Promise and Perils of Primary HPV Testing

Abstract

Cervical cancer screening has reduced morbidity and mortality in many countries, but efforts to optimize screening modalities and schedules are ongoing. Using data from a randomized trial conducted in British Columbia, Canada, in conjunction with a provincial screening registry, Gottschlich and colleagues demonstrated that the estimated risk for precancerous disease (cervical intraepithelial neoplasia grades 2 or worse) at 8 years following a negative human papillomavirus (HPV) test was similar to the current standard of care (Pap testing after 3 years). The study supports extending screening intervals for those with a negative HPV test beyond currently recommended 5-year intervals. In an ideal world, the resources saved through less frequent routine cervical screening could be redirected to increasing screening uptake and follow-up of abnormalities to improve equity in cervical cancer prevention. However, implementation of extending screening intervals remains less than straightforward in settings with fragmented healthcare systems that lack information systems to support patient call/recall, such as the United States. To achieve the full promise of primary HPV testing, stakeholders at every level must commit to identifying and addressing the diverse spectrum of barriers that undergird existing inequities in care access, appropriately resource implementation strategies, and improve health information systems.

See related article by Gottschlich et al., p. 904

Despite being highly preventable through vaccination against human papillomaviruses (HPV) and cervical screening, cervical cancer remains a major source of morbidity and mortality worldwide, with the vast majority of cases in developing countries. In high-income countries, the introduction of cervical cancer screening has drastically reduced the burden of disease. These successes have subsequently driven research targeting refinements in screening modalities and intervals as well as risk-based management approaches to enable early and optimized disease detection, reductions in overscreening and overtreatment, and maximization of resources.

In this issue of Cancer Epidemiology, Biomarkers & Prevention, Gottschlich and colleagues (1) used data from the randomized HPV FOCAL trial and the British Columbia (BC) provincial Cervix Screening Registry to examine the risk of precancerous disease [cervical intraepithelial neoplasia grades 2 and 3 or worse (CIN2+ and CIN3+)] after one or two negative cervical screening tests. FOCAL trial data included two non-overlapping cohorts of participants with one or two negative HPV tests who entered the BC Cervix Screening (BCS) program after exiting the trial to capture a total of 14 years of follow-up. Two cohorts of individuals with one or two negative cytology-based screens (Pap tests) were constructed from the BC general population participating in the BCS program for comparison with the FOCAL HPV cohorts. The BCS program cohort inclusion required a negative Pap test during the HPV FOCAL recruitment period (2008–2012) and follow-up through the BCS program in an identical manner to the FOCAL HPV cohorts. All cohorts included individuals aged 25 to 65 years.

The study demonstrated that cohorts with one or two negative primary HPV tests had about half the risk of CIN2+ detection over 10 to 14 years compared with cohorts with one or two negative Pap tests for all age groups, confirming that primary HPV screening is a more effective screening tool than cytology for early detection of precancerous lesions. The study also demonstrated that the estimated CIN2+ risk at 8 years after one or two negative HPV tests was similar to the risk associated with the current standard of care (Pap testing after 3 years).

Relative benefits of primary HPV testing compared with Pap testing have been shown in other settings (2), but this study adds to the existing literature through the combined use of trial data with population-based registry data which enabled up to 14 years of follow-up. The study findings also support moves toward cervical cancer screening with primary HPV testing accompanied by longer than the currently recommended 5-year intervals between negative screening tests. An important implication of the study is the reduced use of healthcare resources which, as Gottschlich and colleagues (1) suggest, would allow the potential redirection of resources toward increasing screening uptake in those who are severely underscreened and ensuring appropriate follow-up testing and management after an abnormal finding.

The redistribution of healthcare resources toward screening equity would be an ideal outcome, largely achieved through lengthened screening intervals (thereby reducing costs and potential harms) among those with negative primary HPV test results. However, this is not a straightforward endeavor, even for settings with universal healthcare and may be especially challenging in settings such as the United States, where current healthcare delivery happens through a series of disconnected payers and ecosystems.

In the United States, changes in cervical cancer screening recommendations across the last few decades have underscored the challenges of the highly fragmented healthcare environment. Both over- and underscreening are common, implementation of HPV testing has been highly heterogeneous across settings and populations, and follow-up management of screen-detected and diagnostic abnormalities remains inadequate (3). As an example, data comparing health records across three large healthcare systems found that Black patients were twice as likely and Hispanic patients were three times as likely as non-Hispanic White patients to be receiving Pap-only testing, a less sensitive test than HPV-based screening for the detection of cervical precancer (4). This pattern is a result of the segregated nature of care across the United States, with minoritized populations more often served by safety-net and low-resourced settings. Patterns of care access across the country have led to persistent inequities in cervical cancer screening that are rooted in social determinants of health, subject to the environmental and community characteristics that impact a wide range of health, functioning, quality-of-life outcomes and disease risks (5).

Given the existing state of US health care, there are numerous barriers to equitable implementation of primary HPV screening. First, reimbursement for HPV testing would need to align across payers. State and federal programs (including Medicare, Medicaid, and National Breast and Cervical Cancer Early Detection Program) must reimburse appropriately for primary HPV testing. Historically, these programs have been delayed relative to private insurance in aligning reimbursement schedules with national guidelines. For example, the US Preventive Services Task Force 2018 recommendations supported cervical screening every 3 years with a Pap test, every 5 years with primary HPV testing alone (high-risk HPV testing), or every 5 years with a co-test (high-risk HPV and Pap tests performed together; ref. 6). However, as of 2024, the national coverage determination of the US Centers for Medicare and Medicaid Services has not yet addressed reimbursement for primary HPV screening, which was only recently posted on the national coverage determination dashboard waitlist (7). These delays in reimbursement approvals result in inequities in the delivery of improved cervical screening options for marginalized groups who would realize the greatest benefit. Data for the uptake of primary HPV testing in the United States remain limited but is low in the National Breast and Cervical Cancer Early Detection Program (8). It is worth noting here that cervical cancer screening by self-collection of vaginal samples was just approved by the FDA for use in healthcare settings. In-home use of vaginal self-collection, if approved in the future, could further expand this screening option for US women. Self-collection requires primary HPV testing, as cellularity is not sufficient for use in routine Pap cytology. Realizing potential benefits of primary HPV screening and self-collection (e.g., reductions in disparities and greater population screening coverage) requires expedient formal recommendations from policymakers, aligning payers, significant fiscal resources across all implementation fronts, and education of patients and providers.

Second, US healthcare and health data are both highly fragmented. Even among individuals with private insurance, changing insurance often leads to changes in primary care provider, resulting in a loss of essential medical history information important to optimal screening and management for a variety of health conditions. For those who are low income and may be chronically or transiently uninsured, continuity of care and availability of medical history is even more challenging. The study by Gottschlich and colleagues was made possible through the availability of high-quality trial data and comprehensive population-level longitudinal screening and outcomes data. To improve screening efficiency and equity in the United States, we need improved health information systems, ideally including state or regional cancer screening registries.

Comprehensive integrated and portable health information systems are important not only to better health outcomes but to patient safety. The ability to effectively extend intervals between cervical screens requires availability of data and systems to support active outreach for timely re-screening and follow-up management. The BCS program provides support to primary care providers by notifying participants when they are due for cervical screening and facilitates referral to the nearest colposcopy clinic as needed (9). Furthermore, the program reminds providers when their patients are due for screening, tracks adherence to screening recommendations, and monitors system performance and outcomes of cervix screening activities. Data monitoring healthcare delivery and outcomes is absent in many settings including in the United States, with limited exceptions. Without patient recall systems and outreach capacity, as is available in countries with national or regional systems of care, extending cervical screening intervals can have deleterious impacts including increases in delayed diagnosis or screening-related harms as an unintended consequence (3).

Finally, comprehensive health information supports management of abnormal screens to better estimate immediate and history-based disease risks, both which contribute to improving the quality of cervical cancer prevention (10). One example of a unique statewide health information system in the Unites States is the New Mexico HPV Pap Registry which, under state regulations, captures comprehensive health information that is harmonized from disparate data sources across the continuum of cervical screening, diagnosis, and precancer treatment (11). The New Mexico HPV Pap Registry’s information system transcends the elements of US healthcare delivery, collecting cervical cancer prevention information for New Mexicans, regardless of the location where care was received, the laboratory performing testing, the payer, affiliated-organizations, and provider or patient characteristics.

In summary, primary HPV testing offers an important opportunity to improve the quality of cervical cancer screening with lower resource demand. The potential of this to address the long-standing inequities in cervical cancer is alluring, but this will not be successful without policymakers and public health authorities directing expedient attention to the setting-specific and broad policy barriers that drive inequitable access to care at every level. Without a strong commitment to overcoming a diverse spectrum of barriers coupled to adequate resources enabling well-designed implementation strategies, primary HPV testing in the Unites States and elsewhere may further grow inequities. Efforts to improve outreach, align reimbursement, and strengthen information systems are essential to improve cervical cancer preventive care for all.

Authors’ Disclosures

J.C. Spencer reports grants from Cancer Prevention Research Institute of Texas and NIH outside the submitted work. C.M. Wheeler reports grants and cooperative agreements from NIH and other support from Hologic and Becton Dickinson outside the submitted work.