The Human Papillomavirus Vaccine: Lost in SpaceIf there were a vaccine available that could prevent an infectious disease, wouldn't you jump at the chance to be vaccinated? No, not for HIV infection -- although this disease is equally important. Instead, think smallpox, poliomyelitis, tetanus, and hepatitis A and B. Following in the exalted footsteps of these earlier vaccines, there are a couple of new kids on the block in the fight against infectious diseases. Gardasil®, from Merck & Co., Inc., and Cervarix™, from GlaxoSmithKline, were recently approved to fight certain sexually transmitted strains of human papillomavirus (HPV), which is associated with genital warts and the development of cervical cancer. In March 2007, the Centers for Disease Control and Prevention (CDC) recommended that Gardasil be used as a routine vaccination for adolescent girls and young women.

One would think that implementing an immunization program against a highly communicable disease would be straightforward, but Gardasil has become the subject of much debate, probably because the disease in question is one that is transmitted sexually. Sound familiar? But we're getting ahead of ourselves. Let's back up a bit to figure out how vaccination against HPV became such a controversial subject.

The Missing Link ... Cervical Cancer

Cervical cancer is the second most common cancer in women worldwide, with estimates indicating that it affects approximately 500,000 women annually.1 Each year, between 250,000 and 1 million American women are diagnosed with cervical dysplasia. About 11,000 American women are diagnosed with cervical cancer, and about 3,700 die of the disease.2 Cervical cancer develops in four phases: HPV transmission, viral persistence, transformation of infected cells into a precancerous form, and invasion of cancerous cells into healthy tissues.1 There is ample evidence that cervical cancer is preceded by a squamous intraepithelial lesion (SIL), an abnormal growth pattern in which some of the epithelial cells have features of malignancy. SIL, also known as dysplasia or cervical intraepithelial neoplasia (CIN), is divided into two categories: low-grade SIL, which is characterized by early, subtle changes in the size and shape of cells that form the surface of the cervix, and high-grade SIL, which is characterized by a large number of precancerous cells that constitute a high-grade lesion. The most severe form is known as carcinoma in situ, which indicates that the entire epithelial thickness has been replaced by cytologically malignant cells but the disease still has not broken through the basement membrane of the cervix.3 Once the abnormal cells break through into the cervical tissue, the cancer is considered to be invasive.

The highest risk of invasive cervical cancer occurs sooner than most other types of adult cancer, reaching a plateau from about 35 to 55 years of age.4 This plateau occurs because cervical cancer originates primarily from HPV infections transmitted sexually in late adolescence or in early adulthood. Epidemiologists have noted a relationship between the risk of developing abnormal changes in cervical tissue and certain other factors, including early sexual debut, multiple sexual partners, cigarette smoking, taking oral contraceptives, and previous infection with HPV. HPV is a DNA virus whose different types cause skin warts, genital warts, and other abnormal skin and body surface disorders.

It has been shown to lead to many of the changes in cervical cells that may eventually lead to cancer. In addition, women who have been diagnosed with HPV are more likely to develop a cervical cancer that has genetic material matching the strain of HPV that caused the infection. These findings demonstrate a strong link between HPV and cervical cancer. Because HPV can be transmitted by sexual contact, early sexual debut and having multiple sexual partners have been identified as strong risk factors for the development of cervical lesions that may progress to cancer. This route of transmission indicates that men can also become infected with HPV.

The Root Cause ... HPV

Box 1: Examples of the Factors That Predict Human Papillomavirus (HPV) Infection

Exposure factors

  • Increased number of sexual partners
  • Early age of first intercourse
  • Never being married

Endogenous factors

  • Oral contraceptive use
  • Immunosuppression secondary to infection or therapy

Cervical microenvironment factors

  • Sexually transmitted infections

From: Dawar et al. CMAJ. 2007; 177-456-461.

Human papillomavirus is highly communicable and affects a large percentage of the American population. During 2003-2004, at any given time, 26.8% of women between 14 and 59 years of age were infected with at least one type of HPV. This percentage is higher than previous estimates. In 2000, HPV infection accounted for approximately 6.2 million of all sexually transmitted diseases (STDs) among Americans between the ages of 15 and 44 years. It is estimated that 74% of infections occurred in people between ages 15 and 24 years. Genital HPV infection is very common, with estimates suggesting that more than 50% of women will become infected with one or more of the sexually transmitted HPV types at some point during adulthood.5

The 19 "high-risk" genotypes that can lead to cervical cancer and to other types of anogenital cancer include genotypes 16, 18, 31, 33, 35, 39, and others. Infections with other genotypes, termed "low-risk," can cause benign or low-grade cervical tissue changes and genital warts.6 However, it is the HPV-16 and HPV-18 strains that are the two most carcinogenic HPV types and are responsible for 70% of cervical cancer cases. In fact, "the main burden of HPV-related disease is due to cervical cancer," causing 100% of the almost 260,000 deaths from cervical cancer worldwide.6 On the other hand, HPV-6 and HPV-11 are responsible for about 90% of genital warts.1 Although only a small percentage of women infected with HPV eventually develop cervical cancer, most studies have found that HPV infection is responsible for virtually all cases of cervical cancer.7,8

A recent study found that among women infected with HIV, almost 40% of those without cervical cytological abnormalities had HPV infection. Moreover, women infected with HIV have a significant risk of abnormal cells of the cervix, vagina, and genital area and a higher incidence of CIN.9-11 Abnormal cervical cells have been found to occur at a younger average age in HIV-infected women and to progress to more serious stages if left untreated. These risks become greater as immune deficiency advances.9 Furthermore, prolonged survival of HIV disease because of antiretroviral treatment is associated with a greater risk of cervical cancer. Based on studies of the natural history of HIV infection, the CDC12 recognized the significance of cervical dysplasia and cancer in HIV-infected women and added HPV infection to the list of AIDS-defining opportunistic infections and invasive HPV-mediated cervical cancer to the list of AIDS-related diseases in January 1993. Concurrent infection with multiple HPV genotypes is more common in HIV-positive women than in HIV-negative women. Moreover, HIVinfected men and women are at increased risk of HPV-mediated anal cancer.6

The presence of active HPV infection in 81% of HIV-infected women with cervical dysplasianeoplasia suggests an HIV-induced impairment to the cellular immune response. Levine13 has suggested that because immune control of HPV requires CD4 T-cell immunity, women dually infected with HPV and HIV might be at increased risk for cervical disease. On the other hand, Vermund14 proposed that immunosuppression associated with the consequences of HIV infection accelerates HPV-mediated cervical pathogenesis. Williams15 finds it unclear whether the correlation between the two diseases is a result of infection with more virulent HPV types in HIV-positive women or if it results is from an exacerbation of HPV infection by HIV-mediated immunosuppression. The increased frequency of HPV infection in HIV-positive individuals could be the result of concomitant infection acquired through exposure to both organisms during high-risk sexual activities.15

Whatever the connection between HIV, HPV, and cervical cancer, clinical findings have shown that the progression of CIN is more aggressive in HIV-positive women, with rapid evolution to malignant disease and poorer response to therapy.13,16 Brettle and Leen10 also noted that advancing immunodeficiency is significantly associated with worsening CIN. In another study of women with preinvasive and invasive cervical cancer, those women who were HIV-positive had more advanced cervical disease and experienced a recurrence of their cervical disease 1 month (median) after treatment; whereas, HIV-negative women had a recurrence 9 months (median) after treatment. The median time to death was 10 months among HIV-infected women and 23 months among HIV-negative women. Of the 10 HIV-positive women with advanced cervical disease who died, 9 died of cervical cancer and only 1 of an AIDS-defining condition.9 Clark et al.17 have also documented that HIV-positive women with CIN have lower CD4 T-cell counts. Because of the increased risk of HPV and CIN in HIV-seropositive women, access to early medical care and intervention could influence the progression of HIV disease. For this reason, surveillance at an earlier age with careful and frequent pelvic examinations, including Papanicolaou (Pap) smears and cervicovaginal smears, is recommended.16

A Means to an End ... HPV Vaccines

In the early 1990s, the identification of HPV as an etiologic link to cervical cancer encouraged researchers to develop an HPV vaccine. The preventive HPV vaccines are based on noninfectious, hollow virus-like particles assembled from recombinant HPV coat proteins. Gardasil and Cervarix are designed to elicit virus-neutralizing antibody responses that prevent initial infection with the HPV types covered by the vaccine. The vaccines have been shown to offer 100% protection against the development of cervical precancerous lesions and genital warts caused by the HPV types the vaccine targets, with few or no side effects. The protective effects of the vaccine are expected to last a minimum of 4.5 years after the initial vaccination.18 Although the study period for the two newly available vaccines was not long enough for cervical cancer to develop in study participants, the prevention of these cervical precancerous lesions (or dysplasias) is believed to be highly likely to result in the prevention of those types of cancer.19

Gardasil and Cervarix are preventative -- rather than therapeutic -- vaccines, recommended for women who are 9 to 25 years of age and who have not contracted HPV. The rationale for routine immunization at 11 to 12 years of age is that it will be most effective in females who have not become sexually active.20 Since it is unlikely that a woman will have already contracted all four types of HPV targeted by the vaccines, and because HPV is primarily sexually transmitted, the CDC has recommended vaccination of women as old as 26 years of age. New evidence suggests, however, that all HPV vaccines are effective in preventing cervical cancer in women up 45 years of age.6 The widespread use of quality Pap smears in cervical cancer screening programs in developed countries has reduced the incidence of invasive cervical cancer by 50% or more. Nevertheless, experts recommend that women combine the benefits of vaccination with annual screening with Pap smears.

Although HPV-6 and HPV-11 do not cause cervical cancer, they can cause genital warts. "Warts cause considerable discomfort and psycho-social trauma, so this makes the vaccine more attractive and also provides a reason other than altruism for men to be immunized," explains John Schiller of the National Cancer Institute.21 The benefit of Gardasil, as compared to Cervavix, is that the former also targets HPV-6 and HPV-11, which together currently cause about 90% of all cases of genital warts.7

Both men and women are carriers of HPV. In fact, HPV also causes anal and penile cancer. Furthermore, condoms do not provide comprehensive protection against HPV.22-24 Consequently, from a public health point of view, vaccinating both men and women is important because it decreases the virus pool within the general population. Ultimately, vaccines that are effective for both men and women will be needed to eradicate the disease, a situation that has prompted American public health experts to recommend eventual mandatory HPV vaccination for men and women.25 Studies are now being conducted to determine the efficacy of vaccinating boys with the current vaccines.

The Debate ... To Give or Not to Give

America declared the War on Cancer more than 30 years ago, yet few curative treatments or vaccines have been discovered since. Given the epidemiology and etiology of cervical cancer and its mediation by HPV, the development and approval of not one, but two, prophylactic vaccines is an amazing medical breakthrough that should have caused widespread celebration. Instead, there has been a huge backlash. When Texas Governor Rick Perry, in a rare forward-thinking move, issued an executive order requiring that girls entering 6th grade be vaccinated with the HPV vaccine, the public health community was thrilled. That would have made Texas the first state to mandate the vaccination. The excitement, however, was short-lived. The Texas legislature overrode the executive order and barred mandatory vaccination until at least 2011.2

The debate surrounding the HPV vaccine is an old one. It's the same argument that surrounded the early years of HIV prevention efforts and that today affects family planning efforts worldwide. Supported by a political administration in the United States that has made abstinence-only its guiding principle in sex education, conservative groups have revived their battle cry that any sexual education would invariably promote sexual activity among adolescents. There are concerns about the morality of vaccinating young girls against an STD because it communicates tacit acceptance of promiscuous sexual behaviors. The Family Research Council said, "It sends the wrong message." Echoing that sentiment, a Dallas physician stated, "[I]f you don't want to suffer these diseases, you need to abstain, and when you find a partner, stick with that partner." This is an overly simplistic and reductionist viewpoint -- it is naive to think that abstinence and monogamy will eradicate the morbidity and mortality of cervical cancer, as suggested by some conservative groups.26

The reality is that no matter how much parents want to believe that their teens will remain abstinent until marriage, it is not likely to happen. Studies have consistently shown that abstinence-only programs do not produce the desired level of celibacy that parents hope for. Teens in such programs end up having their first sexual encounter at the same age as teens who have either not participated in these programs or who have had comprehensive sex education classes. Whereas both groups have similar numbers of sexual partners before graduating from high school, it is the teens who have had abstinence-only education who are the least prepared to protect themselves against HIV and other STDs when they finally have sexual intercourse.27 Conversely, preventive measures do not always lead to high-risk behavior: seat belts do not cause reckless driving, and tetanus shots do not cause children to seek out rusty nails.

In an on-target, online editorial, O'Rourke28 astutely pointed out that it takes only one sexual contact to contract a strain of HPV that can lead to cervical cancer. Moreover, no evidence suggests a connection between a decrease in HPV infection and an increase in sexual activity. In truth, HPV is not the most important thing on teenagers' minds, since it takes years to develop; they are more likely to be worried about the immediate effects of gonorrhea, herpes virus, or even HIV. Moreover, a vaccine is available that is designed to prevent another STD -- hepatitis B -- and it is not being protested by anyone on the grounds that it might encourage promiscuity. That vaccine is given to approximately 88% of all American children by the time they are 19 months old. The reason so many legislators and parents have conjured up a tie between vaccination and sex has less to do with objective reality than with the age at which girls are supposed to receive the HPV vaccine. Governor Perry's executive order would have mandated that girls receive the vaccine as they enter 6th grade -- at age 11 or 12 years -- precisely the juncture between childhood and young adulthood that we are the most uncertain about how to conceptualize.28 One pediatric cardiologist was quoted as saying that, given the very real dangers of cervical cancer, "I don't believe that they have pushed [Gardasil] in an unethical manner. They have a product that is almost certainly going to save lives."28

Other critics are opposed to a mandatory vaccination program because they see it as a violation of parental rights. These are the same people who are "dedicated to preventing vaccine injuries and deaths through public education." Such groups regularly oppose vaccinations of any kind; they are highly critical of most vaccinations, including those for influenza, tetanus, chickenpox, and measles, mumps, and rubella. These groups do not undertake their own scientific research but instead distort existing research findings on adverse vaccination events and draw causal relationships where there are none. One wonders if all these protests have to do with the fact that no other vaccine mandated for school-aged children targets a microbe that is spread primarily through sex. James Trussell, director of the Office of Population Research at Princeton University, said, "It all comes down to the evils of sex. That's an ideological position impervious to empirical evidence."

Just the Facts ... Safety and Efficacy

Given that $1.7 billion are spent annually in the United States to treat HPV infections, and that there are 6.2 million new HPV infections every year, it is reassuring to know that numerous studies have shown the new vaccines to be safe, effective, and even cost-effective, despite widespread concerns. One of the presentations at the May 2007 meeting of the Oncology Nursing Society summarized the results of five safety and efficacy studies published between 2001 and 2006.

  • One multicenter, randomized, placebo-controlled trial has demonstrated that Cervarix, the bivalent HPV vaccine targeting HPV-16 and HPV-18 (the strains implicated 70% of the time in HPV-related cervical cancer), is safe and offers a high degree of protection against HPV-16 and HPV-18, as well as some incidental protection against HPV-31 and HPV-45.
  • Four multicenter, randomized, placebo-controlled trials have demonstrated that Gardasil, the quadrivalent HPV vaccine targeting HPV-6, HPV-11, HPV-16, and HPV-18, is safe and effective against the targeted strains. The HPV-6 and HPV-11 strains are almost always implicated in genital warts and recurrent respiratory papillomatosis.
  • HPV vaccination is far more cost-effective than are the alternative means of managing cervical cancer, which involves repeated Pap smears, diagnostic testing, precancer treatment, and cancer treatment, as well as morbidity and mortality costs.

The approval of Gardasil was based on the successful completion of four studies -- one United States study and three multinational studies -- involving 21,000 women between the ages of 16 and 26 years. The results showed that in women who had not already been infected, Gardasil was nearly 100% effective in preventing precancerous cervical lesions, precancerous vaginal and vulvar lesions, and genital warts caused by infection with the HPV types targeted by the vaccine.29 The studies also evaluated whether the vaccine can protect women already infected with some HPV types targeted by the vaccine from developing diseases related to those viruses. The results show that the vaccine is only effective when given before HPV infection. Most adverse experiences that occurred in study participants who received Gardasil included mild or moderate local reactions, such as pain or tenderness at the injection site, not unlike the side effects of the tetanus vaccine. Two studies were also performed to measure the immune response to the vaccine among younger females between the ages of 9 and 15 years. Their immune response was as good as that among females 16 to 26 years of age, indicating that the vaccine should have similar effectiveness when used in the younger age group.

A number of trials are currently underway or in the planning stages that will contribute to our understanding of the HPV vaccines. Trials of Gardasil are being conducted among men, and there are plans to test a 3-dose regimen of Gardasil among people who are immunocompromised and a 2-dose regimen among adolescents. GlaxoSmithKline has announced plans to conduct a head-to-head comparison of Cervarix and Gardasil, and both GlaxoSmithKline and Merck are conducting trials involving older women. Both companies are planning trials of second-generation vaccines that will offer protection against additional high-risk HPV genotypes.30 The question of protection against the long-term outcome -- carcinoma in situ -- is being addressed in a European study of 22,000 adolescent females.31

Why We Should Care ... The HIV Connection

What about other uses for the vaccine? Since HPV can cause anal warts, and probably penile cancer, could it not also be used for men who engage in anal intercourse? Although anyone who is sexually active can be infected with HPV anally, HIV-positive men who have sex with men (MSM) appear to be at the highest risk of anal HPV infection. A recent study of HIV-positive MSM in San Francisco found that 95% of them had anal HPV infection and more than 50% had signs of precancerous lesions.32 In a 1987 paper published in the _New England Journal of Medicin_e, it was estimated that the incidence of anal cancer among HIV-negative MSM who engage in receptive anal intercourse was 35 per 100,000 -- a rate on par with the incidence of cervical cancer before routine Pap smears were initiated in the 1940s. Even more alarming is the incidence rate among HIV-positive MSM. During the late 1980s, the incidence of anal cancer among MSM with AIDS was reported to be twice that of men of the same age, race, and sexual orientation in the years before AIDS emerged (1975-1979). In other words, the incidence of anal cancer may be greater than 70 of every 100,000 HIV-infected MSM who engage in receptive anal intercourse.29 In addition, sexually active HIV-positive heterosexual men and women are very likely to have anal HPV infection regardless of sexual behavior. A French study reported in 2003 found that 46% of heterosexual male injection-drug users who said they had never participated in anal sex had anal HPV infection, whereas a United States study found that about three quarters of HIV-positive women had anal HPV infection and that anal HPV infection was more frequent than cervical HPV infection.33

Although the HPV vaccines appear to be effective for younger women, more research needs to be done. For one thing, it is important to remember that these vaccines are preventative and not therapeutic. For this reason, they will not have much impact on the health of individuals already infected with HPV. On the other hand, if an adult woman or man tests negative for HPV, the vaccine could be effective against HPV-mediated types of cancer. Similarly, it is possible that vaccinating boys and men will have indirect health benefits for girls and women by reducing the spread of HPV. And if adolescents receive the vaccine when they are young, it could help reduce malignancies if they ever become HIV-positive.34 At this time, the safety and effectiveness of Gardasil has not been determined in HIV-positive people; nor has it been established as a preventive vaccine against precancerous lesions and cancer of the anus in HIV-negative or HIV-positive men or women.

One caveat is that the younger the individual, the more likely the HPV vaccine is to be effective, because it is the most effective in individuals who have not yet acquired any of the four HPV types targeted by the vaccine. Once a person becomes sexually active, he or she may receive less benefit from the vaccine since he or she may have already acquired one or more HPV types covered by the vaccine. The encouraging news is that few young people are infected with all four of these HPV types, so they would still get protection from the types they have not acquired. Currently, there is no test available to indicate if a girl or woman has been infected with any or all of these four HPV types. Research on the safety and efficacy of the HPV vaccines among women older than 26 years of age has only recently begun. The Food and Drug Administration will consider licensing the vaccines for these women when there is evidence to show that it is safe and effective for them. Furthermore, therapeutic vaccines are being developed to treat established HPV infections and HPV-mediated types of cancer, which would further control HPV infection and its related malignancies.

Next Steps ... Reducing HPV Morbidity and Mortality

Box 2: HPV Vaccine Knowledge Gaps

  • Will HPV vaccines affect cervical cancer incidence and mortality?
  • Is the priming vaccine series sufficient or will a booster dose be required?
  • Will exposure to wild-type HPV contribute to natural boosting?
  • Will other HPV genotypes fill the niche previously filled by HPV types 16 and 18?
  • Do the vaccines provide cross-protection against a few related types?
  • Do the vaccines protect against other HPV-related cancers, such as oropharyngeal and anal cancers?
  • How will the vaccination program affect current cytology screening programs?
  • Will current cytology screening programs need to be adapted to identify vaccine failures?
  • Are there rare but serious adverse effects of vaccination that have not yet been detected?
  • Do the vaccines prevent infection in men and reduce the possible transmission to their partners?
  • Who can afford to get vaccines, even with tiered pricing, in view of competing health priorities?
From: Dawar et al. CMAJ. 2007;177-456-461 and Schiffman et al. Lancet 2007;370:890-907.

Public awareness of HPV, and its relation to cervical cancer, was limited until the recent approval of the HPV vaccines. Regrettably, most people are still unaware that HPV is sexually transmitted or that it is linked to anogenital diseases, like cervical cancer or genital warts. In 2005, only 40% of women between the ages of 18 and 75 years had heard of HPV, and less than half of that group knew of its association with cervical cancer. This lack of knowledge may explain why the risk of acquiring HPV infection is commonly underestimated. Moreover, lack of assurance from a trusted source that the vaccine is safe and effective, and that it has minimal side effects, continues to impact the development of a positive perception of the HPV vaccines.31 And not surprisingly, cancer fears and a lack of knowledge were identified as the foremost barriers to vaccine acceptance. This is not surprising, because STDs, including HPV, have long been associated with high levels of stigma and shame.

The controversy and debate over mandating the vaccine for school-aged children have been fueled by extensive attention in the lay media that has focused on the sexual nature of HPV transmission. By awakening parents' fears about earlier sexual debut and promiscuity, the vaccine could well be underutilized as a preventive measure. The media has also diverted attention from the benefits of the vaccine to its potential side effects, especially fainting and pain at the injection site, causing parents to be suspicious of a new vaccine does that not have a long safety record. Despite these misguided efforts of the media, research on parental attitudes about vaccines suggests that opposition to vaccination against STDs, particularly HPV, is not widespread. Studies indicate that most parents favor HPV vaccination, with 65% to 84% indicating they would want their child immunized against HPV if the vaccine were available.35 And, in an ironic turn of events, the controversy ignited by Governor Perry in Texas has generated positive interest in the HPV vaccine and "has really helped us get the word out," said Chris Turley, vice chair for Clinical Services in the Department of Pediatrics at the University of Texas Medical Branch in Galveston, Texas. He noted, "[M]oms are coming out and asking for [the vaccine] .... [T]hey come in knowing about Gardasil and wanting it for their daughters.

The difficulties inherent in promoting the use of the HPV vaccine is that its acceptance is related to perceived risk of infection, its safety and effectiveness, and the recommendation or opinion of health-care providers. Therefore, to achieve high immunization rates, public health officials must create demand for the vaccine among the target populations, their parents, and health-care providers by assuring that they understand the significance of this vaccine. Education campaigns targeted at both health-care providers and the public must communicate the importance of vaccination before an adolescent becomes sexually active, especially because of the high risk of HPV infection within a short time after sexual debut. When developing messages about HPV and the vaccine against it, the following should all be considered: fear, confusion, potential mistrust of the pharmaceutical industry and the federal government, and the STD-related stigma of the vaccine. A recent study has shown that these attitudes can be effectively countered by informing women of the high prevalence of HPV infection, thereby demonstrating how common its occurrence actually is. In a similar way, normalizing communication about STDs could lead to the destigmatization of these diseases.

To obtain high vaccination coverage rates, every state must implement these efforts with or without a school mandate. But success will also require an examination of the policies concerning who will be covered, who will provide the coverage, and what amount will be paid. Widespread access to the vaccine can only be accomplished with sufficient financing from private and public sources. Whereas most girls and women in the target age range for the vaccine group have private insurance, 1 in 10 (12%) are currently uninsured. Private insurers typically follow the guidelines put forth by the Advisory Committee on Immunization Practices and are likely to cover the vaccine; several major insurers have already begun to cover it. The federally funded Vaccines for Children Program pays for vaccines approved by the Advisory Committee on Immunization Practices for children 18 years of age and younger, including those who are uninsured or underinsured. Unfortunately, this program still omits a large portion of the target population -- women between 19 and 26 years of age -- as well as a large portion of uninsured United States adults.36

Because the new HPV vaccines protect against only a handful of HPV types, these vaccines are not expected to prevent all cases of cervical cancer or other HPV-related diseases, even with widespread utilization. Consequently, ongoing adherence to the guidelines established for cervical cancer screening and for the treatment of cervical dysplasia will be necessary, and patients will need to be educated about the need for continued routine cervical cancer screening, even after vaccination for HPV.35

Because HPV infection is endemic in males, education campaigns targeting the general public may be especially important if policies promoting HPV vaccination in males are to be adopted in the future. Although more clinical data are needed on the efficacy of HPV vaccine in men and boys, health professionals understand the benefits of including them in educational campaigns. Even so, there is another important reason to educate males: programs targeting females alone run the risk of branding HPV, genital warts, and HPV-mediated cancer as female-centered diseases.37 Focusing additional attention on the indirect benefits to women of widespread HPV vaccination of men (i.e., herd immunity) may be useful for promoting the use of HPV vaccines among both sexes. Men must be included in HPV vaccination and education programs if they are expected to share in the responsibility of primary and secondary prevention of STDs. Finally, excluding men and boys could disenfranchise the homosexual community, in whom genital warts and anal cancer are as real a burden as they are in females.

In the United States, the HPV vaccine has the potential to prevent many cases of cervical cancer and to reduce the cost and emotional burden for the millions of women who receive abnormal Pap smear results attributable to HPV infection.36 Although the federal government has recommended universal vaccination for girls and young women in the United States, there are challenges related to financing, public awareness, and system delivery that must be met to ensure the far-reaching adoption of this new advance in women's health care. The complexity of the issues surrounding HPV vaccination means that thoughtful and careful planning is needed to ensure that the vaccine is widely accepted and that it is utilized in a way that benefits as many people as possible.

And what about HIV infection? Some proponents of HPV vaccination have suggested that vaccinations could be coupled with routine HIV testing among older adolescents. The CDC recently issued recommendations for routine HIV screening among all people between the ages of 13 and 64 years of age during clinic visits, with the expectation being that the adoption of these guidelines could create an opportunity to identify, treat, and prevent HIV disease among youth. Universal screening for HIV and HPV could further reduce the stigma associated with both diseases. Since it is anticipated that there will be an HIV vaccine within several years, adolescents may be the ideal population to target with an HIV vaccine once it becomes available. Combining routine HIV testing with HPV vaccination for older adolescents will facilitate the adoption of new universal testing guidelines for HIV and set the stage for the HIV testing that will be needed before vaccination for HIV.38 Let's hope that those universal guidelines become a public health reality and not just a tantalizing possibility.


  1. Schiffman M, Castle PE, Jeronimo J, et al. Lancet. 2007;370:890-907.
  2. Wikipedia. HPV Vaccine. 2008. Accessible at:
  3. Sheldon H. Boyd's Introduction to the Study of Disease. 1992. Philadelphia, PA: Lea and Febiger.
  4. Gustafsson L, Ponten J, Zack M, et al. Int J Cancer. 1997;71:159-165.
  5. Wikipedia. HPV. 2008. Accessible at:
  6. Cutts FT, Franceschi S, Goldie S, et al. Bull World Health Organ. 2007;85:719-726.
  7. Lowy DR, Schiller JT. J Clin Invest. 2006;116:1167-1173.
  8. Centers for Disease Control and Prevention. HPV Vaccine Questions and Answers. 2006. Accessible at:
  9. Berer M. Women and HIV/AIDS: An International Resource Book. 1993. Hammersmith, England: Pandora Press.
  10. Brettle RP, Leen CL. AIDS. 1991; 5:1283-1292.
  11. Wright TC, Ellerbrock V, Chiasson MA, et al. Obstet Gynecol. 1994;84:591-597.
  12. Centers for Disease Control and Prevention. MMWR. 2007;56(RR-2):1-24.
  13. Levine AM. J Natl Cancer Inst. 1993;85:1382-1397.
  14. Vermund SH, Kelley KF, Klein RS, et al. Am J Obstet Gynecol. 1991;165:392-400.
  15. Williams AB. Nurse Pract. 1992;17:27-38.
  16. Stretch E. J Naturopathic Med. 1992;3:12-19.
  17. Clark RA, Brandon W, Dumestre J, et al. Clin Infect Dis. 1992;17:165-172.
  18. Harper D, Franco E, Wheeler C, et al. Lancet. 2006;367:1247-1255.
  19. Connett H. Nat Med. 2001;7:388.
  20. Committee on Infectious Diseases. Pediatrics. 2007;120:666-668.
  21. Roberts M. Gay Men Seek "Female Cancer" Jab. BBC News Online. Feb. 27, 2007.
  22. Liang W. N Engl J Med. 2006;355:1388-1389.
  23. Winer RL, Hughes JP, Feng Q, et al. N Engl J Med. 2006;354:2645-2654.
  24. Baldwin SB, Wallace DR, Papenfuss MR, et al. Sex Transm Dis. 2004;31:601-607.
  25. Stewart A. HPV Vaccination: Should It Be Recommended or Required? 2007. White Paper. The School of Public Health and Health Services, The George Washington University Medical Center.
  26. Monk BJ, Wiley DJ. Obstet Gynecol. 2006;108:420-424.
  27. Ohri LK. Ann Pharmacother. 2007;41:1899-1902.
  28. O'Rourke M. Cancer Sluts. Accessible at:
  29. Horn T. HPV Vaccine Receives FDA Approval. Accessible at:
  30. Dawar M, Deeks S, Dobson S. CMAJ. 2007;177:456-461.
  31. Vetter KM, Geller SE. J Women's Health. 2007;16:1258-1268.
  32. Palefsky JM, Holly EA, Efirdc JT, et al. AIDS. 2005;19:1407-1414.
  33. Palefsky JM, Holly EA, Ralston ML, et al. J Infect Dis. 2001;183:383-391.
  34. Protecting Against HPV: The Next Battleground. Accessible at:
  35. Dempsey AF, Davis MM. Am J Manag Care. 2006;12:S484-S491.
  36. The Henry J. Kaiser Family Foundation. HPV Vaccine: Implementation and Financing Policy Fact Sheet. January 2007.
  37. Pallecaros A, Vonau B. Curr Opin Obstet Gynecol. 2007;19:541-546.
  38. Lally MA, Lemei K, Bonney LE, et al. J Adolesc Health. 2007;40:384-385.