1. Based on the evidence presented in this draft Recommendation Statement, do you believe that the USPSTF came to the right conclusions?
- Yes; I believe the USPSTF came to the right conclusions.
- Somewhat; I believe the USPSTF came to the right conclusions in some ways but not in others.
- No; I do not believe the USPSTF came to the right conclusions.
- Unsure; I am not sure if the USPSTF came to the right conclusions.
Somewhat; I believe the USPSTF came to the right conclusions in some ways but not in others.
2. Please provide additional evidence or viewpoints that you think should have been considered.
Our main disagreement is that our review determined that the data are insufficient to conclude that HPV is superior to cytology for women ages 30-65, taking into consideration all patient outcomes, including diagnosis, overtreatment, survival, psychosocial impact, and costs.
We agree with the USPSTF statements about the high sensitivity of HPV testing, but the USPSTF statement underemphasizes the anxiety and overtreatment for women with a positive HPV test result from a transient infection. The major disadvantage of HPV testing is that a positive HPV result for women from 30-65 years is likely to result in a colposcopy. We therefore question whether HPV testing should be considered preferable to Pap cytology, since the two have comparable effectiveness for many women and Pap cytology avoids diagnosing transient HPV infections. Moreover, while HPV testing can identify more precancerous lesions earlier, its impact on reducing invasive cancer and improving survival is unclear and may depend heavily on follow-up care and screening adherence.
The ARTISTIC trial (Kitchener et al., 2009) found that HPV testing was more sensitive than cytology for detecting CIN3+ lesions in the initial round of screening. However, it did not demonstrate a significant reduction in invasive cervical cancer rates by the second round. Castle et al. (2018) demonstrates that while HPV testing detects more high-grade lesions earlier, it does not significantly reduce invasive cervical cancer rates or improve survival outcomes. Similarly, McCredie et al. (2008) demonstrated that while many high-grade lesions progress to invasive cancer if left untreated, a significant proportion regress spontaneously. These studies suggest that while HPV testing can identify more precancerous lesions earlier, its impact on reducing invasive cancer and improving survival may depend heavily on follow-up care and screening adherence.
In contrast, a pooled analysis looking at the results of 4 studies with a total of more than 170,000 patients, Ronco et al. (2014) found that HPV-based screening significantly reduced the incidence of invasive cervical cancer compared to cytology alone over a 6.5-year period. The fact that patients enrolled in these 4 studies lived in Europe and Scandinavia could explain why these findings seem to contradict the Kitchener, Castle, and McCredie trials cited in our previous paragraph. It is possible that HPV testing may be more effective than cytology in countries where health care is free and very widely available. Overall, the results suggest that the incremental benefit of HPV testing over cytology is unclear but may be strongest in countries where access to care is not limited. These results do not justify considering it the preferred option for women between the ages of 30 and 65 in the U.S., given the increased costs, uncertain access to follow-up care, psychological stress, and patients’ desire to avoid the cost of potentially unnecessary procedures.
The importance of follow-up care is evident in studies like Dillner et al. (2008), which emphasized the critical need for systems to manage HPV-positive results effectively in order to avoid unnecessary interventions without compromising cancer prevention. Since colposcopies are invasive and more expensive and anxiety-producing than a cytology test, we strongly urge the USPSTF to specify that if HPV is used as the primary test, a positive HPV result should be followed by cytology as the next step before proceeding to colposcopy. This approach is supported by international guidelines such as those in the Netherlands and Australia. Specifically, the Dutch program incorporates cytology as a triage step following a positive HPV test to reduce unnecessary colposcopies, while maintaining sensitivity for clinically significant lesions (Rijkaart et al., 2012). Similarly, Australia’s National Cervical Screening Program transitioned to primary HPV screening with reflex cytology for non-HPV16/18-positive cases to improve cost-effectiveness and patient outcomes (Lew et al., 2017). Similarly, in the four countries studied by Ronco et al, for women whose initial screening was an HPV test, if the results were positive that was followed by cytology rather than colposcopy. If the cytology test was negative despite the positive HPV test, the women underwent a follow-up HPV test approximately one year later. These strategies show that cytology offers a balanced approach to triage, reducing unnecessary referrals after a positive HPV test, while maintaining detection rates.
In addition, the USPSTF draft does not sufficiently address the impact of self-collected HPV samples in real-world settings. Studies like Arbyn et al. (2014) and Polman et al. (2019) highlight logistical barriers, accuracy concerns, and the importance of robust follow-up systems.
References
Arbyn M, Verdoodt F, Snijders PJ, et al. Accuracy of human papillomavirus testing on self-collected versus clinician-collected samples: a meta-analysis. Lancet Oncol. 2014;15(2):172-183. doi:10.1016/S1470-2045(13)70570-9
Castle PE, Kinney WK, Xue X, et al. Effect of Several Negative Rounds of Human Papillomavirus and Cytology Co-testing on Safety Against Cervical Cancer: An Observational Cohort Study. Ann Intern Med. 2018;168(1):20-29. doi:10.7326/M17-1609
Dillner J, Rebolj M, Birembaut P, et al. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ. 2008;337:a1754. Published 2008 Oct 13. doi:10.1136/bmj.a1754
Kitchener HC, Almonte M, Gilham C, et al. ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening. Health Technol Assess. 2009;13(51):1-iv. doi:10.3310/hta13510
Lew JB, Simms KT, Smith MA, et al. Primary HPV testing versus cytology-based cervical screening in women in Australia vaccinated for HPV and unvaccinated: effectiveness and economic assessment for the National Cervical Screening Program. Lancet Public Health. 2017;2(2):e96-e107. doi:10.1016/S2468-2667(17)30007-5
McCredie MR, Sharples KJ, Paul C, et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. 2008;9(5):425-434. doi:10.1016/S1470-2045(08)70103-7
Polman NJ, Ebisch RMF, Heideman DAM, et al. Performance of human papillomavirus testing on self-collected versus clinician-collected samples for the detection of cervical intraepithelial neoplasia of grade 2 or worse: a randomised, paired screen-positive, non-inferiority trial. Lancet Oncol. 2019;20(2):229-238. doi:10.1016/S1470-2045(18)30763-0
Rijkaart DC, Berkhof J, Rozendaal L, et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncol.2012;13(1):78-88. doi:10.1016/S1470-2045(11)70296-0
Ronco G, Dillner J, Elfström KM, et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials [published correction appears in Lancet. 2015 Oct 10;386(10002):1446. doi: 10.1016/S0140-6736(15)00411-0]. Lancet. 2014;383(9916):524-532. doi:10.1016/S0140-6736(13)62218-7
3. How could the USPSTF make this draft Recommendation Statement clearer?
- USPSTF’s statement should acknowledge and take into account the psychosocial and economic impacts of unnecessary colposcopies, particularly for low-income and underserved populations.
- UPSTF should review and include well-designed studies on invasive cancer and survival outcomes tied to HPV testing versus cytology, or clearly state that such data are unavailable or inconclusive. Detection alone is not a meaningful endpoint without demonstrated survival benefits.
- USPSTF should provide clearer guidance on triage pathways, emphasizing cytology as the next step after a positive HPV result instead of immediate colposcopy.
4. What information, if any, did you expect to find in this draft Recommendation Statement that was not included?
- A more comprehensive review of comparative data on invasive cancer and survival for HPV testing and cytology as primary screening strategies.
- More nuanced recommendations for women over 65, which consider individual risk factors such as new sexual partners or immunosuppressive conditions.
- Greater detail on the feasibility and cost-effectiveness of implementing self-collected HPV testing in the U.S. in the real world, not just in research or clinical settings, including follow-up protocols to prevent gaps in care.
5. What resources or tools could the USPSTF provide that would make this Recommendation Statement more useful to you in its final form?
The USPSTF could enhance the utility of this Recommendation Statement by providing:
- Decision-making algorithms or flowcharts for clinicians and patients that clearly outline the steps following various screening outcomes (e.g., HPV-positive, cytology-positive, or combined). This would be particularly helpful in reinforcing the role of cytology as a triage step before colposcopy.
- Cost-effectiveness analysis summaries comparing different screening strategies (e.g., HPV testing alone, Pap cytology alone, and co-testing) in terms of cancer detection, survival outcomes, and healthcare utilization.
- Guidance on self-collection implementation, including best practices for ensuring accuracy and follow-up care, particularly for underserved populations.
- Risk calculators or interactive tools to help patients better understand their individualized risk and the potential benefits or harms of different screening intervals or modalities.
6. The USPSTF is committed to understanding the needs and perspectives of the public it serves. Please share any experiences that you think could further inform the USPSTF on this draft Recommendation Statement.
From a clinical perspective, patients often express significant anxiety about abnormal HPV results, particularly when the next step involves immediate colposcopy. This underscores the need for clear communication about the low risk of invasive cancer in many HPV-positive cases and the rationale for using cytology as an intermediate triage tool. Additionally, underserved populations face barriers such as lack of follow-up after abnormal results or inadequate access to colposcopy services. Unfortunately, when patients are concerned about cost or access associated with a positive HPV test, they may delay follow-up until their condition is much worse. In such cases, the absence of robust systems for patient navigation exacerbates disparities in cervical cancer outcomes.
Based on our experiences with patients, it is especially essential to integrate follow-up protocols into any recommendations involving self-collection or HPV primary screening.
7. Do you have other comments on this draft Recommendation Statement?
Yes, there are additional points to consider:
- The Recommendation Statement could benefit from a stronger focus on survival outcomes rather than cancer detection alone. Current evidence does not consistently demonstrate that HPV testing translates into better survival outcomes compared to cytology. For example, the ARTISTIC trial found no significant reduction in invasive cancer rates despite increased lesion detection with HPV testing (Kitchener et al., 2009).
- The USPSTF should provide greater emphasis on individualized screening decisions, especially for women over 65, where risk factors like recent sexual activity or changes in immune status may necessitate continued screening despite adequate prior testing.
- To ensure equitable care, the Statement should explicitly address the logistical challenges of access to colposcopy and to implementing self-collected HPV testing in real-world settings, including the importance of integrating results into electronic health records (EHRs) and ensuring timely follow-up.
- Lastly, the draft should clarify the USPSTF’s position on triage pathways for HPV-positive results. Cytology following HPV-positive results should usually serve as an intermediate step before colposcopy, and should be described as the preferred strategy after a positive HPV because it is more cost-effective and patient-centered.