A new American College of Obstetricians and Gynecologists (ACOG) practice bulletin says clinicians can consider using the human papillomavirus (HPV) assay approved by the Food and Drug Administration (FDA) as a primary screening test for cervical cancer (HPVpr). However, ACOG’s preferred strategies remain co-testing with both HPV and cytology, or cytology alone (Obstet Gynecol 2016; 128:923–25).
The October 2016 bulletin’s stance on HPVpr echoes interim guidelines issued in 2015 by the American Society for Colposcopy and Cervical Pathology (ASCCP) and the Society of Gynecologic Oncology (SGO). All three organizations now say HPVpr can be considered, but do not identify it as the screening test of choice.
“ACOG’s practice bulletin recommends cytology alone or in combination with the HPV test. Regarding primary screening with HPV, if you choose to use it, ACOG offers some guidance,” said David P. Chelmow, MD, who drafted the ACOG bulletin. He is professor and chair of obstetrics and gynecology at Virginia Commonwealth University in Richmond and an ASCCP board member. The recommendation for consideration of HPVpr is based on “limited and inconsistent scientific evidence,” he added.
Meanwhile, other recent developments show wider adoption of co-testing in the U.S. First, in July 2015, Medicare began covering high-risk HPV testing once every 5 years as an additional preventive service benefit in conjunction with cytology for asymptomatic beneficiaries ages 30 to 65. One year later, in July 2016, FDA approved Roche Molecular Systems’ cobas HPV test, the sole HPV test approved for primary screening, as the first HPV test that can be used along with cervical cells obtained for a Pap test and collected in SurePath preservative fluid.
Guidelines and Evidence
ACOG gives little guidance on HPVpr and refers clinicians to ASCCP/SGO recommendations, which say it should be used only in women age 25 or older. With negative HPVpr results, women should not be retested for at least 3 years, while women with positive results for HPV 16 and 18 should have colposcopy, according to ASCCP/SGO. Women with positive results for the 12 other high-risk HPV genotypes should have reflex cytology. If genotyping and cytology tests are negative, ASCCP/SGO guidelines call for follow-up testing in 1 year, but do not specify a method (Obstet Gynecol 2015;125:330–7). Co-testing is “reasonable,” ACOG says.
Meanwhile, ASCCP, SGO, and ACOG all say co-testing is not appropriate until age 30. From ages 30 to 65, co-testing with cytology and HPV testing every 5 years is preferred, and screening with cytology alone every 3 years is acceptable.
However, some experts say HPVpr is a superior test. One such individual is Mark Stoler, MD, professor emeritus of pathology, cytology, and gynecology and associate director of surgical pathology and cytopathology at University of Virginia School of Medicine in Charlottesville, and former president of the American Society for Clinical Pathology. An investigator in the ATHENA (Addressing THE Need for Advanced HPV Diagnostics) trial, on which cobas’s FDA approval was largely based, Stoler described HPVpr’s advantages over cytology and co-testing as: a single FDA-approved algorithm for handling abnormal results; and better sensitivity and negative-predictive value (NPV) for cervical intraepithelial neoplasia grade 3 (CIN3) or higher, as demonstrated by ATHENA data (Gynecol Oncol 2015;136:189–97). Stoler has served as a consultant and speaker for Roche Molecular Diagonostics.
However, HPVpr’s increased sensitivity results in more colposcopies than co-testing or cytology, although the number of colposcopies needed to detect a single case of CIN3 after HPVpr is roughly equal, ATHENA also found.
Attila Lorincz, PhD—professor of molecular epidemiology at Wolfson Institute for Biomedical Research at University College London—regards HPVpr more cautiously. ACOG is right to wait for a greater body of evidence to expand its recommendations to fully back HPVpr, he said. “The ATHENA results are pretty good,” Lorincz observed, but he cautioned that ATHENA “is just one randomized controlled trial on one manufacturer’s product. Data, no matter how stellar, is more limited when one manufacturer puts it out.”
Trials outside of the U.S. are poised to deliver more data on HPVpr, particularly optimum screening intervals and triage strategies. Lorincz is collaborating with Mexican researchers on FRIDA (Forwarding Research for Improved Detection and Access for Cervical Cancer Screening), which involves 100,000 women, but no HPV testing for those younger than age 30. Other triage studies are ongoing at Vrije Universiteit Medical Center in the Netherlands, and in Canada, where researchers are finishing the HPV Testing for Cervical Cancer Screening (HPV FOCAL) study, which involves 33,000 women. In Australia, the ongoing COMPASS trial is the first to assess HPVpr in a population with high HPV vaccination rates.
Method Ratings and Reviews
Debate over which screening method is best “is to some degree splitting hairs,” said Ryan Fortna, MD, PhD, director of molecular pathology at Northwest Pathology in Bellingham, Washington, which offers HPVpr. “These days in the U.S., when you find cervical cancer, it is usually in patients who didn’t get any screening for years, mostly uninsured people. That’s the majority of women who end up with invasive cancers,” he added. “The question is, which method is a little better?”
Fortna considers co-testing the most thorough screening strategy. Because the HPV test is not completely specific or sensitive for the virus and cytology may miss some dysplasia, “there’s a benefit for doing two things.” Cytology also spots lesions and other abnormalities, including herpes, yeast, Trichomonas vaginalis, and endometrial carcinoma, he pointed out. But HPVpr “by itself is almost as sensitive as co-testing. It is also easier and cheaper to do one thing,” Fortna added.
He is a proponent of having women self-collect samples for HPV testing, noting multiple studies in the U.S. and other countries that show this scenario provides safe, effective screening, especially for women who miss regular exams for financial, geographic, or cultural reasons (Cancer Med 2015;4:620–31; J Womens Health 2016; 5:489–97). The downside, however, is that many women may not schedule regular checkups and would miss out on exams, Fortna said.
A Boost to Co-Testing?
FDA’s approval of the Roche cobas test for use with cervical cells obtained for a Pap test and collected in SurePath media might have marked a watershed moment for co-testing. Previously, use of cells collected in SurePath for both cytology and HPV testing had been problematic, prompting SurePath’s manufacturer, Chicago-based BD, to issue a warning in 2012 that the practice could lead to false negative results. The Roche cobas test now provides specific instructions for processing cervical samples to minimize this risk.
FDA’s approval of SurePath use with cobas will be especially important for reference labs, said Bryan Moore, PhD, director of marketing for molecular diagnostics for Roche Diagnostics USA, in Indianapolis. Many reference labs accept cervical samples in both SurePath and Hologic’s ThinPrep liquid.
FDA’s approval will make clinically validated co-testing easier for labs that choose to use SurePath. “The question is, will labs use it?” said Stoler.
According to Moore, the answer is yes. “Our lab customers tell us they have been waiting for an FDA-approved option for HPV testing using SurePath,” he said. “Within just eight weeks following the FDA approval, more than half of the labs had already converted from their own lab-developed tests.”
Medicare’s July 2015 announcement about covering co-testing may also make it a more popular choice. The Centers for Medicare and Medicaid Services has estimated that this policy change will help only about five million women ages 30 to 65 who are enrolled in the Medicare program as part of federal disability insurance. However, Stoler and Fortna said Medicare’s new policy might reinforce other insurers’ coverage of co-testing.
New Vaccine Recommendations
In October, the U.S. Centers for Disease Control and Prevention (CDC) revised its HPV recommendation that 11- to 12-year-olds receive just two doses of HPV vaccine—at least 6 months apart—rather than the previously recommended three doses. Meanwhile, FDA approved adding a two-dose schedule for the 9-valent HPV vaccine Gardasil 9 for adolescents ages 9 through 14. CDC has encouraged clinicians to begin implementing the two-dose schedule in order to protect preteen patients from HPV-related cancers.
Teens and young adults who begin the HPV vaccine series later, at ages 15 through 26, will still need three doses of HPV vaccine, according to the CDC. “There’s evidence that maybe two shots are enough, if you get people before they have sex,” Stoler pointed out (JAMA 2013;309:1793–802). Vaccination at younger ages, before sexual activity begins, spurs more antibody production than vaccination after that point, he explained.
In the U.S., HPV vaccination rates have remained below those for other childhood vaccines and far short of the roughly 80% seen in countries with school-based immunization programs, such as the United Kingdom and Australia. In 2015, among U.S. teens ages 13 to 17, 56.1% had received one dose, 45.4% had two doses, and just 34.9% had three doses (MMWR Morb Mortal Wkly Rep 2016;65;850–8). Rates were higher for girls than boys.
ACOG’s practice bulletin says HPV vaccination is an important cervical cancer prevention measure, but that it doesn’t negate the need for routine screening. While ACOG recommends vaccination for both sexes through age 26, the practice bulletin also notes that the latest 9-valent vaccine does not cover all high-risk HPV subtypes, and that some women may acquire a pathogenic subtype before getting the vaccine, decreasing its efficacy. When most young people are fully vaccinated, HPV as a primary test “may be the way to go,” Chelmow said, because the predictive value of cytology will “go way down.”
The International Perspective
Some nations have hit the inflection point where they believe cytology provides less valuable information and have back-seated this method in favor of HPVpr. In Australia, the National Cervical Screening Program will implement primary HPV testing every 5 years for women ages 25 to 74, starting in May 2017. Sweden and parts of Italy have also implemented HPVpr, while New Zealand is preparing to start in 2018. Like Australia, these countries all have single-payer health systems and high vaccination rates.
In the U.S., cytology and co-testing make more sense, given the patchwork of government and private insurers with various payment policies as well as a mobile society, Chelmow maintained. “Patients move to different doctors who use different tests. They don’t know what their last doctor did,” he pointed out. Sticking with the two more highly recommended screening scenarios raises chances that women get tested at proper intervals, he explained.
“We should all appreciate that cervical cancer screening is pretty good. The discussion now is about nuances,” says Fortna. “Focus more on those people who have not had screening. The discussion should be about how to get them screened, rather than the exact screening method.”
With three testing methods and multiple algorithms, laboratorians need to be prepared to help clinicians understand the different performance characteristics of each, Lorincz said. “You want to give clear information to clinicians, so be a subject matter expert on cytology, HPV, and genotyping,” he emphasized.
One Lab’s Experience Implementing HPV Primary Screening
In 2014, Northwest Pathology in Bellingham, Washington, was the first pathology group in the U.S. to offer HPV primary screening (HPVpr), now on the menu of more than 100 U.S. labs, according to Roche Diagnostics. Northwest’s greatest challenge in implementing HPVpr was changing requisition forms and reports, according to Ryan Fortna, MD, PhD, Northwest’s director of molecular pathology. His lab updated its requisition form to include a separate section for HPV primary screening, describing the Food and Drug Administration-approved testing scenario, and explaining when the lab would perform reflex cytology.
Fortna’s lab also changed HPV results reports according to whether the test was performed as primary screening, co-testing, or reflex testing. For example, with HPV primary screening, “we list the HPV result first, and automatically include both the HPV-16/18 results and the 12 other HPV results, and list the reflex cytology—if performed—last,” he noted. “This change was meant to make the reporting follow the logic of the testing algorithm, which is reversed from the typical algorithm.”
After implementing HPVpr, Fortna got many questions from clinicians who did not understand the American Society for Colposcopy and Cervical Pathology (ASCCP) algorithms that explained how to handle HPVpr results. “But I hardly get questions anymore,” he said. “If there is an abnormality, the algorithm [for HPVpr] really is not that complicated. It is much simpler than the larger ASCCP algorithm for co-testing,” Fortna added.
Noting that HPVpr represents only about 1% of his lab’s total volume, he advised labs considering offering HPVpr to first determine clinicians’ interest in this testing method. Labs that offer the test should avoid confusion by making HPVpr a clear, separate offering on requisition forms, he added.
Uptake of co-testing has also been slow, according to Fortna. He attributes this to a combination of medical association endorsements that leave in place cytology alone as a recommended option. “With more experience, clinicians will see the combined approach gives higher overall sensitivity,” he predicted.
Deborah Levenson is a freelance writer in College Park, Maryland. + EMAIL: [email protected]