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.
Full Title of Study: “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)”
- Study Type: Interventional
- Study Design
- Allocation: Randomized
- Intervention Model: Parallel Assignment
- Primary Purpose: Screening
- Masking: None (Open Label)
- Study Primary Completion Date: November 2020
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.
- 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: Observation Alone
- No treatment to AIN-2 or AIN-3, only active surveillance.
Arms, Groups and Cohorts
- 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.
- Active Comparator: Active Surveillance
- The control arm includes active surveillance with observation alone; no treatment in AIN-2 and -3.
Clinical Trial Outcome Measures
- 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.
- Resolution of high-grade AIN at 3 and 6 months 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.
- Acceptance rate of participants recruited into the study
- Time Frame: Participants will be followed after recruitment into the study, up to 4 years
- Acceptance rates of participant recruitment into the study via an invitational package for anal cancer screening which includes an invitation and educational brochure. Rates of acceptance will account for participants who positively respond to the invitational letter and reminder.
- Recurrence rates of high-grade AIN
- Time Frame: Participants will be followed after post-treatment completion, an expected average of 36 months
- Recurrence rates of high-grade AIN following ablative therapy on a per lesion basis.
- 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.
Participating in This Clinical Trial
- 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.
- 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 Eligibility: Male
Minimum Age: 18 Years
Maximum Age: N/A
Are Healthy Volunteers Accepted: Accepts Healthy Volunteers
- Lead Sponsor
- University Health Network, Toronto
- Canadian Institutes of Health Research (CIHR)
- Provider of Information About this Clinical Study
- Principal Investigator: Irving Salit, Immunodeficiency Clinic Director, Toronto General Hospital – University Health Network, Toronto
- Overall Official(s)
- Irving Salit, MD, Principal Investigator, Toronto General Hospital, University Health Network
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