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UK Trial Suggests HPV Co-Test Not Significantly Better Than Standard Screening

NEW YORK (GenomeWeb News) – Adding genetic testing for human papillomavirus to the existing cervical screening program did not significantly increase the detection of pre-cancerous cervical lesions in a randomized control study of women in the UK, according to a paper appearing online last night in the journal Lancet Oncology.

British researchers involved in the ARTISTIC randomized clinical trial compared the effectiveness of liquid-based cytology screening with or without HPV co-testing in more than 24,000 women. Based on their results from two rounds of testing over about three years, they concluded that cytology alone was as effective as co-testing for identifying high-risk cervical intraepithelial neoplasia, or CIN lesions, pre-cancerous cell growths on the cervix.

"We don't think that routine co-testing ... is going to be a cost-effective strategy," lead author Henry Kitchener, chair of gynecologic oncology at the University of Manchester, told GenomeWeb Daily News. Even so, he added, there are reasons to believe that the HPV test as a stand-alone test may be beneficial.

In their study, the researchers used the Qiagen Digene Hybrid Capture 2 test, which is designed to detect 13 HPV strains that increase cervical cancer risk. Representatives from Qiagen were not available for comment before this article went to press.

Earlier this year, the US Food and Drug Administration also approved two Hologic HPV tests, one that tests for 14 high-risk HPV strains and another that specifically tests for HPV16 and HPV18, the two strains associated with the majority of cervical cancers.

Results from an Indian study published this spring suggest the test can decrease cancer risk in previously unscreened populations. And previous studies in both Europe and North America have indicated that HPV testing is more sensitive for detecting CIN than conventional cytological testing alone.

But there is ongoing debate about the added benefit of HPV testing in combination with cytology-based screening. Co-testing based on HPV testing and cytology is an approved primary screening method in the US. And a study by researchers at Kaiser Permanente Northern California, published this March in Obstetrics & Gynecology, supported the use of genetic tests in combination with standard screening methods.

For the latest study, researchers recruited 24,510 eligible women between the ages of 20 and 64 years old through the UK's National Health Service Cervical Screening Programme. In the UK, cervical screening is recommended every three to five years.

Three-quarters of the women (18,386) were randomly assigned to the "revealed group." In this group, women were screened both by liquid-based cytology and HPV testing. Both the women and their doctors were told the results of this test. The other 6,124 women, who were in a "concealed group," were also screened using both LBC and cytology. But neither the women nor their doctors were told the results of the HPV test.

The team then compared the pre-cancerous lesion detection rates in the revealed and concealed groups.

The liquid-based cytology method used in the study is the same as that used in the national cervical screening program in the UK, Kitchener explained. It differs from conventional cytology in that cells scraped off the cervix are not placed directly onto a slide but first suspended in liquid. Kitchener said the method makes it easier to analyze the results and lends itself to automated testing since some of the liquid can be sent for HPV testing.

In the revealed arm of the trial, women who had positive HPV tests but negative cytology tests were invited back a year later for a second HPV test, Kitchener said. If the second HPV test was positive, the women chose between colposcopy or a third HPV test another 12 months later.

In the first round of screening, the researchers detected the most serious pre-cancerous lesions — grade 3 or higher cervical dysplasia, also called CIN3+ — in 1.27 percent of women in the co-test group and 1.31 percent of women in the LBC-alone group.

Nearly two-thirds of women participated in a second round of screening before data for the paper was analyzed. In that screening round, the team saw a huge drop in the incidence of pre-cancerous lesions in both groups: CIN3+ lesions were found in just 0.25 percent of those in the revealed group and 0.47 percent in the concealed group.

In contrast, results from two previous European randomized trials — which used conventional rather than liquid-based cytology — did not see such a dramatic decrease between screening rounds, Kitchener noted, suggesting liquid-based cytology may be a more sensitive method than conventional cytology.

Nearly 1,700 women in the revealed group were cytology negative and HPV positive women. Of these, 10 women were subsequently shown to have CIN3+ lesions. Ten had grade 2 or higher lesions. In the second round, the team detected 13 CIN2+ lesions and 15 CIN3+ lesions in women who were HPV positive but cytology negative.

Even though co-testing picked up a few dozen lesions that would have been missed otherwise, the researchers found that it did not significantly increase the detection of high-risk CIN cases over both rounds of screening.

"When primary cervical screening with LBC was combined with HPV testing there was a small but statistically significant reduction in the detection of CIN2+ and CIN3+ at the next screening round compared with LBC alone," the authors wrote. "When rounds [one] and [two] were combined, LBC with HPV testing did not identify significantly more CIN2+ or CIN3+ cases than LBC alone."

The team plans to extend the current study through a third round of screening. They predict that analyzing the results over six years from the time of enrollment should provide clues about whether HPV testing can stretch out screening intervals over cytology testing.

"We think it's quite likely that you'll get a longer period a protection from a negative HPV test than a negative cytology test," Kitchener said.

Even so, while previous scientific studies and epidemiology suggest stand-alone HPV testing may be beneficial, Kitchener said, so far there are no national programs based on HPV testing alone. Before that happens, he explained, researchers and health officials will need to come up with a sound strategy for handling positive HPV tests. Because women under 30 years old frequently test positive for HPV, doing colposcopy procedures on all HPV positive individuals is generally considered impractical.

If HPV testing does become the primary screening method, the authors emphasized, it will likely be important to distinguish between HPV types in women with positive tests — both for identifying persistent HPV infections that might lead to cancer and for gauging the effect that HPV16 and HPV18 vaccines have on other HPV types.