Prevention and Control of Neoplasms Associated With HPV in High-risk Groups in Mexico City: The Condesa Study
Condition: Cancer of Cervix
MeSH terms: Neoplasms; Uterine Cervical Neoplasms
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      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 neoplasms in the
      anogenital region and oral cavity among men who have sex with men, people with HIV, homeless
      people, transgender women, female sex workers and rape victims.

      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.

      Conclusions: This study will generate scientific evidence on effectiveness of a combined
      vaccination-screening strategy to reduce the burden of HPV-associated neoplasms within
      vulnerable populations in Mexico.
    

Detailed description: 
      Men who have sex with men (MSM), people with HIV, homeless people (many of whom participate
      in survival sex), female sex workers, transgender women and rape victims are at high risk for
      human papillomavirus (HPV) infection and consequently developing cancers associated with
      chronic HPV infection including cervical, vaginal , vulvar , and anal cancers in women,
      cancer of the penis , anal cancer, in men, and cancer of the oropharynx , tongue, and tonsils
      in both men and women, In part, this is related to increased life expectancy among people
      with HIV (given greater anti-retroviral treatment coverage).

      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 . 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 .

      The HPV FASTER concept combines HPV vaccination with HPV screening. It is based on the HPV
      vaccine's high efficacy and the high sensitivity of high-risk HPV testing for primary
      detection of anogenital cancer precursor lesions (as documented by our research group in more
      than 200,000 Mexican women). 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-infections16. 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 , . 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 . 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 , . Moreover, some research has shown that
      vaccination against HPV in populations with HIV is cost-effective.

      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.
      These vaccines are highly effective, provide high levels of immunogenicity , have acceptable
      security profiles and have been incorporated into public vaccination policies with 3-dose
      schedules over a 6-month period 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 . Later, in Mexico, a similar vaccination program recommended by a group of
      experts coordinated by the National Institute of Public Health was initiated. 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 . In 2012 , 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 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, it can be affirmed 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 .

      Methods Hypotheses

        -  The application of a combined HPV vaccination scheme and screening through the
           identification of high-risk HPV subtypes will reduce the prevalence of HPV infection in
           the oral and anogenital cavities in the different study groups, at 12 months
           post-vaccination. Consequently, the occurrence of grade 2 or higher anal intraepithelial
           neoplasia (AIN 2+) lesions in men and high-grade or higher cervical intraepithelial
           neoplasia (CIN 2+) lesions in women will decrease.

        -  Alternative vaccination schedules of one versus two doses of prophylactic vaccines
           against HPV are equivalent in terms of effectiveness.

        -  Urine and self-collected vaginal, anal canal, and oral cavity samples constitute an
           alternative epidemiological surveillance approach for monitoring the impact of a
           combined strategy HPV vaccination and screening for high-risk HPV subtypes in vulnerable
           populations.

      Objectives Primary objective

      • To evaluate the effectiveness of a combined strategy of HPV vaccination and screening for
      high-risk HPV subtypes to reduce the occurrence of HPV in the anogenital region and oral
      cavity in five highly vulnerable groups in Mexico City, Mexico: men who have sex with men,
      female sex workers, transgender women, subjects living in street situations, and people who
      have suffered rape.

      Secondary objectives

        -  To evaluate the effectiveness of alternative HPV vaccination schedules.

        -  To evaluate the usefulness of the collection of self-collected vaginal, anal, and urine
           samples as alternatives for monitoring the impact of a combined strategy of HPV
           vaccination and screening based on the detection of high-risk HPV subtypes.

        -  To assess the barriers to and facilitators of the introduction of a combined HPV
           vaccination and primary screening strategy with tests for high-risk HPV subtypes in the
           study groups.

      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, 2500 female sex
      workers. 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. 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. The investigators 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 the participant
      attend 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.

      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 centrifuged
      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:

        -  Hepatitis B and hepatitis C. Automated enzyme-linked immunosorbent assay. The analytical
           procedure will be conducted according to the corresponding manufacturer's laboratory
           instructions , .

        -  Syphilis. The Venereal Disease Research Laboratory (VDRL) screening test and the Serodia
           Treponema pallidum (TP) confirmatory test by particle agglutination. The analytical
           procedures will be performed in accordance with the laboratory instructions of the
           corresponding manufacturers .

        -  Herpes simplex virus type 2. Microplate immuno-enzymatic assay for the detection of
           type-specific viral antibodies. Confirmation of positive samples by Western blotting
           assay. The analytical procedures will be performed in accordance with the laboratory
           instructions of the corresponding manufacturers 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 .

      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.
    

Intervention name(s): Gardasil® [Quadrivalent Human Papillomavirus (Types 6,11,16,18) Recombinant vaccine]; Two dose; Control group; 2 dose vaccination over 6 month
Intervention type(s): Biological; Biological; Other; Biological
Intervention description(s): HPV vaccination in an alternative schedule for MSM of 1 dose (M0).; HPV vaccination in an alternative schedule for MSM of 2 doses over a 6-month period (M0,6); HPV vaccination at 12 months; 2-dose HPV vaccination regimen over a 6-month period (M0,6)
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: 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. 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.
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: NEOPLASMS; HPV; PREVENTION; CONTROL; HIGH RISK