Ignite Creation Date:
2024-05-06 @ 1:08 PM
Last Modification Date:
2024-10-26 @ 1:09 PM
Study NCT ID:
NCT03947775
Status:
NOT_YET_RECRUITING
Last Update Posted:
2022-06-13
First Post:
2019-05-09
Brief Title:
HPV-SAVE_Merck_Sub-Study for Preventing Recurrence of HSIL
Sponsor:
University Health Network Toronto
Organization:
University Health Network Toronto
Study Overview
Official Title:
A Multicenter Randomized Controlled Trial of the Efficacy Safety and Immunogenicity of HPV Vaccination in Preventing Recurrence of HSIL in HIV-positive MSM
Status:
NOT_YET_RECRUITING
Status Verified Date:
2022-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Human papillomavirus HPV is the most common sexually transmitted infection STI 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 was funded by the Canadian Institutes of Health Research CIHR via its Boys and Mens Health Team Grant Competition It aims to 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 large-scale screening and treatment trials on a national level A key part of this research program involves an analysis of the potential role played by the HPV vaccine in the overall management of HIV-positive MSM
Planned vaccine-related projects include
A mixed-methods analysis of the knowledge attitudes and acceptability of HPV vaccination amongst HIV-positive MSM through quantitative eg cross-sectional survey and qualitative eg in-depth interviews means
A comprehensive assessment of the 9-valent HPV vaccine in HIV-positive MSM including safety and immunogenicity as well as its potential role in secondary prevention of high-grade anal dysplasia This is the study on which the current proposal is based
The HPV Screening and Vaccine Evaluation in MSM HPV-SAVE study team was funded by the Canadian Institutes of Health Research CIHR via its Boys and Mens Health Team Grant Competition It aims to 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 large-scale screening and treatment trials on a national level A key part of this research program involves an analysis of the potential role played by the HPV vaccine in the overall management of HIV-positive MSM
Planned vaccine-related projects include
A mixed-methods analysis of the knowledge attitudes and acceptability of HPV vaccination amongst HIV-positive MSM through quantitative eg cross-sectional survey and qualitative eg in-depth interviews means
A comprehensive assessment of the 9-valent HPV vaccine in HIV-positive MSM including safety and immunogenicity as well as its potential role in secondary prevention of high-grade anal dysplasia This is the study on which the current proposal is based
Detailed Description:
Advances in the treatment of HIV-infected individuals with the advent of the combination antiretroviral therapy cART era has led to dramatic reductions in mortality and morbidity These dramatic strides in survival within HIV-positive populations have led to a focus on longer-term morbidities in these individuals including malignancies Indeed an increase in a variety of malignancies in HIV-infected individuals has been noted in the cART era Amongst these are cancers associated with HPV responsible for the vast majority of cervical cancers itself a well-established acquired immune deficiency syndrome AIDS-defining illness and 40-90 of anal vulvar vaginal penile and oropharyngeal cancers More specifically a recent meta-analysis indicates that the overall prevalence of HPV in anal carcinoma is approximately 84 with HPV type 16 being isolated in 73 of all cases making it the most prevalent type implicated in anal carcinoma
Though infrequent at a rate of one per 100 000 squamous cell anal carcinoma is on the rise in the general population It occurs at significantly higher rates in HIV-positive men - particularly among MSM - with an estimated rate of 60 to 160 per 100 000 A recent study of thirteen North American AIDS Cohort Collaboration on Research and Design NA-ACCORD with over 34000 HIV-infected patients found that anal cancer rates were highest in HIV-infected MSM with a rate of 131 per 100000 person years 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 In addition to its etiologic association with HPV anal cancer shares many similarities with cervical cancer Both are squamous cell cancers occurring at the squamo-columnar junction and both likely arise from histologically-similar dysplastic precursor lesions It is postulated that a critical step in anal cancer carcinogenesis is the establishment of persistent infection conventionally defined as greater than six or twelve months with oncogenic HPV in the anal canal Though the majority of HPV infections are considered transient and will eventually clear even in HIV-positive individuals HIV-positive individuals have higher rates of persistent infection especially with oncogenic HPV types
Of the greater than 170 HPV types over 30 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 IARC
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 felt to be responsible for 66 and 5 of anal cancers respectively However a recent study from France examining the distribution of HPV types in cases of anal cancer found even more dramatic results HPV was found in 967 of all cases with HPV-16 being the most prevalent type 75 with other high risk types HPV-18 -52 -33 and -51 found in 4 to 6 of cases Further HPV-16 and -18 - either alone or in combination - were found in over 78 of cases HPV lesions caused by low-risk types include condylomata or commonly known as 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 that rely on a combination of cytology Papanicolaou or Pap smear and high-resolution anoscopy HRA analogous to colposcopy both of which screen for high-grade anal intraepithelial neoplasia HGAIN typically graded as anal intraepithelial neoplasia AIN AIN-2 or -3 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 the performance of such strategies in anal cancer screening in either men or women
In addition to the scant literature on the efficacy of screening programs for anal cancer and HPV in all men - but particularly those who are HIV-positive - there remains an even greater paucity of data on issues surrounding primary prevention of HPV The HPV quadrivalent recombinant vaccine or Gardasil protects against HPV types 6 and 11 which are the most common types implicated in condylomata acuminata anogenital warts as well as the most common oncogenic strains types 16 and 18 The use of this vaccine has been shown to prevent persistent cervical HPV infection caused by vaccine types in women as well as preventing nearly all high grade genital lesions in women - the latter of which are considered precursor lesions to invasive cancers Additionally a retrospective pooled analysis of two large efficacy trials of quadrivalent HPV vaccine has also demonstrated a treatment effect from HPV vaccine in preventing recurrences of previously treated high grade cervical disease
Few studies have been done on the use of the quadrivalent HPV vaccine in men there has only been one study examining the use of the HPV vaccine in HIV-positive men and this study found the vaccine to be safe and immunogenic Overall these studies have shown promise demonstrating a reduction in vaccine-type genital lesions in young men who were vaccinated versus those receiving placebo evidence of protection against HGAIN in MSM and a 50 reduction rate in HGAIN recurrence in MSM previously treated for dysplastic lesions This latter study lays the foundation of the currently proposed study However the role of the HPV vaccine in secondary prevention of HGAIN has not been examined in a systematic prospective way Given the unacceptably high rates of HGAIN recurrence in those having undergone ablative therapy from 62 to 91 within two years in HIV-positive MSM exploring this potentially novel benefit of the HPV vaccine is certainly warranted and could potentially change the way clinicians address HPV-related disease in this high-risk group
Until recently there existed no standard recommendation for the use of HPV vaccinations in males regardless of HIV serostatus however these studies have prompted the Centres for Disease Control and Preventions CDC Advisory Committee on Immunization Practices ACIP to recommend that boys be routinely vaccinated for HPV beginning at age 11 or 12 Canadas National Advisory Committee on Immunizations NACI went further recommending vaccination in all males between 9 and 26 years of age as well as any MSM 9 years of age or older
Gardasil-9 is a novel 9-valent HPV recombinant vaccine which expands the coverage of oncogenic HPV types with the addition of HPV types 31 33 45 52 and 58 to the existing quadrivalent vaccine types The addition of these five oncogenic types is estimated to improve cancer coverage to 90 versus 70 for the quadrivalent vaccine With its expanded coverage of oncogenic HPV types its proven efficacy in primary prevention and its potential role in mitigating HGAIN recurrences - all coupled with the disproportionate burden of HPV-related anal cancers borne by HIV-positive MSM - it is critical that its use be comprehensively assessed in this very high risk population
Though infrequent at a rate of one per 100 000 squamous cell anal carcinoma is on the rise in the general population It occurs at significantly higher rates in HIV-positive men - particularly among MSM - with an estimated rate of 60 to 160 per 100 000 A recent study of thirteen North American AIDS Cohort Collaboration on Research and Design NA-ACCORD with over 34000 HIV-infected patients found that anal cancer rates were highest in HIV-infected MSM with a rate of 131 per 100000 person years 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 In addition to its etiologic association with HPV anal cancer shares many similarities with cervical cancer Both are squamous cell cancers occurring at the squamo-columnar junction and both likely arise from histologically-similar dysplastic precursor lesions It is postulated that a critical step in anal cancer carcinogenesis is the establishment of persistent infection conventionally defined as greater than six or twelve months with oncogenic HPV in the anal canal Though the majority of HPV infections are considered transient and will eventually clear even in HIV-positive individuals HIV-positive individuals have higher rates of persistent infection especially with oncogenic HPV types
Of the greater than 170 HPV types over 30 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 IARC
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 felt to be responsible for 66 and 5 of anal cancers respectively However a recent study from France examining the distribution of HPV types in cases of anal cancer found even more dramatic results HPV was found in 967 of all cases with HPV-16 being the most prevalent type 75 with other high risk types HPV-18 -52 -33 and -51 found in 4 to 6 of cases Further HPV-16 and -18 - either alone or in combination - were found in over 78 of cases HPV lesions caused by low-risk types include condylomata or commonly known as 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 that rely on a combination of cytology Papanicolaou or Pap smear and high-resolution anoscopy HRA analogous to colposcopy both of which screen for high-grade anal intraepithelial neoplasia HGAIN typically graded as anal intraepithelial neoplasia AIN AIN-2 or -3 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 the performance of such strategies in anal cancer screening in either men or women
In addition to the scant literature on the efficacy of screening programs for anal cancer and HPV in all men - but particularly those who are HIV-positive - there remains an even greater paucity of data on issues surrounding primary prevention of HPV The HPV quadrivalent recombinant vaccine or Gardasil protects against HPV types 6 and 11 which are the most common types implicated in condylomata acuminata anogenital warts as well as the most common oncogenic strains types 16 and 18 The use of this vaccine has been shown to prevent persistent cervical HPV infection caused by vaccine types in women as well as preventing nearly all high grade genital lesions in women - the latter of which are considered precursor lesions to invasive cancers Additionally a retrospective pooled analysis of two large efficacy trials of quadrivalent HPV vaccine has also demonstrated a treatment effect from HPV vaccine in preventing recurrences of previously treated high grade cervical disease
Few studies have been done on the use of the quadrivalent HPV vaccine in men there has only been one study examining the use of the HPV vaccine in HIV-positive men and this study found the vaccine to be safe and immunogenic Overall these studies have shown promise demonstrating a reduction in vaccine-type genital lesions in young men who were vaccinated versus those receiving placebo evidence of protection against HGAIN in MSM and a 50 reduction rate in HGAIN recurrence in MSM previously treated for dysplastic lesions This latter study lays the foundation of the currently proposed study However the role of the HPV vaccine in secondary prevention of HGAIN has not been examined in a systematic prospective way Given the unacceptably high rates of HGAIN recurrence in those having undergone ablative therapy from 62 to 91 within two years in HIV-positive MSM exploring this potentially novel benefit of the HPV vaccine is certainly warranted and could potentially change the way clinicians address HPV-related disease in this high-risk group
Until recently there existed no standard recommendation for the use of HPV vaccinations in males regardless of HIV serostatus however these studies have prompted the Centres for Disease Control and Preventions CDC Advisory Committee on Immunization Practices ACIP to recommend that boys be routinely vaccinated for HPV beginning at age 11 or 12 Canadas National Advisory Committee on Immunizations NACI went further recommending vaccination in all males between 9 and 26 years of age as well as any MSM 9 years of age or older
Gardasil-9 is a novel 9-valent HPV recombinant vaccine which expands the coverage of oncogenic HPV types with the addition of HPV types 31 33 45 52 and 58 to the existing quadrivalent vaccine types The addition of these five oncogenic types is estimated to improve cancer coverage to 90 versus 70 for the quadrivalent vaccine With its expanded coverage of oncogenic HPV types its proven efficacy in primary prevention and its potential role in mitigating HGAIN recurrences - all coupled with the disproportionate burden of HPV-related anal cancers borne by HIV-positive MSM - it is critical that its use be comprehensively assessed in this very high risk population
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None