Dr. Michael A. Gold
For about a decade, physicians have had access to a human papillomavirus test to help stratify a patient's risk for cervical cancer. However, this spring the FDA approved two new options to further refine early identification of the HPV variants most often linked with cancers of the cervix, vulva and vagina.
On March 13, the FDA approved both the Cervista 16/18 and Cervista HPV HR assays, manufactured by Hologic Inc., as viable alternatives to Qiagen's digene HPV HC2 DNA test that received pre-market approval in 1999.
Prior to receiving FDA approval, Hologic asked Michael A. Gold, MD, FACS, FACOG, to review their data. Gold, who is double board certified in gynecologic oncology and obstetrics-gynecology, is nationally known for his patient care and research expertise in cervical cancer and dysplasia. He is also the new director of the gynecologic oncology division at Vanderbilt University Medical Center and an associate professor with the medical school.
"Traditionally, we have had one commercially available test that was a cocktail of 13 high risk HPV types, which are the cause of 95 percent of cervical cancer," Gold said.
Although there are more than 100 different variants of HPV, types 16 and 18 are known to be a precursor to cervical cancer in about 70-75 percent of cases. Cervista 16/18 uses HPV genotyping to flag these two variants so that providers can closely monitor patients at highest risk for developing cervical cancer.
"HPV testing, in general, allows you to identify who is at risk for having or developing a high-grade cervical lesion," said Gold. "The 16/18 test helps you further stratify your risk groups."
He added human papillomavirus is very common and typically uneventful. According to the Centers for Disease Control and Prevention, the body's immune system naturally clears an HPV infection –– including the HPV types considered most dangerous –– in 90 percent of cases.
"At any given point and time in a woman's life, about 10-40 percent will be HPV positive," Gold noted. When the original HPV screen was approved, usage was only as a follow up to an abnormal Pap test. Since 2003, however, the FDA has approved use of HPV high risk testing in conjunction with a Pap test in women 30 and older.
"Abnormal Pap tests only make up about 5 percent of Pap tests annually," Gold continued. "Of those, about half are ASC-US –– Atypical Squamous Cells of Undetermined Significance."
With the HPV triage test, physicians and technicians are able to divide the ASC-US group into HPV High Risk Negative (about 40 percent) or HPV High Risk Positive (60 percent). According to Gold, those in the negative group only have about a 2 percent chance of having a high-grade precancerous lesion. For this population, the recommendation is that the women return to a normal Pap test schedule. For those who are ASC-US HPV High Risk Positive, however, the chances of having a high-grade lesion jumps to 20-25 percent so these women all go on to have colposcopy.
In women 30 and older –– where HPV testing is used in conjunction with Pap –– who have a normal Pap and negative HPV, the guidelines by the American Society of Colposcopy and Cervical Pathology (ASCCP) call for a diagnostic Pap test only once every three years. In the HPV Positive but Pap normal group, the chance of a precancerous lesion is about 10 percent. For these women, it has been recommended they repeat their Pap and HPV tests in one year. At that time, if they are still HPV Positive, they, too, are referred for colposcopy.
The plus, Gold said, of any of the HPV co-tests is that it eliminates unnecessary Pap tests and colposcopy for women in the negative group and helps speed diagnosis and detection in the positive group as compared to Pap tests alone.
With the advent of the HPV 16/18 test, physicians now have the ability to employ new ASCCP guidelines for women who are HPV positive on their co-test to quickly determine if the HPV strain is one of the two known to cause most cervical cancers. "If you are 16/18 positive, you can go to colposcopy immediately," explained Gold. "If not, you revert back to the old guidelines and repeat a Pap and HPV test in a year."
While the benefits of the 16/18 variant test are clear, Gold said the new Cervista HPV HR also has some clinical differences that set it apart. First, it does include one more HPV type in the testing mix than Qiagen's traditional hybrid capture test. More importantly, however, is the new test requires a smaller volume of specimen and has controls that help minimize false negatives.
"I'm told in some centers as many as 10 percent of specimens will be of insufficient quantity to run the hybrid (test)," Gold said. "I've not seen that high a percent, but I'm told some centers see it frequently."
Gold continued, "Cervista also has a built-in control to let you know if there is enough DNA in the specimen to actually run the HPV test. Then you know if you need to repeat the test … which would require another visit … or if your patient truly is HPV negative."
He clarified that HPV testing is run off a liquid vial containing the human DNA specimen. In the first problem seen with the older test, there is an insufficient quantity of liquid. With the second issue associated with the Qiagen assay, there is enough liquid to perform the test but not enough DNA to make an accurate assessment so physicians receive a false negative. "That doesn't mean the patient is HPV negative, it means what I sent didn't have enough cells to run the HPV test," Gold noted.
For patients and physicians, the new tests with higher specificity offer another layer of early warning and detection.
"If you are at high risk, you know you need to be evaluated further with colposcopy," Gold said. "In all likelihood, you will be under closer surveillance during the immediate future," he continued, adding this extra attention should help catch abnormalities before they become major problems.