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 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.
    

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 Type

Interventional


Primary Outcome

Anal dysplasia treatment on a per-patient basis

Secondary Outcome

 Resolution of high-grade AIN at 3 and 6 months 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

3000

Start Date

November 2015

Completion Date

December 2020

Primary Completion Date

November 2020

Eligibility 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.
      

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

HPV-SAVE


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

September 2016