Houston study augurs possible shift in hrHPV genotypes

It’s possible that HPV 90 functioned as a “bystander” genotype in this group of women patients, Dr. Ge adds. “All of these women had cervical disease before, and there’s a reasonable argument that the cervical lesions with a concurrent HPV genotype might be a residual effect of previously high-risk HPV that has since cleared up, with HPV 90 acting only as a bystander—in other words, it showed up on tests but it’s not the real cause of the disease.”

However, the study notes, the absence of other HPV genotypes and presence of unequivocal viral cytopathic effect in concurrent cytologic and histologic specimens strongly argue against the bystander notion. “The only way to definitively prove that is to study the cancer tissues to see which genotypes are incorporated in the cancer cells,” Dr. Ge says.

For three of the patients with abnormal cytology and HPV 90 infection, the researchers also performed HPV-ISH (in situ hybridization tests) to look for evidence of residual high-risk HPV, and didn’t find any, Dr. Quiroga-Garza says. “That’s why we think, although we cannot predict with 100 percent certainty, that the HPV 90 was probably an independent infectious agent associated with cervical dysplasia.”

The HPV 90 associated with the three cases with cervical lesions might not be a “wild” type of HPV but rather a potent mutant that may act as powerfully as HPV 16 in tumorigenesis, Dr. Ge says. “We do know that high-risk HPVs cause cancer by degrading the tumor suppressor gene p53, and ‘wild’ type HPV 90 doesn’t have the ability.” However, it was demonstrated recently that the mutation of HPV 90 E6 enables it to fully degrade p53, he says. It is possible that the HPV 90 associated with the three cases of cervical disease might not be the wild type of HPV 90; rather, it could be a potent HPV 90 mutant that may act as powerfully as HPV 16 in tumorigenesis. “Unfortunately, we could not discriminate the wild type from a mutant HPV 90 in the current study, and further investigation is certainly warranted,” Dr. Ge says.

While the study authors urge that their results be interpreted with caution—for example, HPV 90 could be over-represented in this particular population—it’s clear that unexpected changes in the risk levels of various HPV genotypes could have implications for the HPV vaccine, which the Centers for Disease Control and Prevention considers a strong weapon of prevention.

The two current HPV vaccines (Gardasil and Cervarix) vaccinate against only two high-risk HPV types: HPV 16 and 18, Dr. Schwartz notes. (Gardasil also vaccinates against HPV 6 and 11, which are not high-risk for cervical cancer but are the most common causes of genital warts.) “Merck is working on a nine-valent HPV vaccine, but HPV 90 is not included; the vaccine is directed against HPV 16, 18, 6, 11, 31, 35, 45, 52, and 58. So these Latina women who get one of the current HPV vaccines, or who will get the nine-valent vaccine if and when approved, will also not be protected against HPV 90.”

With Houston’s dramatic surge in Hispanic population, the city now has the third highest concentration of Hispanic residents in the country, Dr. Zhou notes. But Houston is not alone; Los Angeles, Miami, Chicago, New York, and other cities are also showing significant growth in the percentage of Hispanic population. “So for future vaccination programs, we need a broader strategy that will take the demographic change into consideration and monitor the dynamics of HPV composition and emerging genotypes.”

As Dr. Ge points out, the origin of HPV 90 infection in these patients may be difficult to prove, but this virus is here to stay. “It will impact the future trend of HPV makeup of the U.S. population,” Dr. Ge says.

In addition, “If the HPV vaccination program is successful, we don’t know which genotypes will emerge as the dominant HPV genotypes in 10 years.” The vaccination programs may be knocking down the current top high-risk genotypes, HPV 16 and HPV 18, but it’s difficult to predict which genotypes will take their place, Dr. Ge says.

“The next one may not necessarily be HPV 31, even though by prevalence it is next in line, because of the complexity of host-viral interactions and competition among the HPV genotypes. But we think this study is kind of a wakeup call, because some of the previously unnoticeable genotypes may be emerging into important genotypes after the vaccination programs.” All of this information will be important in defining future generations of vaccines against HPV, Dr. Ge adds.

The recently changed clinical guidelines for Pap test screening, which now recommend longer intervals for women in lower-risk age groups as well as co-testing for high-risk HPV, may need another look if, indeed, high-risk categories are more in flux than predicted. Says Dr. Schwartz: “The commercial tests for high-risk HPV testing—for example, Cervista HPV HR and Digene Hybrid Capture assay—do not test for HPV 90. So if you are a woman with an HPV 90 infection, your HPV infection will not be detected by current high-risk HPV assays, and you will not benefit from management pathways recommended for women found to have high-risk HPV infections.”

The Methodist study is also likely to provide information for optimizing the future screening strategy for cervical cancer. The new guidelines say that for women ages 30 to 65, co-testing with cytology and HPV testing is the “preferred” approach, with cytology alone rated “acceptable.” But “whether to screen for cervical cancer and its precursors using primary HPV screening is controversial,” Dr. Schwartz says.

In Europe, in fact, the trend is to shift to HPV testing and leave cytology behind. “HPV testing has been traditionally used as a reflex test for patients with ASC-US on cytology,” notes Dr. Ge, who has written a paper on HPV testing and cytology testing. But more clinicians are now likely to order both HPV and cytology as kind of a double screen. “We’re looking into the data and we’re finding if they order single testing, either HPV only or cytology only, they actually miss some high-grade lesions or cancer. We believe that cytology and HR-HPV testing are complementary, and the co-testing strategy will greatly increase the sensitivity for detecting squamous intraepithelial lesions, while retaining the ability to identify other significant lesions that are unrelated to HPV infection.”

Since HPV testing currently tests for only 14 genotypes out of the 40-plus that are known, “We often get calls from clinicians to question the abnormal cytology diagnosis when the HPV test is negative. A negative HPV test often gives clinicians as well as patients a false assurance. A variety of factors may cause a negative HPV test. Either the viral titer is not high enough or the genotype is simply not included in the testing panel.”

“All science is based on the accumulation of data, and our study is just one piece of information,” Dr. Ge says. But the study is important, in his view, first, because HPV 90 has never been reported in a North American population, and, second, they proved an association with cervical disease. “And because this has never been studied before, we may need further study of this genotype, especially in the general U.S. population.”

It is difficult to screen for all HPV genotypes, Dr. Quiroga-Garza notes. “But we’re in a new era now, especially with vaccination.” As further HPV studies proceed, she believes that particular attention must be paid to the nation’s changing demographics. “HPV genotypes are going to change, and genotypes that might be actually considered non-carcinogenic might emerge as important. And that might have prevention implications in the future.”

Anne Paxton is a writer in Seattle.