高危型HPV载量与分型检测对宫颈高级别病变预测价值的前瞻性队列研究

Prospective cohort study on the value of high- risk human papillomavirus viral load and subtype tests in predicting cervical intraepithelial neoplasia

目的：评价高危型人乳头瘤病毒（high risk human papillomavirus,hrHPV）载量和分型检测在中国农村地区妇女人群中预测宫颈鳞状上皮高级别病变发生的价值。方法：2012年5月至2015年5月以农村妇女人群为基础选取江西省兴国县、靖安县和玉山县2 257例,年龄35~64岁纳入本前瞻性队列研究。同时采用HC-2（hybrid capture-2）和导流杂交技术（HybriMax）两种方法分别检测hrHPV载量和亚型,两种方法中任一亚型阳性者行阴道镜及活检检查,并将HC-2检测阳性结果中病毒载量〈10.0 RLU/CO认定为低病毒载量,病毒载量≥10.0 RLU/CO为高病毒载量。对hrHPV结果阴性或病理诊断为CIN1的2 211例妇女行24个月无干预随访。根据随访分别评价hrHPV载量和HybriMax分型两种检测方法预测宫颈鳞状上皮高级别病变（CIN grade 2 or worse,CIN2＋）的效果。结果：纳入基线、随访数据完整的女性共1 636例。2年内采用HC-2检测的132例基线高病毒载量妇女中CIN2＋的发生率为3.03%（4/132）,其相对危险度（RR）值为42.24（95%CI为4.76~375.2）;采用HybriMax分型检测的159例基线分型HPV16或18型阳性妇女中CIN2＋的发生率为2.51%（4/159）,RR值为33.06（95%CI为3.72~293.9）。对2年内HC-2检测中高病毒载量例数和HybriMax分型检测中HPV16/18型别阳性例数进行比较,CIN2＋的发病率差异无统计学意义（P〉0.05）。结论：HPV高载量和HPV16/18型别阳性妇女人群进展为CIN2＋的风险均较高。在不具有持续监测hrHPV条件的农村地区,HC-2检测的病毒载量≥10.0 RLU/CO阈值设定,与HybriMax分型检测HPV16/18型别均对hrHPV初筛有分流作用,并对CIN2＋发生有预测作用。

To evaluate high-risk human papillomavirus（hrHPV） genotyping and viral load in predicting CIN（cervical intraepithelial neoplasia（CIN） grade 2 or worse in a Chinese rural area population with limited health resources. Methods： We performed a population- based prospective study and enrolled 2,257 women aged 35 to 64 years from three rural screening sites of Jiangxi province. We conducted a hybrid capture（HC-2） assay to predict viral load. A HC-2 relative light unit（RLU） threshold of 10 was set to differentiate samples between low（〈10） and high（≥10） viral loads. We also carried out a HybriMax test to detect different hrHPV genotypes in the samples. Women exhibiting positive HC-2 or HybriMax results underwent colposcopy and colposcopically directed biopsy.Women with negative or positive hrHPV test results but with normal biopsy or CIN1 were followed-up for 24 months without intervention（n=2,211）. We used histopathological findings as outcome. Results： Of the 2,211 women, 1,636 provided complete follow-up data.Of the 132 women with a high viral load, 4（3.03%） developed CIN2＋ in the same period. The relative risk（RR） of CIN2＋ for HC-2 positivity at baseline was 42.24（95% CI=4.76-375.2）. Of the 159 women who were positive for HPV16 or HPV18 upon screening, 4（2.52%）progressed to CIN2＋（RR=33.06, 95% CI=3.72- 293.9）. The 2-year cumulative incidence rates of CIN2＋ did not significantly differ between the high viral load group and the HPV16/18 group. Conclusion： The risks of CIN2＋ progression were higher among women with a high viral load or HPV16/18 positivity than among women with negative hrHPV. Increasing the HC-2 cut-off value to 10 RLU or using HPV16/18 positivity may be similarly used to triage hrHPV- positive women for immediate colposcopy and comprehensive follow- up.Both approaches were equally predictive of the CIN2＋ risk in rural area. Increasing the HC-2 cut-off value to 10 RLU may also help allocate health resources effectively.