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

June 9, 2022 updated by: Irving Salit, University Health Network, Toronto

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)

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

71

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada, V6T 1Z4
        • University of British Columbia
      • Vancouver, British Columbia, Canada, V5Z 4R4
        • BC Centre for Disease Control
    • Ontario
      • Ottawa, Ontario, Canada, K1Y 4E9
        • Ottawa Hospital Research Institute
      • Toronto, Ontario, Canada, M5G 2C4
        • University Health Network - Toronto General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

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;

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / 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 Names:
  • 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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
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.
Participants will be followed after post-treatment completion, an expected average of 6 months
Recurrence rates of high-grade AIN
Time Frame: Participants will be followed post-treatment completion, at 12, 24 and 36 months after randomization
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
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.
Participants will be followed after post-treatment completion, an expected average of 36 months
Acceptability of treatment
Time Frame: Within 6 months of randomization
Questionnaire-assessed acceptability by intervention arm
Within 6 months of randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Health Network, Toronto

Collaborators

Merck Sharp & Dohme LLC
Canadian Institutes of Health Research (CIHR)
Ontario HIV Treatment Network
CIHR Canadian HIV Trials Network

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2015

Primary Completion (Actual)

November 1, 2021

Study Completion (Actual)

April 14, 2022

Study Registration Dates

First Submitted

July 10, 2015

First Submitted That Met QC Criteria

July 16, 2015

First Posted (Estimate)

July 20, 2015

Study Record Updates

Last Update Posted (Actual)

June 13, 2022

Last Update Submitted That Met QC Criteria

June 9, 2022

Last Verified

June 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CTN 292B

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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