyme immunoassay (LAg-Avidity EIA), was developed in these years, the pilot study showed that less factors can affect this new assay and the false recent rate of this assay was much lower than BED assay, which could result in the HIV-1incidence calculated by this LAg-Avidity assay was much closer to the true value.
Objectives
1. To evaluate the repeatability and accuracy of LAg-Avidity EIA kits, to find out if it can be applied in China HIV network laboratories;
2. To obtain the mean duration of recent HIV-1infection of LAg-Avidity assay used in China for incidence calculation;
3. To abtain the false recent rate of LAg-Avidity assay used in China for incidence calculation, to find out if the CD4+T cell count is one of the factors which could affect the accuracy of the assay;
4. To find out if the antiretroviral therapy could affect the accuracy of the LAg-Avidity assay.
Methods
1. Evaluate repeatability of the LAg-Avidity kit by testing the controls and calibrator in it and calculating precision of different runs and wells, examining the correlation of ODn values of BOCA101of four technicians, and the correlation of the average ODn values of BOCA101tested by foure technicians with the expected results of this panel; at the same time, evaluating the accuracy of the kit by interpretating the BOCA101panel.
2. By testing531seroconversional specimens from two cohort studies (151seroconvertors), analyzing the data by SPSS17.0to obtain the mean duration of recency of the LAg-Avidity assay.
3. By testing513long-term infection (diagnosed time longer than two mean duration of recency of LAg-Avidity assay), antiretroviral therapy naive specimens to analyzing the false recent rate of the LAg-Avidity assay.
4. By testing720specimens collected from patients under antiretroviral therapy for different years, to find out the influence of the therapy years and the viral load after therapy to the LAg-Avidity assay.
Results
1. After calibration, the Coefficient of Variation (CV) of high positive control and low positive control were less than10%; the correlation of4technicians was high, and the correlation of the ODn average values of the4technicians with the ODn valuses presented by US CDC was0.9849; the precision of different wells was not so good, which showed the amounts of antigen coated in the wells maybe heterogeneous in lot production. The BOCA101panel had the same interpretation results with the USA CDC expected.
2. The false recent rate of LAg-Avidity assay used in China was0.39%(2/513,95%CI0.00%-0.93%), and CD4+T cell counts could not affect this assay (0/52).
3. When the cutoff value of LAg-Avidity assay was1.0. the mean duration of recency of this assay used in China was126days.
4. Antiretroviral therapy could affect the accuracy of the LAg-Avidity assay, the false recent rate was10.00%(72/720,95%C17.81%-12.19%), there was no evidence showed that the false recent rate correlated with the therapy time, but low viral load (less than1000copies/ml) after therapy could resulted in high false recent rate.
Conclusions
1. The repeatability and accuracy of the LAg-Avidity kit were better, and this assay can be used in network HIV laboratories all over the China; but the quality of the kits in batch production still needed to be improved.
2. Obtained the mean duration of recency and false recent rate of LAg-Avidity assay used in China, the false recent rate was much lower than BED assay's false recent rate, which could improve the accuracy of HIV-1incidence calculated by the new assay.
3. CD4+T cell counts could not affect the LAg-Avidity assay; the antiretrivoral therapy was an important influence factor of the assay, and the specimens collected from patients under antiretroviral therapy should be excluded from cross-sectional survey.
引文
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