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