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HPV TESTING: Detect cervical precancers earlier than cytology.

Women who received only a primary human papillomavirus test were 58% less likely to develop grade 3 or worse cervical intraepithelial neoplasia (CIN3+) by 48 months than women who had the traditional Pap cytology screen.

The primary HPV test also reduced the 2-year risk of CIN2+ neoplasia, compared with Pap smear alone, Gina Suzanne Ogilvie, MD, and her colleagues reported in JAMA.

"These results have demonstrated that primary HPV testing detects cervical neoplasia earlier and more accurately than cytology," wrote Dr. Ogilvie of the University of British Columbia, Vancouver, and her colleagues.

HPV FOCAL (the Human Papilloma Virus for Cervical Cancers Screening trial) enrolled 19,009 Canadian women aged 25-65 years and randomized them to two cervical cancer screening paradigms: Pap liquid-based cytology (LBC) or primary HPV testing.

The intervention group (9,552) had cervical cancer screening with a high-risk HPV DNA test that detects types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. If either test was positive, they were referred for colposcopy. If both tests were negative, they returned for their final screen with both tests at 48 months.

The control group underwent primary LBC testing, followed by HPV testing for women with atypical squamous cells of unknown significance (ASCUS). If these tests were both positive, they were referred for colposcopy. Women who were positive for ASCUS and HPV negative returned in 12 months and were referred for colposcopy if they had ASCUS or any higher-grade abnormality. At 48 months, they also returned and underwent both screening tests.

The primary outcome was the rate of CIN3+ at 48 months. Secondary endpoints included the 48-month rate of CIN2+, the threshold for colposcopy referral, and the effect of primary HPV testing on colposcopy.

In the first round of screening, HPV testing detected significantly more cases of CIN3+ than did LBC (risk ratio, 1.61). This was an absolute difference of 2.67 more cases per 1,000 screened women.

At 48 months, the rate of CIN3+ was significantly lower in the intervention group than in the control group (2.3 vs. 5.5 per 1,000; RR, 0.42). This represents an absolute difference of 3.2 fewer cases per 1,000, the investigators said.

Overall, however, the two methods detected about the same number of cases by 48 months, the investigators said.

"Cumulative CIN3+ incidence curves show no significantly different disease detection across trial groups in the intervention group. The cumulative incidence was higher earlier in the trial at 18 months and 42 months, compared with the control group. ... By the end of trial follow-up (72 months), incidence was similar across both groups."

Women who were HPV negative at baseline reaped the biggest benefit. The 48-month HPV incidence rate among them was 1.4 per 1,000, compared with 5.4 per 1,000 in the control group. This 75% risk reduction (RR, 0.25) represents an absolute reduction of 4 cases per 1,000 women.

The intervention group was 61% more likely to have a CIN2+ result by 12 months (RR, 1.61), but they were also 53% less likely to have it at 48 months (RR, 0.47).

"By 48 months, significantly fewer CIN2+ cases were detected overall and across all age groups in the intervention group, compared with the control group," the team said. At 48 months, the CIN2+ rate was 5 per 1,000 vs. 10.6 per 1,000 a 53% reduced risk (RR, 0.47) and an absolute reduction of 5.6 cases per 1,000.

Again, the benefit accrued early and mostly in women who were negative by HPV or cytology at baseline. Among these, the CIN2+ risk for the intervention, compared with the control group, was 64% lower (RR, 0.36), and the absolute difference in incidence was 6.38 per 1,000.

This early detection came at a cost, however. Colposcopies were significantly more common in the intervention group in the first screening round (57 vs. 30.8). However, by 48 months, colposcopy rates were lower in the intervention group, compared with the control group (49.2 vs. 70.5). By the end of the study, cumulative colposcopy referral rates were similar (106.2 vs. 101.5).

Dr. Ogilvie and her colleagues suggested that this ultimate similarity in colposcopy rate shows that fears about overdiagnosis with HPV testing are unfounded.

"One of the concerns for adopting HPV-based screening is the lower CIN2+ specificity of HPV testing, compared with cytology, leading to higher screen positive rates and the resulting need for more colposcopies and biopsies. Unnecessary colposcopies potentially cause unintended harm for women and increased costs to health care systems. In this trial, round 1 colposcopy rates in the HPV-tested group were significantly higher than the cytology-tested group. However, by 48 months, the colposcopy rate in the intervention group was reduced while the control group rate increased.

"This increase is partly a result of HPV and cytology co-testing at trial end. Of the 513 control-group women referred for colposcopy at exit, 304 (59%) were cytology negative and HPV positive. In the HPV-tested group, the colposcopy rate decreased in the second round of screening, which more accurately reflects the ongoing impact of HPV-based screening on a colposcopy program. The baseline colposcopy referral rate reflects what happens when HPVbased screening is first implemented, when both prevalent and incident infections will be detected," the investigators said.

The Canadian Institute of Health Research funded the study. Dr. Ogilvie was a coinvestigator on adjunct studies funded by Hologic and Roche, designed to compare the performance of different HPV assays. Funding for the adjunct studies was not applied to the main HPV FOCAL trial.

SOURCE: Ogilvie GS et al. JAMA. 2018;320:43-52.




Fortunately for women, both modalities are effective

PRIMARY HPV TESTING HAS BEEN available since 2014 in the United States, but has yet to replace Pap smears, L. Stewart Massad, MD, said in an accompanying editorial (JAMA. 2018;320:35-37).

The reasons are complex and numerous, beginning with the probability that the more sensitive HPV test can run up alarming, but unnecessary, red flags, especially for younger women.

"Adoption of primary HPV screening has been delayed by the suboptimal specificity of this approach, estimated at 85%-95%, especially among populations of young women who often carry HPV infections that regress without oncogenic consequence. These HPV infections represent true-positive HPV assays, but are false-positive cancer screens."

Lack of patient education is another factor.

"HPV is almost universally acquired by sexually active adults. The virus usually clears in response to immune recognition, although clearance of this intraepithelial virus may take more than a year, and yet HPV may recur and first be detected decades later in the context of long-term monogamy or abstinence.

"Communicating a positive HPV test result requires sensitivity by the clinician and may entail lengthy counseling about the natural history of HPV, the lack of curative therapy, and the low absolute risk of progression to cancer. The clinical implications of an HPV diagnosis for sexual partners and offspring are marginal yet may be quite distressing for an affected woman."

The HPV vaccine is already affecting cervical cancer rates and will complicate the picture even more. HPV FOCAL completed recruitment in 2012. Since then, rates of HPV 16 and 18, the most cervically carcinogenic serotypes, have fallen in the wake of the 2006 vaccine approval.

This reduction is becoming more apparent as women who were adolescents at vaccination and at the time the study was launched are now aging into screening cohorts. Lower prevalence of cervical precancer has changed the accuracy of screening tests in ways that are only now being appreciated, but that will further favor adoption of primary HPV screening by lowering its false-positive rate."

The HPV test used in the FOCAL study was also suboptimal, compared with newer versions. The test incorporated all carcinogenic HPV serotypes in a single positive or negative result.

"More recent assays provide HPV genotyping that allows nuanced risk stratification, especially immediate referral to colposcopy for women who screen positive for HPV 16 or HPV 18. Triage for women who test positive for HPV was by cytology, which may not be the optimal triage test because other assays that do not depend on cytotechnologists' vigilance are becoming available for this purpose. However, these advances should result in fewer false-positive results, further favoring HPV screening over cytology."

The future of the Pap test remains unclear. Organizations that develop cancer screening guidelines continue to debate the issue.

"A draft recommendation on cervical screening from the U.S. Preventive Services Task Force recommended either cytology testing at 3-year intervals or primary HPV testing at 5-year intervals for women 30-65 years of age, but the final recommendation statement has not yet been released. Fortunately for women, both modalities are so effective for cancer screening that an adequately powered comparative effectiveness trial is likely impossible."

Dr. Massad is a gynecologic oncology surgeon at Washington University, St. Louis. He has consulted with malpractice attorneys in cases alleging missed cervical cancer but has no financial ties with pharmaceutical companies.
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Author:Sullivan, Michele G.
Publication:OB GYN News
Date:Aug 1, 2018
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