Anal Cancer Prevention in HIV-Positive and HIV-Negative Men who have Sex with Men: (Exploring Screening tests of Another Disease State (Cervical Cancer) to Inform Future Screening Strategies for Anal Cancer and its Precursor Lesions among a High-Risk Population in Ireland.)

Abstract

Introduction: Human Papillomavirus (HPV) is the commonest sexually transmitted infection (STI) in the world. “high-risk” (hr) HPV types are associated with causing or contributing to intraepithelial neoplasia and carcinoma of the vagina, vulva, cervix, penis, anus, and oropharynx. HPV is the causative agent for over 90% of anal cancers. An uncommon cancer in the general population, certain populations are at far higher risk for the development of anal cancer, including men who have sex with men (MSM) and HIV positive MSM in particular. Anal cancer, like cervical cancer (for which there exists international screening guidelines), develops from epithelial precursor lesions. Though anal cancer screening is practiced in some jurisdictions, at the time of commencement of this research, no international guidelines exist for anal cancer screening. In order to inform future anal cancer screening strategies in Ireland, this research aims to explore attitudes of MSM and healthcare professionals towards HPV infection, HPV vaccination and anal cancer screening. Additionally, it aims to characterise, using molecular and cytological biomarkers, the burden of anal hrHPV infection as well as anal cytological abnormalities among an MSM population in Ireland.

Methods Questionnaires, exploring themes related to HPV infection, vaccination and anal cancer screening, were adapted from relevant published questionnaires in the area and disseminated to MSM and healthcare professionals in Ireland. In addition, 252 MSM participants were recruited to undergo anal swab collection to examine different screening tests that have been used in cervical cancer screening internationally. Swab specimens, placed in ThinPrep solution, underwent molecular analysis for the presence of hrHPV DNA and mRNA. Samples also underwent cytological analysis using p16/Ki-67 dual-staining and Papanicolaou staining. 148 participants underwent repeat sample collection at 1 year.

Results The findings from MSM and healthcare professional questionnaires demonstrated a growing awareness among both groups of the risk of HPV infections and HPV-related cancers in MSM. hrHPV mRNA was present in the anal swab specimens of 40% of MSM participants. On multivariate analysis, current smoking was significantly associated with an increased risk of hrHPV mRNA positivity (adjusted odds ratio 1.9, p = 0.042) compared to never smokers. hrHPV DNA was found to be present in the anal swab specimens of 64% of MSM participants. HIV positivity was significantly associated with an increased risk of exhibiting hrHPV DNA positivity (adjusted odds ratio 2.4, p = 0.025) on multivariate analysis. Specimen samples that exhibited hrHPV DNA positivity underwent staining for the presence of p16/Ki-67 dual-staining. 34% of these samples exhibited p16/Ki-67 dual staining positivity. Being born in Ireland was significantly associated with decreased rates of p16/Ki-67 positivity on multivariate analysis (adjusted odds ratio 0.289, p=0.006). Positivity rates for hrHPV mRNA, hrHPV DNA and p16/Ki-67 dual-staining were similar at baseline compared to 1 year follow-up.

45% of participants with valid specimens for anal cytological analysis exhibited normal cytology. 33% exhibited cytological results consistent with low-grade squamous epithelial neoplasia (LSIL) and 22% exhibited cytological results consistent with high-grade squamous epithelial neoplasia (HSIL). On multivariate analysis, practicing receptive anal intercourse often or frequently was associated with a statistically significant increase in rates of HSIL positivity compared to those who never or rarely practice receptive anal intercourse (adjusted odds ratio 7.9, p = 0.009). Of those with normal cytology at baseline, 27% continued to exhibit normal cytology at 1 year follow-up, with 58% progressing to LSIL and 15% progressing to HSIL. Of those with LSIL at baseline, 31% regressed to normal cytology at 1 year follow-up, with 59% persisting as LSIL and 10% progressing to HSIL. Of those exhibiting HSIL at baseline, 12.5% regressed to normal cytology at 1 year follow-up with 66% regressing to LSIL and 22% persisting as HSIL.

Conclusion: This research highlights the acceptability of HPV vaccination and anal cancer screening among an MSM population in Ireland. It also demonstrates a recognition among healthcare professionals that anal cancer screening for high-risk patients is an important area to develop in Ireland. The results of the biomarker studies in this PhD reveals for the first time in an Irish context the high rates of anal hrHPV mRNA and DNA infection, as well as considerable rates of p16/Ki-67 dual-staining positivity, among an MSM population in Ireland. It also reveals, for the first time in an Irish context, the high burden of anal cytological abnormalities in this population. The publication in 2022 of the results of the ANCHOR trial and in 2024 of the IANS consensus guidelines for anal cancer screening will change practice with regards to anal cancer screening globally. The findings from this research will inform the planning of future local and national recommendations for anal cancer screening for this high-risk group in Ireland.