Addressing emerging health system priorities in cervical cancer prevention: determining optimal strategies for human papillomavirus test-based screening and triage

背景：以细胞学为基础的宫颈癌筛查已成为最广泛使用和最成功的方法之一 北美几十年来的公共卫生筛查干预措施。然而，有很大的局限性， 单是细胞学筛查就导致了数千例可预防的死亡。高灵敏度分子工具 用于检测宫颈癌的原因--高危型HPV， 在美国和加拿大的项目。HPV筛查有望降低宫颈癌发病率 与细胞学检查相比提高了30%，这是由于HPV对癌前病变的敏感性提高。采用改进的 HPV检测的阴性预测值，筛查间隔可延长至每4-5年， 节省了大量的医疗费用。尽管有这些优点，但由于检测HPV而丧失了特异性， 暂时性感染不会导致疾病，特别是在年轻妇女中， 阴道镜治疗在其他方面良好的妇女。因此，在预防更多宫颈癌病例的同时， 频繁筛查，HPV筛查可能会对育龄妇女造成意外伤害 以及如果在没有适当的筛查和分类算法的情况下部署，不可持续的医疗保健系统成本。 采用替代分子方法（即，mRNA和基因分型）的HPV阳性妇女或采用这些 作为初级筛选的方法可以提供改进的特异性而不降低灵敏度。然而，如果，如何和 在全球范围内，何时将这些测试最佳地整合到筛查算法中仍然是一个关键的知识差距。 目的：这项研究解决了北美决策者的优先问题，以评估 HPV检测与细胞学联合检测和非细胞学联合检测的有效性，确定原发性HPV的不良反应 检测，并最终为宫颈癌筛查的最佳筛查算法提供信息。特别是 该项目将：1）确定单次HPV初筛后的长期疗效（120个月）， 和多轮筛查，与细胞学和联合检测相比; 2）确定3种不同的 HPV检测用于HPV阳性标本的分诊和癌前病变的初步筛查; 3）定义 不同方案对宫颈癌发病率的人群和系统级结果建模的参数 方法：一个已建立的，高度参与的队列（n= 25，223）的参与者，来自一个纵向随机 将进行一项比较HPV初次检测与细胞学检查的对照试验，随访120个月。试验参与人员 目前距离基线48个月，并且具有完整的回顾性和前瞻性宫颈癌 筛查、阴道镜检查和治疗记录，并与基于人口的癌症登记处联系起来。基线 阴性妇女将通过集中筛查计划随访120个月，而 参与者将接受前瞻性的额外HPV检测。临床终点、灵敏度/特异性和其他 参数将用于数学建模和成本效益分析。

Background: Cytology-based cervical cancer screening has been one of the most widely used and successful public health screening interventions in North America for decades. However, there are significant limitations to cytology alone as a screening test leading to thousands of preventable deaths. Highly sensitive molecular tools for detection of high-risk HPV, the cause of cervical cancer, are poised to transform cervical cancer screening programs in the United States and Canada. HPV-based screening is expected to reduce cervical cancer rates by 30% compared to cytology, due to improved sensitivity of HPV for pre-cancerous lesions. With the improved negative predictive value of HPV testing, screening intervals can be extended to every 4-5 years leading to substantial health care savings. Despite these advantages, the loss of specificity with HPV due to detection of transient infections that do not result in disease, particularly in young women, leads to twice the number of colposcopy treatments in otherwise well women. Thus, while preventing more cervical cancer cases with less frequent screening, HPV-based screening could lead to unintended harm for well women of reproductive age and unsustainable health care system costs if deployed without appropriate screening and triage algorithms. Triage with alternate molecular methods (ie. mRNA and genotyping) in HPV positive women or adopting these methods as a primary screen could offer improved specificity without reducing sensitivity. However, if, how and when to optimally integrate these tests into screening algorithms remains a critical knowledge gap globally. Aims: This study addresses priority questions from North American policy makers to evaluate the effectiveness of HPV testing with and without cytology co-testing, determine adverse effects of primary HPV testing, and to ultimately inform optimal screening algorithms for cervical cancer screening. Specifically the project will: 1) determine the long-term efficacy (120 months) of HPV-based primary screening after a single and multiple screening rounds, compared to cytology and co-testing; 2) determine the efficacy of 3 different HPV assays for triage of HPV positive specimens, and primary screening for precancerous lesions; 3) define parameters for modeling population and systems-level outcomes of different protocols on cervical cancer rates Methods: Participants of an established, highly engaged cohort (n=25,223) from a longitudinal randomized controlled trial comparing primary HPV testing to cytology will be followed to 120 months. Trial participants are currently 48 months years from baseline and have complete retrospective and prospective cervical cancer screening, colposcopy and treatment records, with linkage to a population-based cancer registry. Baseline negative women will be followed to 120 months though the centralized screening program, while a subset of participants will receive prospective additional HPV testing. Clinical endpoints, sensitivity/specificity and other parameters will be used for mathematic modelling & cost-effectiveness analysis.