1. Anal cancer in people with HIV Andrew Grulich HIV Epidemiology and Prevention Program, Kirby Institute, UNSW Australia, Sydney AIDS 2016, Durban

2. Disclosure research funding from CSL Australia, Gilead, Viiv, Hologic honoraria for educational presentations from Merck, Sanofi-Pasteur, Gilead and Viiv.

3. Outline Epidemiology of anal cancer in people with HIV Prevention by vaccination Prevention by screening

4. Incidence of anal cancer in PLWHIV PopulationRelative riskAnnual Incidence (per 100,000) HIV negative people1 (referent)1-2 HIV positive women, injecting drug users, heterosexual men 10+20 HIV positive gay and bisexual men (GBM) 50100

5. Anal cancer is now among the most common cancers in HIV disease E Lanoy et al, Int J Cancer, 2011

6. Anal cancer incidence in PLWHIV, USA, 1992-2003 P Patel P et al, Ann Intern Med 2008

7. Anal cancer trends in people with HIV: Australia van Leeuwen M et al, AIDS 2009

8. Richel O et al, J AIDS 2015;69:602-

9. Anal cancer and immune function KP cohort, California. Anal cancer increases only moderately with declining CD4 count Silverberg M et al, CEBP 2011

10. Preventing anal cancer NormalAnal HPVAnal HSILAnal Cancer Infection Clearance Progression Regression Invasion Primary prevention HPV vaccination Adolescents Catch-up in Adults Secondary prevention Screening and treatment for HSIL: Immune modulators Therapeutic HPV vaccination Destructive therapies Watchful waiting Tertiary prevention Screening for cancer: Early diagnosis + curative chemo +and radiotherapy HSIL = high-grade squamous intra-epithelial lesions

11. Vaccination

12. HPV vaccination will prevent anal cancer in decades to come J Palefsky et al, NEJM, 2011 Young gay and bisexual men, aged 18-26

13. HPV vaccination in people with HIV Multiple safety and immunogenicity studies performed HPV vaccine is safe and immunogenic –Mixed evidence of slightly lower antibody levels, of uncertain clinical significance Studies done in men, women and children

14. ACTG A5298: efficacy trial of the quadrivalent HPV Vaccine in Older (>26) HIV-infected Adults Trial population was majority gay men, also included women Trial stopped early, no clear effect T Wilkins et al, CROI 2016

15. NIH guidelines

16. Screening

17. M Arbyn et al, Int J Cancer, 2012

18. The cervical analogy: the screening test Cervical cancer/CIN Women, general population Anal cancer/AIN Homosexual men, HIV positive Screening testCervical PapAnal swab Diagnostic testColposcopyHigh resolution anoscopy Threshold for referral for diagnostic test HSIL/pHSIL LSIL – rescreen 12/12 Any abnormality SensitivityMean 53%55-87% (best in HIV positive) SpecificityMean 96%37-76% (best in the HIV negative) Threshold for treatmentCIN2+. Watchful waiting of CIN2 in the young, pregnant Unclear. Some advocate AIN2+

19. The cervical analogy: HPV Cervix Women, general population Anus HIV positive homosexual men Prevalence of High risk HPV 15%75% AgePrevalence peaks at <25 (30%), then rapidly declines Prevalence constant with age, does not decline HR-HPV types in cancer100% HR HPV 55% HPV16; 15% HPV18 90% HR HPV 80% HPV16; 5% HPV18

20. The cervical analogy: HSIL High grade SIL (CIN2+; AIN2+) Cervical cancer/CIN Women, general population Anal cancer/AIN Homosexual men, HIV positive Prevalence1-2%30-40%+ RegressionCIN2: 40-50% CIN3: 33% Probably common ?40%/year Progression to cancerCIN3: about 1 in 80/yearAIN2+: about 1 in 400- 600/year (estimated)

21. The cervical analogy: HSIL Treatment Cervical cancer/CIN Women, general population Anal cancer/AIN Homosexual men, HIV positive Aim of treatmentRemoval of lesion and all of the transformation zone to prevent recurrence Destruction of identified lesions Number of treatments for cure Single (failure rate around 15%) Multiple (failure rate around 70%). Ongoing treatment Early morbidityLittle.Poorly described but substantial. Pain, bleeding. Late morbidityImpact on fertilityPoorly described.

22. The cervical cancer screening analogy is incomplete The natural history of anal SIL has not been adequately described Prevalence of HPV/HSIL is much higher in the anus –Lower progression rates than for cervical HSIL –Emerging evidence suggests that regression is common Treatment is difficult, unproven, and associated with higher morbidity than is CIN treatment

23. NIH guidelines for anal cancer screening in PLWHIV “At this time, no national recommendations exist for routine screening for anal cancer. However, some specialists recommend anal cytologic screening or high resolution anoscopy for HIV positive men and women (CIII)” “An annual digital anal examination may be useful to detect masses on palpation that could be anal cancer (BIII)”

24. A research agenda in anal cancer prevention Can an understanding of the natural history of anal HPV inform screening methods? –Sydney based Study of the Prevention of Anal Cancer Can we identify biomarkers that predict HSIL persistence? (as a marker of cancer risk) Does HSIL treatment work? –NCI funded ANCHOR study RCT of ablative therapy versus watchful waiting for anal HSIL in HIV positive people. Now recruiting, reporting 2022/23 Should we be vaccinating all GBM? –A RCT of 9valent vaccine in older (26+) GBM is required

25. Acknowledgements Kirby Institute, UNSW St Vincent’s Hospital, Sydney University of Sydney Andrew Grulich Andrew Carr Mary Poynten Carmella Law Kirsten McCaffery Jeff Jin Winnie Tong Kirsten Howard Patrick Kelly David Templeton Daniel Seeds Marko Grande Garrett Prestage Douglass Hanly Moir Pathology Leonie Crampton Patrick McGrath Annabelle Farnsworth Brian Acraman Melbourne Sexual Health Centre Jennifer Roberts Robert Mellor Kit Fairley Clare Biro Adele Richards Matthew Law Julia Thurloe Deborah Ekman Ross McDonald Marjorie Adams Piero Pezzopane Kathy Petoumenos Community representatives Royal Women’s Hospital, Melbourne Lance Feeney Russ Gluyas Suzanne Garland Sepehr Tabrizi Alyssa Cornall Samuel Philips Dorothy Machalek The SPANC team thanks the participants. The SPANC study is funded by a NHMRC program grant (# 568971) and a Cancer Council NSW Strategic Research Partnership Program grant (#13-11). Cytological testing materials are provided by Hologic (Australia) Pty Ltd. The Kirby Institute is affiliated with the Faculty of Medicine, University of New South Wales and funded by the Australian Government of Health and Ageing. The views expressed in this publication do not necessarily represent the position of the Australian Government. RPA Sexual Health Western Sydney Sexual Health Richard Hillman