Background: Cervical cancer continues to pose a disproportionate burden in low-and-middle-income countries (LMICs), including India, despite the availability of effective preventive interventions. The absence of an organized, population-wide screening program and challenges related to follow-up and treatment contribute significantly. The World Health Organization (WHO) recommends HPV DNA testing as the primary screening modality due to its superior sensitivity; however, evidence on large-scale implementation integrating decentralized treatment pathways across diverse socio-demographic settings in India remains limited. Generating population-level evidence on HPV epidemiology, self-sampling acceptance and community-based “see-and-treat” effectiveness is critical to inform scalable strategies aligned with WHO’s cervical cancer elimination goals.

Objectives: This study evaluated the effectiveness of large-scale opportunistic HPV DNA screening in India, with objectives to assess HPV prevalence and genotype distribution, treatment compliance, diagnostic performance, and effectiveness of a community-based “see-and-treat” approach across diverse geographic and socio-demographic contexts. Uptake and acceptance of self-sampling were also examined.

Methods: This multicentric, prospective cohort study was conducted between 2022 and 2025 across 20 Indian states. A total of 63,427 women aged 26–70 years were screened through community outreach clinics (75.1%) and hospital-based services (24.9%). Cervical samples were collected via assisted or self-sampling (10.5%) and tested using the cobas 6800. HPV-positive women were triaged by colposcopy and managed through a “see-and-treat” approach equipped with point-of-care devices, targeting treatment completion within 3 weeks. Clinic-based HPV-positive women were managed directly by gynecologists. Statistical analyses included descriptive estimates of HPV prevalence and genotype distribution, age and region-specific comparisons, and /multivariable assessments of diagnostic accuracy, overtreatment, treatment efficacy and correlation between colposcopy and histopathology.

Results: Overall HPV prevalence was 8.21%, with substantial regional variation, ranging from 14.0% in Madhya Pradesh to 4.58% in Kerala. While HPV 16/18 are primary targets, other high-risk genotypes accounted for 54.53% of infections and were consistently distributed across all geographical and age strata. Kerala demonstrated the lowest HPV 16/18 prevalence, whereas Andhra Pradesh, Madhya Pradesh and Maharashtra showed higher proportions. No significant differences were observed across rural, urban, and semi-urban populations. Age-specific analysis demonstrated a primary peak in HPV positivity among women aged 26–35 years and a smaller peak at 46–55 years. Self-sampling uptake was 10.5%, predominantly in urban settings. The “see-and-treat” approach demonstrated high diagnostic accuracy and performance (AUC 0.951; sensitivity 0.98; specificity 0.91), strong correlation between colposcopy and histopathology (r = 0.71), low overtreatment (10.7%), and treatment efficacy of 68% (95% CI: 66–71%). Four invasive cancers and pre-cancerous lesions (CIN I-III) in 44.4% of HPV-positive women were identified, with treatment compliance of 52.6% in the community cohort.

Conclusions: This study demonstrates HPV DNA-based opportunistic screening integrated with a decentralized see-and-treat model is feasible, accurate, and programmatically effective in India. Geographic variance underscores the need for region-specific screening strategies, while the substantial burden of non-16/18 genotypes highlights the importance of broad-spectrum HPV detection and vaccination. These findings provide actionable evidence to support national scale-up of HPV screening with treatment delivery to accelerate toward WHO cervical cancer elimination.