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Are we closer to the prevention of HPV-related diseases?

Background and cost burden of HPV infection

Human papillomavirus (HPV) infects squamous and glandular epithelial tissues. Noncancerous hand and plantar warts (HPV types 1, 2, and 4) as well as flat warts (HPV types 3 and 10) are common in almost all people. Butcher's warts (HPV types 2 and 7) occur in 70% of meat handlers, and genital warts (HPV types 6 and 11) occur in more than 1 million people per year; and will infect approximately 75% of the US population over their lifetime. (1,2) Periungual warts (HPV types 16 and 18) around the fingernail bed develop into squamous carcinomas in approximately 1% of those infected. (3,4) Oral warts (HPV types 6 and 11) and focal epithelial hyperplasia (HPV types 13 and 32), or Heck's Disease, are almost always benign, whereas 20% to 40% of mouth, throat, tongue, and lung cancers, much more rare, are associated with HPV types 16 and 18. (5) Likewise, esophageal warts, and both squamous and glandular esophageal cancers, occur in about 3% of the population (HPV types 6, 16, 18, 66, and 52), and 40% of conjunctival papillomas and carcinomas (HPV types 6, 11, 16, and 18) are caused by HPV infections. (6-10)

HPV is a significant medical burden worldwide. Although infection with low-risk HPV types 6 and 11 causes medically benign cervical, vaginal, vulvar; anal, penile, scrotal, and perineal warts, persistent infection with high-risk, oncogenic types 16 and 18 can cause a number of epithelial cancers. Approximately 10,000 women are diagnosed with cervical cancer, 2160 women are diagnosed with vaginal, 2000 women are diagnosed with vulvar, 1400 men are diagnosed with anal, 1100 men are diagnosed with penile, and 500 men are diagnosed with scrotal cancers each year. (11-15) This year, the National Toxicology Program recognized the body of evidence that has accumulated over the past 10 years and declared HPV an official carcinogen that is as dangerous as asbestos. (16)

The cost of HPV infection can be classified by the milestones of infection. These include diagnosis of genital or cervical HPV infection, cervical cytology or HPV DNA testing, and treatment. A second stratification of costs for both infection and cancer occurs across organ sites and includes cervical, vaginal, penile, scrotal, and anal sites. DNA screening for high-risk HPV types, with tests such as Hybrid Capture 2 (Digene, Gaithersburg, MD), is reserved for cases where cytologic changes have been observed. Since HPV infection can be subclinical, identifying people at risk can be problematic, and while there is no treatment for subclinical HPV, the costs of testing are usually attributed to patient demand for knowledge that may affect their quality of life or future. These total costs cause a considerable health burden in the United States.

Costs for HPV diagnosis and treatment, in the disease's warty form, include the costs of a visual clinical exam, often with bright light, magnification, and 5% acetic acid application on any of the anogenital sites, and have been estimated to cost approximately $400 per incident case. Many of the wart diagnoses in women are made as a consequence of an abnormal Papanicolaou (Pap) test, whereas all of the wart diagnoses in men are visually detected by either self-exam or physician-directed examination. The incidence of anogenital wart disease in the United States is approximately 1.7 to 2 cases per 1000, with costs exceeding $160 million annually for the adult US population. (17,18) These costs do not include those of the self-applied medications, obtained from pharmacies, that are often used for genital wart treatment.

The cervical cancer screening program of repeated Pap tests, adopted in the United States for detecting dysplasia and other grades of cervical lesions, is the only standardized longitudinal screening system for predictive cancer detection. As it exists, screening alone reaches a cervical cancer prevention threshold of 2 to 3 of every 100,000 women. (19) Despite the excellence of the Pap test to detect squamous cell carcinoma of the cervix, early cervical changes from HPV infection of the squamous and glandular cervical epithelium are not always reproducible or predictive of cervical cancer. (20) This means that there will always be women who are screened, yet who develop cervical cancer; and there will always be a large number of women whose cervical cytology results are interpreted as abnormal, in the absence of clinical disease. Insinga et al (21) recently estimated that while 0.4% of all Pap tests showed HPV infection, 2.4% were false positive, 0.5% revealed cervical cancer precursors, and 0.02% were indicative of invasive cancer. The costs of follow-up for false-positive cases constituted nearly 25% of all cervical cancer screening costs but did not take into account the discomfort, inconvenience, psychologic distress, and time costs women additionally experience.

Overall, the cervical cytology screening program practiced in the United States is the most expensive preventive health measure in the world, and is still not accessed by all female racial and ethnic populations. Approximately 80% of women undergo cervical cancer screening on an annual basis, sometimes needlessly. (21) Without adjusting for quality of life, the cost of the Pap screening program, repeated annually, per year of life saved, is estimated to be approximately $186,000. After adjusting for quality of life, a closer estimate of actual costs approaches $280,000 per quality-adjusted life year (QALY). (22,23) The increase of nearly $100,000 per QALY is due to the decreased quality of life that most women with abnormal Pap results experience. In contrast, other interventions, such as administering [beta]-blockers after myocardial infarction to prevent reinfarction, cannot be more expensive than $50,000 per QALY to be adopted by US insurers. FIGURE 1 compares the cost per QALY of other preventive cancer screening programs (eg, mammography, colonoscopy, and skin surveillance) to the cervical cancer system. (23) Taken overall as an infection and a cancer precursor; the cost of HPV infection is estimated to be $3.4 billion (2002 US dollars), without including the indirect costs of quality of life and lost work time. (24)


The commercialization of the Hybrid Capture 2 HPV test for high-risk types of HPV may improve the efficiencies of our cervical cancer screening program by reducing the number of repeated Pap tests necessary to ensure the absence of cancel, (23) or by triage after a mildly abnormal Pap test result, (25) but it is not approved for screening other possible anogenital HPV-infected tissues. Anal cytology, with and without HPV testing, is being evaluated but is less refined for accurate disease prediction. Head and neck, upper aerodigestive, conjunctival, and other anogenital sites are at risk for HPV infection and cancerous development but have no preventive, precancerous detection system in place. As new biomarkers of HPV integration and precancerous changes evolve, all organ sites susceptible to an HPV-related disease may be able to be screened.

In addition to improved primary screening systems, HPV prevention measures, such as vaccination, may avert some of the costs of cervical screening and treatment of HPV-related diseases. The overall cost burden of HPV infection is so great that even small reductions in incidence could lead to considerable reductions in treatment costs.

HPV vaccination

HPV is the primary cause of and is necessary for the formation of cervical and anal cancer. It is also a cause of vaginal, vulvar, scrotal, penile, oral, nasopharyngeal, sinus, conjunctival, and esophageal cancers. Increasingly rigorous epidemiologic studies have proved this causation over the past 10 years. The proportion of cervical cancers attributed to HPV is higher than smoking is to lung cancer; a setting in which billions of dollars are spent in support of prevention efforts annually (FIGURE 2). (26) In addition, low-risk HPV types disrupt the normal physiology of epithelial tissues, and infection by low-risk HPV types can cause death in cases of respiratory laryngeal papillomatosis and occlusive esophageal warts.


Of specific interest is the routine rubella vaccination program. Congenital rubella syndrome occurs only in the offspring of women who contract rubella while pregnant, yet public policy has been set to vaccinate both sexes at birth, and in doing so has led to a subsequent marked decrease in the incidence of congenital rubella syndrome. Adolescent vaccination schedules are currently being considered in a manner parallel to the series of infant vaccines currently given. The adolescent platform could contain such vaccines as meningococcal, hepatitis A, hepatitis B, HPV, and possibly herpesvirus. Direct-to-consumer television advertisements are currently promoting adolescent meningococcal vaccination in some regions of the United States, setting the stage for acceptance of an adolescent platform of vaccinations. All childhood and adolescent vaccines are intended to prevent infection prior to exposure, as would be the case for an HPV vaccine. Therefore, to provide the greatest level of protection, HPV vaccines must be administered prior to initiating any sexual activity.

Developing an HPV vaccine

Seven candidate proteins expressed by mucosal types of HPV DNA are antigenic. The early genes, E1, E2, E4, E6, and E7, are expressed in the basal and intermediate squamous cell layers and are necessary for malignant transformation. The late genes, L1 and L2, code for the outer capsid proteins that encompass the entire virion at the final differentiated superficial squamous epithelial stage and are necessary to make HPV infectious. The major capsid protein is L1, and comprises the outermost layer of the virus; L2 is a minor capsid protein less important to structure. The capsid proteins are mostly homologous among types (ie, have remained genetically unchanged and therefore are good vaccine candidate proteins) but do differ phylogenetically, offering type-specific antigenicity. Advantages to this approach are detailed in the TABLE. The outer capsid proteins are the sentinel antigens to present if HPV is to be detected immunologically prior to infection. (27-29) Efforts to develop biologic systems to replicate the L1 proteins include copying the success of the hepatitis B vaccine. Vaccinia virus, baculovirus, or yeast can act as the biologic host for L1 viruslike protein (VLP) assembly. (30) The physical properties of the protein require it to self-assemble into a vacant 72-sided icosahedron. (30) Viruslike proteins are purified, concentrated, and distributed in 20 [micro]gram aliquots per HPV type and are added together with an adjuvant to make up the standard 0.5 mL injection.

HPV vaccines for prevention

The most common oncogenic infection is HPV type 16, accounting for approximately 50% of all cervical cancers. HPV types 18, 31, 33, and 45 are the next most common, each responsible for 10% (HPV type 18) to 5% (HPV types 31, 33, and 45) of cervical cancers. (31-33) The most common nononcogenic HPV infection is HPV type 6, followed closely by HPV type 11. Together HPV types 6 and 11 account for 95% of external genital warts, as well as laryngeal, conjunctival, and esophageal papillomas. (34) Types 16, 18, 6, and 11 are together responsible for 75% of all CIN (cervical intraepithelial neoplasia) lesions. (33,35) Developing a vaccine targeted to these 4 HPV types will prevent the majority of HPV-related diseases, albeit not all.

The National Cancer Institute (NCI) first developed the HPV-16 L1 VLP vaccine in animal models and showed that neutralizing antibodies could be elicited. Early phase I trials in humans showed that the vaccine provoked a similar high-titer antibody response, (36) was well tolerated, and resulted in seroconversion in all recipients. Most recipients achieved neutralizing serum antibody titers approximately 40-fold higher than what is observed for natural infection. (37) Early phase II trials of a monovalent HPV-16 vaccine showed that after 2 doses and 1 booster of vaccine, recipients exhibited robust B-cell responses and Ll-specific T-cell responses, (36,37) with some cell-mediated immunogenicity in cervical mucosa. (38) Monovalent VLP vaccines to other HPV types have been successfully modeled on the HPV-16 vaccine. Furthermore, early evidence from clinical trials suggests that prevention of HPV infection, abnormal cytologic results, and low- and high-grade cervical lesions is possible when women are vaccinated prior to exposure to HPV.

Keeping population health in mind, the NCI shared the HPV L1 VLP knowledge with the industry so that HPV vaccines could be developed on a large-scale yet reproducible manufacturing platform. The first phase II study of the HPV-16 L1 VLP vaccine to be made by commercial manufacturing processes was published in 2002, showing that the vaccine induces seroconversion, produces antibody titers significantly higher than natural infection, and prevents persistent HPV type 16 infection. (39) No safety issues were documented and the vaccine was considered tolerable by the recipients. Despite the fact that prevention of cervical lesion development was not a statistically planned outcome for this study, prevention of HPV-type-16-related cervical lesions did occur in the vaccinated group. This proof-of-principle study paved the way for accelerated development of other monovalent and multivalent HPV vaccines.

Monovalent HPV-18 and HPV-11 L1 VLP vaccines quickly followed and were tested for safety, immunogenicity, and tolerability in young women. Similar results were reported for each HPV type, with indications that type-specific HPV infections were prevented both at viral and cervical cytology levels. (34,40,41)

Clinical trials that combined monovalent HPV L1 VLPs were designed to investigate the human immune response to different HPV types. Since HPV type 16 is phylogenetically unrelated to HPV type 18, it was unknown if the immune response would reflect the antibody titers of each monovalent vaccine separately, or result in a synergistic or even competitive response. The first proof-of-principle trial of a commercially-designed, intended-for-regulatory-approval, bivalent vaccine evaluated more than 1000 young women with no history of abnormal cytologic and few opportunities for prior HPV exposure. (42) This study showed that the vaccine was well tolerated, no incidence of serious adverse events occurred, there was complete seroconversion among the vaccinees, and antibody titers were higher synergistically than both single types alone. Furthermore, the bivalent vaccine was 100% effective in preventing persistent HPV 16 and HPV 18 infection.

The results of a phase II study of a quadravalent vaccine that protects against the 4 most common disease-causing HPV types have recently been reported. (43) This vaccine incorporates HPV 6 and 11, the 2 HPV types responsible for nearly all genital warts and some low-grade cervical lesions, as well as HPV 16 and 18. The vaccine was safe and well tolerated, induced sero-conversion in all recipients, and was 100% efficacious in preventing clinical disease associated with the 4 vaccine HPV types.

Phase III clinical trials of commercially developed bivalent and quadravalent HPV vaccines are ongoing. The bivalent vaccine targets HPV 16 and 18, and is intended to be a cancer prevention vaccine alone. The quadravalent vaccine also targets oncogenic HPV 16 and 18, but adds protection against HPV 6 and 11. These randomized, placebo-controlled trials will each involve more than 18,000 young women with surrogate end points of antibody titers, persistent HPV infection prevention, abnormal cytology development due to the involved HPV types, and type-specific CIN lesions. Secondary end points include the prevention of vaginal, vulvar, and perineal HPV infection. Natural history studies of Costa Rican populations will add to the knowledge of the HPV vaccine behavior over time, indicating whether there will be HPV type substitution infections, variant migration within the vaccine specific types, or increasing virulence of type-specific HPV infections. HPV vaccination in young men and women older than 25 years is also being studied to determine efficacy, antibody titer response, tolerability, and safety.

Population health and economic impact of an HPV vaccine

Several studies have examined the potential health and economic impact of an HPV vaccine; all are limited by model assumptions and incomplete knowledge of transition probabilities from different HPV infection states. All models are mathematically based, some using Markov methods, some using microsimulation alone, and some using Monte Carlo simulations. All models compared the effect of the HPV vaccine on the prevalence of cervical cancer via different vaccine implementation programs combined with different cervical cancer screening tests and intervals of screening. Each model found similar results, and reported public-health cost-savings with HPV vaccination prior to a cervical cancer screening program. (23,44-46) For example, projected reductions in HPV infection, squamous intraepithelial lesions, cervical cancer, and cervical cancer-related deaths are demonstrated in FIGURE 3. (46) In another study, the impact of vaccinating males as well as females was modeled and is demonstrated in FIGURE 4. (47) Each model differed in results varying on the penetrance of vaccine uptake within the population, effectiveness of the vaccine, sex vaccinated, type of cervical cancer screening program, age of screening implementation, and interval of screening in normal women. The cost of the vaccine did not drive public health savings in any of the models. Furthermore, none of the models accounted for the current state of incomplete penetrance of cervical cancer screening among the most "at-risk" women in the US population, quality-of-life costs associated with HPV infection, abnormal screening results, or treatment methods for cure.


Potential HPV vaccination programs

When to vaccinate, the need for boosters, who to vaccinate (eg, ages, sex, and risk status), where to vaccinate, the supply and storage of vaccine, and surveillance for vaccine effectiveness regarding HPV infections and cancer incidence are all necessary components of a successful vaccination program. At the present time, the cost of a surveillance program for type-specific HPV infection is prohibitory, as HPV infections are universally common. As diagnostic tests for type-specific HPV vaccines are developed and refined, a surveillance program will become an affordable, integral part of the annual report card on vaccine performance. Current cancer surveillance programs will be monitored for decreases in incidence, mortality, and morbidity from the other less common HPV-related cancers such as anal, vaginal, vulvar, oral, pharyngeal, esophageal, and conjunctival.

Recommendations by the American Committee for Immunization Practices (ACIP), the Centers for Disease Control and Prevention, professional societies (American Academy of Pediatrics, American Academy of Family Physicians, Society of General Internal Medicine, American College of Obstetricians and Gynecologists, Association of Teachers of Preventive Medicine, National Medical Association, etc), national, regional, and local public health departments, as well as individual physicians are also necessary for any real nationwide vaccination program to be successful. HPV-related disease awareness and demonstrating the importance of a vaccine are paramount to public acceptance. Both provider and patient educational programs are immediately necessary to convey the accuracy of the biology of HPV transmission and infection, and the advantages of a national vaccination program.

Just as infant vaccines have become routine for 20 possible infectious diseases, an adolescent platform of vaccines that includes HPV is a rational mechanism to protect preadolescents and adolescents against diseases that are most common to them now and later in adulthood. National recommendations for a group of adolescent vaccines that will provide protection against multiple diseases without singling out any 1 disease process to prevent will likely occur.

The future of HPV vaccines

"Chimeric" VLP vaccines combine the L1 major capsid proteins with the oncogenic HPV proteins E6 or E7. These vaccines are thought to be active in the basal squamous cell layer; where L1 is not yet expressed, therefore, conferring a possible therapeutic effect on that epithelium already infected with HPV, something that preventive L1 VLP vaccines do not do. (48,49) Therapeutic vaccines are designed to eradicate cells that are already infected with HPV but present far more challenges than preventive vaccines; though viral load of infection is often too great to be reduced with immunostimulation alone. Vaccines targeting the E1 and E2 genes, expressed in early squamous differentiation controlling the viral replicative cycle, are also in early development. (50)


HPV infection is highly prevalent in the United States and other nations. The sequelae of HPV infection include psychosocial morbidity from genital warts, and, in some cases, mortality of invasive cervical cancer. HPV vaccines are expected to be effective, tolerable, and without serious side effects. Furthermore, multivalent vaccines are expected to provide coverage for the most prevalent HPV types associated with genital warts and cervical cancer, and may have the greatest impact on the incidence of HPV-related diseases in the future. Global expansion and prevention of other HPV-related diseases will occur as longitudinal phase III clinical trial data are accrued.


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Diane M. Harper, MD, MPH, MS

Gynecologic Cancer Prevention Research Group

Norris Cotton Cancer Center

Dartmouth Medical School

Lebanon, NH

Advantages of various approaches
to vaccine development

Approach        Advantages

HPV L1 VLP      * Used successfully to prevent
                  hepatitis B-induced hepatocarcinoma and
                  Lyme disease

Chimeric VLP    * Targets viral protein thought to
                  be responsible for malignant
                * Would be expected to elicit responses
                  in basal cells that do not express
                  capsid antigens

HPV DNA         * Simplicity
                * Stability
                * Safety
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Title Annotation:human papillomavirus
Author:Harper, Diane M.
Publication:Journal of Family Practice
Geographic Code:1USA
Date:Jul 15, 2005
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