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

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Brief Title

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

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)

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 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

      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


Primary Outcome

Anal dysplasia treatment on a per-patient basis

Secondary Outcome

 Resolution of high-grade AIN at 3 and 6 months after randomization, on a per-lesion basis

Condition

Anal Dysplasia

Intervention

The Hyfrecator ® 2000 Electrosurgical System

Study Arms / Comparison Groups

 Ablative therapy
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Device

Estimated Enrollment

71

Start Date

November 2015

Completion Date

April 14, 2022

Primary Completion Date

November 1, 2021

Eligibility Criteria

        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;
      

Gender

Male

Ages

18 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Irving Salit, MD, , 

Location Countries

Canada

Location Countries

Canada

Administrative Informations


NCT ID

NCT02503111

Organization ID

CTN 292B


Responsible Party

Principal Investigator

Study Sponsor

University Health Network, Toronto

Collaborators

 Canadian Institutes of Health Research (CIHR)

Study Sponsor

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


Verification Date

June 2022