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HPV vaccine impacts disease, screening

From the February ACP Internist, copyright © 2017 by the American College of Physicians

By Mollie Durkin

At some point in their lives, most people who have sex become infected with a genotype of human papillomavirus (HPV), the most common sexually transmitted infection in the United States. Before the HPV vaccine became available, the average lifetime probability of acquiring the virus among U.S. men and women with at least one partner of the opposite sex was about 91% and 85%, respectively, CDC researchers estimated in a 2014 article published in Sexually Transmitted Diseases.

Although most people who acquire HPV generally resolve it without health problems, certain persistent types of HPV cause most cervical cancers and many cancers of the genitals, anus, rectum, and oropharynx. HPV vaccination can prevent most of these cancers from ever developing by preventing infections with cancer-causing HPV types, according to the CDC.

A molecular surface model of the human papillomavirus. Image by Evan Oto / Science Source

A molecular surface model of the human papillomavirus. Image by Evan Oto / Science Source



While HPV immunization is recommended during adolescence and might seem less useful in older adults, internists practicing in the postvaccine era have their own host of considerations: namely, screening for cervical cancer and providing catch-up vaccination.

In the U.S., three vaccines are licensed to prevent HPV infection: a bivalent vaccine (Cervarix, approved by the FDA in 2009), which protects against types 16 and 18; a quadrivalent vaccine (Gardasil, approved in 2006) against types 6, 11, 16, and 18; and a nine-valent vaccine (Gardasil 9, approved in 2014) against types 6, 11, 16, 18, 31, 33, 45, 52, and 58. As of 2017, only the nine-valent vaccine is distributed in the U.S., according to the CDC.

HPV types 16 and 18 account for about 70% of all cervical cancers, types 6 and 11 cause 90% of genital warts, and the five additional types covered by the nine-valent vaccine account for 15% to 20% of cervical cancers, according to the CDC.

The CDC recommends that girls and boys get vaccinated at age 11 or 12, or as early as age 9, when efficacy is highest. Ideally, vaccination can be completed prior to any exposure to HPV (often within the first few sexual experiences), but this is not a requirement, according to the CDC. As of 2015, about 63% of girls and 50% of boys ages 13 to 17 in the U.S. had started the vaccine series, the agency reported last August.

The cancer conundrum

Despite the available vaccines, the incidence of HPV-related cancers increased from 2008 to 2012, compared with the previous five-year period, the CDC reported in July 2016. But the increase is not at all indicative of the vaccine's efficacy, experts said.

“It's one of the more controversial issues. It shouldn't be, but it is,” said Philip Castle, PhD, a professor of epidemiology and population health at Albert Einstein College of Medicine in New York. “The anti-vaccine lobby points to that and says, ‘Well, the vaccines haven't prevented any cancer.’” However, he noted, it takes about 20 years for HPV to start causing significant numbers of cancer cases in the first place. For this reason, vaccine-related reductions in cancer could take years to detect.

The recent increase in HPV-related cancers (seen mostly in oropharyngeal cancers) merely demonstrates the continued increase of exposure of the virus—almost a “baseline” prior to any impact from HPV vaccination, said Mona Saraiya, MD, MPH, associate director of the CDC's Division of Cancer Prevention and Control's Office of International Cancer Control. “That's why the vaccine is going to have a lot of potential in preventing these cancers,” she said.

Although they've not yet proven their full cancer-preventing potential, the vaccines have shown an impact in preventing HPV infection, genital warts, and precancerous lesions like cervical intraepithelial neoplasia (CIN), including high-grade lesions (CIN2 and CIN3), Dr. Saraiya noted. “In Denmark and Australia and, more recently, a study that was done in the U.S. from New Mexico, we're seeing a [reduction] in the youngest age group of the high-grade precancerous lesions … compared to much older women, where you're not seeing any kind of impact of HPV vaccination,” she said.

If detecting and treating precancerous lesions detected by Pap testing prevent cervical cancer (as is widely, if not universally, accepted), and the vaccines are preventing those same lesions, then HPV vaccination will eventually make an impact at the cancer level, Dr. Castle said. “We would expect, probably in the next 10 years in some places, to start seeing large decreases [in cancer]. In some places where they have excellent surveillance, we might see a smaller decrease earlier,” he said.

Impact on screening

There are no routine screening tests for HPV-related cancers other than cervical cancer, according to the CDC. But even with HPV-fighting vaccines in hand, U.S. guidelines for cervical cancer screening do not vary for vaccinated subgroups. Experts predicted that this won't always be the case.

Since 2012, the U.S. Preventive Services Task Force (USPSTF) has recommended cervical cancer screening in women ages 21 to 65 with cytology every three years. For women ages 30 to 65 who want a longer screening interval, the Task Force recommends screening with a combination of cytology and HPV testing every five years.

In May 2015, the USPSTF began the process of updating the recommendation, said Kirsten Bibbins-Domingo, MD, PhD, chair of the USPSTF and professor at the University of California, San Francisco. “Next, the Task Force will issue a draft recommendation statement and evidence review,” she said, although she could not confirm when those items will be published.

Notably, the USPSTF is reviewing HPV immunization status as part of the update, according to its final research plan, published in June 2016. The 2012 recommendation states that because of limited data, researchers did not previously review evidence on how HPV vaccination might affect screening.

A recent model-based study suggested that screening for cervical cancer later and less often in HPV-vaccinated women may provide more benefit with lower harms and costs than current screening guidelines, according to results published in October 2016 in the Journal of the National Cancer Institute. This makes sense in theory, but it won't be successful without good vaccine uptake, said medicine-pediatrics subspecialist Angela T. Dearinger, MD, MPH, FACP, associate professor at the University of Kentucky College of Medicine in Lexington.

Even though current HPV vaccination rates in the U.S. are higher than ever, completion of the entire vaccine series remains poor: about 42% in girls and 28% in boys as of 2015, the CDC reported last August. “The Healthy People 2020 goal for both boys and girls to complete a three-dose regimen of HPV vaccine is 80%. So clearly, we're way behind there,” Dr. Dearinger said. “I don't know that we can talk about decreasing screening vaccinated persons when we aren't vaccinating very well.”

In the future, however, it would make sense to do less cervical cancer screening in a much lower-risk population, Dr. Castle said. “For every precancer you detect that will prevent cancer, you're going to spend a lot more money because there's just fewer of them,” he said. “So it's not a change in the denominator, it's a change in the numerator—how many women will actually benefit.”

Dr. Saraiya added that the demonstrated impacts of the vaccine on HPV infection, genital warts, and precancerous lesions are likely enough evidence to change screening guidelines, especially for fully vaccinated girls. “I believe there is more and more evidence out there,” she said. “I think eventually, we will see a later starting age for cervical cancer screening … and then also extending the interval between screenings and, of course, changing the type of test.”

Such changes are already underway in Australia, where 86% of girls and 77% of boys had received one or more vaccine doses as of 2015, according to the National HPV Vaccination Program Register. Australian physicians continued to screen for cervical cancer starting at age 18 and every two years thereafter until the decrease in CIN2 and CIN3 became apparent, Dr. Saraiya noted. “They gathered the thought leaders and guideline groups and decided to make changes in one fell swoop,” she said.

As a result, the country's guidelines will change in May 2017 to begin cervical cancer screening for all women at age 25 and rescreen every 5 years, according to the Australian Government Department of Health. Notably, instead of screening with cytology, clinicians will use the HPV test (which has the ability to differentiate genotypes), “which makes sense because the HPV vaccine that they had used is going to show a decrease in [HPV types] 16 and 18, but not necessarily in the other types,” Dr. Saraiya noted.

Since most of its young people are getting vaccinated, Australia did not have to make separate guidelines for vaccinated populations, she said, but the potential need for separate guidelines in the U.S. is unclear. “We have to review the data here because in some of these countries, the data systems speak so well that one can tell who's vaccinated and who's not,” Dr. Saraiya said. “Here in the U.S., we probably don't have that sophistication.”

Dr. Dearinger pointed out that having to keep up with multiple guidelines for different subgroups would increase complexity of screening. “When you have six recommendations on one subject, the internists can't keep up with all that. No one can,” she said.

To that end, Dr. Castle foresees a risk-based approach to cervical cancer screening that will incorporate vaccination status, screening history, and other factors that are relevant to a woman's risk of cervical cancer. “The next change will have to be accompanied by some sort of risk-measurement tool that will allow internists, who only have a few minutes, to make the right decision,” he said, noting that such a tool could be based in the EHR and provide simple, direct screening and management recommendations.

Vaccination verification

While vaccinating adolescents is great for prevention purposes, it presents continuity issues when they need to be screened 10 or 15 years later, Dr. Castle said. “The challenge for the internists, of course, is finding out accurately whether the person's been vaccinated,” he said.

It's important for physicians to know whether their patients have been vaccinated and to make a strong recommendation to complete their series, said Elissa Meites, MD, MPH, a medical epidemiologist with the CDC's Division of Viral Diseases. “The best way for an internist to find out about someone's vaccination history for HPV would be to ask them,” she said. “We know that self-reported vaccination history for HPV, because it's an adolescent vaccine, is better than self-report of childhood vaccinations, which people might not remember.”

As far as obtaining an accurate vaccination history, “You take anything that you can get,” including medical records from health departments or doctors' offices, Dr. Dearinger said, adding that state-based immunization registries vary but can also be helpful. “I think that increasing our ability to keep track of immunizations is going to be really, really important,” she said.

Ideally, by the time patients see an internist, they would already be fully vaccinated against HPV, Dr. Meites said. “But since not everyone is, the catch-up recommendations for those who have not been adequately vaccinated previously do go up through age 26 for women or up through age 21 for most men,” she said. The recommendations also extend through age 26 for gay, bisexual, and other men who have sex with men, for transgender people, and for men with certain immunocompromising conditions, Dr. Meites noted.

The cutoff is age 26 because that's the age range for which HPV vaccines are licensed in the U.S., Dr. Meites said. “So use over age 26 is off-label in the United States. If clinicians choose to use it, it's not part of the CDC recommendations,” she said. (This recommendation is based on data that have shown that the benefit of HPV vaccination decreases with increasing age.) Dr. Meites clarified that patients who've started the HPV vaccination series on time should still complete it even after age 26. Interestingly, in Australia, the bivalent and quadrivalent vaccines are licensed for women up to age 45 (although uptake among women ages 27 to 45 has been limited), and the nine-valent vaccine is not yet available there, according to the National Centre for Immunisation Research & Surveillance.

Vaccination of older women has reduced cost-effectiveness because many have already been exposed to HPV, Dr. Castle said, noting that high coverage in adolescent girls seems paramount. “The great example is in Australia: Not only did they very early on see a reduction in genital warts in the girls who were vaccinated, but the male population of the same age also saw a reduction in genital warts because of herd protection,” he said. “So the best first thing we should do is get our vaccination coverage up in the adolescent females.”

New CDC recommendations may help. The agency has typically recommended three doses of the vaccine, but in December 2016, it lowered the recommended number of doses to two for those initiating the vaccination series before age 15. This change was made based on data showing that two doses in younger adolescents provided a similar or higher immune response compared to three doses in older adolescents. “The way that would apply to an adult patient is if they got one dose before their 15th birthday, they'd need just one more dose to complete the series,” Dr. Meites said.

Dr. Dearinger added, “It's a lot easier to get two doses in children than three doses, and the dosing schedule is going to be different, too.” In a three-dose series, the second dose is given one to two months after the first, and the third is given six months later, she said, whereas in a two-dose regimen, the second dose is recommended anywhere from six to 12 months after the first. As of 2015, about 52% of girls and 39% of boys ages 13 to 17 in the U.S. had received at least two doses, the CDC reported last August. “I certainly think that vaccine uptake will improve with a two-dose regimen,” Dr. Dearinger said.

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