Long-Term Effectiveness of HPV Screen-and-Treat Strategy Versus Cytology in Cervical Cancer Screening: Insights from El Salvador’s CAPE Program

Introduction

Cervical cancer remains a major public health challenge globally, especially in low- and middle-income countries (LMICs) where resources for effective screening and timely treatment are often limited. Persistent infection with high-risk human papillomavirus (HPV) types is the primary etiological factor for cervical intraepithelial neoplasia (CIN) and invasive cervical cancer. Traditional cytology-based screening has proven effective in high-income settings but faces challenges of accessibility, infrastructure, and follow-up adherence in LMICs. To address these issues, El Salvador piloted the Cervical Cancer Prevention in El Salvador (CAPE) program between 2012 and 2017, introducing a primary HPV screen-and-treat strategy.

Study Background

Prior to CAPE, El Salvador predominantly relied on conventional cytology for cervical cancer screening, which requires multiple visits and has variable sensitivity. The CAPE initiative aimed to pilot and expand an HPV-based screening strategy with immediate treatment for positive cases (screen-and-treat) to improve early detection and reduce the burden of cervical neoplasia. While initial implementation outcomes were promising, long-term clinical effectiveness in reducing high-grade lesions and HPV prevalence remained unclear. This study presents a comparative analysis between women screened with the CAPE HPV screen-and-treat method and those screened with cytology over a 5-year interval, assessing subsequent detection of CIN2+ and HPV infection.

Study Design and Methods

This observational comparative study recruited two cohorts of women in El Salvador:

1. The screen-and-treat group: Women who underwent primary HPV screening with immediate treatment if positive, at least 5 years prior under the CAPE program (n=4087).
2. The cytology group: Age-matched women who had conventional cytology-based screening 2 to 3 years prior (n=2544).

Both groups were recalled for repeat primary HPV testing. Women testing HPV positive were referred for colposcopy and biopsy to confirm histopathological diagnosis of cervical lesions. Those testing HPV negative resumed routine screening schedules per national guidelines. Key endpoints included the prevalence of CIN2+ lesions and HPV positivity at repeat screening. Statistical analysis compared proportions and calculated risk ratios (RR) with 95% confidence intervals (CI).

Key Findings

A total of 6631 women participated. The main findings were:

– CIN2+ Detection: The screen-and-treat group had significantly lower detection of CIN2+ lesions at 0.7% (29/4087) compared to 2.1% (54/2544) in the cytology group (p<0.001). The risk of CIN2+ was reduced by 59% in the screen-and-treat group (RR 0.41, 95% CI 0.26 to 0.61).

– HPV Positivity: HPV prevalence at follow-up was also significantly lower among the screen-and-treat cohort at 9.5% versus 11.5% in the cytology group (p=0.008).

– Screening Interval: Notably, the screen-and-treat group’s interval between baseline and repeat screening was longer (≥5 years) compared to 2–3 years in the cytology cohort, suggesting durable protection and effectiveness of the HPV-based strategy.

These data imply that the HPV primary screen-and-treat approach not only results in fewer high-grade precancerous lesions at follow-up but also reduces ongoing HPV infections, a necessary step in cervical carcinogenesis.

Expert Commentary

These findings reinforce the global shift towards HPV testing as the preferred first-line screening tool, particularly in resource-constrained environments. The decreased detection of CIN2+ and HPV positivity indicates successful early intervention and possible reduction in cervical cancer incidence long-term. The longer screening interval with maintained safety provides a critical advantage over cytology, limiting healthcare costs, patient burden, and loss to follow-up.

Limitations include the observational design and potential selection biases inherent in real-world programmatic settings. However, the large sample size, standardized protocols, and histologic confirmation of outcomes enhance the validity and generalizability to analogous LMIC contexts.

Biologically, HPV testing targets the causal agent of cervical neoplasia more directly than cytology’s morphological endpoint, facilitating earlier detection of high-risk infections before morphological alterations occur. Immediate treatment under screen-and-treat reduces progression risk, explaining the lower lesion rates years later.

Conclusion

The CAPE program’s implementation of a primary HPV screen-and-treat strategy in El Salvador demonstrates substantial long-term benefits over conventional cytology screening. Lower CIN2+ detection and HPV positivity after extended screening intervals provide robust evidence supporting adoption of HPV-based, single-visit strategies in LMICs. These results highlight the feasibility and effectiveness of scaling up HPV screening with same-day treatment to enhance cervical cancer prevention and could inform policy adaptations regionally and globally.

Further longitudinal research is warranted to monitor invasive cancer incidence and cost-effectiveness outcomes. Meanwhile, these findings should encourage health systems to prioritize HPV testing integration and optimize cervical cancer control efforts worldwide.

Funding and Trial Registration

The study was supported by institutional and public health funding aligned with national cervical cancer prevention initiatives. Details on funding sources were not specifically provided in the referenced publication. The pilot and scale-up nature of CAPE suggests governmental and international collaboration. There was no clinical trial registration number indicated.

References

1. Alfaro K, Lopez L, Soler M, et al. Long-term outcomes after cervical cancer screening in El Salvador: primary human papillomavirus screen-and-treat compared with cytology. BMJ Glob Health. 2025;10(10):e017983. doi:10.1136/bmjgh-2024-017983

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