Understanding Human Papillomavirus and cervical cancer.

"You can get so confused
that you'll start in to race
down long wiggled roads at a break-necking pace
and grind on for miles across wierdish wild space ..."
--Dr. Seuss

Indeed, charting a course through the HPV maze can be confusing. Once fairly obscure, genital Human Papillomavirus (HPV) has become much more widely known--if not completely understood. It has been at the heart of political and scientific research and debate and a source of media attention.

Human Papillomavirus is a nearly universal STI that most sexually active Americans are thought to contract at some point, though most are never diagnosed clinically. At any one time, about 20 million people are infected with HPV although most will have no visible symptoms and are unaware that they are infected. The increased awareness of HPV is driven largely by new diagnostic methods (such as HPV DNA testing), the prospects of prophylactic vaccines looming on the near horizon, and its role in sexual health politics.

HPV--THE BASICS

Genital HPV is one of the most common sexually transmitted infections (STIs) in the United States. About 6.2 million people get genital HPV each year. It is estimated that about 80% of sexually active people have been infected with HPV at some point in their lives.

HPV is a group of DNA viruses that infect the skin. There are well over 100 different types, many of which are associated with benign lesions such as common warts of the hands and feet. About 30 HPV types are associated with anogenital skin and sexual transmission--of these, some are "low-risk" HPV types that can cause lesions such as genital warts, which are usually harmless. Of greater concern are the "high-risk" types that can lead to abnormal cell changes (most often detected of the cervix). Most HPV infections resolve spontaneously and generally do not lead to health complications.

Prevention, Diagnosis, and Treatment

Outside of sexual abstinence, the surest way to prevent HPV (and other STIs) is to refrain from sexual contact with an infected person or to be in a long-term mutually monogamous relationship with an uninfected person. Although condoms may not provide complete protection, multiple studies have shown that using condoms consistently and correctly can reduce the risk of HPV-related diseases such as genital warts and precancerous and cancerous changes to the cervix.

Because HPV is so widespread, prevention is particularly challenging. The most promising prevention method would, of course, be a vaccine. Groundbreaking research indicates the stunning potential these vaccines have as public health interventions--recent data from a large phase III trial shows Merck's Gardasil vaccine is 100% effective at preventing high-grade cervical diseases associated with the oncogenic HPV types found with about 70% of cervical cancers. Vaccines to prevent HPV are expected to be available within the next year. Young people ages 8-17 are presumed to be the target recipients of these vaccines. The initial indication of HPV vaccines will almost certainly be to prevent infection in females, which means the target population will be young girls who are not yet sexually active.

Until the FDA approves a vaccine, the age of immunizations will not be known. However, immunization for young girls prior to sexual activity and "catch up" vaccines for older populations are likely to be recommended. An effective strategy to ensure wide coverage would be for states to make vaccines mandatory for children at some school entry point.

The most common diagnostic methods for HPV involve visual exams, Pap tests, and HPV DNA tests. Pap tests can detect abnormal cell changes in the cervix, but cannot directly diagnose HPV. Specialized DNA tests can diagnose HPV in the cervix. These tests are routinely used to clarify abnormal Pap test results. They are also approved for primary screening in women over 30, in combination with conventional Pap testing. Regular screening through Pap and HPV DNA tests can catch cervical cancer in its early stages, when there are no symptoms. Since cervical cancer typically takes years to develop, with regular screening, nearly all cases can be prevented or cured.

Genital warts (which do not cause cancer) can now be treated with patient applied topical therapies, as well as through conventional clinic-based approaches--these include health care provider-applied chemicals and outpatient surgical options like cryotherapy (freezing with liquid nitrogen), scalpel excision, electrocautery (burning), and in some cases laser surgery. The choice of therapy varies depending on the size, location, and number of warts.

The Cervical Cancer Link

The immune system of most healthy people is able to suppress HPV within a few months. In some cases, though, these cell changes persist over many years and if left undetected can eventually progress to cervical cancer. Although most HPV infections do not lead to cancer, about 99% of cervical cancer tissue contains high-risk HPV.

It is not clear why some cases fail to clear naturally and progress along the continuum to cancer. However, co-factors linked with cervical cancer include smoking or exposure to second-hand smoke, having intercourse at an early age, and long-term use of oral contraceptives.

Cervical cancer develops slowly, often taking ten years or more, and is seldom detected in women who have regular Pap screening (either alone or in combination with HPV DNA tests). Mortality related to this disease is especially tragic considering that it is virtually always preventable through screening at consistent intervals. According to the American Cancer Society, the number of cervical cancer deaths in the U.S. has dropped 74% since the advent of Pap screening in 1955--there are now approximately 10,000 cases of cervical cancer in the U.S. each year, and nearly 4,000 deaths as a result. Yet cervical cancer is preventable, treatable, and curable.

The burden of cervical cancer is now experienced most keenly in countries lacking screening programs. The World Health Organization (WHO) estimates approximately 80% of global cervical cancer deaths occur among women in developing nations. WHO estimates that there are more than 500,000 cases of cervical cancer worldwide annually and nearly 300,000 deaths, making it the second-leading cause of death from cancer among women globally.

Psychosocial Impact

The psychosocial impact of HPV can be devastating. HPV can cause emotional anguish that many newly diagnosed women find overwhelming. Research by Ellen Daly, Ph.D. and Kay Perrin, Ph.D. found that 94% of infected women felt the need to hide the fact that they had HPV. More than 75% of women diagnosed with HPV reported feelings of anxiety and blamed themselves for the diagnosis, as if they were "paying" for past sexual behaviors. Similarly, a survey of health care providers conducted by the Centers for Disease Control and Prevention (CDC) found patients commonly react with fear and anger upon diagnosis.

CDC is conducting additional studies in this area. Initial data from surveys of women recently diagnosed with HPV reveal that many are concerned about the source of HPV transmission, lack of support and communication with partners, and potential damage the diagnosis may have on relationships. Interestingly, women are more affected when HPV is viewed as an STI than as a precursor to cervical cancer.

HPV and Men

As confusing and unfamiliar as the subject of HPV is for women, it's even more difficult to find information for men. Not a great deal is known about the "natural history" of the virus in males. Diagnostic options are essentially limited to a visual inspection to detect lesions (warts or cell changes)--there is no direct test for the virus itself currently approved for clinical use with men. Health issues with HPV occur even less often with males than females, but "high-risk" HPV types are associated with some penile and anal cancers, the latter of which raises discussions on the need for anal screening for men who have sex with men (and women with a history of anal sex). This is often elusive, though, as many health care providers and laboratory staff are unfamiliar with means of anal cytology sampling and specimen interpretation.

HPV AND POLITICS

Given the ubiquitous nature of the infection and the need for awareness of both the potentially harmful outcomes of the virus and the importance of screening to prevent them, one might assume HPV discussions would be a straightforward, apolitical addition to the public health agenda in the U.S. and around the world. Things are seldom that simple where matters pertaining to sex are concerned, and HPV is drawing attention both from groups touting an abstinence-only approach to prevention as well as those who promote comprehensive sexual education programs. It is sometimes difficult to separate the intertwined, often ideological, messages surrounding HPV, condoms, and abstinence.

HPV found its way into the forefront of political debate in 2001. A provision inserted into the Fiscal Year 2001 Labor, Health and Human Services, and Education (Labor-HHS) appropriations bill by former Representative Tom Coburn (R-OK), now a U.S. senator, fueled a political debate around HPV and condoms. The provision required the CDC to conduct research projects and a series of public education efforts to better inform providers and the general public about HPV. It also required the Food and Drug Administration (FDA) to reexamine condom labels to determine whether they are medically accurate with respect to condoms' "effectiveness or lack of effectiveness" in preventing HPV.

It isn't currently known exactly how effective condoms are at blocking HPV transmission. The virus isn't likely to penetrate condoms made of latex; however, because HPV can exist on skin that condoms don't cover, protected sex is not a guarantee that transmission won't occur. Some legislators are urging the FDA to alter current condom labeling to specifically state these limitations. However, listing limitations could discourage rather than encourage condom use. Those who are concerned about STI prevention see this as a major problem--condoms are currently the best product available to prevent STIs.

This equation may soon be made even more complex. Preliminary data presented by researchers from the University of Washington in Seattle offer evidence that consistent, correct condom use does reduce risk (perhaps as much as 70%) of HPV acquisition. This will likely come to a head soon, as the FDA recently issued revised condom labeling for public comment.

Like condoms, the potential for an HPV vaccine is becoming the center of controversy. Beyond the normal concerns found with any new childhood vaccine (such as worries that kids are becoming little "pincushions"), HPV vaccines have the added element of offering protection against a virus acquired through sexual activity--this juxtaposition of children and STIs is a potentially volatile combination that many find unnerving.

There is concern, for example, among some abstinence-only proponents that HPV vaccines may lead to a false sense of security that will ultimately encourage promiscuity and lead to risky sexual behavior among youth. Others, however, counter that these vaccines will be of incalculable value in preventing cervical cancer and reducing the medical and psychosocial burdens associated with a diagnosis of HPV-related diseases, and should be universally implemented.

The pharmaceutical companies with vaccines in clinical trials, Merck and GlaxoSmithKline, are keenly aware of these controversies and, like many advocates of a comprehensive approach to STI prevention and sexual education, are trying to "normalize" discussions by focusing strongly on women's health and cervical cancer prevention components, and less on a sexually transmitted virus as the causative factor.

FDA approval for the first vaccine is anticipated early in 2006. National and state organizations have begun to prepare for the myriad social and access issues that the vaccines may raise. In the midst of potential controversy, maintaining the central public health goal of preventing cervical cancer will be essential.

LOOKING FORWARD

HPV presents multi-faceted challenges, impacting individuals on many levels. As vaccines come to market and new diagnostic technologies inevitably gain wider use, these issues are likely to receive even greater scrutiny. Resources that give clear, consistent information are of paramount importance as increasing numbers of patients, partners, and health care providers become aware of HPV and ask questions.

This is evident in the comments made by one newly diagnosed woman who wrote to HPVnet, a service operated by the American Social Health Association that responds to more than 3,000 emails about HPV each year: "I am 19 years old and so scared out of my mind, I can't put it all into perspective. Maybe you can tell me something that will make sense to me and help me better understand what I may be facing with HPV." Clearly, she's not alone.

Fred Wyand

Program Coordinator, HPV and Herpes Resource Center

Deborah Arrindell

Vice President of Health Policy

American Social Health Association

Washington, DC