High risk HPV infection prevalence and associated cofactors: a population-based study in female ISSSTE beneficiaries attending the HPV screening and early detection of cervical cancer program

According to the latest systematic analysis from the Global Burden of Disease Study 2015, 530,000 new cervical cancer (CC) cases were attributable to Human Papillomavirus (HPV) infection [1]. Estimates from the Mexican Burden of Disease Study (MBD-2013) established in 102,241 the number of cancer cases in women, being CC the second most incident neoplasia, only after breast cancer. Age-standardized incidence rate for CC was 12 per 100,000 (12,562 new cases). A ranking of age-standardized mortality rates among Mexican women showed that CC ranked first in those states with higher marginality scores [2].

Worldwide prevalence of HPV infection in women with no cervix abnormalities is 11–12%, with the highest rates being found in sub-Saharan Africa (24%), Eastern Europe (21%), and Latin America (16%) [3]. Age-specific HPV distribution exhibits a peak at young ages (< 25-year-old), and a rebound at older ages (> 45-year-old) in the Americas and Africa. The most prevalent HPV genotypes are HPV-16 (3.2%), HPV-18 (1.4%), HPV-52 (0.9%), HPV-31 (0.8%), and HPV-58 (0.7%) [4]. The prevalence of oncogenic HPV genotypes is increased in women with cervical pathology in proportion to the severity of the premalignant lesion and the burden of HPV infection; thus, cancer is explained by a higher prevalence of potentially oncogenic − 16 and − 18 HPV genotypes [3].

In Mexico, the official standard NOM-014-SSA2–1994 supported by national government covers CC prevention, detection, diagnosis, treatment, control, and epidemiological surveillance. The program for early CC detection consists of a Papanicolaou smear test, along with biomolecular tests for HPV detection as a support for cervical cytology and direct visualization with acetic acid (only when Papanicolaou smear is not available). This detection test should be performed on any asymptomatic women between 25- to 64-year-old or women under 25 and over 64 years of age who show reduced morbidity and the presence of some risk factor associated with CC [5]. The CC Action Program has been implemented to “reduce mortality from cervical cancer in the female population from Mexico”; to achieve this, strategic actions have been taken, including “inter- and intra-sector coordination, timely detection, diagnosis, treatment, quality control, supervision, evaluation and research, and infrastructure strengthening” [6].

About 10% (12 449,609) of the Mexican population is affiliated to the Institute of Security and Social Services for State Workers (ISSSTE); of these, 26.9% (3 346,043) are women in ages from 25 to 64 years, the target group of the Program for HPV Screening and Early Detection of Cervical Cancer and registered in the Women’s Cancer Detection System (SIDECAM); in turn, 1 602,754 ISSSTE affiliates were users of the program in 2013. This study is aimed to assess the prevalence of high-risk- (HR)-HPV infection and associated cofactors among users of the Program for HPV Screening and Early Detection of Cervical Cancer and registered in the SIDECAM.

In Mexico, CC prevention has been one of the main objectives in the public health sector for several decades. This led to the development and implementation of the national program of early detection of cancer; in terms of research, this objective also encouraged studies to determine the prevalence of HR-HPV infection. In addition to early CC detection, identifying the prevalence of risk factors involved in HR-HPV infection is relevant, for this would allow the implementation of interventions to prevent and/or treat the disease.

This study is the second largest conducted in Latin America, and the most extensive population-based study to date using the Cobas 4800 system, a highly sensitive and specific test to detect HR-HPV, discriminating HPV-16 and HPV-18 [7]. The overall prevalence of HPV infection in the female ISSSTE-affiliated population in 2013–2015 was 13%, a result comparable with other studies conducted in Mexico. Only two previous studies based on large populations in Mexico have reported HR-HPV specific prevalence estimates. The age distribution of HR-HPV infection in our studied population is similar from those previously reported [8‐11].

In the population of our study, the prevalence of HR-HPV shows a first increase at an age of 18, a finding that can be correlated with the sexual initiation in younger women, when they are exposed to HPV for the first time and their adaptive immune response has yet to develop, showing a gradual descent from an age of 25. The maximum peak of HR-HPV prevalence was in ages from 18 to 24 years, with a decrease in older ranges and a marked prevalence increase from the age of 65. Previously, have been reported examples of the U-shaped curve of age-specific HPV prevalence areas in Latin America (Chile, Colombia and Mexico) [12, 13], similar to the findings of our study, regions where a second peak in the oldest group seems to be more prominent [14], could be the result of immune depression, leading to reactivation of previous quiescent infections [15, 16]. However, the second peak in oldest age group could be influenced by the selection criteria inside the program for HPV Screening and Early Detection of Cervical Cancer of women over 64 years of age who show reduced morbidity and the presence of some risk factor associated with CC.

Interestingly, HPV-16/18 prevalence was similar to that reported in a previous study in Mexico [8], but lower than values reported in other populations throughout Latin America; unfortunately, due to the differing designs of these studies, it is difficult to draw conclusions about comparative infection burdens [10, 12, 17, 18]. In addition to the differences in patient-referred symptoms and the signs reported by colposcopists between HR-HPV-positive and negative groups, the variables age, number of sexual partners, history of hormonal contraception, and smoking habit were found to be risk factors for HR-HPV infection, HPV-16 infection, and infection by non-16/18 HR-HPV.

Previous studies found a similar association of a higher number of sexual partners [19‐21], history of hormonal contraception [22], and smoking habit [23, 24] with the risk of HR-HPV infection. Higher number of sexual partners as a risk factor for acquiring new HR-HPV infections could be due to changes in the sexual behavior of women and/or their partners, or to a cohort effect [25‐27].

Although the association between HR-HPV infection and hormonal contraception found in the multivariate analysis was weak, the proposed association is biologically plausible because the estrogens and progestagens have been reported to interact with hormone receptors, mainly progesterone receptors, in the cervical tissue; additionally, sex steroid hormones are thought to enhance the expression of HPV-16 E6 and E7 oncogenes, promoting the degradation of p53 tumor suppressor genes and enhancing the ability of viral DNA to transform cells [22].

Smoking is another risk factor associated with HR-HPV infection; this could be explained considering that tobacco smoke contains well-known carcinogens that could have a direct transformation effect on cervix tissues and/or cause immunosuppression, allowing HPV infection to persist and progress to cancer [24].

The association herein found between HR-HPV infection and premalignant lesion in the cervix confirms the already known etiological role of HPV in this disease [28‐32].

While no cancer records exist to date in Mexico at the national, regional, nor state levels, great efforts have been made within the program for screening and co-testing for CC in the ISSSTE to integrate such screening with an comprehensive care model with a process-oriented approach, going from the traditional cytology-only scheme to a combination of cytology and HR-HPV genotyping, aiming to implement liquid-based cytology in the future, along with HR-HPV genotyping and immunohistochemical tests (p16, ki67). To this end, the ISSSTE has reinforced its infrastructure in terms of cytology laboratory services, molecular biology laboratory, and colposcopy rooms; it also increased its personnel (cytotechnologists, cytopathologists, chemists, and colposcopists) and installed capacity, as reflected in the number of cytology and HR-HPV tests performed per year, to avoid follow-up interruption in women screened as positive.

This study provides information about the prevalence of HR-HPV infection among the female ISSSTE beneficiaries attending in the Program for HPV Screening and Early Detection of Cervical Cancer and registered in the Women’s Cancer Detection System as part of primary care services. It can help policymakers to make better-informed decisions on resource allocation when trying to determine the best screening and triage practices in Mexico.

The main strength of this study is its large-population-based approach. This is the second largest study in Mexico to assess the prevalence of HR-HPV (both HPV-16/18 and non-16/18 HR-HPV). As such, it can also be used in the future to evaluate the impact of HPV vaccination within the ISSSTE female user population. On the other hand, the main limitation of our study is the difficulty to generalize its findings to other populations.

HR-HPV prevalence in female users of the Program for HPV Screening and Early Detection of Cervical Cancer of the ISSSTE is similar to the population-based prevalence previously reported in Mexican women without cervical alterations. Age, number of sexual partners, history of hormonal contraception, and smoking habit were found to be positively associated with HR-HPV infection; and number of sexual partners and smoking with HPV-16 infection and infection by non-16/18 HR-HPV. The ISSSTE has a robust early detection program based in cytology studies and HPV testing, that allows us to know the prevalence of HR-HPV infection in the female user population.