BETHESDA, MD—Human papillomavirus (HPV) vaccines against this common virus are highly effective in preventing cervical cancer, but less than 50% of the target population of young US women has been vaccinated, a problem that was explored at a National Cancer Institute seminar here held on the grounds of the National Institutes of Health. And currently the Centers for Disease Control and Prevention has not made a recommendation on these vaccines for young men to prevent HPV infection. (In 2009, a US Food and Drug Administration advisory panel voted to recommend expanded use of the Gardasil HPV vaccine for males age nine to 26 for the prevention of genital warts caused by HPV types 6 and 11.)
Because HPV vaccines are expensive and type restrictive, there could be a role for another preventive strategy: topically applied HPV inhibitors that could serve as an adjunct or intermediate substitute for vaccination, especially if they were inexpensive and had broad-spectrum activity, noted John T. Schiller, PhD, Head of the NCI's Neoplastic Disease Section in the Center for Cancer Research.
If developed for clinical use, HPV-inhibiting microbicides could be especially helpful in reducing HPV-associated oral cancer, particularly in men with multiple sex partners, he said. “In contrast to other sexually transmitted diseases, studies indicate that condoms afford at best limited protection against sexual HPV transmission, at least under normal patterns of use,” so that is another reason HPV-inhibiting microbicides could be useful, especially in developing countries where vaccine costs and availability are a barrier to vaccination.
“In about one and a half to two years we'll actually know if they will work,” he said. “I'm actually quite optimistic.” On the downside, though, because topical microbicides must be applied before each potential exposure—that is, before each sex act—whereas vaccinations are administered infrequently, such as in one series of vaccinations during a lifetime, compliance could be an issue.
So far, the development of HPV-inhibitors is nowhere near as advanced as that of HPV vaccines, said Dr. Schiller, although some controlled clinical trials have taken place and others are beginning. He noted that HPV inhibitors received a lot of publicity after an article on the efficacy of topical microbicides in preventing HPV infection was published in July 2006 in PLoS Pathogens.
After screening a large number of compounds for activity against HPV, Dr. Schiller and his colleagues found that carrageenans—polysaccharides extracted from the cell walls of red algae in the North Atlantic ocean—are potent inhibitors of HPV type 16, the most carcinogenic of HPV types, causing about half of cervical cancers.
Genital HPVs are highly susceptible to carrageenan, and carrageenans are already in widespread use in the commercial marketplace as food thickeners, Dr. Schiller said.
“Our hypothesis was that existing sexual lubricant products might already incorporate carrageenan as a thickening agent,” and indeed that turned out to be the case. Dr. Schiller found several marketed sexual lubricant products with anti-HPV 16 activity that use carrageenan as a primary gelling agent.—“This is the most serendipitous finding I've ever had in my research career,” he said.
He is now studying carrageenans in vivo in the mouse genital challenge model, where the compound prevents HPV infection. Globally, he said, a South African trial sponsored by the Population Council of a carrageenan gel product called Carraguard demonstrated the product's safety. And at the end of the study HPV infection rates in the Carraguard arm were 50% lower in a subset of women with good compliance. However, overall compliance was poor in this study, he said. “This is not a perfect trial by any means, but it is moving in the right direction.”
Dr. Schiller said that currently two clinical trials of anti-HPV carrageenan microbicide products are planned: a year-long randomized controlled trial of Carraguard with 200 young women, at Albert Einstein College of Medicine; and a trial at McGill University of a product known as Divine #9.
He also described an Australian dendrimer product called VivaGel, which also has HPV antiviral activity but is fundamentally different from the carrageenan products. The compound appears to have antiviral in vitro and in vivo activity in experimental animals not only against HPV 16, but also against HIV and HSV, Dr. Schilller explained. Five Phase I safety clinical trials of VivaGel have been completed: in Australian women, in Australian men, and in Kenyan women.
Negotiations are currently underway, he said, for an NCI-sponsored trial of VivaGel—a randomized, placebo-controlled trial, with the primary endpoint of prevention of incident genital HPV infection.
Asked by OT if an anti-HPV microbicide could lower the risk of oropharyngeal cancer, should a clinically tested, approved product become available, Dr. Schiller answered that it potentially could—“presumably it could dampen down the infection rate.”
He noted that since carrageenan is used in edible products as a thickener, the FDA considers it to be generally recognized as safe (GRAS) for ingestion. “What the microbicides could do would be to enable an individual man or woman to lower his or her [HPV infection] risk, but we don't want to encourage use of them before we run a controlled clinical trial.” He also cautioned that currently available over-the-counter sexual lubricant products containing carrageenan are not manufactured to the same standards as a pharmaceutical product would be.
Warning About Overscreening
Also speaking at the meeting, Mark Schiffman, MD, PhD, Senior Investigator in the Clinical Genetics Branch of NCI's Division of Cancer Epidemiology and Genetics, said that HPV testing is going to be introduced into screening for young women; the current recommendation is to start testing for persistent HPV infection at age 30, with retesting at three-year intervals.
He warned against HPV overscreening, which almost always picks up new HPV infections that are not harmful: “Screening too often would be bad. The first HPV screen detects prevalent, persistent, long-duration infections associated with precancer. Subsequent screens get worse and worse at risk discrimination; we need a way to triage women found to be HPV positive, without over-reacting, and we should use HPV testing at prolonged intervals.”
Dr. Schiffman pointed out that: new infections are most common at young ages (when sexual activity begins), and then the incidence declines sharply; that each infection is independent of others caught at the same time or later; that infections typically go away within months or within two to three years; and that it is the persistent HPV infections that pose a risk of precancer and cancer.
The bottom line, he said, is that becoming infected with HPV is very common, but invasive cancer due to the virus is rare—“Infection is common. Make sure it goes away—that is the message.”
The HPV & Oral Cancer Connection
New research is uncovering a strong connection between HPV and oral cancer, a connection that has caused HPV-associated oral cancers to increase steeply. According to the NCI, while oral cancers caused by smoking have dropped over the last 30 years, oral cancers associated with HPV have mushroomed—to the point where today about 70% of all newly diagnosed oral cancer cases are caused by HPV infection, usually due to sexual activity.
The research of Maura Gillison, MD, PhD, Professor of Internal Medicine and Epidemiology at Ohio State University's Comprehensive Cancer Center, has confirmed that HPV causes oral cancer, and she has identified men who have multiple sex partners as being at high risk for the disease.
Dr. Gillison, an NCI-supported investigator, found that exposure to HPV 16 was strongly associated with oropharyngeal cancer; antibodies against HPV 16 were found in 64% of cancer patients, but only 4% of people without cancer. Risk factors included a high lifetime number of vaginal-sex partners (26 or more) or oral-sex partners (six or more), and men were at especially high risk.