Abstract:

Objective:

To evaluate the effectiveness of a combined strategy of human papillomavirus virus (HPV) vaccination and high-risk HPV screening to reduce the occurrence of anogenital and oropharyngeal neoplasms among men who have sex with men, people with HIV, homeless people, transgender women, female sex workers and rape victims.

Materials and methods:

This mixed methods study evaluates the effectiveness of a combined vaccination-screening strategy to reduce HPV prevalence/incidence and occurrence of cervical intraepithelial neoplasms grade 2+ and/or anal intraepithelial neoplasms grade 2+, using Kaplan-Meier. The time-to-event method will evaluate time from positive results for specific anogenital HPV to incidence of anogenital lesions containing that HPV type.

Results:

People vaccinated against HPV and screened for HPV as a primary test will have lower prevalence and incidence of HPV infection and consequently lower frequency of HPV-related anogenital and oropharyngeal lesions.

Conclusions:

This study will generate scientific evidence on effectiveness of a combined vaccination-screening strategy to reduce the burden of HPV-associated neoplasms.

Keywords:
Condesa Study; HPV vaccines; cancer screening; Mexico

Resumen:

Objetivo:

Evaluar la efectividad de una estrategia combinada de vacunación contra el virus de papiloma humano (VPH) y tamizaje de VPH de alto riesgo para reducir neoplasias anogenitales y orofaringeas entre hombres que tienen sexo con hombres, personas con VIH, personas en situación de calle, mujeres transgénero, trabajadoras sexuales y víctimas de violación.

Material y métodos:

Este estudio evaluará la efectividad de una estrategia combinada de vacunación y tamizaje para reducir la ocurrencia de neoplasias intraepiteliales cervicales grado 2+ o neoplasias intraepiteliales anales grado NIA2+ utilizando Kaplan-Meier. Se evaluará tiempo de resultados positivos para tipos específicos de VPH anogenital a incidencia de lesiones anogenitales con ese tipo de VPH.

Resultados:

Las personas vacunadas contra VPH y con tamizaje de VPH tendrán menor prevalencia e incidencia de infecciones por VPH y por ende menor frecuencia de lesiones anogenitales y orofaringeas relacionadas con VPH.

Conclusiones:

Este estudio generará evidencia científica sobre la efectividad de una estrategia combinada de vacunación y tamizaje para reducir la carga de neoplasias asociadas al VPH.

Palabras clave:
Estudio Condesa; vacuna contra VPH; tamizaje de cáncer; México

Introduction

Men who have sex with men (MSM),¹1. Combes JD, Clifford GM, Egger M, Cavassini M, Hirsch HH, Hauser C, et al. Human papillomavirus antibody response following HAART initiation among MSM. AIDS. 2017;31(4):561-9. https://doi.org/10.1097/QAD.0000000000001354
https://doi.org/10.1097/QAD.000000000000... people with HIV,²2. Raghavendran A, Hernandez AL, Lensing S, Gnanamony M, Karthik R, Sivasubramanian M, et al. Genital Human Papillomavirus Infection in Indian HIV-Seropositive Men Who Have Sex With Men. Sex Transm Dis. 2017;44(3):173-80. https://doi.org/10.1097/OLQ.0000000000000564
https://doi.org/10.1097/OLQ.000000000000... ^,33. Nyitray AG, da Silva RJ, Baggio ML, Lu B, Smith D, Abrahamsen M, et al. The prevalence of genital HPV and factors associated with oncogenic HPV among men having sex with men and men having sex with women and men: the HIM study. Sex Transm Dis . 2011;38(10):932-40. https://doi.org/10.1097/OLQ.0b013e31822154f9
https://doi.org/10.1097/OLQ.0b013e318221... homeless people (many of whom participate in survival sex), female sex workers,⁴4. Peng RR, Li HM, Chang H, Li JH, Wang AL, Chen XS. Prevalence and genotype distribution of cervical human papillomavirus infection among female sex workers in Asia: a systematic literature review and meta-analysis. Sex Health. 2012;9(2):113-9. https://doi.org/10.1071/SH11066.
https://doi.org/10.1071/SH11066... transgender women⁵5. Loverro G, Di Naro E, Caringella AM, De Robertis AL, Loconsole D, Chironna M. Prevalence of human papillomavirus infection in a clinic sample of transsexuals in Italy. Sex Transm Infect. 2016;92(1):67-9. https://doi.org/10.1136/sextrans-2014-051987
https://doi.org/10.1136/sextrans-2014-05... and rape victims⁶6. Garland SM, Subasinghe AK, Jayasinghe YL, Wark JD, Moscicki AB, Singer A, et al. HPV vaccination for victims of childhood sexual abuse. Lancet. 2015;386(10007):1919-20. https://doi.org/10.1016/S0140-6736(15)00757-6
https://doi.org/10.1016/S0140-6736(15)00... are at high risk for human papillomavirus (HPV) infection and consequently developing cancers associated with chronic HPV infection including cervical, vaginal,⁷7. Bogani G, Martinelli F, Ditto A, Signorelli M, Taverna F, Lombardo C, et al. The association of pre-treatment HPV subtypes with recurrence of VIN. Eur J Obstet Gynecol Reprod Biol. 2017;211:37-41. https://doi.org/10.1016/S0140-6736(15)00757-6
https://doi.org/10.1016/S0140-6736(15)00... vulvar,⁸8. Wakeham K, Kavanagh K, Cuschieri K, Millan D, Pollock KG, Bell S, et al. HPV status and favourable outcome in vulvar squamous cancer. Int J Cancer. 2017;140(5):1134-46. https://doi.org/10.1002/ijc.30523
https://doi.org/10.1002/ijc.30523... and anal cancers in women, cancer of the penis,⁹9. Feber A, Arya M, de Winter P, Saqib M, Nigam R, Malone PR, et al. Epigenetics markers of metastasis and HPV-induced tumorigenesis in penile cancer. Clin Cancer Res. 2015;21(5):1196-206. https://doi.org/10.1158/1078-0432.CCR-14-1656
https://doi.org/10.1158/1078-0432.CCR-14... anal cancer¹⁰10. Keglovitz K, Richardson AD, Lancki N, Walsh T, Schneider JA. Anal squamous intraepithelial lesions and HPV among young black men who have sex with men. LGBT Health 2017;4(1):72-74. https://doi.org/10.1089/lgbt.2016.0049
https://doi.org/10.1089/lgbt.2016.0049... ^,1111. Palefsky JM. Human papillomavirus-associated anal and cervical cancers in HIV-infected individuals: incidence and prevention in the antiretroviral therapy era. Curr Opin HIV AIDS . 2017;12(1):26-30. in men, and cancer of the oropharynx,¹²12. Lydiatt WM, Patel SG, O’Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, et al. Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):122-37. https://doi.org/10.3322/caac.21389
https://doi.org/10.3322/caac.21389... tongue, and tonsils in both men and women.¹³13. Clemente N, Alessandrini L, Vaccher E, De Paoli A, Buttignol M, Canzonieri V, et al. Multiple preinvasive and invasive HPV-related lesions of the anogenital tract in a female patient with HIV infection: A case report. Medicine (Baltimore). 2017;96(4):e5948. https://doi.org/10.1097/MD.0000000000005948
https://doi.org/10.1097/MD.0000000000005... ^,1414. Rob F, Tachezy R, Pichlík T, Rob L, Kružicová Z, Hamšíková E, et al. High prevalence of genital HPV infection among long-term monogamous partners of women with cervical dysplasia or genital warts-Another reason for HPV vaccination of boys. Dermatol Ther. 2017;30(1). https://doi.org/10.1111/dth.12435
https://doi.org/10.1111/dth.12435... ^,1515. Colon-Lopez V, Ortiz AP, Soto-Salgado M, Torres-Cintrón M, Perez N, Mercado-Acosta JJ, et al. Survival from anal cancer among Hispanics-Puerto Rico, 2000-2007. J Gastrointest Cancer. 2014;45(2):234-8. https://doi.org/10.1007/s12029-014-9607-x
https://doi.org/10.1007/s12029-014-9607-... In part, this is related to increased life expectancy among people with HIV (given greater anti-retroviral treatment coverage).¹⁶16. Piketty C, Darragh TM, Heard I, Da Costa M, Bruneval P, Kazatchkine MD, et al. High prevalence of anal squamous intraepithelial lesions in HIV-positive men despite the use of highly active antiretroviral therapy. Sex Transm Dis . 2004;31(2):96-9.

Some countries have implemented HPV vaccination policies that include men. This is based on promotion of protection against an increased risk of HPV infection, universal increase in coverage and a gender equity perspective.¹⁷17. Lowy DR. HPV vaccination to prevent cervical cancer and other HPV-associated disease: from basic science to effective interventions. J Clin Invest. 2016;126(1):5-11. https://doi.org/10.1172/JCI85446
https://doi.org/10.1172/JCI85446... Since population-level introduction of HPV vaccines, there has been a dramatic impact in areas with over 60% vaccination coverage. Decreases of approximately 90% have been reported for HPV-6/11/16/18 infections, over 90% for new cases of genital warts, 45% for low-grade cytological abnormalities, and 85% for anogenital high-grade histological lesions.¹⁸18. Garland SM, Kjaer SK, Muñoz N, Block SL, Brown DR, DiNubile MJ, et al. Impact and Effectiveness of the Quadrivalent Human Papillomavirus Vaccine: A Systematic Review of 10 Years of Real-world Experience. Clin Infect Dis. 2016;63(4):519-27. https://doi.org/10.1093/cid/ciw354
https://doi.org/10.1093/cid/ciw354...

The HPV FASTER concept combines HPV vaccination with HPV screening. It is based on the HPV vaccine’s¹⁹19. Salmerón J, Torres-Ibarra L, Bosch FX, Cuzick J, Lörincz A, Wheeler CM, et al. HPV vaccination impact on a cervical cáncer screening program: methods of the FASTER-Tlalpan Study in Mexico. Salud Publica Mex. 2016;58:211-219. https://doi.org/10.21149/spm.v58i2.7790
https://doi.org/10.21149/spm.v58i2.7790... high efficacy and the high sensitivity of high-risk HPV testing for primary detection of anogenital cancer precursor lesions²⁰20. Bouchard-Fortier G, Hajifathalian K, McKnight MD, Zacharias DG, Gonzalez-Gonzalez LA. Co-testing for detection of high-grade cervical intraepithelial neoplasia and cancer compared with cytology alone: a meta-analysis of randomized controlled trials. J Public Health (Oxf). 2014;36(1):46-55. https://doi.org/10.1093/pubmed/fdt057
https://doi.org/10.1093/pubmed/fdt057... (as documented by our research group in more than 200 000 Mexican women).²¹21. Lazcano-Ponce E, Lőrincz AT, Torres L, Salmerón J, Cruz A, Rojas R, et al. Specimen self-collection and HPV DNA screening in a pilot study of 100,242 women. Int J Cancer . 2014;135(1):109-16. https://doi.org/10.1002/ijc.28639
https://doi.org/10.1002/ijc.28639... ^,2222. Lazcano-Ponce E, Lorincz AT, Cruz-Valdez A, Salmerón J, Uribe P, Velasco-Mondragón E. et al. Self-collection of vaginal specimens for human papillomavirus testing in cervical cancer prevention (MARCH): a community-based randomised controlled trial. Lancet . 2011;378(9806):1868-73. https://doi.org/10.1002/ijc.28639
https://doi.org/10.1002/ijc.28639... ^,2323. Lazcano-Ponce E, Lörincz AT, Salmerón J, Fernández I, Cruz A, Hernández P, et al. A pilot study of HPV DNA and cytology testing in 50,159 women in the routine Mexican Social Security Program. Cancer Causes Control. 2010;21(10):1693-700. https://doi.org/10.1007/s10552-010-9598-2
https://doi.org/10.1007/s10552-010-9598-... ^,2424. Torres-Ibarra L, Lazcano-Ponce E, Franco EL, Cuzick J, Hernández-Ávila M, Lorincz A, et al. Triage strategies in cervical cancer detection in Mexico: methods of the FRIDA Study. Salud Publica Mex . 2016;58(2):197-210. https://doi.org/10.21149/spm.v58i2.7789
https://doi.org/10.21149/spm.v58i2.7789... This strategy is effective because HPV vaccination among women and men over a wide age range offers protection to those not currently infected and protects against subsequent re-infections.¹⁶16. Piketty C, Darragh TM, Heard I, Da Costa M, Bruneval P, Kazatchkine MD, et al. High prevalence of anal squamous intraepithelial lesions in HIV-positive men despite the use of highly active antiretroviral therapy. Sex Transm Dis . 2004;31(2):96-9. Thus, a combined HPV vaccination and screening strategy will potentially: 1) mitigate the demand for timely screening tests by expanding screening intervals; 2) improve the cost-benefit balance of secondary prevention programs, and 3) provide greater protection and quality of life to more people by reducing the burden of diseases attributable to HPV. This intervention can save many lives over the next 30 years and be more cost-effective than traditional approaches.

Recently, the US vaccination advisory group recommended HPV vaccination among sexually abused children, recognizing their increased risk of HPV infection.²⁵25. Advisory Committee on Immunization Practices. IPVS Policy statement on safety of HPV vaccines. Papillomavirus Res. 2016;2:9-10. https://doi.org/10.1016/j.pvr.2015.11.001
https://doi.org/10.1016/j.pvr.2015.11.00... ^,2626. Garland SM, Subasinghe AK, Jayasinghe YL, Wark JD, Moscicki AB, Singer A, et al. HPV vaccination for victims of childhood sexual abuse. Lancet . 2015;386(10007):1919-20. https://doi.org/10.1016/S0140-6736(15)00757-6
https://doi.org/10.1016/S0140-6736(15)00... The US Centers for Disease Control recommends administering the HPV vaccine to subjects with immunosuppressive conditions, HIV infection, and men who have sex with men.²⁷27. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Recommended Immunization Schedule for Adults Aged 19 Years or Older. United States: CDC, 2018. [cited October 15, 2018]. Available at: http://www.cdc.gov/vaccines/schedules/hcp/imz/adult-conditions-shell.html
http://www.cdc.gov/vaccines/schedules/hc... HPV vaccination in HIV-positive people is safe and reduces the incidence of HPV-associated cancers, including anal cancer, which is increasing in these populations.²⁸28. Stier EA, Chigurupati NL, Fung L. Prophylactic HPV vaccination and anal cancer. Hum Vaccin Immunother. 2016;12(6):1348-51. https://doi.org/10.1080/21645515.2016.1149274
https://doi.org/10.1080/21645515.2016.11... ^,2929. Toft L, Tolstrup M, Storgaard M, Ostergaard L, Søgaard OS. Vaccination against oncogenic human papillomavirus infection in HIV-infected populations: review of current status and future perspectives. Sex Health . 2014;11(6):511-23. https://doi.org/10.1071/SH14015
https://doi.org/10.1071/SH14015... Moreover, some research has shown that vaccination against HPV in populations with HIV is cost-effective.³⁰30. Li X, Stander MP, Van Kriekinge G, Demarteau N. Cost-effectiveness analysis of human papillomavirus vaccination in South Africa accounting for human immunodeficiency virus prevalence. BMC Infect Dis. 2015;15:566. https://doi.org/10.1186/s12879-015-1295-z
https://doi.org/10.1186/s12879-015-1295-... ^,3131. Deshmukh AA, Chhatwal J, Chiao EY, Nyitray AG, Das P, Cantor SB. Long-Term Outcomes of Adding HPV Vaccine to the anal intraepithelial neoplasia treatment regimen in HIV-positive men who have sex with men. Clin Infect Dis . 2015;61(10):1527-35. https://doi.org/10.1093/cid/civ628
https://doi.org/10.1093/cid/civ628...

HPV serotypes 16 and 18, found in the HPV bivalent and tetravalent vaccines, have an estimated relative contribution to invasive cervical cancer of at least 70% in Latin America.³²32. Forman D, de Martel C, Lacey CJ, Soerjomataram I, Lortet-Tieulent J, Bruni L, et al. Global burden of human papillomavirus and related diseases. Vaccine. 2012;30(Suppl 5):F12-23. https://doi.org/10.1016/j.vaccine.2012.07.055
https://doi.org/5https://doi.org/10.1016... These vaccines are highly effective,³³33. Brisson M, Laprise JF, Drolet M, Van de Velde N, Franco EL, Kliewer EV, et al. Comparative cost-effectiveness of the quadrivalent and bivalent human papillomavirus vaccines: A transmission-dynamic modeling study. Vaccine . 2013;31(37):3863-71. https://doi.org/10.1016/j.vaccine.2013.06.064
https://doi.org/10.1016/j.vaccine.2013.0... provide high levels of immunogenicity,³⁴34. Stanley M, Pinto LA, Trimble C. Human papillomavirus vaccines immune responses. Vaccine 2012;30 Suppl 5:F83-7. https://doi.org/10.1016/j.vaccine.2012.04.106
https://doi.org/10.1016/j.vaccine.2012.0... have acceptable security profiles³⁵35. Reisinger KS, Block SL, Lazcano-Ponce E, Samakoses R, Esser MT, Erick J, et al. Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial. Pediatr Infect Dis J. 2007;26(3):201-9. https://doi.org/10.1097/01.inf.0000253970.29190.5a
https://doi.org/10.1097/01.inf.000025397... and have been incorporated into public vaccination policies with 3-dose schedules over a 6-month period³⁶36. Kane MA, Serrano B, de Sanjosé S, Wittet S. Implementation of human papillomavirus immunization in the developing world. Vaccine . 2012;30(Suppl 5):F192-200. https://doi.org/10.1016/j.vaccine.2012.06.075
https://doi.org/10.1016/j.vaccine.2012.0... based on pharmaceutical industry recommendations.

Alternative schedules of population vaccinations have been implemented in spite of the conflict of interest with the pharmaceutical industry. The first of these schedules was conducted in Quebec, Canada where the extended 0-6-60 month schedule was promoted for girls under 16 years.³⁷37. Franco EL. Bernard Duval: the architect of Quebec’s HPV immunization programme. Public Health Genomics. 2009;12(5-6):261-3. https://doi.org/10.1159/000214916
https://doi.org/10.1159/000214916... Later, in Mexico, a similar vaccination program recommended by a group of experts coordinated by the National Institute of Public Health was initiated.³⁸38. Hernández-Ávila M, Torres-Ibarra L, Stanley M, Salmerón J, Cruz-Valdez A, Muñoz N, et al. Evaluation of the immunogenicity of the quadrivalent HPV vaccine using 2 versus 3 doses at month 21: An epidemiological surveillance mechanism for alternate vaccination schemes. Hum Vaccin Immunother . 2016;12(1):30-8. https://doi.org/10.1080/21645515.2015.1058458
https://doi.org/10.1080/21645515.2015.10... ^,3939. Lazcano-Ponce E, Stanley M, Muñoz N, Torres L, Cruz-Valdez A, Salmerón J, et al. Overcoming barriers to HPV vaccination: non-inferiority of antibody response to human papillomavirus 16/18 vaccine in adolescents vaccinated with a two-dose vs. a three-dose schedule at 21 months. Vaccine . 2014;32(6):725-32. https://doi.org/10.1016/j.vaccine.2013.11.059
https://doi.org/10.1016/j.vaccine.2013.1... Mexico was a pioneer in adopting a 2-dose alternative vaccination schedule in April 2014. Currently, there is evidence that alternative schedules are not inferior to the traditional schedule in terms of immunogenicity.⁴⁰40. Neuzil KM, Canh do G, Thiem VD, Janmohamed A, Huong VM, Tang Y, et al. Immunogenicity and reactogenicity of alternative schedules of HPV vaccine in Vietnam: a cluster randomized noninferiority trial. JAMA. 2011;305(14):1424-31. https://doi.org/10.1001/jama.2011.407
https://doi.org/10.1001/jama.2011.407... In 2012,⁴¹41. Vassilakos P, Untiet S, Petignat P. Cervical cancer prevention in Switzerland: the challenges of the vaccine era. Rev Med Suisse. 2012;8(359):2015-6. Switzerland adopted a 2-dose vaccination schedule against HPV in girls under 15 years old under assuming age was the main mediator of the protection induced by the vaccine and not the number of doses. This assumption would explain why the vaccine was the main inducer of IgG responses, plasma cells, and memory B cell formation and why 2 doses administered with a 6-month interval provided similar protection during the initial years of vaccination.

In April 2014, the Council officially pronounced the adoption of a vaccination schedule against HPV with only 2 doses with a periodicity of 0 and 6 months. The justification for this resolution, in which Mexico was a pioneer and was subsequently officially recommended by the WHO as a vaccination policy at a global level, was that the immunological responses of girls aged 9 to 11 years after two doses of HPV vaccine were similar to or greater than those obtained after three doses in women aged 16 to 26 years.

The benefits of this decision are logistical and economic; increasing coverage and providing greater flexibility in the application of the second dose. Moreover, the savings generated from not administering a third dose are considerable. Alternative schedules with two doses and schedules with a third dose at 60 months in girls 9-11 years of age can offer a) improvements in the immune response in the medium- and long-term, because there is evidence that a new exposure to HPV increases the expression of antibodies logarithmically, and b) advantages in its administration, since it is easier to organize these schedules within the framework of schools and consequently provides a better opportunity for equity in obtaining greater coverage and adherence to complete schedules in the captive population before leaving compulsory schooling. However, although the recommendation is plausible from an immunological perspective, there is no evidence from clinical trials of efficacy to support this determination for ethical reasons.

Currently, a paradigm shift is perceived toward the application of a single dose of vaccine against HPV. Research groups at a global level are evaluating the hypothesis that men and women who receive one versus two doses do not have a higher prevalence of HPV and that consequently the effect of the intervention is equivalent.

In this regard, demonstration studies are being conducted in population universes to evaluate the effect of a single dose of HPV vaccine. The strategy is to evaluate the effect of administering 1 versus 2 doses in a specific community using a randomized intervention allocation strategy. In the 2-dose intervention group, the most biologically and logistically efficient approach is to administer the second intervention between 6 and 12 months after the first intervention. The outcome to be evaluated in men who have sex with men is the presence of HPV DNA in the anal canal, which is obtained and determined in the basal measurement during the administration process of the first dose. This type of intervention is feasible in Mexico due to its invaluable tradition of innovation in public policies for the prevention and control of anogenital cancer and its implementation of large demonstration studies. Currently, we can affirm that with the current evidence, vaccination of all groups at risk of anogenital cancer with a single dose will be the preamble to the attenuation of the impact of persistent HPV infections and their consequent lesions.⁴²42. Wheeler C. Numbers game: Researchers explore whether fewer than 3 doses of HPV vaccine are effective. Cancer. 2016;122(1):11-2. https://doi.org/10.1002/cncr.29815
https://doi.org/10.1002/cncr.29815...

Materials and methods

Hypotheses

Objectives

Primary objective

Secondary objectives

Study population and procedures

The sample sizes for the five cohorts are: 6 000 MSM, 500 transgender women, 400 homeless men and women, 400 sexual assault victims, 2 500 female sex workers (figure 1). This study is a mixed methods study combining public health interventions offering primary and secondary prevention of HPV to populations highly vulnerable to these health problems with evaluation of the interventions in a 12-month follow-up (figures 1,2,3). In addition the study includes qualitative interviews that will undergo systematic analysis on the perceptions, meanings, and individual experiences of the intervention, within the study groups.

A central element of the present project is a parallel study of five sentinel cohorts of the adult population ≥14 years and ≤45 years of age that is operationally coordinated by the Condesa and Iztapalapa Specialized Clinics, which belong to the health services of Mexico City and the Program of Care for rape victims. This program is coordinated by the Specialized Clinics in collaboration with the Mexico City Attorney General of Justice, especially the Victims Care Center, which is a program of the Center for Therapy in Support of Victims of Sex Crimes. We will attempt to include at least 80% of the population of each interest group in the epidemiological component of the project. Study subjects will be recruited (2018-2019) during their routine care within any program or service they participate in within the Condesa and Iztapalapa Specialized Clinics; in addition, posters will be placed within the clinics inviting potential study subjects to participate and civil society organizations which collaborate with the clinics will be visited regularly to invite persons involved in their activities to participate in the study.

For the qualitative intervention component, individuals from the five vulnerable groups will be selected for voluntary participation in qualitative semi-structured interviews. This sub-sample will be purposely selected to include the maximum variation of characteristics, and 12 to 16 semi-structured individual interviews will be conducted for each study group. These interviews will explore perceptions of HPV, experiences as users of preventive care for HPV and related cancers, acceptability of and meanings related to HPV vaccination and barriers to and facilitators of primary prevention (vaccination) and secondary prevention (screening and treatment) of HPV.

The study protocol and instruments were approved by the Research, Ethics and Biosecurity Committees of the National Institute of Public Health. All study participants will provide signed informed consent before participating in any study procedure or completing any study instruments (and consent forms will be signed by two witnesses).

Sample collection and vaccination

At the beginning of the study, all MSM who agree to participate in the study will receive the HPV vaccination in an alternative schedule for MSM of 1 versus 2 doses over a 6-month period. In addition, a control group will be screened for high-risk HPV and vaccinated at 12 months. For transgender women, women and men living on the street, and women and men who have suffered rape, a 2-dose regimen of the tetravalent HPV vaccine will be administered over a 6-month period. The additional combined strategy corresponds to screening for high-risk HPV subtypes to identify intraepithelial lesions in the transformation zone of the anal and/or cervical canals (figures 2 and 3).

Additionally, samples will be self-collected from the anal canal, oral cavity, and vaginal canal. These samples will be collected both at the baseline measurement and at 12 months after vaccination to assess changes in the prevalence and incidence of new HPV infections in the different study groups. All HPV-positive anal and cervical samples will be evaluated using liquid-based cytology; analysis will be done at the National Institute of Public Health.

On a single occasion, additional samples will be collected from a proportional sample of the different study groups (70% of MSM and 90% of women, not including transgender women) for the identification of other STIs, including Neisseria gonorrhea, syphilis, HIV, herpes simplex virus type 2, hepatitis B virus, and hepatitis C virus. Positive cases will be referred to the corresponding medical care within their respective affiliated clinics.

The HPV detection test has been installed at the National Institute of Public Health with the Cobas 4800 HPV platform. This test is a qualitative test that detects 14 high-risk genotypes using specific probes. It detects genotypes 16 and 18 individually and a pool of other types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) cataloged as high risk.

Cytological evaluation will be conducted for all HPV-positive samples from both the anal canal and cervix. A urine sample will be obtained, centrifuged, and prepared for DNA extraction. The sample will be stored at −20°C prior to processing for HPV detection. The techniques for these purposes are under evaluation. Blood samples (10-ml) will be collected from the study participants by vacuum venipuncture. The collected samples will be subjected to centrifugation to separate the sera into 2-ml aliquots, which will be stored in cryo-vials at −20°C prior to processing. Antibody responses to viral and bacterial etiological agents will be conducted as follows:

In cervical samples, an automated chemo-luminescent assay for bacterial DNA detection will be performed using polymerase chain reaction (PCR). The analytical procedure will be conducted according to the corresponding manufacturer’s laboratory instructions.⁴⁷47. Moncada J, Schachter J, Liska S, Shayevich C, Klausner JD. Evaluation of self-collected glans and rectal swabs from men who have sex with men for detection of Chlamydia trachomatis and Neisseria gonorrhoeae by use of nucleic acid amplification tests. J Clin Microbiol 2009;47:1657-1662. https://doi.org/10.1128/JCM.02269-08
https://doi.org/10.1128/JCM.02269-08...

Data analysis

To estimate the effectiveness of the strategy of combining HPV vaccination with HPV screening, the differences in the prevalence of HPV and the cumulative incidence of HPV infection and/or development of CIN 2+ and/or AIN 2+ will be estimated during the first 12 months of follow-up using the Kaplan-Meier method. The time-to-event method will be applied to evaluate the time from the specific type of HPV genital positivity to the incidence of anogenital lesions harboring the same HPV subtype within the lesion. The analytical unit for this study is HPV 16/18 type-specific infection and generic high-risk strain infection.

The transcripts of individual interviews will be analyzed with through coding transcribed material, which implies the classification of pieces of the interviews into a priori and emerging categories to systematize the information and search for patterns, similarities, and differences.

Results

Women and men vaccinated against HPV and screened for HPV as a primary test in the future will have a lower prevalence and incidence of HPV infection and consequently a lower frequency of anogenital and oropharyngeal lesions caused by HPV. This decrease will greatly reduce the burden of HPV-associated neoplasms. Secondary prevention of the STIs included in this project will be achieved among individuals belonging to vulnerable groups who are the target population of this intervention. The detected STIs will be treated, and thus the negative impact on the health of these people will be reduced.

Discussion

In all of the vulnerable groups included in this proposal, the burden of diseases associated with HPV (genital warts and anogenital and oropharyngeal cancers) as well as STIs is a public health problem that has a strong negative impact on their health and quality of life. The proposal will benefit individuals of these vulnerable groups in terms of their physical and emotional health in relation to their social and sexual relationships and in general in terms of their quality of life. It will also imply a benefit in economic terms for the health services of Mexico City, since the proposed intervention has been shown to be cost-effective, especially in vulnerable populations, such as those included in this proposal.

This study has limitations: whether HPV infections occurring in adults (after onset of sexual activity) are an important cause of anogenital (or oral) cancers at a population level in vulnerable groups such as those studied here has not been fully proven, in part due to insufficient studies in some of these populations.⁴⁸48. Brown B, Poteat T, Marg L, Galea JT. Human papillomavirus-related cancer surveillance, prevention, and screening among transgender men and women: neglected populations at high risk. LGBT Health . 2017;4(5):315-9. https://doi.org/10.1089/lgbt.2016.0142
https://doi.org/10.1089/lgbt.2016.0142... However, as anogenital cancer rates are high in adults,⁴⁹49. Machalek DA, Poynten M, Jin F, Fairley CK, Farnsworth A, Garland SM, et al. Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: a systematic review and meta-analysis. Lancet Oncol. 2012;13(5):487-500. https://doi.org/10.1016/S1470-2045(12)70080-3
https://doi.org/10.1016/S1470-2045(12)70... including older adults,⁵⁰50. de Sanjose S, Wheeler CM, Quint WGV, Hunt WC, Joste NE, Alemany L, et al. Age-specific occurrence of HPV16- and HPV18-related cervical cancer. Cancer Epidemiol Biomarkers Prev. 2013;22(7):1313-8. https://doi.org/10.1158/1055-9965.EPI-13-0053
https://doi.org/10.1158/1055-9965.EPI-13... and high-risk (oncogenic) HPV types are also high in both younger and older adults,⁵¹51. Hammer A, Rositch A, Qeadan F, Gravitt PE, Blaakaer J. Age-specific prevalence of HPV16/18 genotypes in cervical cancer: A systematic review and meta-analysis. Int J Cancer . 2016;138(12):2795-803. https://doi.org/10.1002/ijc.29959
https://doi.org/10.1002/ijc.29959... it seems likely that some of this disease burden is related to infections occurring during adulthood. Another possible limitation of the study is that, in order to effect changes in screening algorithms and populations in vaccination campaigns, policy- and decision-makers, healthcare administrators and providers will need to be convinced of the advantages, cost-effectiveness and sustainability of the combined screening and vaccination strategy for vulnerable populations which this study proposes.⁵²52. Bosch FX, Robles C, Díaz M, Arbyn M, Baussano I, Clavel C, et al. HPV-FASTER: broadening the scope for prevention of HPV-related cancer. Nat Rev Clin Oncol. 2016;13(2):119-32. https://doi.org/10.1038/nrclinonc.2015.146
https://doi.org/10.1038/nrclinonc.2015.1... ^,5353. Wigle J, Coast E, Watson-Jones D. Human papillomavirus (HPV) vaccine implementation in low and middle-income countries (LMICs): health system experiences and prospects. Vaccine . 2013;31(37):3811-7. https://doi.org/10.1016/j.vaccine.2013.06.016
https://doi.org/10.1016/j.vaccine.2013.0... ^,5454. Curotto M, Zalacaín-Colombo J, Paolino M, Arrossi S. Adopción e implementación del ofrecimiento de la autotoma VPH por agentes sanitarios en Jujuy, Argentina. Salud Publica Mex . 2018;60. https://doi.org/10.21149/8854
https://doi.org/10.21149/8854...

This study results from the current discussion of the need to evaluate the relevance of the introduction of vaccines that protect against HPV not only in the target population of national vaccination programs (i.e., girls and pre-adolescents) but also in vulnerable groups of men and women who are at high risk of exposure to HPV types 6 and 11, which are responsible for most genital warts, and the high-risk (oncogenic) types of HPV, including boys and girls who have suffered rape.⁵⁵55. Garland SM, Subasinghe AK, Jayasinghe YL, Wark JD, Moscicki AB, Singer A, et al. HPV vaccination for victims of childhood sexual abuse. Lancet . 2015;386(10007):1919-20. https://doi.org/10.1016/S0140-6736(15)00757-6
https://doi.org/10.1016/S0140-6736(15)00... With an intervention such as the one presented here, which includes the proposed actions, an organized social response will be provided to control one of the most recurrent sexually transmitted diseases, which produces anal, cervical, and oropharyngeal intraepithelial neoplasia as well as genital warts and has other impacts on the sexual, reproductive, and overall health of people.

This combined vaccination-screening strategy must be implemented in groups with very high social vulnerability. This approach constitutes the optimal organized social response to prevent and treat lesions derived from persistent HPV infections in a timely manner and the negative impact.

Acknowledgments

This study is being funded by the Secretariat of Science, Technology and Innovation (La Secretaría de Ciencia, Tecnología e Innovación - SECITI) of Mexico City under reference number SECITI/094/2017 entitled “Prevention and control of neoplasms associated with HPV in high-risk groups in Mexico City: an intervention with a social dimension”.

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