Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT05149248 |
| Other study ID # |
SECITI/094/2017 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2/Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
May 30, 2018 |
| Est. completion date |
November 28, 2019 |
Study information
| Verified date |
November 2021 |
| Source |
Instituto Nacional de Salud Publica, Mexico |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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.
