PROGRESS: Prevention of Cervical Cancer Using the Genotyping Screening and Same-day Self-sampling

In the fight against cancer, cervical cancer prevention strategies in high-resource settings have been extremely successful. Secondary prevention with cervical cytology, linked with timely treatment of precancer, has led to declines in invasive cervical cancer (ICC) rates by more than 75% over the past half century in the United States and other high-resource nations. In stark contrast, low- and middle-income countries (LMIC), where ICC is the leading cause of cancer death in women in 42 countries, carry the global burden with about 85% of new cases per year. In 2018, the WHO called for action to achieve the global elimination of ICC. An elimination strategy was ratified by member states in August 2020 and launched in November 2020. If the proposed WHO strategies are followed it would take a century to truly make an impact on disease burden. Thus, it is imperative to speed up this timeline. Low-cost and effective strategies that increase access to screening and treatment of cervical precancer will enable these goals to be met sooner. The purpose of this study is to clinically validate the modified AmpFire® which provides a platform for effective, simple, rapid and affordable cervical cancer screening in low resource settings.

Aim 1. To estimate the test performance of self- and provider- collected modified AmpFire® screening platform in Honduras.

Activities: The investigators will test 4,000 women with both self- and provider-collected AmpFire® and quantify the ability of each collection modality to detect CIN2+. To do this, all HPV+ women by either modality and 5% randomly chosen HPV negative (HPV-) women on both modalities will undergo a pelvic exam where visual inspection with acetic acid (VIA), Automated Visual Evaluation (AVE), colposcopy, and biopsy will be conducted. VIA and AVE will be done to conduct retrospective, secondary analyses comparing screening and triage efficacy of these methods vs. AmpFire® genotyping. Colposcopy and biopsy will be done to ascertain true disease prevalence. All patients who are HPV+ will be offered immediate ablation treatment, if eligible. Women will be deemed ineligible for treatment if they have lesions that cover more than 75% of the cervix, extend into the endocervical canal or onto the vagina, have evidence of ICC, and/or have obstructing or unusual anatomy that makes it difficult to visualize the entire cervix. Participants with suspected ICC will be referred per Honduran guidelines.

Pathologist readings: Cervical biopsies and ECC specimens will be sent to a private lab with extensive experience with cervical cancer pathology. Additionally, an expert pathologist will evaluate slides with CIN2+ diagnoses and a 5% random sample of cervical intraepithelial neoplasia grade 1(CIN1)/normal pathology slides every six months to ensure quality and for expert confirmation of study endpoints. In cases of disagreement between the local and expert pathology analyses, a third expert pathologist will adjudicate the discrepancy.

Analysis: The primary analysis will separately assess the test performance (sensitivity, specificity, PPV, NPV) of provider collected modified AmpFire® and self-collected modified AmpFire® for the detection of high grade cervical precancer (CIN2+). All women who are positive with either test and 5% of women who test negative on both tests will undergo colposcopy and biopsy to ascertain true disease prevalence. Estimates of sensitivity and specificity and corresponding 95% confidence intervals will be calculated using the approach of Begg and Greenes to correct for the verification biased sampling of true disease status. A study of 4,000 women will result in 751 women receiving colposcopy and biopsy-580 women who screen positive on at least one modified AmpFire® test assuming 14.5% AmpFire® test positivity and 171 women who correspond to the 5% random sample of the 3,420 women who screen negative on both tests. Of the women receiving colposcopy and biopsy, it estimated that 56 women will have CIN2+. PPV and NPV will be estimated as proportions along with corresponding exact 95% confidence intervals. If 580 screen positive on the modified AmpFire® test, PPV can be estimated with a precision of 0.029 for a PPV of 0.145). NPV can be estimated with a precision of 0.033 if there are 171 women who screen for AmpFire and receive colposcopy and biopsy and a true NPV of 0.95. VIA and VAT results will be retrospectively correlated to biopsy pathology and used as data points for the cost-effectiveness analysis.