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Amanda F. Dempsey, MD, PhD, MPH; and Matthew M. Davis, MD
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Decreasing Risk: Impact of HPV Vaccination on Outcomes
Pamela Ann Hymel, MD, MPH
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Helen Trottier, PhD, MSc; and Eduardo L. Franco, DrPH, MPH

Decreasing Risk: Impact of HPV Vaccination on Outcomes

Pamela Ann Hymel, MD, MPH

Cervical cancer, caused by oncogenic types of human papillomavirus (HPV), remains a major health problem worldwide. The recent introduction of a quadrivalent vaccine (Gardasil®), which targets HPV strains responsible for approximately 70% of cervical cancer cases and 90% of genital warts, has ushered in new hope of substantially reducing global prevalence of HPV disease. A further bivalent HPV vaccine (Cervarix) is in the offing. However, many issues still need to be addressed, including actual vaccine efficacy in preventing cervical cancer, public acceptance, use of the vaccine in men, vaccine access, costs, and impact of the vaccine on cervical cancer screening programs. This review analyzes some of these issues, and emphasizes the need for a coordinated effort of patients, parents, health professionals, hospitals, and policymakers to ensure successful implementation of vaccination programs in the United States.

(Am J Manag Care. 2006;12:S473-S483)

Worldwide, cervical cancer is second only to breast cancer as the leading cause of cancer-related mortality in women.1-3 About 500 000 cases of cervical cancer are seen globally each year, accounting for close to a quarter of a million deaths.2,4,5 The largest burden of cervical cancerapproximately 80% of casesis seen in developing countries, related to lack of infrastructure and resources required to establish and maintain high-quality Papanicolau (Pap)-based screening programs.4,6-8

Although organized Pap-based screening has led to a significant reduction in incidence rates of cervical cancer and attendant mortality in the United States over the past several decades,8,9 the current rates are by no means acceptable. Cervical cancer represents the eleventh most frequent cancer in the United States and was responsible for more than 3500 deaths in the United States in 2005; more than 10 000 new cases were diagnosed during that year alone.3 Screening and cytological evaluations performed in the United States exact an enormous economic burden,10,11 and many annual cases of cervical cancer in the United States are still seen in women who are being screened.5 Although current interventions for treating precursor cervical lesions are effective, response is still not seen in some women, and there is room for improvement. Thus, cervical cancer still constitutes a major health problem in all geographic regions.

There is indisputable evidence that cervical cancer is related to persistent infection with sexually transmitted, oncogenic types of human papillomavirus (HPV), also labeled cancer-associated HPV or high-risk HPV.1,7,12,13 There is also evidence of nonsexual transmission of the virus. With use of sensitive polymerase chain reaction techniques, high-risk HPV deoxyribonucleic acid was seen in at least 99% of cervical cancers.2,12,14 Of the 15 types of high-risk HPV, any one type can result in cervical cancer; however, the most predominant are HPV-16 and HPV-18, which account for approximately 70% of cases (50%-60% and 10%-20%, respectively).1,2,14 Other HPV types, such as 31, 33, 45, 52, and 58, account for most other additional cases, depending on geographic region.5,7

Cancers caused by a viral agent are unique in that they are subject to immunologic intervention via vaccines. In developing countries, an effective HPV vaccine may be the only practical method of reducing disease and cervical cancer in ensuing decades. In the United States, HPV vaccination has the potential to significantly reduce healthcare costs and the emotional burden related to detection of cervical lesions, in addition to further limiting disease in conjunction with screening programs.1,7

This article will discuss the development and clinical efficacy of emerging HPV vaccines, the potential impact of vaccination programs in the United States, the cost-effectiveness of vaccination, and issues related to US vaccine implementation. The epidemiology of HPV and natural course of infection are discussed elsewhere in this supplement.

HPV Vaccines

Initial attempts at development of an HPV vaccine were met with difficulty, because of the poor growth of HPV in cell cultures and inability to cause infection in nonhuman species.7,14 The presence of viral oncogenes in a developed live attenuated vaccine was also problematic. Research focus shifted to potential use of subunit vaccines, based on the major capsid protein of the virus, L1. It was discovered that L1 proteins were capable of self-assembling into virus-like particles (VLPs) when expressed in cells. These VLPs share great similarity to native HPV virions, are noninfectious and nononcogenic, and can induce high levels of neutralizing antibodies; vaccination with VLPs has protected against HPV infection in animal models.7,14,15

Several VLP vaccines directed at specific types of HPV are either under development, in the clinical evaluation phase, or have reached US Food and Drug Administration (FDA) approval status.1,7,9,16 To assess vaccine efficacy, the most relevant outcomes recommended by an FDA advisory panel are reductions in vaccine type-specific persistent HPV infection and cervical intraepithelial neoplasia (CIN)2+. CIN1 represents low-grade dysplasia, which is not thought to be a true cancer precursor, whereas CIN2 and CIN3 are moderate- and high-grade dysplasias, respectively, and immediate precursors of cervical cancer.1,17 In keeping with these outcome markers, a controlled proof-of-principle efficacy study (n = 2392) conducted by Koutsky et al13 demonstrated 100% efficacy of an HPV-16 VLP vaccine in women. All cases of new HPV-16 infections, including HPV-16-related CIN, occurred in the placebo group. Additional follow-up of these patients revealed protection against persistent infection and HPV-16-related CIN2-3 for an average of 3.5 years.17

Two of the initial vaccines incorporating more than 1 HPV type have focused on types most frequently associated with cervical cancer. Thus, a bivalent VLP vaccine (Cervarix™, GlaxoSmithKline) is composed of VLPs assembled from recombinant HPV-16 and HPV-18 L1. Cervarix is in phase III trials and will likely be considered for FDA approval before 2007. A quadrivalent VLP-based vaccine (Gardasil®, Merck & Co) encompasses HPV-16 and HPV-18, as well as HPV-6 and HPV-11; the latter types, combined, cause the majority of genital warts (approximately 90%) in both men and women.1,16 Although HPV-6 and HPV-11 can cause cervical infection, they are not associated with cervical cancer. Gardasil was approved by the FDA in June 2006 for use in women 9 to 26 years of age to prevent cervical cancer, as well as genital warts and precancerous lesions (cervical, vaginal, vulvar).

Cervarix and Gardasil differ with respect to adjuvants. The former uses AS04 (aluminum hydroxide plus 3-deacylated monophosphoryl lipid A [MPL]), whereas the latter employs amorphous aluminum hydroxyphosphate sulfate.2,7,16 It is unclear if greater and more sustained antibody responses are obtained with the AS04 adjuvant compared with aluminum salt-based adjuvants without MPL, as some investigators suggest.2,7 Direct comparisons of the immunogenicity of HPV vaccines are lacking.

Published and unpublished double-blind, placebo-controlled phase II and phase III trials have demonstrated the efficacy of the bivalent and quadrivalent vaccines in producing high rates of seroconversion and significant type-specific protection against HPV infection (incident and persistent) and cervical intraepithelial lesions.1,2,7,13,16-20 Based on according-to-protocol analyses, efficacy rates for clinical outcomes (infection, cervical lesions) have approached 100% with each vaccine. Gardasil has also shown efficacy in protecting against vulvar/vaginal neoplasia and anogenital warts.7,18 Some relevant findings for both vaccines from clinical trials are shown in Table 1.

Approval of Gardasil in very young girls was not based on clinical efficacy, but rather "bridging immunogenicity and safety studies," where efficacy was inferred from immunologic responses in women aged 9 to 15 years of age when compared with immunologic responses in women aged 16 to 26 years of age with known efficacy against HPV disease.18,21,22 Significant antibody responses were seen in more than 99% of these girls, and were higher than those observed in 16- to 26-year-old women.18

Effect on Cervical Cancer. The ultimate goal of immunization against HPV types is to prevent cervical cancer. At present, no study has clearly demonstrated a reduction in cervical cancer with vaccine use, owing to short trial durations. Long-term efficacy data from ongoing phase III trials and extensions are needed to fully assess vaccine effects on this outcome, although modeling techniques predict high efficacy.

Ongoing Studies in Various Age Groups. Cervarix is currently being evaluated in phase III trials in the United States and other countries that involve women up to 55 years of age.7,23 Results from these trials are not yet available. In addition to the phase III data in Table 2, Gardasil is undergoing phase III investigations in girls and boys 10 to 15 years of age, women 16 to 45 years of age, and men 16 to 24 years of age.7

Duration of Immunity. The duration of vaccine protection is uncertain at present, and will be determined by long-term follow-up of vaccinated subjects. The longest duration of effective immunogenicity with Gardasil comes from published data of Harper and associates,19 who found significant protection against infection with HPV-16 and HPV-18 and associated cervical lesions for up to 4.5 years. Unpublished study data suggest duration vaccine protection of about 5 years for Gardasil.22

There are no data at present regarding the efficacy or required frequency of booster doses, or even if boosters will be required. This is an important cost consideration. Antibody titers postvaccination have been higher than after natural infection, suggesting a potentially longer duration of protection compared with natural infection.2,8 However, 1 or 2 decades may be required to define the need for a clear booster interval; determination of therapeutic antibody titers, or if these even exist, is also needed. Both of these areas will likely be the focus of much debate, as seen with hepatitis B vaccine.

Cross-immunogenicity. There is evidence (published and unpublished) that Cervarix and Gardasil may confer some degree of cross-immunogenicity against HPV-31 and HPV-45, each of which has been associated with cervical cancer.1,19 This protection was not as complete as that against HPV-16 and HPV-18, and results of long-term studies are needed to clarify clinical significance (eg, whether this phenomenon will confer significant protection against precursor lesions). It is also unclear if cross-immunogenicity may occur against other HPV types.

Safety. All VLP HPV vaccines have been relatively well tolerated in clinical trials. Local reactions are by far the most common events compared with placebo, including injection-site pain, swelling, and erythema; in some studies, however, these effects were seen with similar frequency in the placebo group. Injection-site reactions have not compromised adherence with a full vaccine course.

Systemic adverse effects have generally been similar in placebo and vaccine groups. Headache and fever (usually low-grade) have occurred more often than placebo in some studies. Urticaria and bronchospasm were reported rarely.

There are no data from available studies to suggest superior tolerability of one vaccine over another. Long-term safety of VLP-type vaccines against HPV will be determined in ongoing trials.

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