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

Anal Cancer Clinical Trial

— HPV-SAVE  

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02503111
• Other study ID #: CTN 292B
• Status: Terminated
• Phase: N/A
• Start date: November 2015
• Est. completion date: April 14, 2022

Study information

• Verified date: June 2022
• Source: University Health Network, Toronto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 71
• Est. completion date: April 14, 2022
• Est. primary completion date: November 1, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years and older

Eligibility

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;

Related Conditions & MeSH terms

• Anal Cancer
• Anal Dysplasia
• Anus Neoplasms
• Human Papillomavirus

Intervention

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.

Locations

Country	Name	City	State
Canada	Ottawa Hospital Research Institute	Ottawa	Ontario
Canada	University Health Network - Toronto General Hospital	Toronto	Ontario
Canada	BC Centre for Disease Control	Vancouver	British Columbia
Canada	University of British Columbia	Vancouver	British Columbia

Sponsors (5)

Lead Sponsor	Collaborator
University Health Network, Toronto	Canadian Institutes of Health Research (CIHR), CIHR Canadian HIV Trials Network, Merck Sharp & Dohme LLC, Ontario HIV Treatment Network

Country where clinical trial is conducted

Canada, 

References & Publications (22)

Bjørge T, Engeland A, Luostarinen T, Mork J, Gislefoss RE, Jellum E, Koskela P, Lehtinen M, Pukkala E, Thoresen SØ, Dillner J. Human papillomavirus infection as a risk factor for anal and perianal skin cancer in a prospective study. Br J Cancer. 2002 Jul 1;87(1):61-4. Erratum in: Br J Cancer. 2004 Sep 13;91(6):1226. — View Citation

Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Benbrahim-Tallaa L, Guha N, Freeman C, Galichet L, Cogliano V; WHO International Agency for Research on Cancer Monograph Working Group. A review of human carcinogens--Part B: biological agents. Lancet Oncol. 2009 Apr;10(4):321-2. — View Citation

Chiao EY, Krown SE, Stier EA, Schrag D. A population-based analysis of temporal trends in the incidence of squamous anal canal cancer in relation to the HIV epidemic. J Acquir Immune Defic Syndr. 2005 Dec 1;40(4):451-5. — View Citation

Crum-Cianflone NF, Hullsiek KH, Marconi VC, Ganesan A, Weintrob A, Barthel RV, Agan BK; Infectious Disease Clinical Research Program HIV Working Group. Anal cancers among HIV-infected persons: HAART is not slowing rising incidence. AIDS. 2010 Feb 20;24(4):535-43. doi: 10.1097/QAD.0b013e328331f6e2. — View Citation

de Ruiter A, Mindel A. Anal intraepithelial neoplasia. Eur J Cancer. 1991;27(11):1343-5. — View Citation

Giuliano AR, Lu B, Nielson CM, Flores R, Papenfuss MR, Lee JH, Abrahamsen M, Harris RB. Age-specific prevalence, incidence, and duration of human papillomavirus infections in a cohort of 290 US men. J Infect Dis. 2008 Sep 15;198(6):827-35. doi: 10.1086/591095. — View Citation

Hoots BE, Palefsky JM, Pimenta JM, Smith JS. Human papillomavirus type distribution in anal cancer and anal intraepithelial lesions. Int J Cancer. 2009 May 15;124(10):2375-83. doi: 10.1002/ijc.24215. Review. — View Citation

Jay N, Berry JM, Hogeboom CJ, Holly EA, Darragh TM, Palefsky JM. Colposcopic appearance of anal squamous intraepithelial lesions: relationship to histopathology. Dis Colon Rectum. 1997 Aug;40(8):919-28. — View Citation

Kjaer SK, Tran TN, Sparen P, Tryggvadottir L, Munk C, Dasbach E, Liaw KL, Nygård J, Nygård M. The burden of genital warts: a study of nearly 70,000 women from the general female population in the 4 Nordic countries. J Infect Dis. 2007 Nov 15;196(10):1447-54. Epub 2007 Oct 31. — View Citation

Lohse N, Hansen AB, Pedersen G, Kronborg G, Gerstoft J, Sørensen HT, Vaeth M, Obel N. Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med. 2007 Jan 16;146(2):87-95. — View Citation

Palefsky JM, Holly EA, Hogeboom CJ, Ralston ML, DaCosta MM, Botts R, Berry JM, Jay N, Darragh TM. Virologic, immunologic, and clinical parameters in the incidence and progression of anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual men. J Acquir Immune Defic Syndr Hum Retrovirol. 1998 Apr 1;17(4):314-9. — View Citation

Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998 Mar 26;338(13):853-60. — View Citation

Parkin DM, Bray F. Chapter 2: The burden of HPV-related cancers. Vaccine. 2006 Aug 31;24 Suppl 3:S3/11-25. Review. — View Citation

Patel P, Hanson DL, Sullivan PS, Novak RM, Moorman AC, Tong TC, Holmberg SD, Brooks JT; Adult and Adolescent Spectrum of Disease Project and HIV Outpatient Study Investigators. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992-2003. Ann Intern Med. 2008 May 20;148(10):728-36. — View Citation

Piketty C, Selinger-Leneman H, Bouvier AM, Belot A, Mary-Krause M, Duvivier C, Bonmarchand M, Abramowitz L, Costagliola D, Grabar S. Incidence of HIV-related anal cancer remains increased despite long-term combined antiretroviral treatment: results from the french hospital database on HIV. J Clin Oncol. 2012 Dec 10;30(35):4360-6. doi: 10.1200/JCO.2012.44.5486. Epub 2012 Oct 22. — View Citation

Piketty C, Selinger-Leneman H, Grabar S, Duvivier C, Bonmarchand M, Abramowitz L, Costagliola D, Mary-Krause M; FHDH-ANRS CO 4. Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy. AIDS. 2008 Jun 19;22(10):1203-11. doi: 10.1097/QAD.0b013e3283023f78. — View Citation

Public Health Agency of Canada. Available at: http://www.phac-aspc.gc.ca/cd- mc/cancer/cervical_cancer_figures-cancer_du_col_uterus-eng.php. Accessed on: 28 July 2014.

Qualters JR, Lee NC, Smith RA, Aubert RE. Breast and cervical cancer surveillance, United States, 1973-1987. MMWR CDC Surveill Summ. 1992 Apr 24;41(2):1-7. — View Citation

Silverberg MJ, Chao C, Leyden WA, Xu L, Tang B, Horberg MA, Klein D, Quesenberry CP Jr, Towner WJ, Abrams DI. HIV infection and the risk of cancers with and without a known infectious cause. AIDS. 2009 Nov 13;23(17):2337-45. doi: 10.1097/QAD.0b013e3283319184. — View Citation

Trottier H, Franco EL. The epidemiology of genital human papillomavirus infection. Vaccine. 2006 Mar 30;24 Suppl 1:S1-15. Review. — View Citation

van Leeuwen MT, Vajdic CM, Middleton MG, McDonald AM, Law M, Kaldor JM, Grulich AE. Continuing declines in some but not all HIV-associated cancers in Australia after widespread use of antiretroviral therapy. AIDS. 2009 Oct 23;23(16):2183-90. doi: 10.1097/QAD.0b013e328331d384. — View Citation

Watson AJ, Smith BB, Whitehead MR, Sykes PH, Frizelle FA. Malignant progression of anal intra-epithelial neoplasia. ANZ J Surg. 2006 Aug;76(8):715-7. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	Acceptability of treatment	Questionnaire-assessed acceptability by intervention arm	Within 6 months of randomization