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

背景：基于细胞学的宫颈癌筛查已成为应用最广泛、最成功的筛查方法之一。 公共健康筛查干预措施在北美已有数十年的历史。然而，有很大的局限性 仅细胞学作为一种筛查测试就导致了数千例可预防的死亡。高灵敏分子工具 用于检测高危HPV，这是宫颈癌的原因，有望改变宫颈癌筛查 在美国和加拿大的项目。基于HPV的筛查有望降低宫颈癌发病率 与细胞学相比增加了30%，这是由于HPV对癌前病变的敏感性提高。随着改进的 HPV检测的阴性预测价值，筛查间隔可延长至每4-5年，导致 节省了大量的医疗费用。尽管有这些优点，但由于检测到HPV的特异性的丧失 不会导致疾病的短暂感染，特别是在年轻女性中，会导致两倍于 其他身体状况良好的女性的阴道镜检查。因此，在预防更多宫颈癌病例的同时，用更少的资金 频繁的筛查，基于HPV的筛查可能会对育龄健康妇女造成意外伤害 如果在没有适当的筛查和分类算法的情况下部署，医疗保健系统的成本是不可持续的。 使用交替分子方法进行分类(即HPV阳性妇女或采用这些方法 方法作为主要筛查方法可以在不降低敏感性的情况下提供更高的特异性。然而，如果、如何以及 何时以最佳方式将这些测试整合到筛查算法中，仍然是全球一个关键的知识缺口。 目的：这项研究解决了北美政策制定者提出的优先问题，以评估 联合细胞学检测与不联合检测HPV的有效性：确定原发HPV的不良反应 测试，并最终为宫颈癌筛查的最佳筛查算法提供信息。具体地说 该项目将：1)确定基于HPV的初步筛查的长期疗效(120个月) 和多轮筛查，比较细胞学和联合检测；2)确定3种不同的疗效 对HPV阳性标本进行分选和癌前病变的初步筛查的HPV检测；3)确定 用于模拟不同方案对宫颈癌发病率的人群和系统水平结果的参数 方法：一个已建立的、高度投入的队列(n=25,223)的参与者来自纵向随机 将初步HPV检测与细胞学进行比较的对照试验将持续120个月。试验参与者是 目前距基线48个月，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，并与基于人群的癌症登记相联系。基线 通过集中筛查计划，阴性妇女将被跟踪到120个月，而 参与者将接受预期的额外HPV检测。临床终点、敏感性/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.