The HPV-SAVE Study Team: HPV Screening and Vaccine Evaluation in Men Who Have Sex With Men (HPV-SAVE)

• ClinicalTrials.gov Identifier: NCT02503111
• Recruitment Status: Unknown
• First Posted: July 20, 2015
• Last Update Posted: September 15, 2016
• Sponsor: University Health Network, Toronto
• Collaborators: Canadian Institutes of Health Research (CIHR); Ontario HIV Treatment Network; CIHR Canadian HIV Trials Network; Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Irving Salit, University Health Network, Toronto

Study Description

Brief Summary:

Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide. Infection by certain high-risk oncogenic types of HPV (HR-HPV) is the major cause of several cancers in men, notably squamous cell carcinoma (SCC) of the anal canal. Rates of anal infection with these HR-HPV strains and the resultant high-grade anal dysplasia and anal cancer are much higher in men who have sex with men (MSM) than in the general population. Co-infection with human immunodeficiency virus (HIV) further amplifies this burden, making the rates of anal SCC in HIV-positive MSM higher than the historic rates of cervical cancer prior to the adoption of routine cervical cytology screening. Despite these alarming statistics, there are no established protocols for optimal screening and treatment of anal HPV and cancer precursors, nor has there been any widespread rollout of organized screening programs anywhere in Canada. Further, not only does HPV directly cause significant disease in these men, but there is growing epidemiologic evidence that HPV infection may enhance sexual transmission of HIV. These significant knowledge gaps translate into fundamental deficiencies in care for HIV-positive MSM.

The HPV Screening and Vaccine Evaluation in MSM (HPV-SAVE) study team will recruit a large group of MSM to carry out a number of different studies. One key component of recruitment entails the mailing of invitations with educational materials in an invitational package to subjects in order to determine who would be interested in having anal cancer screening. In this way, the investigators will reveal factors that are important in acceptance of screening.

The HPV-SAVE team brings together community and internationally-recognized experts in HPV and HIV disease and mucosal immunology, to better define the optimal approaches for primary and secondary prevention and treatment of HPV-associated anal disease among HIV-positive MSM, and to explore biological mechanistic evidence regarding the potential role of HPV as a co-factor for HIV transmission. This will yield critical information which can lead to improvement in the health of MSM, and will provide a foundation on which to build further, large-scale screening and treatment trials on a national level.

Condition or disease	Intervention/treatment	Phase
Anal Dysplasia; Human Papillomavirus; Anal Cancer	Device: The Hyfrecator ® 2000 Electrosurgical System; Other: Observation Alone	Not Applicable

Detailed Description:

Since the 1990s, combination antiretroviral therapy (cART) has markedly reduced HIV-related opportunistic infections and mortality, and increased the life expectancy of people living with HIV. While AIDS-defining malignancies have declined non-AIDS defining malignancies continue at higher rates in HIV-infected persons than in the general population. Amongst these are cancers associated with HPV which is responsible for 90% of SCC of the anal canal. The incidence of anal SCC is increasing in the cART era, and as such, there is an urgent need to find effective ways of preventing anal SCC in those living with HIV. This includes screening for anal cancer precursors and ablative treatment of these lesions.

Though it is infrequent at a rate of 1 per 100 000, anal SCC is on the rise in the general population. It occurs at significantly higher rates in HIV-positive MSM with an estimated rate of 60 to 160 per 100 000. Rates of anal cancer among HIV infected MSM are comparable to rates of cervical cancer in women prior to the adoption of routine screening for cervical dysplasia. Anal cancer shares many similarities with cervical cancer.

Of the >170 HPV types, most anal cancers (and cervical cancers) are caused by two high-risk HPV types: 16 and 18 that are responsible for 66% and 5% of anal cancers, respectively. HPV lesions caused by low-risk types include genital warts, of which 90% are caused by HPV types 6 and 11. Prevention strategies for anal cancers have emerged that are analogous to strategies used in cervical cancer screening, in that the aim is to identify precursor lesions which can then be removed before progression to cancer. Screening and detection rely on a combination of anal cytology (Pap smear), anal HPV detection and high-resolution anoscopy (HRA). Despite the clear evidence indicating the benefit of screening and treatment procedures in cervical cancer screening, no rigorous studies have assessed such strategies in anal cancer prevention in men or women.

Anal SCC is very similar histologically to cervical cancer, and precancerous lesions of the anus (AIN) and cervix (cervical intraepithelial neoplasia [CIN]) are graded similarly (normal, low-grade [AIN- or CIN-1], high-grade [AIN- or CIN-2 or 3], SCC). Rates of progression of high-grade dysplasia in HIV-infected MSM is around 15%, over mean follow-up periods of 2 and 5 years. In HIV-uninfected persons, anal cancer detection at an earlier stage improves survival. Thus, early cancer detection in HIV-infected patients may also be beneficial.

Using HRA, the anal mucosa is visualized under magnification through a plastic anoscope after the application of acetic acid and Lugol's iodine. Abnormal-appearing areas are biopsied and if histologic AIN 2/3 is detected treatment is generally, but not always, offered. For anal dysplasia, treatment with surgery, infrared coagulation (IRC) electrocautery (EC) and topical therapies (e.g. trichloroacetic acid, or TCA) has been evaluated in case series. Similarly, given the high recurrence rate of CIN in women with HIV of about 65% after arguably more radical therapy, long-term, controlled trials of ablative therapies are still needed in HIV-infected MSM with high-grade AIN. There is some preliminary evidence that HPV immunization may reduce the likelihood of recurrent high-grade anal lesions in MSM after ablative therapy. These findings need further confirmation.

In 2004, the investigators initiated the Toronto Research for Anal Cancer Evaluation (TRACE) study to evaluate the performance characteristics of anal cytology and anal HPV testing for the detection of anal cancer precursors in 401 HIV-infected MSM. Overall, the information gleaned from this large cohort demonstrated that the burden of HPV disease was high in HIV-positive MSM, but that anal Pap smears are too insensitive a tool to rely on for diagnosis. Due to the poor test performance of anal cytology as a single, primary screening test, its use has not resulted in widespread uptake for screening. Exploration of the potential benefit and utility of other screening tests such as HPV-DNA testing, perhaps in conjunction with anal cytology, is needed.

Even though a number of centres in the United States, Canada, Europe and the United Kingdom have reported studies on anal cancer screening tests, anal cancer screening has not been implemented in an organized fashion in high-risk populations in any of these jurisdictions. In considering organized anal cancer screening for MSM, it would be logical to extrapolate from algorithms used in organized cervical cancer screening programs (e.g. screen using cytology and proceed to more aggressive intervention [i.e. HRA] if high grade squamous intraepithelial lesion (HSIL) is present) and apply them to anal cancer screening.

The currently proposed study aims to address several of these key knowledge gaps with the following two primary objectives: (1) to systematically compare ablative therapy versus intensive observation alone in outcomes relating to high-grade anal dysplasia; and (2) to better define evidence-based criteria for anal cancer screening using both anal cytology and HPV testing through the validation of an algorithm.

Overall aims of the study include:

• Aim #1: To assess knowledge of, the attitudes regarding HPV, anal cancer, HPV vaccination, and anal cancer screening to determine the acceptability of vaccination and screening among HIV-positive MSM.
• Aim #2: To evaluate the acceptance rate of HIV-positive MSM to an invitation for anal cancer screening which includes an educational brochure in the invitational package.
• Aim #3: To optimize decision making about which HIV-positive MSM should be sent for high resolution endoscopy (HRA).
• Aim #4: To compare the efficacy, safety, and tolerability of ablative therapies for anal dysplasia versus observation alone in a cohort of HIV-positive MSM with high-grade anal dysplasia.
• Aim #5: To further elucidate the role played by anal HPV infection as a mucosal immune determinant of HIV transmission and susceptibility in MSM.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 3000 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Screening
• Official Title: A Randomized Controlled, Open-label Trial Examining the Efficacy, Safety, and Tolerability of Ablative Therapies for High-grade Anal Dysplasia Versus Observation Alone in HIV-positive Men Who Have Sex With Men (MSM)
• Study Start Date: November 2015
• Estimated Primary Completion Date: November 2020
• Estimated Study Completion Date: December 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ablative therapy; Ablative therapy involving electrocautery (EC) will occur for participants with AIN-2 and AIN-3. The Hyfrecator ® 2000 Electrosurgical System will be used for EC therapy.	Device: The Hyfrecator ® 2000 Electrosurgical System; Lesion is ablated by the The Hyfrecator ® 2000 Electrosurgical System. During electrocautery (EC) with The Hyfrecator, a gentle brushing technique occurs and the tissue is removed with forceps.; Other Name: EC
Active Comparator: Active Surveillance; The control arm includes active surveillance with observation alone; no treatment in AIN-2 and -3.	Other: Observation Alone; No treatment to AIN-2 or AIN-3, only active surveillance.

Outcome Measures

Primary Outcome Measures :

1. Anal dysplasia treatment on a per-patient basis [ Time Frame: Participants will be followed after post-treatment completion, an expected average of 6 months ]
   Histologic resolution of high-grade AIN after treatment completion, with ablative therapies or surveillance alone. Resolution of high-grade AIN will be defined as histologic diagnosis of AIN-1 or normal at the post treatment HRA.

Secondary Outcome Measures :

1. Resolution of high-grade AIN at 3 and 6 months on a per-lesion basis [ Time Frame: Participants will be followed after post-treatment completion, an expected average of 6 months ]
   Resolution of high-grade AIN after treatment on a per-lesion basis. Histologic resolution of high-grade AIN after treatment completion, with ablative therapies or surveillance alone. Resolution of high-grade AIN will be defined as histologic diagnosis of AIN-1 or normal at the post treatment HRA.
2. Acceptance rate of participants recruited into the study [ Time Frame: Participants will be followed after recruitment into the study, up to 4 years ]
   Acceptance rates of participant recruitment into the study via an invitational package for anal cancer screening which includes an invitation and educational brochure. Rates of acceptance will account for participants who positively respond to the invitational letter and reminder.
3. Recurrence rates of high-grade AIN [ Time Frame: Participants will be followed after post-treatment completion, an expected average of 36 months ]
   Recurrence rates of high-grade AIN following ablative therapy on a per lesion basis.
4. Number of participants with adverse events [ Time Frame: Participants will be followed after post-treatment completion, an expected average of 36 months ]
   Number of participants assessed on safety, tolerability and acceptability of the different intervention arms and the different treatments in the ablative therapies arms. Evaluation of adverse events and questionnaire-assessed acceptability by intervention arms and ablative treatment type.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Males, aged ≥ years at baseline;
• Identify as a man who has sex with a men (MSM);
• Laboratory documentation of HIV-1 infection (enzyme-linked immunoassay and Western Blot);
• For those on combination antiretroviral therapy, the participant must be on a stable regimen (i,e, virologically suppressed with HIV-1 RNA below the assay's limit of detection for a minimum of sex months).This is one attempt to minimize confounding from dramatic shifts in viral load and/or CD4 count;
• An ability to give informed consent;
• An ability to attend clinic for all study visits;
• For those continuing to the treatment randomized controlled trial (RCT), AIN-2 or -3 found on biopsy of anal canal lesion(s), and willingness to undergo ablative therapy.

Exclusion Criteria:

• Participants having previously undergone anal cancer screening;
• Prior history of documented treatment of anal dysplasia;
• Prior receipt of any HPV vaccine;
• Current or prior history of cancer of the anogenital regions (e.g. penile, anal, or rectal);
• Inability to consent.

Contacts and Locations

Locations

Canada, British Columbia

BC Centre for Disease Control

Vancouver, British Columbia, Canada, V5Z 4R4

University of British Columbia

Vancouver, British Columbia, Canada, V6T 1Z4

Canada, Ontario

Ottawa Hospital Research Institute

Ottawa, Ontario, Canada, K1Y 4E9

University Health Network - Toronto General Hospital

Toronto, Ontario, Canada, M5G 2C4

Sponsors and Collaborators

University Health Network, Toronto

Canadian Institutes of Health Research (CIHR)

Ontario HIV Treatment Network

CIHR Canadian HIV Trials Network

Merck Sharp & Dohme Corp.

Investigators

• Principal Investigator: Irving Salit, MD; Toronto General Hospital, University Health Network

More Information

Publications:

Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998 Mar 26;338(13):853-60.

Lohse N, Hansen AB, Pedersen G, Kronborg G, Gerstoft J, Sørensen HT, Vaeth M, Obel N. Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med. 2007 Jan 16;146(2):87-95.

Patel P, Hanson DL, Sullivan PS, Novak RM, Moorman AC, Tong TC, Holmberg SD, Brooks JT; Adult and Adolescent Spectrum of Disease Project and HIV Outpatient Study Investigators. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992-2003. Ann Intern Med. 2008 May 20;148(10):728-36.

Silverberg MJ, Chao C, Leyden WA, Xu L, Tang B, Horberg MA, Klein D, Quesenberry CP Jr, Towner WJ, Abrams DI. HIV infection and the risk of cancers with and without a known infectious cause. AIDS. 2009 Nov 13;23(17):2337-45. doi: 10.1097/QAD.0b013e3283319184.

Parkin DM, Bray F. Chapter 2: The burden of HPV-related cancers. Vaccine. 2006 Aug 31;24 Suppl 3:S3/11-25. Review.

Crum-Cianflone NF, Hullsiek KH, Marconi VC, Ganesan A, Weintrob A, Barthel RV, Agan BK; Infectious Disease Clinical Research Program HIV Working Group. Anal cancers among HIV-infected persons: HAART is not slowing rising incidence. AIDS. 2010 Feb 20;24(4):535-43. doi: 10.1097/QAD.0b013e328331f6e2.

van Leeuwen MT, Vajdic CM, Middleton MG, McDonald AM, Law M, Kaldor JM, Grulich AE. Continuing declines in some but not all HIV-associated cancers in Australia after widespread use of antiretroviral therapy. AIDS. 2009 Oct 23;23(16):2183-90. doi: 10.1097/QAD.0b013e328331d384.

Piketty C, Selinger-Leneman H, Grabar S, Duvivier C, Bonmarchand M, Abramowitz L, Costagliola D, Mary-Krause M; FHDH-ANRS CO 4. Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy. AIDS. 2008 Jun 19;22(10):1203-11. doi: 10.1097/QAD.0b013e3283023f78.

Chiao EY, Krown SE, Stier EA, Schrag D. A population-based analysis of temporal trends in the incidence of squamous anal canal cancer in relation to the HIV epidemic. J Acquir Immune Defic Syndr. 2005 Dec 1;40(4):451-5.

Piketty C, Selinger-Leneman H, Bouvier AM, Belot A, Mary-Krause M, Duvivier C, Bonmarchand M, Abramowitz L, Costagliola D, Grabar S. Incidence of HIV-related anal cancer remains increased despite long-term combined antiretroviral treatment: results from the french hospital database on HIV. J Clin Oncol. 2012 Dec 10;30(35):4360-6. doi: 10.1200/JCO.2012.44.5486. Epub 2012 Oct 22.

Qualters JR, Lee NC, Smith RA, Aubert RE. Breast and cervical cancer surveillance, United States, 1973-1987. MMWR CDC Surveill Summ. 1992 Apr 24;41(2):1-7.

Bjørge T, Engeland A, Luostarinen T, Mork J, Gislefoss RE, Jellum E, Koskela P, Lehtinen M, Pukkala E, Thoresen SØ, Dillner J. Human papillomavirus infection as a risk factor for anal and perianal skin cancer in a prospective study. Br J Cancer. 2002 Jul 1;87(1):61-4. Erratum in: Br J Cancer. 2004 Sep 13;91(6):1226.

Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano AR, Wheeler CM, Koutsky LA, Malm C, Lehtinen M, Skjeldestad FE, Olsson SE, Steinwall M, Brown DR, Kurman RJ, Ronnett BM, Stoler MH, Ferenczy A, Harper DM, Tamms GM, Yu J, Lupinacci L, Railkar R, Taddeo FJ, Jansen KU, Esser MT, Sings HL, Saah AJ, Barr E. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol. 2005 May;6(5):271-8.

Jay N, Berry JM, Hogeboom CJ, Holly EA, Darragh TM, Palefsky JM. Colposcopic appearance of anal squamous intraepithelial lesions: relationship to histopathology. Dis Colon Rectum. 1997 Aug;40(8):919-28.

Kjaer SK, Tran TN, Sparen P, Tryggvadottir L, Munk C, Dasbach E, Liaw KL, Nygård J, Nygård M. The burden of genital warts: a study of nearly 70,000 women from the general female population in the 4 Nordic countries. J Infect Dis. 2007 Nov 15;196(10):1447-54. Epub 2007 Oct 31.

Hoots BE, Palefsky JM, Pimenta JM, Smith JS. Human papillomavirus type distribution in anal cancer and anal intraepithelial lesions. Int J Cancer. 2009 May 15;124(10):2375-83. doi: 10.1002/ijc.24215. Review.

Trottier H, Franco EL. The epidemiology of genital human papillomavirus infection. Vaccine. 2006 Mar 30;24 Suppl 1:S1-15. Review.

Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Benbrahim-Tallaa L, Guha N, Freeman C, Galichet L, Cogliano V; WHO International Agency for Research on Cancer Monograph Working Group. A review of human carcinogens--Part B: biological agents. Lancet Oncol. 2009 Apr;10(4):321-2.

Giuliano AR, Lu B, Nielson CM, Flores R, Papenfuss MR, Lee JH, Abrahamsen M, Harris RB. Age-specific prevalence, incidence, and duration of human papillomavirus infections in a cohort of 290 US men. J Infect Dis. 2008 Sep 15;198(6):827-35. doi: 10.1086/591095.

Palefsky JM, Holly EA, Hogeboom CJ, Ralston ML, DaCosta MM, Botts R, Berry JM, Jay N, Darragh TM. Virologic, immunologic, and clinical parameters in the incidence and progression of anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual men. J Acquir Immune Defic Syndr Hum Retrovirol. 1998 Apr 1;17(4):314-9.

Watson AJ, Smith BB, Whitehead MR, Sykes PH, Frizelle FA. Malignant progression of anal intra-epithelial neoplasia. ANZ J Surg. 2006 Aug;76(8):715-7.

FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007 May 10;356(19):1915-27.

Garland SM, Hernandez-Avila M, Wheeler CM, Perez G, Harper DM, Leodolter S, Tang GW, Ferris DG, Steben M, Bryan J, Taddeo FJ, Railkar R, Esser MT, Sings HL, Nelson M, Boslego J, Sattler C, Barr E, Koutsky LA; Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007 May 10;356(19):1928-43.

Joura EA, Garland SM, Paavonen J, Ferris DG, Perez G, Ault KA, Huh WK, Sings HL, James MK, Haupt RM; FUTURE I and II Study Group. Effect of the human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: retrospective pooled analysis of trial data. BMJ. 2012 Mar 27;344:e1401. doi: 10.1136/bmj.e1401.

Giuliano AR, Palefsky JM, Goldstone S, Moreira ED Jr, Penny ME, Aranda C, Vardas E, Moi H, Jessen H, Hillman R, Chang YH, Ferris D, Rouleau D, Bryan J, Marshall JB, Vuocolo S, Barr E, Radley D, Haupt RM, Guris D. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. N Engl J Med. 2011 Feb 3;364(5):401-11. doi: 10.1056/NEJMoa0909537. Erratum in: N Engl J Med. 2011 Apr 14;364(15):1481.

Palefsky JM, Giuliano AR, Goldstone S, Moreira ED Jr, Aranda C, Jessen H, Hillman R, Ferris D, Coutlee F, Stoler MH, Marshall JB, Radley D, Vuocolo S, Haupt RM, Guris D, Garner EI. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med. 2011 Oct 27;365(17):1576-85. doi: 10.1056/NEJMoa1010971.

Swedish KA, Factor SH, Goldstone SE. Prevention of recurrent high-grade anal neoplasia with quadrivalent human papillomavirus vaccination of men who have sex with men: a nonconcurrent cohort study. Clin Infect Dis. 2012 Apr;54(7):891-8. doi: 10.1093/cid/cir1036. Epub 2012 Jan 30.

Wilkin T, Lee JY, Lensing SY, Stier EA, Goldstone SE, Berry JM, Jay N, Aboulafia D, Cohn DL, Einstein MH, Saah A, Mitsuyasu RT, Palefsky JM. Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in HIV-1-infected men. J Infect Dis. 2010 Oct 15;202(8):1246-53. doi: 10.1086/656320.

Centers for Disease Control and Prevention (CDC). Recommendations on the use of quadrivalent human papillomavirus vaccine in males--Advisory Committee on Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep. 2011 Dec 23;60(50):1705-8.

Rank C, Gilbert M, Ogilvie G, Jayaraman GC, Marchand R, Trussler T, Hogg RS, Gustafson R, Wong T; ManCount Study Team. Acceptability of human papillomavirus vaccination and sexual experience prior to disclosure to health care providers among men who have sex with men in Vancouver, Canada: implications for targeted vaccination programs. Vaccine. 2012 Aug 24;30(39):5755-60. Epub 2012 Jul 15.

Ortoski RA, Kell CS. Anal cancer and screening guidelines for human papillomavirus in men. J Am Osteopath Assoc. 2011 Mar;111(3 Suppl 2):S35-43.

Ostör AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol. 1993 Apr;12(2):186-92. Review.

McCredie MR, Sharples KJ, Paul C, Baranyai J, Medley G, Jones RW, Skegg DC. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. 2008 May;9(5):425-34. doi: 10.1016/S1470-2045(08)70103-7. Epub 2008 Apr 11.

Scholefield JH, Castle MT, Watson NF. Malignant transformation of high-grade anal intraepithelial neoplasia. Br J Surg. 2005 Sep;92(9):1133-6.

Machalek DA, Poynten M, Jin F, Fairley CK, Farnsworth A, Garland SM, Hillman RJ, Petoumenos K, Roberts J, Tabrizi SN, Templeton DJ, Grulich AE. Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: a systematic review and meta-analysis. Lancet Oncol. 2012 May;13(5):487-500. doi: 10.1016/S1470-2045(12)70080-3. Epub 2012 Mar 23. Review.

John M, Flam M, Palma N. Ten-year results of chemoradiation for anal cancer: focus on late morbidity. Int J Radiat Oncol Biol Phys. 1996 Jan 1;34(1):65-9.

Edelman S, Johnstone PA. Combined modality therapy for HIV-infected patients with squamous cell carcinoma of the anus: outcomes and toxicities. Int J Radiat Oncol Biol Phys. 2006 Sep 1;66(1):206-11.

Goldstone SE, Kawalek AZ, Huyett JW. Infrared coagulator: a useful tool for treating anal squamous intraepithelial lesions. Dis Colon Rectum. 2005 May;48(5):1042-54.

Marks DK, Goldstone SE. Electrocautery ablation of high-grade anal squamous intraepithelial lesions in HIV-negative and HIV-positive men who have sex with men. J Acquir Immune Defic Syndr. 2012 Mar 1;59(3):259-65. doi: 10.1097/QAI.0b013e3182437469.

Chang GJ, Berry JM, Jay N, Palefsky JM, Welton ML. Surgical treatment of high-grade anal squamous intraepithelial lesions: a prospective study. Dis Colon Rectum. 2002 Apr;45(4):453-8.

Goldstone SE, Hundert JS, Huyett JW. Infrared coagulator ablation of high-grade anal squamous intraepithelial lesions in HIV-negative males who have sex with males. Dis Colon Rectum. 2007 May;50(5):565-75.

Goldstone SE, Johnstone AA, Moshier EL. Long-term outcome of ablation of anal high-grade squamous intraepithelial lesions: recurrence and incidence of cancer. Dis Colon Rectum. 2014 Mar;57(3):316-23. doi: 10.1097/DCR.0000000000000058.

Goldstone RN, Goldstone AB, Russ J, Goldstone SE. Long-term follow-up of infrared coagulator ablation of anal high-grade dysplasia in men who have sex with men. Dis Colon Rectum. 2011 Oct;54(10):1284-92. doi: 10.1097/DCR.0b013e318227833e.

Tate DR, Anderson RJ. Recrudescence of cervical dysplasia among women who are infected with the human immunodeficiency virus: a case-control analysis. Am J Obstet Gynecol. 2002 May;186(5):880-2.

Salit IE, Lytwyn A, Raboud J, Sano M, Chong S, Diong C, Chapman W, Mahony JB, Tinmouth J. The role of cytology (Pap tests) and human papillomavirus testing in anal cancer screening. AIDS. 2010 Jun 1;24(9):1307-13. doi: 10.1097/QAD.0b013e328339e592.

Murphy J, Kennedy EB, Dunn S, McLachlin CM, Kee Fung MF, Gzik D, Shier M, Paszat L. HPV testing in primary cervical screening: a systematic review and meta-analysis. J Obstet Gynaecol Can. 2012 May;34(5):443-452. doi: 10.1016/S1701-2163(16)35241-0. Review.

Murphy J, Kennedy EB, Dunn S, McLachlin CM, Kee Fung MF, Gzik D, Shier M, Paszat L. Cervical screening: a guideline for clinical practice in Ontario. J Obstet Gynaecol Can. 2012 May;34(5):453-458. doi: 10.1016/S1701-2163(16)35242-2.

Lacey HB, Wilson GE, Tilston P, Wilkins EG, Bailey AS, Corbitt G, Green PM. A study of anal intraepithelial neoplasia in HIV positive homosexual men. Sex Transm Infect. 1999 Jun;75(3):172-7.

Salit IE, Blitz S, Collins E, Aggarwal B, Raboud J, Tinmouth J, Kovacs C, Conway D, Hedgcock M, Merkley B, Fletcher D, Calzavara L. Anal cancer screening in HIV primary care: uptake and outcomes. Sex Health 2013;10(6): 588.

Richel O, de Vries HJ, van Noesel CJ, Dijkgraaf MG, Prins JM. Comparison of imiquimod, topical fluorouracil, and electrocautery for the treatment of anal intraepithelial neoplasia in HIV-positive men who have sex with men: an open-label, randomised controlled trial. Lancet Oncol. 2013 Apr;14(4):346-53. doi: 10.1016/S1470-2045(13)70067-6. Epub 2013 Mar 15.

Castle PE, Follansbee S, Borgonovo S, Tokugawa D, Schwartz LM, Lorey TS, LaMere B, Gage JC, Fetterman B, Darragh TM, Rodriguez AC, Wentzensen N. A comparison of human papillomavirus genotype-specific DNA and E6/E7 mRNA detection to identify anal precancer among HIV-infected men who have sex with men. Cancer Epidemiol Biomarkers Prev. 2013 Jan;22(1):42-9. doi: 10.1158/1055-9965.EPI-12-0984. Epub 2012 Nov 15.

Zubach V, Smart G, Ratnam S, Severini A. Novel microsphere-based method for detection and typing of 46 mucosal human papillomavirus types. J Clin Microbiol. 2012 Feb;50(2):460-4. doi: 10.1128/JCM.06090-11. Epub 2011 Nov 23.

• Responsible Party: Irving Salit, Immunodeficiency Clinic Director, Toronto General Hospital, University Health Network, Toronto
• ClinicalTrials.gov Identifier: NCT02503111
• Other Study ID Numbers: HPV-SAVE
• First Posted: July 20, 2015
• Last Update Posted: September 15, 2016
• Last Verified: September 2016

Keywords provided by Irving Salit, University Health Network, Toronto:

Men who have sex with men; Human immunodeficiency virus; Human papillomavirus; Anal intraepithelial neoplasia; Squamous cell carcinoma; High-resolution anoscopy; Anal cancer; High-risk oncogenic; Intraepithelial lesion; Low-risk non-oncogenic; Dysplasia; High-grade squamous intraepithelial lesion; Low-grade squamous intraepithelial lesion; Ablative therapy; Electrocautery; Infrared coagulation; Active surveillance

Additional relevant MeSH terms:

Anus Neoplasms; Rectal Neoplasms; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Anus Diseases; Rectal Diseases