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Abstract

Despite widespread adoption of HPV-based cervical screening in high-income countries, a critical evidence gap exists regarding its effectiveness in women aged ≥50 years. Current screening recommendations for this age group largely extrapolate from studies of broader populations or historical cytology-based programs, potentially failing to account for older women's unique risk profiles. The effectiveness, safety, and implementation challenges of HPV-based screening specifically in this age group remained unknown, hindering evidence-based screening protocols for older women. This thesis provided the first comprehensive evaluation of HPV-based screening among women ≥50 years through analyses of the HPV FOCAL randomized controlled trial (n=6,471), linked British Columbia provincial screening records, and a systematic review incorporating 1.5 million women. We evaluated cervical pre-cancer detection rates, long-term protective effect, and colposcopy referral patterns followed by HPV-based cervix screening over 14 years of follow-up. HPV testing demonstrated superior detection of cervical precancers in this age group, with significantly higher CIN3+ detection at baseline (1.55 vs 0.31 per 1000) compared to cytology. Notably, women who tested HPV-negative showed a 92% lower risk of developing cervical precancer over 14 years compared to cytology-negative women (adjusted HR=0.08, 95% CI: 0.03-0.20), with no high-grade lesions detected in HPV-negative women over age 60. While HPV testing initially led to increased colposcopy referrals, these rates declined with cytology triage, and when former HPV-tested participants later received routine cytology screening, their referral rates were lower than in participants who had cytology screening throughout. This research represents the first comprehensive evaluation of HPV testing's long-term protective effect and colposcopy referral patterns specifically in women ≥50 years. By establishing the superior effectiveness of HPV testing in this population and characterizing its implementation challenges, this work provides the foundation for future research to determine optimal screening intervals and evidence-based cessation ages. These findings lay critical groundwork for developing personalized, risk-based screening protocols that optimize cervical cancer prevention in older women, contributing to global efforts toward cervical cancer elimination through more effective, evidence-based screening strategies.