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To assess determinants for histologically proven high-grade anal intraepithelial lesions (hHSIL) in HIV-positive men who have sex with men (MSM), a population at high-risk of HPV-related anal cancer.APACHES is a prospective study of anal HPV and related-lesions in 513 HIV-positive MSM aged at least 35 years in six centres across France.At baseline, participants underwent high-resolution anoscopy (HRA) with biopsy of suspicious lesions, preceded by anal swabs for liquid-based cytology, p16/Ki67 immunostaining, and HPV DNA. hHSIL diagnosis was established by histopathological review panel consensus, and determinants assessed by logistic regression.Baseline hHSIL prevalence was 10.4% and did not differ significantly by age, sexual behaviour or HIV/immunodeficiency markers. hHSIL prevalence was significantly elevated in participants who smoked (ORadj = 2.6, 95% CI 1.3–5.5) or who, in concurrent anal swabs, had ASCUS/LSIL (3.6, 95% CI 1.4–9.3) or ASC-H/HSIL (22.2, 95% CI 6.8–72.6) cytologic abnormalities, p16/Ki67 dual positivity (3.4, 95% CI 1.5–7.5), or non-HPV16 HR (13.0, 95% CI 1.7–102), but most notably, HPV16 (46.3, 95% CI 6.1–355) infection. Previous diagnosis of low-grade (2.3, 95% CI 1.0–5.4) or high-grade (3.8, 95% CI 1.5–9.9) anal lesion also conveyed higher hHSIL risk. After controlling for patient-specific determinants, there remained significant centre-specific effects, most clearly in higher risk groups (HPV16-positive participants: 31.3% hHSIL in centres A–D versus 5.1% in centres E and F, P < 0.01).Anal cytology and HPV16 infection are potentially useful determinants of hHSIL risk in HIV-positive MSM, but HIV/immunodeficiency-related variables appear not to be. Controlling for patient-specific hHSIL determinants highlights variability in HRA practice across diverse clinical settings and the need for better standardization of this difficult procedure.