Natural history of anal HSIL and predictive value of cytology and HPV biomarkers in MSM living with HIV: a prospective cohort study

BACKGROUND: Men who have sex with men (MSM) living with HIV are at high risk for anal cancer, which arises from HPV-related high-grade squamous intraepithelial lesions (HSIL). This study describes natural history of HSIL and identifies predictors of incidence and clearance using HPV DNA and E6/E7 mRNA biomarkers. METHODS: Prospective cohort of 354 MSM with HIV, followed for 2-4 years. Visitsisits included anal cytology, HPV DNA/mRNA testing, and high-resolution anoscopy. Composite cytological and histological outcomes were used to define the lesions. RESULTS: Among 291 participants completing ≥2 years of follow-up, composite HSIL (cHSIL) incidence was 27.2% (10.7/100 person-years [PY]; 95%CI=8.2-13.9). Of 108 cHSIL cases, 54.6% cleared (24.8/100 PY; 95%CI=18.9-32). Baseline detectable HIV-1 RNA and abnormal cytology were predictors of incident cHSIL. At month 36, cumulative incidence was highest with LSIL (52%; 95%CI=0-77), DNA HPV-16 (50%; 95%CI=0-77), mRNA HPV-16 (51%; 95%CI=0-80), or the combination of DNA High-Risk HPV and mRNA HPV-16 combined (51%; 95%CI=0-80). The lowest risk was observed in individuals with negative for intraepithelial lesion or malignancy (NILM) cytology and negative biomarkers. Cumulative clearance was higher in incident cHSIL cases that tested negative for HPV-16 biomarkers. CONCLUSIONS: This study provides prospective insight into untreated anal HSIL in MSM with HIV. NILM cytology combined with negative biomarkers identifies individuals at low risk, suitable for extended follow-up intervals. Furthermore, incident HSIL with negative HPV-16 biomarkers is more likely to clear, supporting potential treatment deferral. Reflex biomarker testing after cytological changes may improve cost-effective risk stratification.