Improving specificity of HPV Screen-and-Treat in South Africa

描述（由申请人提供）：如果在首选的“筛查和治疗（SAT）”方法中可以使用强大的护理点（POC）HPV检测，则可以大大增强在低收入和中等收入国家（LMIC）实施宫颈癌筛查的势头。此外，如果修改HPV检测或增加额外的检测，以提高单轮筛查的特异性而不降低宫颈疾病检测的敏感性，SAT计划可能会更具吸引力。这将减少过度治疗的程度，而不会损害该计划对公共卫生的影响。我们在哥伦比亚大学的小组与南非开普敦大学有着良好的合作关系，我们与他们一起在低资源环境下开展了宫颈癌预防的大型临床研究。我们建议与Cepheid合作，Cepheid率先使用自含式实时PCR检测盒进行POC检测（GeneXpert），并因其已成为全球标准的结核病POC检测而广受尊重。Cepheid最近开发了一种HPV POC检测（Xpert HPV Assay），供欧洲使用。我们建议重新设计Cepheid HPV检测，使其更适合LMIC的SAT。该检测将被重新设计，以提高HPV检测的特异性和阳性预测值（PPV）：（1）利用HPV基因型不同分组的循环阈值（CT）截止值，2）研究HPV检测的特异性和阳性预测值（PPV）。 仅选择HPV基因型和（3）研究使用HPV 16和可能的其他基因型的定量HPV“病毒载量”测量的潜力。为了进一步解决SAT方法中过度治疗的挑战，我们建议研究细胞mRNA癌症生物标志物测试的潜在附加值。Cepheid有新的初步数据证明细胞mRNA生物标志物可用于区分高级别宫颈瘤变。其中一些已针对GeneXpert平台进行了格式化。这些方法旨在提高单轮筛查的特异性和PPV，从而减少接受治疗的无宫颈疾病妇女的数量，而不会严重影响敏感性，从而保持SAT计划的公共卫生影响。

DESCRIPTION (provided by applicant): The momentum to implement cervical cancer screening in low and middle income countries (LMIC) could be greatly enhanced if a robust point-of-care (POC) HPV test were available to utilize in the preferred "screen- and-treat (SAT)" approach. Furthermore, SAT programs could be made more attractive if HPV tests were modified, or additional tests added, to improve specificity of a single-round of screening without reducing sensitivity for the detection of cervical disease. This would reduce the magnitude of over-treatment without compromising the public health impact of the program. Our group at Columbia University has a well- established collaboration with the University of Cape Town, South Africa, with whom we have undertaken large clinical studies of cervical cancer prevention in low resource settings. We propose to partner with Cepheid, who have pioneered POC testing (GeneXpert) using self-contained real-time PCR cartridges and who are widely respected for their POC tests for tuberculosis that have become the global standard. Cepheid has recently developed a HPV POC test (Xpert HPV Assay) for use in Europe. We propose to re-engineer the Cepheid HPV test to make it more suitable for SAT in LMIC. The test will be re-engineered to improve specificity and positive predictive value (PPV) of HPV testing by: (1) utilizing differet cycle threshold (CT) cutoffs for different groupings of HPV genotypes, 2) investigating testing for only selected HPV genotypes and (3) investigating the potential of using quantitative HPV "viral load" measurements for HPV 16 and possibly other genotypes. To further address the challenge of over-treatment in the SAT approach, we propose to investigate the potential added value of tests for cellular mRNA cancer biomarkers. Cepheid has novel preliminary data demonstrating the utility of cellular mRNA biomarkers to distinguish high-grade cervical neoplasia. Some have already been formatted for the GeneXpert platform. These approaches are designed to improve the specificity and PPV of a single round of screening, and thereby reduce the number of women without cervical disease undergoing treatment, without seriously compromising sensitivity, so as to preserve the public health impact of a SAT program.