Background: Women living with HIV (WLHIV) face a substantially elevated risk of persistent high-risk human papillomavirus (hrHPV) infection and subsequent cervical cancer due to HIV-associated immunosuppression. Yet evidence on the natural history of hrHPV infection in this high-risk population particularly in low-and-middle-income countries is limited. Longitudinal evidence on hrHPV infection, persistence, clearance and progression is essential to inform risk-stratified screening intervals, optimize treatment and support implementation of HPV screening within HIV care platforms.

Objectives: This study aimed to understand the natural history of hrHPV infection among WLHIV and assess the influence of immunological, behavioural and demographic factors on hrHPV persistence and clearance. Additionally, we evaluate the operational feasibility and effectiveness of integrating HPV DNA testing with a “see-and-treat” approach for high-risk groups and to assess disease progression among the cohort over 12-month follow-up.

Methods: A prospective longitudinal cohort study was conducted among 1,500 WLHIV aged 26–65 years, recruited from seven ART centres in Manipur following informed consent. At baseline, all participants underwent hrHPV DNA testing using the cobas 6800. Demographic characteristics, sexual history, ART duration and CD4 count were recorded. HPV-positive women were referred for colposcopic evaluation, women with colposcopic lesions were treated using Thermal Ablation (TA) or Loop Electrosurgical Excision Procedure (LEEP), while those without lesions were followed without immediate treatment. HrHPV-positive women without lesions were retested at 6 months and managed using the same triage algorithm. All participants were rescreened at 12 months. Statistical analyses included estimates of hrHPV prevalence and genotype distribution, age and CD4-stratified comparisons, assessment of hrHPV persistence, clearance and progression at 6 and 12 months and multivariable analyses of predictors of hrHPV outcomes. Diagnostic accuracy and overtreatment rates of the see-and-treat were evaluated.

Results: Baseline hrHPV prevalence was 16.2%. Non-HPV16/18 genotypes predominated (53.9%), while HPV16 and HPV18 accounted for 18.9% and 11.1% of infections, respectively. Longer ART duration (>10.1 years) was independently associated with reduced hrHPV risk (adjusted odds ratio [AOR] 0.35; 95% CI 0.19–0.67), as were CD4 counts of 501–750 cells/mm³ (AOR 0.47; 95% CI 0.26–0.88). Women aged 30–34 years had higher odds of hrHPV infection (AOR 2.15; p=0.02). Triage compliance was approximately 90%. Among women with lesions, 50.5% were treated (TA 61.8%; LEEP 37.3%). The see-and-treat approach demonstrated moderate diagnostic performance (AUC 0.734) with minimal overtreatment (19.4%). At 6 months (compliance 93.5%), 46% of hrHPV-positive women without lesions demonstrated spontaneous clearance, while 54% progressed and required treatment. At 12 months, follow-up compliance was 85%, with hrHPV positivity of 13.4%.

Conclusions: This study provides longitudinal evidence on hrHPV natural history among WLHIV in India, demonstrating both substantial spontaneous clearance and significant progression risk. While immune reconstitution and prolonged ART are protective, continued cervical cancer screening remains essential. Embedding such risk-adapted cervical cancer prevention strategies within HIV care platforms offers a scalable strategy to reduce inequities and accelerate progress toward cervical cancer elimination among WLHIV.