MÓDULO 2 - Material adicional

1. Información adicional sobre Historia natural y Epidemiologia de

la infección por el VPH

Historial natural de la infección por VPH

Silvia de Sanjosé, Maria Brotons and Miguel Angel Pavón. The natural history of human papillomavirus
infection. Best Pract Res Clin Obstet Gynaecol 2017; XXX, 1-12

Abstract
Human papillomavirus (HPV) is a small double-stranded DNA virus that commonly infects humans. The
oncogenic characteristics of HPV derive from the oncoproteins E6 and E7 that act inhibiting p53 and
pRB tumor suppressors. About 5% of all cancers worldwide are attributable mainly to those known as
high-risk, including HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. Infection with HPV is
common after sexual initiation, but the majority of HPV infections do not cause symptoms or disease
and are cleared within 12-24 months post-infection. Only a small fraction of those infections that
persist or progress to a preneoplastic lesion result in cancer. Persistence of HPV infection is needed to
start the oncogenic process. Clearance of infection is common in young adults. Viral load and viral type
are the main cofactors for progression from infection to cervical intraepithelial lesions and cancer.
Smoking, hormonal exposure, and HIV are additional exposures that increase the risk of progression
to cancer. The adverse health effects of HPV infections can be largely controlled through vaccination
and screening.

https://www.ncbi.nlm.nih.gov/pubmed/28964706

Epidemiologia del VPH

Beatriz Serrano, María Brotons, Francesc Xavier Bosch, Laia Bruni. Epidemiology and burden of HPV-related
disease. Best Pract Res Clin Obstet Gynaecol 2018, 47:14-26

Abstract
Human papillomavirus (HPV) infection is recognized as one of the major causes of infection-related
cancer in both men and women. High-risk HPV types are not only responsible for virtually all cervical
cancer cases but also for a fraction of cancers of the vulva, vagina, penis, anus, and head and neck
cancers. Furthermore, HPV is also the cause of anogenital warts and recurrent respiratory
papillomatosis. Despite the availability of multiple preventative strategies, HPV-related cancer remains
a leading cause of morbi-mortality in many parts of the world, particularly in less developed countries.
Thus, in this review, we summarize the latest estimates of the global burden of HPV-related diseases,
trends, the attributable fraction by HPV types, and the potential preventative fraction.

https://www.ncbi.nlm.nih.gov/pubmed/29037457

Incidencias de cánceres asociados a VPH

Catherine de Martel, Martyn Plummer, Jerome Vignat and Silvia Franceschi. Worldwide burden of cancer
attributable to HPV by site, country and HPV type. Int. J. Cancer 2017; 141, 664–670

HPV is the cause of almost all cervical cancer and is responsible for a substantial fraction of other
anogenital cancers and oropharyngeal cancers. Understanding the HPV-attributable cancer burden
can boost programs of HPV vaccination and HPV-based cervical screening. Attributable fractions (AFs)
and the relative contributions of different HPV types were derived from published studies reporting on
the prevalence of transforming HPV infection in cancer tissue. Maps of age standardized incidence
rates of HPV-attributable cancers by country from GLOBOCAN 2012 data are shown separately for the
cervix, other anogenital tract and head and neck cancers. The relative contribution of HPV16/18 and
HPV6/11/16/18/31/33/45/52/58 was also estimated. 4.5% of all cancers worldwide (630,000 new cancer
cases per year) are attributable to HPV: 8.6% in women and 0.8% in men. AF in women ranges from
<3% in Australia/New Zealand and the USA to >20% in India and sub-Saharan Africa. Cervix accounts
for 83% of HPV-attributable cancer, two-thirds of which occur in less developed countries. Other HPV-
attributable anogenital cancer includes 8,500 vulva; 12,000 vagina; 35,000 anus (half occurring in men)
and 13,000 penis. In the head and neck, HPV‐attributable cancers represent 38,000 cases of which
21,000 are oropharyngeal cancers occurring in more developed countries.

The relative contributions of HPV16/18 and HPV6/11/16/18/31/33/45/52/58 are 73% and 90%,
respectively. Universal access to vaccination is the key to avoiding most cases of HPV-attributable
cancer. The preponderant burden of HPV16/18 and the possibility of cross-protection emphasize the
importance of the introduction of more affordable vaccines in less developed countries.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520228/

2. Información adicional sobre Epidemiologia la infección por VPH

y cáncer cervical en Colombia

Epidemiologia del cáncer cervical en Colombia

Nubia Muñoz and Luís Eduardo Bravo. Epidemiology of cervical cancer in Colombia. Salud Pública Mex 2014;
56:431-439.

Abstract

OBJECTIVE:
To describe the incidence, mortality, time trends and prognostic factors for cervical cancer in Cali,
Colombia, and to review the molecular epidemiological evidence showing that HPV is the major and
necessary cause of cervical cancer and the implications of this discovery for primary and secondary
prevention.

MATERIALS AND METHODS:

Incidence rates of cervical cancer during a 45-year period (1962-2007) were estimated based on the
population-based cancer registry of Cali and the mortality statistics from the Municipal Health
Secretariat of Cali. Prognostic factors were estimated based on relative survival. Review of the
molecular epidemiological evidence linking HPV to cervical cancer was focused on the studies carried
out in Cali and in other countries.

RESULTS:
Incidence rates of squamous cell carcinoma (SCC) declined from 120.4 per 100 000 in 1962-1966 to
25.7 in 2003-2007 while those of adenocarcinoma increased from 4.2 to 5.8. Mortality rates for cervical
cancer declined from 18.5 in 1984-1988 to 7.0 per 100 000 in 2009-2011. Survival was lower in women
over 65 years of age and in clinical stages 3-4. Review of the molecular epidemiological evidence
showed that certain types of HPV are the central and necessary cause of cervical cancer.

CONCLUSIONS:
A decline in the incidence and mortality of SCC and an increase in the incidence of adenocarcinoma
during a 45-year period was documented in Cali, Colombia.

https://www.ncbi.nlm.nih.gov/pubmed/25604289
Distribución de tipos VPH en cánceres cervicales diagnosticados en cali, colombia, entre
1950 y 1999
Gloria Ines Sanchez, Luis Eduardo Bravo, Gustavo Hernandez-Suarez, Sara Tous, Laia Alemany, Silvia de
Sanjose, F. Xavier Bosch, Nubia Muñoz. Secular trends of HPV genotypes in invasive cervical cancer in Cali,
Colombia 1950–1999. Cancer Epidemiology 2016; 40: 173-178.

Abstract
Aim To estimate relative contribution and time trends of HPV types in cervical cancer in Cali, Colombia
over a 50 years' period.

METHODS:
Paraffin blocks of 736 cervical cancer histological confirmed cases were retrieved from the pathology
laboratory at Hospital Universitario del Valle (Cali, Colombia) and HPV genotyped using SPF10-
PCR/DEIA/LiPA25 (version 1) assay. Marginal effect of age and year of diagnosis in secular trends of
HPV type prevalence among HPV+ cases were assessed by robust Poisson regression analysis.

RESULTS:
64.7% (95%CI: 59.9-69.2) of squamous cell carcinomas (SCCs) were attributed to HPV 16 and 18, 78.2%
(95%CI: 74-82) to HPV 16, 18, 31, 33 and 45 and 84.8% (95%CI: 81-88.1) to HPV 16, 18, 31, 33, 45, 52 and
58 while ninety-three percent of adenocarcinomas (ADCs) were attributed to HPV 16, 18 and 45 only.
The prevalence of specific HPV types did not change over the 50-year period. A significant downward
trend of prevalence ratios of HPV16 (P=0.017) and α7 but HPV 18 (i.e., HPV 39, 45, 68, 70, P=0.024) with
increasing age at diagnosis was observed. In contrast, the prevalence ratio to other HPV genotypes of
α9 but HPV 16 genotypes (i.e., HPV 31, 33, 35, 52, 58, 67, P=0.002) increased with increasing age at
diagnosis.

CONCLUSION:
No changes were observed in the relative contribution of HPV types in cervical cancer in Cali, Colombia
during the 50 years. In this population, an HPV vaccine including the HPV 16, 18, 31, 33, 45, 52 and 58
genotypes may have the potential to prevent ∼85% and 93% of SCC and ADC cases respectively.

https://www.ncbi.nlm.nih.gov/pubmed/26771314

Infección cervical por VPH en la población Colombiana (Bogotá)

Molano M, Posso H, Weiderpass E, van den Brule AJ, Ronderos M, Franceschi S, Meijer CJ, Arslan A, Munoz N;
HPV Study Group HPV Study. Prevalence and determinants of HPV infection among Colombian women with
normal cytology. British Journal of Cancer 2002, 87, 324 – 333
Abstract

Human papillomavirus is the principal risk factor associated with cervical cancer, the most common
malignancy among women in Colombia. We conducted a survey, aiming to report type specific
prevalence and determinants of human papillomavirus infection in women with normal cytology. A
total of 1859 women from Bogota, Colombia were interviewed and tested for human papillomavirus
using a general primer GP5+/GP6+ mediated PCR-EIA. The overall HPV DNA prevalence was 14.8%; 9%
of the women were infected by high risk types, 3.1% by low risk types, 2.3% by both high risk/low risk
types and 0.4% by uncharacterized types (human papillomavirus X). Thirty-two different human
papillomavirus types were detected, being human papillomavirus 16, 58, 56, 81(CP8304) and 18 the
most common types. The human papillomavirus prevalence was 26.1% among women younger than
20 years, 2.3% in women aged 45-54 years, and 13.2% in women aged 55 years or more. For low risk
types the highest peak of prevalence was observed in women aged 55 years or more. Compared to
women aged 35-44 years, women aged less than 20 years had a 10-fold increased risk of having
multiple infections. Besides age, there was a positive association between the risk of human
papillomavirus infection and number of regular sexual partners and oral contraceptive use. In women
aged below 25 years, high educational level and having had casual sexual partners predicted infection
risk. In conclusion, there was a broad diversity of human papillomavirus infections with high risk types
being the most common types detected. In this population multiplicity of sexual partners and, among
young women, high educational level and casual sexual partners seem to determine risk

https://www.ncbi.nlm.nih.gov/pubmed/12177803

Desigualdades sociales en la mortalidad por cáncer cervical en Colombia

Esther de Vries, Ivan Arroyave, Constanza Pardo, Carolina Wiesner, Raul Murillo, David Forman, Alex Burdorf,
and Mauricio Avendaño. Trends in inequalities in premature cancer mortality by educational level in
Colombia, 1998–2007. Epidemiol Community Health 2015; 69(5): 408–415.

Abstract

BACKGROUND:
There is a paucity of studies on socioeconomic inequalities in cancer mortality in developing countries.
We examined trends in inequalities in cancer mortality by educational attainment in Colombia during
a period of epidemiological transition and rapid expansion of health insurance coverage.

METHODS:
Population mortality data (1998-2007) were linked to census data to obtain age-standardised cancer
mortality rates by educational attainment at ages 25-64 years for stomach, cervical, prostate, lung,
colorectal, breast and other cancers. We used Poisson regression to model mortality by educational
attainment and estimated the contribution of specific cancers to the slope index of inequality in cancer
mortality.

RESULTS:
We observed large educational inequalities in cancer mortality, particularly for cancer of the cervix
(rate ratio (RR) primary vs tertiary groups=5.75, contributing 51% of cancer inequalities), stomach
(RR=2.56 for males, contributing 49% of total cancer inequalities and RR=1.98 for females, contributing
14% to total cancer inequalities) and lung (RR=1.64 for males contributing 17% of total cancer
inequalities and 1.32 for females contributing 5% to total cancer inequalities). Total cancer mortality
rates declined faster among those with higher education, with the exception of mortality from cervical
cancer, which declined more rapidly in the lower educational groups.

CONCLUSIONS:
There are large socioeconomic inequalities in preventable cancer mortality in Colombia, which
underscore the need for intensifying prevention efforts. Reduction of cervical cancer can be achieved
through reducing human papilloma virus infection, early detection and improved access to treatment
of preneoplastic lesions. Reinforcing antitobacco measures may be particularly important to curb
inequalities in cancer mortality.

https://www.ncbi.nlm.nih.gov/pubmed/25492898

3. Información adicional sobre Introducción de la vacuna VPH en

los programas de inmunización nacionales

Laia Bruni, Mireia Diaz, Leslie Barrionuevo-Rosas, Rolando Herrero, Freddie Bray, F Xavier Bosch, Silvia de
Sanjosé and Xavier Castellsagué. Global estimates of human papillomavirus vaccination coverage by region
and income level: a pooled analysis. Lancet Glob Health 2016; 4: e453–63
Abstract

BACKGROUND:
Since 2006, many countries have implemented publicly funded human papillomavirus (HPV)
immunisation programmes. However, global estimates of the extent and impact of vaccine coverage
are still unavailable. We aimed to quantify worldwide cumulative coverage of publicly funded HPV
immunisation programmes up to 2014, and the potential impact on future cervical cancer cases and
deaths.

METHODS:

Between Nov 1 and Dec 22, 2014, we systematically reviewed PubMed, Scopus, and official
websites to identify HPV immunisation programmes worldwide, and retrieved age-specific HPV
vaccination coverage rates up to October, 2014. To estimate the coverage and number of
vaccinated women, retrieved coverage rates were converted into birth-cohort-specific rates, with
an imputation algorithm to impute missing data, and applied to global population estimates and
cervical cancer projections by country and income level.

FINDINGS:
From June, 2006, to October, 2014, 64 countries nationally, four countries subnationally, and 12
overseas territories had implemented HPV immunisation programmes. An estimated 118 million
women had been targeted through these programmes, but only 1% were from low-income or lower-
middle-income countries. 47 million women (95% CI 39-55 million) received the full course of vaccine,
representing a total population coverage of 1·4% (95% CI 1·1-1·6), and 59 million women (48-71 million)
had received at least one dose, representing a total population coverage of 1·7% (1·4-2·1). In more
developed regions, 33·6% (95% CI 25·9-41·7) of females aged 10-20 years received the full course of
vaccine, compared with only 2·7% (1·8-3·6) of females in less developed regions. The impact of the
vaccine will be higher in upper-middle-income countries (178 192 averted cases by age 75 years) than
in high-income countries (165 033 averted cases), despite the lower number of vaccinated women (13·3
million vs 32·2 million).

INTERPRETATION:
Many women from high-income and upper-middle-income countries have been vaccinated against
HPV. However, populations with the highest incidence and mortality of disease remain largely
unprotected. Rapid roll-out of the vaccine in low-income and middle-income countries might be the
only feasible way to narrow present inequalities in cervical cancer burden and prevention.

https://www.ncbi.nlm.nih.gov/pubmed/27340003