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

Study Overview
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Brief Summary
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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 from various Ontario and Vancouver clinics, in order to carry out a number of different studies. 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. The primary aim of the current study is to systematically compare ablative therapy versus intensive observation alone (also known as 'watchful waiting') in outcomes relating to high-grade anal dysplasia.

Detailed Description
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Since the 1990s, combination antiretroviral therapy (cART) has markedly reduced HIV-related opportunistic infections and mortality [1], and increased the life expectancy of people living with HIV [2]. While acquired immune deficiency syndrome (AIDS)-defining malignancies have declined [3,4], non-AIDS defining malignancies continue to occur at higher rates in HIV-infected persons than in the general population [4]. Amongst these are cancers associated with HPV which is responsible for the vast majority of cervical cancers (itself a well-established AIDS-defining illness), and an estimated 90% of SCC of the anal canal [5]. cART not only fails to protect against anal pre-cancers and cancers [4,6,7], but the incidence of anal SCC is increasing in the cART era [6,8]. Because of this increasing burden of disease, 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 [9]. It occurs at significantly higher rates in HIV-positive men - particularly among men who have sex with men (MSM) - with an estimated rate of 60 to 160 per 100 000 [4], and no evidence of slowing in the era of increased cART use [10] (See Figure 1). In fact, 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 [11]. According to data from the Public Health Agency of Canada, rates of cervical cancer in 1972 were 18 per 100 000, dropping to just under 8 per 100 000 in 2004 [12]. In addition to its etiologic association with HPV, anal cancer shares many similarities with cervical cancer. Both are squamous cell cancers occurring at the squamocolumnar junction [13,14] and both likely arise from histologically-similar dysplastic precursor lesions [15,16]. It is postulated that a critical step in anal cancer carcinogenesis is the establishment of persistent infection with oncogenic HPV in the anal canal [16]. Though the majority of HPV infections are considered transient and will eventually clear even in HIV-positive individuals [17], HIV-positive individuals have higher rates of persistent infection, especially with oncogenic HPV types [18]. Of the greater than 170 HPV types, over 50 favour the anogenital area and, on the basis of epidemiologic and phylogenetic data, these have been classified by the International Agency for Research on Cancer [19]. The vast majority of anal cancers (as well as cervical cancers) are caused by two high-risk HPV types: HPV type 16 and HPV type 18 which are responsible for 66% and 5% of anal cancers, respectively [20]. HPV lesions caused by low-risk HPV (LR-HPV) types include condylomata (commonly known as 'genital warts'), of which 90% are caused by HPV types 6 and 11 [21]. 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 (Papanicolaou, or Pap smear), anal HPV detection and high-resolution anoscopy (HRA) which is analogous to colposcopy). Visually-directed anal biopsy during HRA is considered the gold standard for detecting dysplastic lesions such as high-grade anal intraepithelial neoplasia (HGAIN; typically graded as AIN-2 or -3) [16,22]. Anal cytology is generally used as a screening test to determine whether HRA is needed; however, cytology is an imperfect predictor of intra-anal HGAIN. Despite the clear evidence indicating the benefit of screening and treatment procedures in cervical cancer screening, no large rigorous studies have been performed to assess such strategies in anal cancer prevention in men or women.

Official Title
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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)

Conditions
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Anal Cancer, Anal Dysplasia, Human Papillomavirus

Intervention / Treatment
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* Device: The Hyfrecator ® 2000 Electrosurgical System
* Other: Observation Alone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males, aged ≥18 years at baseline; Identify as a man who has sex with a men (MSM); HIV-positive; laboratory documentation of HIV-1 infection; For those on combination antiretroviral therapy (cART), the participant must be on a stable regimen; An ability to give informed consent; An ability to attend clinic for follow-up, including possible HRA and biopsy; AIN-2 or -3 found on biopsy of anal canal lesion(s); Willingness to be randomized to undergo ablative therapy or active surveillance. Exclusion Criteria: Current or prior history of cancer of the anogenital regions (e.g. penile, anal, or rectal).; Previous treatment of high grade dysplasia;

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ablative therapy<br>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<br>* 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.<br>* Other names: EC;|
| Active Comparator: Active Surveillance<br>The control arm includes active surveillance with observation alone; no treatment in AIN-2 and -3. | Other: Observation Alone<br>* No treatment to AIN-2 or AIN-3, only active surveillance.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anal dysplasia treatment on a per-patient 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. | Participants will be followed after post-treatment completion, an expected average of 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resolution of high-grade AIN at 3 and 6 months after randomization, on a per-lesion basis | 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. | Participants will be followed after post-treatment completion, an expected average of 6 months | 
| Recurrence rates of high-grade AIN | Recurrence rates of high-grade AIN following ablative therapy on a per lesion basis. | Participants will be followed post-treatment completion, at 12, 24 and 36 months after randomization | 
| Number of participants with adverse events | 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. | Participants will be followed after post-treatment completion, an expected average of 36 months | 
| Acceptability of treatment | Questionnaire-assessed acceptability by intervention arm | Within 6 months of randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intraepithelial lesion, 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, Low-risk non-oncogenic, Dysplasia, High-grade squamous intraepithelial lesion, Low-grade squamous intraepithelial lesion, Ablative therapy, Electrocautery, Infrared coagulation, Active surveillance