Keywords

Introduction

An estimated 34,800 cancers in the United States were caused by HPV between 2012 and 2016. Among those cancers (cervical, vulvar, vaginal, anal, oropharyngeal, and penile), the overwhelming majority can be prevented with vaccination and cervical cancer screening and treatment. While the incidence of cervical cancer has significantly declined in all populations in the United States since 1975, Hispanic women continue to have significantly higher rates of cervical cancer than non-Hispanic White and Black women.

A large community internationally has acknowledged for some time that we have the tools to prevent cervical cancer, but what is needed is to make elimination of cervical cancer an agenda. Between 2014 and 2018, two fortuitous events occurred—FDA approval of the vaccine Gardasil 9 and a strategic initiative from the World Health Organization (WHO). In 2018, the newly elected WHO Director-General (DG) announced a call to action to eliminate cervical cancer worldwide, which was critical in defining a path forward and engaging with partners and member states to overcome challenges and scale-up cost-effective interventions. The WHO DG recognized that several countries and UN agencies had already moved forward under the UN Global Joint Programme on Cervical Cancer Prevention and Control; however, to succeed, our partnerships must be expanded to include everyone who can help us reach our goal. In addition to reaching out to new partners, a key message of this call to action was that this work should be carried out in a more coordinated manner globally to accelerate progress in eliminating cervical cancer.

Cervical Cancer Elimination

It is possible to make cervical cancer and other HPV-related cancers a thing of the past, but we need more research. There are still knowledge gaps to be filled; and for Hispanic populations, this is especially true with cervical cancer. However, we already have the tools to make cervical cancer elimination a reality. The national strategy for eliminating cervical cancer is like the legs of a three-legged stool—vaccine (e.g., Gardasil and Gardasil 9), cervical cancer screening, and treatment. Why are there still high cervical cancer incidence rates in the Hispanic population? One answer may be that treatment, the third leg of the stool, tends to be left off of our national goals. The message is that we should screen 93% of women for cervical cancer, but what is not conveyed is to ensure that those who are diagnosed with precancerous lesions are actually treated.

Disease Control, Elimination, and Eradication: A Continuum

Disease reduction can be thought of as a continuum from control to elimination to eradication, and it is important in our communications that we use these terms correctly [1, 2].

  • Control is a reduction in incidence, prevalence, morbidity, or mortality to a locally acceptable level.

  • Elimination of disease is a reduction to zero in incidence in a defined geographical area as a result of deliberate efforts (e.g., measles in the Americas). Elimination of infection caused by a specific agent is a reduction to zero in a defined geographical area as a result of deliberate efforts (e.g., Chagas). Elimination of a public health problem is a reduction to low disease incidence, but not zero; this term should only be used if clear target definitions are commonly agreed upon (e.g., neonatal tetanus).

  • Note that disease control and elimination both require continued intervention measures.

  • Eradication is a permanent reduction to zero of the worldwide incidence of infection (e.g., smallpox); it no longer requires intervention measures. For example, we no longer continue to vaccinate for smallpox because the virus has been successfully eradicated.

So, our first goal is to eliminate cervical cancer (not eradicate); we will likely have to continue the interventions of the three-legged stool for quite some time, eliminating cervical cancer one geographic region at a time. When we eliminate cervical cancer worldwide, it will then finally be eradicated.

A World Without Cervical Cancer

The World Health Organization has a vision of a world without cervical cancer, and though their strategy to eliminate the disease is slightly different from the United States (Healthy People 2020), the components of the strategies are very similar. The WHO threshold for elimination of cervical cancer is an incidence of less than four cases per 100,000 women-years—something that is achievable for the United States. The 2030 control targets for WHO are: 90% of girls fully vaccinated against HPV by the age of 15; 70% of women screened with a high precision test at age 35 and 45; and 90% of women identified with cervical disease receive treatment and care.

The Pan American Health Organization (PAHO), the health agency for the Americas, also has a strategy for eliminating cervical cancer which predates the WHO call to action. PAHO has a strong history of eliminating immune vaccine preventable diseases; the region under their purview was the first to eliminate smallpox and polio. All of the elements are in place for them to also be the first region in the world to eliminate cervical cancer, and it is imperative that Hispanics in the United States benefit from these interventions. The PAHO plan of action for cervical cancer prevention and control aims to reduce the number of new cases and deaths from cervical cancer 30% by 2030. Their four strategic lines of action include program organization; primary prevention (vaccination); screening and treatment; and access to services.

Evidence for Achievability

Is the WHO threshold of elimination of cervical cancer achievable? To answer this question, an international team of researchers used comparative modelling to project how long it would take to eliminate cervical cancer in the United States [3]. One simulation model under status quo assumptions for vaccination and screening predicted that reaching the WHO incidence threshold of less than four cases per 100,000 women-years could be achieved by 2038 [3]. In another scenario with the assumption of screening, scale-up to 90% predicts cervical cancer elimination by 2028. Interestingly, a third scenario with the assumption of 90% vaccination coverage predicted cervical cancer elimination at about the same time as the status quo scenario. So, this suggests that the most effective intervention and fastest way for the United States to achieve the goal of cervical cancer elimination is to scale up screening and treatment, especially focusing on the underscreened and undertreated [3].

Real-World Evidence for the Effectiveness of the HPV Vaccine

What is the evidence that the vaccine will work? While the HPV vaccine is only one part of the three-legged stool, when it is added to screening and treatment, it reduces infection in the population. In sequence over time, this reduction in infection is followed by a reduction in genital warts, reduction in cervical intraepithelial neoplasia (CIN), and there is evidence that after some decades there is also a reduction in cervical cancer.

Reduction in Infection

There is evidence from multiple countries to support a reduction in HPV infection after the vaccine is rolled out into public health practice. One study comparing HPV prevalence among Australian women aged 18–24 pre- and post-vaccination found a large reduction in the four types of HPV that Gardasil protects against. The prevalence was 22.7% (n = 88) pre-vaccination in the years 2005–2007; and the post-vaccination prevalence dropped to 7.3% (n = 688) from 2010 to 2012 and to 1.5% (n = 200) in 2015 [4].

Reduction in Genital Warts

In the United States, even with a relatively low vaccine dissemination, there are significant reductions in genital wart incidence, pointing to the potential benefits in public health. Flagg and Torrone observed decreases in the prevalence of genital warts in young women likely to be affected by HPV several years after licensure of the HPV vaccine [5]. For example, in 2009 when only 27% of woman were vaccinated, the prevalence of genital warts in women aged 20–24 was 5.5 per thousand person-years; in 2009 when about 40% of women were vaccinated, the prevalence had decreased to 2.7 [5].

Reduction in CIN 2

Similar to the incidence pattern for genital warts, CIN 2 incidence has declined in the United States despite the low dissemination of vaccine. To evaluate the impact of HPV vaccination on the reduction of cervical precancers, McClung et al. examined archived specimens from women aged 18–39 with CIN 2+. They found that between the years 2008 and 2014, the proportion of CIN 2+ cases decreased from 51.0% to 47.3% (P = 0.03) among unvaccinated women and decreased 55.2–33.3% (P < 0.0001) among vaccinated women (n = 1065). The authors concluded that the greater decline in CIN 2+ among vaccinated women provides support for the effectiveness of vaccine and the smaller decline among unvaccinated women may be the result of herd protection [6].

Reduction in Cervical Cancer

Population-based national cancer registry data from the United States show that cervical cancer declined throughout the time period 1999–2015 among all age groups and that the incidence rates declined to <1/100,000 in the youngest age cohorts [Cervical cancer incidence trends by age. There were <6 cases for the group aged 15–20 in 2015, so trends were calculated by combining the last 2 years of data for this age group (2013–2014)] (unpublished graph from Mona Saraiya, MD, MPH; CDC). The total number of cases during this period was 54,770; approximately 1% of cases were among females aged 15–20. Greatest rate declines were among females aged <21 years who were most likely to be affected by the relatively recent introduction of the HPV vaccine; among females aged 15–20 years, cervical cancer rate decreased 6.6% per year during 1999–2014. Over time, as vaccination continues and more data are collected, the expectation is that there will be a spread with significant reductions in each of the successive birth cohorts (21–24; 25–29; 30–34; 35–39 years).

A large study in Sweden demonstrated that the HPV quadrivalent vaccine is not only efficacious and effective against HPV infection, genital warts, and high-grade cervical lesions, but is also associated with a major reduction in the incidence of cervical cancer. Using nationwide registry data from 2006 to 2017, the Swedish study followed an open population of girls and women 10–30 years of age (n = 1,145,112 unvaccinated; 527,871 vaccinated). The age-adjusted incidence rate ratio comparing the vaccinated population with the unvaccinated was .51 (95%CI, 0.32–0.82). Interestingly, the authors found the greatest risk reduction (88% lower than unvaccinated women) occurred among those who were vaccinated before 17 years of age [7].

Reduction in Oral HPV

Finally, there is evidence that oral HPV infection is also declining as a consequence of vaccination. One study in the United Kingdom examined the effect of HPV vaccination on the prevalence of oropharyngeal HPV-16 infection among girls and young adult women and compared infection levels with those in unvaccinated young males of similar age [8]. They found that the UK female-only vaccination program was associated with a significantly lower oral HPV-16 prevalence among vaccinated females compared to unvaccinated females (0.5% vs. 5.6%, P = .04). The HPV prevalence in unvaccinated males was similar to vaccinated females, and the authors proposed that vaccination of females may confer benefits of herd immunity to unvaccinated males of the same age.

Cervical Cancer Elimination Among Hispanics in the United States

The good news is that the incidence of cervical cancer has been declining in all populations over time; the bad news is that Hispanics consistently have a higher incidence of cervical cancer and their gains may not have been as great [9].

Age at Diagnosis

Examination of cervical cancer incidence by age group points to the populations that should be targeted the most for screening and treatment. For all races and for non-Hispanic whites, peak incidences occur in the 40s and then start to decline, but for African Americans and Hispanics, the incidence continues to increase with increasing age [9]. This disparity probably reflects poor utilization of health services; once women are in the post-reproductive age group, they may not be accessing screening as much, or they are accessing screening but failing to get needed treatment. More study and research are needed.

Vaccine Uptake

The Healthy People 2020 goal is for 80% of adolescents aged 13–15 to receive the full recommended dose of HPV vaccine. Unlike the disparities experienced by Hispanics in screening, treatment, and access to health care, vaccination uptake is as high or higher for Hispanic populations than for other populations. In 2018, 75.5% of Hispanic females and males aged 13–17 had received ≥1 dose and 56.6% were up to date, an uptake rate higher than non-Hispanic White (47.8%) and Black (53.3%) adolescents [10]. However, Hispanics who are older than adolescents have a lower rate of uptake than other populations [11].

Pap Smear Screening

Based on national data, the Hispanic population has lower rates of Pap smear screening; however, there is no national measurement of the percentage of women who are diagnosed with an abnormal smear who are Hispanic and who have not received adequate medical treatment. This issue requires more research, especially if the rate of Pap smear screening is actually going down for Hispanic women. If the goal is to achieve cervical cancer elimination, we must be promoting the three-legged stool—vaccination, screening, and timely and appropriate treatment for any abnormal dysplasia that requires treatment.

Progress to Date

There is a movement here in the United States. We worked closely with several of the large cancer centers to get all 70 NCI-designated cancer centers to sign on to the goal of eliminating HPV-related cancers. This was followed in 2019 with a congressional briefing and in 2021 with a congressional filing of the Prevent HPV Cancers Act. Filed by US Representative, Kathy Castor (FL 14), this act is intended to help bolster both the CDC and the NCI’s effort to actually achieve elimination of HPV-related cancers. The current US incidence rate is 8/100,000; not too far down the road, we could meet the WHO goal of 4/100,000 by 2030 if we accelerate our interventions. If we continue those efforts, we can probably go further to true elimination of HPV-related cancer, which is an incidence rate of less than 1/100,000.