Enhancing Cervical Cancer Prevention in South African Women: Primary HPV mRNA Screening with Different Genotype Combinations

SIMPLE SUMMARY: Despite being preventable, cervical cancer remains a lead killer among women in low–middle income countries. The reasons are clear. Global inequity is reflected in limited health resources, such as limited access to HPV-vaccination, screening, and treatment, which are the key pillars for the elimination of cervical cancer. The high burden of HPV-coinfections in women living with HIV/AIDS challenges the use of sensitive HPV-testing, leading to massive over-treatment. As advised by the WHO, a “test-and-treat” strategy could be optimal. In this study, 710 under-screened South African women, about half of them living with HIV, were tested for mRNA expression restricted to the predominant HPV types of cervical cancer. The effectiveness of a test-and-treat strategy to detect and manage severe cervical abnormalities (CIN3+) by increasing the number of HPV types included in the test was modeled. A combination of 6 types (16, 18, 31, 33, 35, 45) resulted in 25% positive tests requiring treatment, with the potential to prevent up to 85% of all cervical cancers. ABSTRACT: Background: Cervical cancer prevention in regions with limited access to screening and HPV vaccination necessitates innovative approaches. This study explored the potential of a test-and-treat strategy using mRNA HPV tests to impact cervical cancer prevention in a high-prevalence HIV population. Methods: A cervical screening study was conducted at three South African hospitals involving 710 under-screened, non-pregnant women (25 to 65 years) without known cervical diseases. Cytology, HPV testing, colposcopy, and biopsies were performed concurrently. Histopathologists determined final histological diagnoses based on biopsy and LLETZ histology. mRNA-HPV-genotyping for 3 (16, 18, 45) to 8 (16, 18, 31, 33, 35, 45, 52, 58) high-risk types was performed on leftover liquid-based cytology material. The preventive potential of the test-and-treat approach was estimated based on published data, reporting the causative HPV types in cervical cancer tissue from South African women. Treatment was provided as needed. Results: The HPV positivity rate more than doubled from 3-type (15.2%; 95% CI: 12.6–17.8) to 8-type mRNA (31.5%; 95% CI: 28.8–34.9) combinations, significantly higher among HIV-positive women. CIN3+ prevalence among HIV-positive women (26.4%) was double that of HIV-negative women (12.9%) (p < 0.01). The 6-type combination showed the best balance of sensitivity, specificity and treatment group size, and effectiveness to prevent cervical cancer. A 4-type combination (16, 18, 35, 45) could potentially prevent 77.6% (95% CI: 71.2–84.0) of cervical cancer burden by treating 20% and detecting 41.1% of CIN3 cases in the study group. Similarly, a 6-type combination (16, 18, 31, 33, 35, 45), treating 25% and including 62% of CIN3 cases, might prevent 85% of cervical cancer cases (95% CI: 79.6–90.6) among HIV-positive and negative women. Conclusion: Employing mRNA HPV tests within a test-and-treat approach holds huge promise for targeted cervical cancer prevention in under-screened populations. Testing for mRNA of the 6 highest-risk HPV types in this population and treating them all is projected to effectively prevent progression from CIN3 to invasive cervical cancer while reducing overtreatment in resource-constrained settings.