1. Background and Role of HPV Infection
Human papillomavirus (HPV) infection is a necessary cause for virtually all cervical cancers and an attributable cause for variable proportions of anal, oropharyngeal, vaginal, vulvar and penile cancers worldwide. In addition to being a necessary cause of all cervical cancers, HPV also causes 88% of anal, 31% of oropharyngeal, 78% of vaginal, 25% of vulvar and 50% of penile cancers worldwide. HPV infection has been widely recognized as a necessary cause of cervical cancer for over 20 years, meaning that all cervical cancers are believed to be caused by an underlying HPV infection. In 2020, the WHO presented a global strategy to eliminate cervical cancer as a public health problem, with goals referred to as the 90–70–90 targets: vaccinating 90% of girls against HPV by 15 years of age, screening 70% of women with a high-performance test at 35 and 45 years of age, and treating 90% of women with cervical disease (precancerous lesions or invasive cancer).
The development of HPV vaccines began in the early 1990s after substantial epidemiology research demonstrated that HPV infection is the necessary causative agent of cervical cancer. All vaccines protect against infection with HPV16 and HPV18, which account for 71% of cervical cancers. Randomized controlled trials have shown that bivalent and quadrivalent vaccines have extremely high prophylactic efficacy against persistent infection and precancerous lesions. Studies have shown that bivalent and quadrivalent vaccines can also provide a certain degree of cross-protection against infection with phylogenetically related non-vaccine HPV types. As of 2022, 125 countries (64%) have introduced HPV vaccination in their national immunization programme for girls, and 47 countries (24%) also include boys aged 9–15 years. Global vaccination coverage with at least one dose in girls by 15 years of age was estimated to be 21% as of 2022. Randomized controlled trials have shown that HPV vaccines have high prophylactic efficacy (95%) in adults with no prior evidence of infection.
2. Temporal and geographical trends
Cervical cancer is the first cancer deemed amenable to elimination through prevention, and thus lessons from the epidemiology and prevention of this cancer type can provide information on strategies to manage other cancers.
The advent of HPV vaccines and screening approaches has created the opportunity to eliminate cervical cancer, a recognized public health problem, by the end of the 21st century. HPV vaccination programmes will probably prevent HPV-associated cancers other than cervical cancer, although research into the optimal screening approaches for these cancers is still ongoing. Marked declines in the prevalence of genital infection with vaccine-type HPV and high-grade cervical lesions have been reported in vaccine-eligible cohorts from many countries worldwide. The countries that were early adopters of HPV vaccination programmes and achieved moderate to high vaccination coverage (>50%) in the late 2000s, such as the UK, Sweden and Denmark, are now (15–20 years later) starting to observe declines in cervical cancer incidence among young adult women who were vaccinated as pre-adolescents. Registry data from Denmark have shown a 70% reduction in the rate of anal high-grade squamous intraepithelial lesions or worse in women who were vaccinated before the age of 17 years relative to unvaccinated women. The prevalence of oral infection with vaccine-type HPV has also declined since 2012 among men in the USA, most probably as a result of herd immunity from women vaccinated during this time period.
3. Incidence and Mortality Rates
Cervical cancer was one of the most frequently diagnosed cancer types worldwide and among those with the greatest incidence in women. Cervical cancer incidence remains highest in low-income and middle-income countries (LMICs), which have low levels of implementation and limited effective coverage of cervical cancer screening. In 172 out of 185 countries or territories, incidence rates still exceed the set elimination threshold, often by a considerable margin. The burden of cervical cancer is very high in countries in Africa, Latin America and Asia, and relatively low in countries in northern and western Europe, and North America. The incidence of oropharyngeal cancer has been increasing in most countries with long-term cancer registry data available, with more marked increases in younger cohorts.
4. Regional Trends Due to Prevention Efforts
Many high-income countries (HICs) in North America and Europe saw steady declines in cervical cancer incidence and mortality rates over the second half of the 20th century, to the point where cervical cancer is now rare in many of these countries. Most of the decline in cervical cancer incidence and mortality in North American and European countries in the 20th century is attributable to improvements in screening. Many countries in Asia and Latin America also saw declines in cervical cancer incidence during this time period despite low screening coverage, which might have been partly driven by a long-term trend of decreasing parity in many countries. Conversely, increases in cervical cancer incidence in China during the period 1990–2019 have been attributed to changes in sexual behavior leading to rising HPV transmission. Data on temporal trends in sub-Saharan Africa are limited, but the available data suggest that the incidence of cervical cancer has increased in many of these countries since the 1990s. This trend is probably the result of a high HPV prevalence combined with the human immunodeficiency virus (HIV) epidemic and low screening coverage in many countries.
5. Prevention Approaches: Vaccination & Screening
The World Health Organization (WHO) recommends administering HPV vaccines before the onset of sexual activity to maximize their prophylactic efficacy. As of 2022, an estimated 48% of 139 countries with cervical cancer screening programmes (35%) recommend HPV testing as the primary screening test, although most of these countries are still transitioning from cytology-based screening and have not yet fully implemented HPV-based screening. The Netherlands was the first country to fully replace cytology testing with HPV testing as the primary screening modality in 2017. At least nine countries worldwide have introduced HPV self-sampling as the primary approach for cervical cancer screening, and this number is expected to increase.
6. Vaccination Coverage and Successful Countries
HPV vaccination coverage of 90% alone can lead to a long-term reduction in the incidence of cervical cancer below the elimination threshold; however, as of 2020, only five countries worldwide have been able to reach 90% vaccination coverage in adolescent girls. The countries that were early adopters of HPV vaccination programmes and achieved moderate to high vaccination coverage (>50%) in the late 2000s, such as the UK, Sweden and Denmark, are now starting to observe declines in cervical cancer incidence among young adult women who were vaccinated as pre-adolescents. Global vaccination coverage with at least one dose in girls by 15 years of age was estimated to be 21% as of 2022.
7. Oncogenic Cofactors: Parity, Tobacco, HIV
Parity, tobacco use and human immunodeficiency virus infections are major cofactors that influence the epidemiology of HPV-associated cancers. An increasing number of full-term pregnancies has been linked to an increased risk of precancerous lesions and cervical cancer in HPV-positive women. Many studies have observed rising cancer risk with increasing number of full-term pregnancies, with the risk being highest in women with seven or more full-term pregnancies who have an odds ratio for cervical squamous cell carcinomas (SCC) of 3.8 compared with nulliparous women, and of 2.3 compared with women with one or two full-term pregnancies. HIV infection substantially increases the incidence of and mortality from cervical cancer. Women living with HIV face a sixfold higher risk of developing cervical cancer relative to uninfected women. HPV-positive women who smoke have a twofold higher risk of cervical squamous cell carcinomas and high-grade lesions relative to HPV-positive women who have never smoked. Tobacco smoking has been associated with increased risk of vaginal, vulvar and anal cancer owing to an increased risk of persistent HPV infection. A systematic review of data from 64 studies involving 29,900 men found an increased risk of anal high-grade squamous intraepithelial lesions associated with HIV in HPV16-positive men who have sex with men.
8. Social Inequalities and Disparities
The incidence of and mortality from HPV-associated cancers remain strongly associated with the socioeconomic status of individuals and the human development index of countries. Socioeconomic factors are also important determinants of outcomes from HPV-associated cancers. In particular, the incidence and mortality rates of cervical cancer are highest in countries with low human development and decrease sharply with increasing human development index levels. Women with low socioeconomic status are more likely to develop and die from cervical cancer relative to their more affluent fellow citizens. Inequalities in the distribution of the cofactors discussed in this Review, especially multiparity, which is strongly related to the socioeconomic status of women and their country of residence, could also contribute to the observed inequalities in the burden of cervical cancer. Substantial evidence indicates that providing free HPV vaccination primarily through a universal schooling system reduces barriers to vaccination and increases vaccination equity. HPV self-sampling tests are widely viewed as another intervention that could help to reduce barriers to cervical cancer screening for many women.
9. Conclusions and Global Elimination Goals
Cervical cancer elimination will require combined primary and secondary prevention approaches, focusing especially on HPV vaccination and effective screening. Meeting the WHO 90–70–90 targets (vaccinating 90% of girls by age 15, screening 70% of women at ages 35 and 45, and treating 90% of cervical disease cases) will be critical to achieve elimination by the second half of the 21st century. Equity-oriented programs and community engagement are essential for successful implementation in underserved populations.
Citation : Malagón, T., Franco, E.L., Tejada, R. and Vaccarella, S. (2024). Epidemiology of HPV-associated cancers past, present and future: towards prevention and elimination. Nature Reviews Clinical Oncology, [online] 21(522–538), pp.1–17. doi:https://doi.org/10.1038/s41571-024-00904-z.
