By Rebecca H. Allen, MD, MPH
Associate Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI
Dr. Allen reports she is a Nexplanon trainer for Merck.
In this randomized, controlled trial of more than 25,000 women, participants with negative high-risk human papillomavirus testing at baseline had rates of CIN 3+ at 48 months that were lower compared to negative liquid-based cytology testing.
Ogilvie GS, et al. Effect of screening with primary cervical HPV testing vs. cytology testing on high grade cervical intraepithelial neoplasia at 48 months: The HPV FOCAL Randomized Clinical Trial. JAMA 2018;320:43-52.
This was a multisite, randomized, controlled trial conducted to evaluate high-risk human papillomavirus (HPV) testing for cervical cancer screening in British Columbia. Inclusion criteria were non-pregnant women 25 to 65 years of age who had not had a Papanicolaou test in the previous 12 months, were HIV-negative, and were not receiving immunosuppressive therapy. Exclusion criteria included women with a total hysterectomy, invasive cervical cancer, or a history of cervical intraepithelial neoplasia (CIN) 2 or more in the previous five years. Women were randomized 1:1:1 to an intervention, control, or safety group. The intervention group underwent primary HPV screening followed by reflex liquid-based cytology (LBC) testing if the results were positive. If their HPV was positive and LBC was negative, the women had 12-month repeat HPV and LBC screening. If either was positive (LBC ≥ ASCUS [atypical typical squamous cells of undetermined significance]), the women were referred for colposcopy. If their HPV was negative at baseline, they were recalled at 48 months for repeat HPV and LBC testing. The control group underwent LBC testing and, if negative, had repeat LBC in 24 months, in accordance with the British Columbia cervical cancer screening guidelines. If this was negative, they were recalled at 48 months for LBC and HPV testing. The LBC was reflexed for HPV in the setting of ASCUS. Women with ASCUS HPV-positive results, as well as any woman with low-grade squamous intraepithelial lesion (LSIL) or greater, were referred to colposcopy. Women with ASCUS HPV-negative results had repeat LBC testing and were referred for colposcopy if this was ASCUS or greater. The safety group and the intervention group were managed the same; however, if the baseline HPV was negative, they were recalled for LBC at 24 months and exited the trial. The primary endpoint was the rate of CIN 3 or greater at 48 months after baseline testing in both groups.
Women were recruited between January 2008 and May 2012. A total of 25,223 women were enrolled — 9,457 in the control group, 6,214 in the safety group, and 9,552 in the intervention group. Only 0.6% of women self-reported any doses of the HPV vaccine. Median follow-up time was 77 months in the intervention group and 77 months in the control group. There was no difference between the two groups regarding sociodemographic and lifestyle characteristics, such as smoking. In the first round of screening, more CIN 3+ cases were detected in the intervention group compared with the control group (relative risk [RR], 1.61; 95% confidence interval [CI], 1.09-2.37). By 48 months, fewer CIN 3+ cases were detected in the intervention compared to the control group (RR, 0.42; 95% CI, 0.25-0.69). Among baseline HPV- or LBC-negative women, rates of CIN 3+ at 48 months were lower in the intervention compared to control group (RR, 0.25; 95% CI, 0.13-0.48). These results also were true for rates of CIN 2+. Cumulative colposcopy referral rates were similar in the two groups (intervention 106/1,000 women vs. control 102/1,000 women), but were higher initially in the intervention group (57/1,000 women vs. 31/1,000 women).
COMMENTARY
This study shows that primary HPV screening detects cervical dysplasia earlier and more accurately than cytology alone. It also confirms that a negative HPV test provides greater reassurance of low CIN 3+ risk than a negative cytology result. Study strengths included a large population, the use of a central laboratory minimizing inter-observer bias, blinding of pathologists, and standardized colposcopy procedures. One design component that limits the evaluation of how well HPV compares to cytology alone for screening is that all participants received both tests at the 48-month exit visit. Nevertheless, the authors reported that adding cytology to the intervention group at 48 months detected an additional three CIN 2+ lesions, while adding HPV testing to the control group at 48 months detected an additional 25 CIN 2+ lesions.
Current ACOG recommendations for cervical cancer screening are to initiate screening at age 21.1 From ages 21 to 29 years, ACOG recommends cytology only every three years. From ages 30 to 65 years, ACOG recommends co-testing with high-risk HPV and cytology every five years. Primary screening with HPV testing starting no earlier than age 25 years also is acceptable per the guidance, as long as the HPV test chosen is FDA-approved for that purpose.2 Per ACOG, primary HPV screening should not be repeated more often than every three years, although the optimal interval is unknown.
In August 2018, the U.S. Preventive Services Task Force (USPSTF) released final guidance on cervical cancer screening that recommended testing with cervical cytology alone every three years or HPV testing alone every five years in women ages 30 to 65 years.3 The USPSTF is balancing the fact that cytology alone is slightly less sensitive for detecting CIN 2+, but HPV testing alone is more sensitive, resulting in more diagnostic colposcopies per case detected. Therefore, the task force recommended that women discuss which testing strategy was best for them. According to one decision analysis, screening every five years with high-risk HPV testing alone in women ages 30 to 65 years translates into a slightly lower mortality rate than screening every three years with cytology alone but results in more colposcopies and follow-up tests (39 colposcopies per each cancer case averted for cytology alone vs. 640 additional colposcopies per additional cancer case averted for high-risk HPV testing alone).4 For co-testing with both HPV and cytology, the USPSTF concluded that co-testing increases the number of colposcopies without resulting in improved detection of CIN 3+ compared to HPV testing alone, so it did not include co-testing in its recommendations. ACOG’s response was to uphold its current screening guidelines until further review.5
Most likely, I believe ACOG will move toward recommending primary high-risk HPV testing alone for cervical cancer screening, but it is unclear at what interval and for what ages. Based on this study, I would guess starting at age 30 years and at four-year intervals. Removing cytology from testing likely will make some providers and patients uncomfortable, given that there can be false-negatives with HPV testing depending on test performance and specimen adequacy. As long as women are screened adequately for cervical cancer with any modality, then cervical dysplasia and cancer will be prevented. Most cases of cervical cancer in the United States occur in women who have been screened inadequately.3 Therefore, we need to do a better job at prevention with the HPV vaccine and screening, especially in underserved populations who face insurance, language, and access barriers.
REFERENCES
- ACOG Practice Bulletin No. 168. Cervical Cancer Screening and Prevention. October 2016.
- Huh WK, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: Interim clinical guidance. Obstet Gynecol 2015;125:330-337.
- US Preventive Services Task Force. Cervical Cancer: Screening. Available at: https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/cervical-cancer-screening2. Accessed Sept. 11, 2018.
- Screening for cervical cancer in primary care: A decision analysis for the US Preventive Services Task Force. AHRQ Publication No. 15-05224-EF-2. Rockville, MD; 2017.
- ACOG Practice Advisory: Cervical Cancer Screening (Update). Available at: https://www.acog.org/Clinical-Guidance-and-Publications/Practice-Advisories/Practice-Advisory-Cervical-Cancer-Screening-Update. Accessed Sept. 11, 2018.
