When the cobas HPV Test (Roche Molecular Systems) was approved for first-line screening of primary cervical cancer by the US Food and Drug Administration (FDA) last week, how and when it should be used was not addressed.
"We are aware that the approval has raised a number of questions about how HPV testing will be used and whether the Pap test will continue to play a role in cervical cancer screening," stated a Society of Gynecologic Oncology (SGO) press release. "Primary HPV testing does not replace the Pap test, and it is extremely unlikely that doctors will stop using the Pap any time soon."
The SGO is working with the American Society for Colposcopy and Cervical Pathology (ASCCP) to produce interim guidelines on the use of the HPV test in first-line screening, but for now there are more questions than answers, and many opinions. Two experts told Medscape Medical News how they envisage its use.
The cobas HPV Test received initial approval in 2011 for use in conjunction with or as a follow-up to cytology testing. But with the current approval, cobas can now be used alone as the primary cervical cancer screening test.
This is the first human HPV DNA test approved in the United States that can be used alone to detect high-risk HPV infection. The test is recommended for first-line screening and can specifically identify HPV genotypes 16 and 18, which are responsible for about 70% of all cervical cancers. It also concurrently detects 12 other high-risk genotypes (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68).
Makes Sense, but With Caveats
"Primary HPV testing makes sense from a scientific, epidemiologic, and population basis," said Diane Harper, MD, professor and chair of the Department of Family and Geriatric Medicine at the University of Louisville, Kentucky.
However, there are some caveats, she notes.
The new approval is for first-line use in women 25 years and older.
"Using this system for those 25 to 30 years of age will cause much confusion, an abundance of false positives leading to colposcopy and biopsy that are not necessary, and immense costs for the healthcare system," Dr. Harper told Medscape Medical News.
The US Preventive Services Task Force (USPSTF) recommends that HPV testing be used with cytology to screen women 30 years and older for the explicit purpose of screening low-risk women less frequently, she pointed out. If both tests are normal, the testing interval should be 5 years.
In 2012, updated guidelines issued jointly by the USPSTF, the American Cancer Society, the ASCCP, and the American Society of Clinical Pathologists recommended that women 21 to 65 years of age should have a Pap test every 3 years. Further screening is not recommended for women with test results indicating no precancerous lesions.
These guidelines also recommend that women 30 to 65 years of age be screened with both cytology and HPV testing every 5 years (preferred) or with cytology alone every 3 years (acceptable). Evidence is insufficient to support a screening interval longer than 3 years for cytology alone, even in women who have had a series of negative tests. Cotesting at 5-year intervals provides a cancer risk similar to or lower than screening with cytology alone at 3-year intervals, the guidelines note.
Dr. Harper said she predicts that "the most likely issue will be the inappropriate use of HPV testing with cytology in women 25 to 30 years of age because of the confusion of cotesting in those 30 years and older," said Dr. Harper.
Strategy 9 Provides "Best Balance"
One of the significant concerns related to screening for HPV only is that it will lead to an overuse of colposcopy. A subanalysis of the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study shows how to avoid this, explained Michael Policar, MD, MPH, clinical professor of obstetrics, gynecology, and reproductive sciences at the UCSF School of Medicine in San Francisco.
The ATHENA trial, which enrolled more than 47,000 women, served as the basis for approval of the expanded use of the cobas HPV Test. The study found that separate testing for high-risk HPV16 and 18 might provide better detection than cytology in women at high-risk for cervical cancer.
A separate analysis of the ATHENA trial compared 10 cervical cancer screening strategies with the current screening standard (cytology with HPV triage of atypical squamous cells of undetermined significance) for the detection of high-grade lesions in a subgroup of women older than 30 (Am J Obstet Gynecol. 2013;208:184.e1-184.e11).
"Strategy 9" had the "best balance of sensitivity (picking up CIN3 lesions) and specificity (avoiding unnecessary colposcopies)," Dr. Policar noted. That strategy calls for colposcopy for women who screen positive for HPV16/18. For women who screen positive for the other high-risk HPV types, a Pap test is conducted and follow-up depends on the cytology results; women with any abnormal cytology of atypical squamous cells of undetermined significance or more severe were referred for colposcopy, and those who were cytology negative/HPV positive for non-HPV16/18 underwent 12-month follow-up.
Potential Economic Impact
Another issue is the economic impact, and whether the HPV test used alone will be cost-effective.
"Everyone is awaiting publication of the 3-year follow-up of ATHENA trial," Dr. Policar told Medscape Medical News. "At that point, they can do the same modeling [to determine] which of the 10 strategies is the most cost-effective."
"Because the laboratories will push for a reflex cytology testing of a positive high-risk HPV test from the liquid sample, women will not have to be called back for another cytology sample," she said. "But this takes the cost control and medical decision of whether to pursue cytology out of the doctor's and patient's hands. At least 30% of the screens done in the United States are done because of an initial abnormal screen and not for routine low-risk screening."
"Overall, this will increase the cost of women's health in the United States, as well as increase the false positives and harms caused by overdiagnosis, with no decrease in the cancer detection rate," she explained.
But the issues of cost and insurance coverage have not been addressed.
"If we go with strategy 9, I believe that the population-based cost of screening will drop dramatically, since most women will not need cytology tests, which run $30 to $50 each, separate from the cost of the HPV DNA test," Dr. Policar explained. "The cost will not change for women consumers because the Affordable Care Act guarantees cervical cancer screening with no cost-sharing. However, payers will likely save on their lab costs."
Dr. Policar emphasized that this is just speculation, and that until a cost-effectiveness analysis is conducted, it is not known which strategy is the best. For now, it might be prudent for clinicians to wait until there are clear guidelines on how to best use this test as a standalone tool.
A recently published review suggests that, on the basis of the evidence collected to date, "the time has come for the implementation of high-risk HPV testing as a primary screening test, as it provides a superior protection against cervical (pre)-cancerous lesions compared with cytology" (Ann Oncol. 2014;25:927-935).
In that review, Chris J.L.M. Meijer, MD, PhD, from VU University Medical Center in Amsterdam, and colleagues note that high-risk HPV testing detects 30% more cervical intraepithelial neoplasia grade 2+ (CIN2+) and 20% more CIN3+ lesions in women older than 30 years. They recommend that this type of primary screening be implemented "preferably within a population-based screening program with a call and recall system." The somewhat lower specificity, which can lead to excess false-positive tests in healthy women, can be overcome by triaging women who test positive for high-risk types.
"At this time, triaging these women by cytology at baseline and repeat cytology testing after 6 months, possibly in combination with baseline HPV16/18 genotyping, seems to be very suitable for this purpose," they write. "Although, as preferences and the quality of cytology will vary between countries, policymakers will have to weigh the pros and cons of the different triage strategies when making a choice."
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Cite this: HPV Test for First-line Cervical Screen: Questions on Use - Medscape - Apr 29, 2014.