Medical Research

Part 2: Why We Should Move Toward Primary HPV Testing for Cervical Cancer

June 27, 2024

In case you missed it, we covered current trends around cervical cancer in Part One “The Problem is Broad, But Solvable.” We discussed the current state of cervical cancer in the United States, highlighting a persistent decline in screening rates and how cervical cancer disproportionately impacts our young women and those of color.  

Now, in Part Two, we explore the various tests that exist in the United States for cervical cancer screening. We highlight why Teal Health uses primary HPV testing, which also enables self-collection. 

Understanding Cervical Cancer Risk

Almost all cervical cancers (around 95%) are caused by persistent infections with high-risk types of HPV, the main risk factor for cervical cancer. However, not all women who test positive for HPV necessarily develop cervical cancer. In fact, research shows that various genetic predispositions as well as socially determined cofactors explain how HPV infections persist and progress into cervical cancer. Many of these cofactors are closely intertwined with low socioeconomic status and related circumstances of inequity, violence, and stress. 

Chronic stress, depression, and life events involving trauma or violence not only compromise the body’s immune response to HPV, but also elevate other high-risk lifestyle practices (e.g., smoking cigarettes, consuming alcohol, insufficient nutrients, unprotected intercourse elevating exposure to sexually transmitted infections). Importantly, risk of developing cervical cancer is higher among women who have experienced childhood sexual abuse, intimate partner violence, or forced sexual experiences, all of which represent extreme stress and trauma that hurts one’s long-term immune response while also increasing vulnerability to social circumstances and behaviors that escalate the risk for cervical cancer

Routine cervical cancer screening is an important way to identify HPV infections when they arise. Screening regularly, per guidelines, allows providers to monitor persistent infections and intervene as early as possible when needed. 

Screening for Cervical Cancer: The Three Tests and How they Compare 

Getting screened routinely is a critical and often life-saving practice. Cervical cancer screening is recommended for women and people with cervixes between 21 and 65 years old. In the United States, there are three main types of recommended cervical cancer screenings

  1. Primary HPV DNA or RNA test (identifies high-risk HPV types associated with cervical cancer)
  2. Pap smear test (cervical cytology)
  3. Co-test which combines the Pap and HPV test. 

Compared to the Pap smear, HPV tests are the most sensitive and primary HPV tests are the preferred screening method in almost all developed countries (and many developing countries). Results from each of these screening tests must be confirmed via diagnostic procedures which usually involves a colposcopy with or without a biopsy. 

HPV tests typically have a high sensitivity (in some studies, above 96% for high risk cervical changes, i.e., CIN1 and CIN3+), and rarely miss cases where HPV-related disease is present. In addition, a negative HPV test result means that a person has a very low risk of HPV-related precancer or cancer developing in the screening interval (good negative predictive value). 

The Pap test differs from HPV testing because it identifies changes in cervical cells after possibly cancerous transformation has taken place. Whereas, HPV tests detect the virus at levels above a threshold indicating increased risk of cervical dysplasia (which is when abnormal cell changes take place that could be a precursor lesion for developing cervical cancer). This early detection can increase the likelihood of curability

Routine Pap screenings have significantly reduced cervical cancer incidence and have been a successful public health intervention. However, when compared to HPV screenings, they more often lead to false positives, overtreatment, and additional diagnostic procedures for women who ultimately are not diagnosed with cervical cancer. Further, due to their lower sensitivity compared to HPV testing, Pap tests need to be conducted more frequently to detect potential disease. 

Co-tests can bring even more false positives and overtreatment than the Pap test alone, making primary HPV testing the favorable screening option. A United States Preventative Services Task Force (USPSTF) model found that primary HPV testing every 5 years (followed by cytology triage as needed) was effective in reducing a woman’s total lifetime cervical tests by 60% and her colposcopies by 12% when compared to co-testing. 

These tests also differ in terms of resulting deaths from cervical cancer. Compared to Pap tests, clinical trials have proven the HPV test alone to be superior in terms of reducing mortality, as represented in the graph below. This model evaluates the use of Pap testing alone (beginning at age 21, at 3-year intervals), co-testing (beginning at age 30, at 5-year intervals), and HPV testing alone (beginning at age 30, at 5-year intervals). We see that those who receive Pap tests alone have almost 40% higher mortality than those screening with primary HPV tests and co-tests. 

Compared to co-tests, primary HPV tests offer similar protection against cervical cancer and related mortality; however, they also bring added benefits of fewer false positives, less possibility of overtreatment, and are especially effective in vaccinated populations. 

Image recreated using source data: USPSTF modeling study evaluating strategies for cervical cancer screening

Overall, HPV-based screening provides 60% to 70% greater protection against cervical cancer compared to the Pap smear alone. This is largely because HPV tests can better identify and “accurately determine the risk of precancerous or cancerous lesions,” allowing for timely subsequent interventions and successful treatments. 

The FDA has Approved Primary HPV Tests  

Research supports that HPV stand-alone testing (e.g. primary HPV testing) offers the best balance between benefits and harms among screening options, particularly in HPV vaccinated populations where they offer fewer false positives and reduce the potential for overtreatment. 

In 2014, the U.S. Food and Drug Administration approved the first HPV DNA test that could be implemented alone, as a primary screening measure, and since then, three additional tests have been FDA approved for this indication. In 2024, the U.S. FDA approved self-collection for cervical cancer screening in-clinic (the self-collection must be conducted in a clinic, and is available to those who are underscreened or refuse a traditional clinic-collection).  This marks an important step toward making self-collection available more widely. 

The USPSTF (among other organizations) includes primary HPV testing in their recommended screening guidelines, and the American Cancer Society underscores primary HPV tests as their preferred cervical cancer screening method. These recommendations are based on the test’s heightened sensitivity, high negative predictive value, and potential for accurate early detection. In addition, the American College of Obstetricians and Gynecologists has endorsed the USPSTF’s recommendations, recognizing primary HPV testing as an effective screening option.

Perhaps the most persuasive argument for prioritizing adoption of primary HPV testing is that, unlike cytology, it can be successfully carried out on self-collected samples, which improves access to potentially life-saving screening. 

Self-collected HPV Samples are as Accurate as Clinician-collected Samples

Numerous studies show self-collected HPV samples are equivalent to those collected by clinicians, providing support for the effectiveness of self-collecting. A large meta-analysis demonstrated that HPV DNA testing using polymerase chain reaction (or, PCR) based HPV tests were as sensitive and accurate on self-collected samples as on clinician-collected specimens (other studies have shown similar results in support of self-collection). It’s worth noting that all the FDA-approved primary HPV tests are PCR based. 

Image source:

Specifically, the meta-analysis evaluated 56 accuracy studies and 25 participation trials, each with at least 400 women including those who were underscreened. It found that relative sensitivity of PCR-based HPV tests was similarly high – above 0.96 – in both self- and clinician-collected CIN2+ and CIN3+ samples. Both self- and clinician-collected PCR-based HPV samples showed similar test positivity rates and positive predictive values. These findings are summarized in the table above, which highlights the very high relative sensitivity of high-risk HPV assays using modern and widely available PCR-based assays when compared with older signal amplification (SA) for self- versus clinician-collected samples. 

To clarify, ‘relative sensitivity’ here is a ratio that represents how self-collection compares to clinician-collection when detecting HPV-related disease (cervical dysplasia or cancer). A relative sensitivity value of ‘1’ means the tests are equally sensitive, so in this case (0.96) self- and clinician-collection are very similar in terms of accurately detecting the presence of cervical disease. 

Self-collected HPV Samples: The Future of Cervical Cancer Screening

Self-collection, enabled by primary HPV testing, is imperative to improve access and equity to cervical cancer screening. Not only do we know that self-collection is widely preferred – in the United States, and globally – data from countries that have implemented self-collection shows its effectiveness in helping people with cervixes overcome screening barriers and participate in routine cervical cancer screenings. 

In Part Three, we will dive further into self-collection, exploring how this option is critical to improving screening engagement rates. We discuss research from other countries that incorporate self-collection in their national cervical cancer screening programs, and talk about what it would mean to bring self-collection to the United States. Stay tuned!

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