Study: primary HPV test ‘merits consideration’

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• For women ages 21 to 65, screening with cytology every three years.
• For women ages 30 to 65 who want to lengthen the screening interval, screening with a combination of cytology and HPV testing every five years.

With triennial Pap tests, HPV testing is recommended for triage of ASC-US results.

In the algorithm for primary HPV testing that the FDA approved, women whose specimens are positive for HPV genotypes 16/18 go directly to colposcopy. Those whose specimens are positive for one of the other 12 high-risk genotypes are triaged with a Pap test. Patients whose specimens are ASC-US or worse cytology are referred for colposcopy.

In the KPNC cotesting program, HPV testing is based on the Hybrid Capture 2 test performed from a separately collected sample. Women testing HPV positive/Pap negative or HPV negative/Pap equivocal (ASC-US) returned after one year. Women testing HPV positive/Pap ASC-US or HPV negative with a low-grade or worse Pap were referred for colposcopy. Women testing HPV negative/Pap negative returned for repeat screening in three years. For the 571,880 women who were followed beyond enrollment, the mean follow-up time was 4.36 years. (About half of women had been enrolled too recently to have a repeat visit. Also, some left the KPNC program.) Total follow-up time was 2,495,946 person-years.

Looking just at results five years after a negative screen, these were the CIN3 or worse outcomes:

• For negative Pap testing: 310 cases per 100,000 women.
• For negative HPV testing: 140 cases.
• For negative cotesting: 110 cases.

The same comparison for cancer looked like this:

• For negative Pap testing: 31 cases per 100,000 women.
• For negative HPV testing: 17 cases.
• For negative cotesting: 14 cases.

Thus, compared with cotesting, HPV testing results in an additional 30 cases of CIN3 and an additional three cases of cancer over five years per 100,000 women screening HPV negative.

Comparing results with the same interval, Dr. Gage tells CAP TODAY: “Risk estimates between HPV-negative and cotest-negative algorithms are very close. How to interpret these close risks will come down to traditional health decision analyses to understand the optimal screening interval and preferred strategy.”
What HPV testing would prevent is a large number of screening tests, the investigators wrote: “If a negative HPV test can provide the same safety (ie, reassurance against future risk of precancer and cancer) as a negative Pap or negative cotest (currently recommended strategies), most of the Pap tests now conducted in screening would no longer be required.” They estimated that over 15 years HPV screening at a five-year interval could reduce the total number of screening tests by one-third to one-half compared with primary Pap every three years or cotesting every five years.

Initially there would be fewer colposcopies with primary HPV screening, Dr. Gage says. But, she adds, “I think it’s important to consider that women who screen HPV positive/Pap negative are recommended to return in a year for rescreening, and a portion of them will also be referred to colposcopy at that time.”

Expanding on KPNC’s adoption of the three-year screening interval for cotesting, Dr. Lorey called it “a progression from what was the gold standard—annual Pap smear cytology.” Using annual Pap smear screening, rather than three-year cytology, as the benchmark for implementing new screening strategies resulted in a three-year, as opposed to five-year, interval for cotesting.

“When we introduced cotesting at three-year intervals in 2003,” he says, “we were able to demonstrate that it provided the same or better protection against the risk of cancer and precancer with fewer tests and fewer visits compared to an annual Pap. We may evolve to a five-year interval in the future, providing we have very good data that aligns well with the risk provided by the annual Pap smear.”
Adoption of the five-year interval for cotesting by the Preventive Services Task Force and the ACS/ASCCP/ASCP group, on the other hand, was based on its protection and risk being equivalent to those of the prevailing screening algorithm at that time—Pap testing at three-year intervals.

Any laboratory or health care institution could adopt cotesting at a three-year interval, and a five-year interval might be acceptable as well, Dr. Lorey says. “One of the interesting features of the HPV molecular assay is that it has superior negative predictive value,” he says. He raises the possibility that cotesting at five-year intervals could approach the level of protection of annual cytology after several rounds if women experience a cumulative benefit with consecutive negative HPV results. However, he emphasizes, right now this is no more than conjecture.

Dr. Lorey attributes the slightly higher sensitivity of cotesting relative to HPV-only at the same screening interval to the small increment of additional sensitivity provided by the Pap test. “Unlike HPV-only,” he says, “the Pap component of cotesting identifies a subgroup of HPV-negative/Pap-positive patients, and in this subgroup, there is a small number of patients who will have disease. However, as we know, there is a corresponding decrease in specificity due to the many HPV-negative/Pap-positive patients who do not have disease.”

“We remain hopeful,” he says, “that development of new screening tests, impact of vaccination, and promise of newer medical therapies will simplify the decisionmaking process when we decide to change our current testing strategy. That said, any change to our program, tests, and/or intervals will have to preserve or increase the current level of protection provided by our three-year cotesting program.”

Looking into the future, he says, “Along with other tests, vaccination too will likely offer the opportunity to extend increased screening intervals.”
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William Check is a writer in Ft. Lauderdale, Fla.