The announcement of FDA approval of a vaccine for human papillomavirus (HPV) was highly publicized in both the professional and lay media. The vaccine has been incorporated into the guidelines of both the American Cancer Society1 and the Centers for Disease Control and Prevention?s (CDC) Advisory Committee on Immunization Practices.2 Cervical cancer rates dropped dramatically after implementation of the Pap test in the 1950s. Similarly, the use of the HPV vaccine has the potential to further reduce rates of cervical cancer as well as to decrease rates of HPV infections.
Background on HPV
HPV currently is the most common sexually transmitted infection in the United States. Each year, 6.2 million people aged 14 to 44 years will acquire the infection. More than 80% of sexually active women will have HPV by age 50.2
A majority of HPV infections are asymptomatic and resolve spontaneously within 2 years. The consequences of HPV infection, however, include anogeni-tal warts, cervical dysplasia, various anal and vaginal cancers, and, rarely, recurrent respiratory papillomatosis, which causes warts along the upper respiratory tract. HPV also is known to be a precursor of most forms of cervical cancer. Although most cases of HPV are detected early through Pap tests, an estimated 3700 women will die from cervical cancer this year.2
HPV exists as 100 types or strains, which are numbered according to their date of discovery. The viral types are classified as being either ?high-risk? or ?low-risk.? High-risk strains are termed ?oncogenic,? because they are highly associated with cervical and other types of cancer. The low-risk strains are always the cause of anogenital warts but only rarely are responsible for malignancies.3 HPV types 6 and 11 cause approximately 90% of anogenital warts, and types 16 and 18 are accountable for 70% of cervical cancers, such as adenocarcinoma in situ (AIS) and cervical intraepithelial neo-plasia (CIN).2
The Quadrivalent HPV
Recombinant Vaccine (Gardasil)
The first vaccine for HPV was approved by the FDA in June 2006. The product, manufactured by Merck, is a recombinant, quadrivalent vaccine that protects against HPV types 6, 11, 16, and 18. Antibodies are created by using virus-like particles (VLPs). VLPs are noninfectious proteins that are isolated from the fermented yeast Saccharomyces cerevisiae. The VLPs resemble the outer shell of each of the 4 types of HPV DNA.4
The prophylactic efficacy of the quadrivalent vaccine has been proved through 2 phase 3 trials called Females United To Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I and II. During the 2 trials, the per-protocol population of >7500 women aged 13 to 26 received the entire vaccine series, while a similar number received a placebo.
The vaccine was 100% effective in preventing any cervical lesions related to HPV types 6, 11, 16, or 18.The intention-to-treat population (n = 12,157) had a 95.2% reduction in AIS and CIN and a 98.9% reduction in anogenital warts.4 The difference in efficacy is attributable to the presence of HPV infection at baseline and incomplete vaccination. Thus, the vaccine cannot be used as treatment for current HPV infections.
Gardasil has a low incidence of systemic adverse events such as fever, nausea, and dizziness, compared with placebo. Fever occurred in 11.4% of patients receiving the vaccine versus 9.6% in the placebo group.(1)Pain, swelling, and erythema were commonly reported injection-site reactions with the vaccine. Although 84% of vaccinated recipients reported these events, 94% judged the reactions to be either mild or moderate.4 Serious adverse events including bron-chospasm occurred in 5 vaccine and 2 placebo patients.
The vaccine is in Pregnancy Category B and is not recommended for pregnant women. More than 1000 women in the clinical trials became pregnant during the vaccination course, and no genetic anomalies related to the vaccine were observed. The safety of the vaccine in lactating women has not been determined.4The Vaccine Adverse Event Reporting System, established through a partnership with the FDA and the CDC, will be vital in collecting postmarketing safety outcome data, including data on use of the vaccine during pregnancy.
An area of interest for HPV vaccine studies is the use of the vaccine in males to prevent anogenital warts and anogenital intra-epithelial neoplasia.2 Results from these data will help determine how vaccination for both sexes can contribute to decreasing transmission between sexual partners. HPV vaccination for male adolescents may become routine, based on the outcomes of these studies.
The duration of the vaccine?s activity is currently unknown and will be the subject of future studies. The longest follow-up period for patients enrolled in clinical trials is 5 years.4 Nordic cancer registries will continue to monitor adolescent patients (aged 9-15 years) for 10 years after completion of the vaccine series.2 These long-term data, along with data from other surveillance studies, will be important in determining the length of protection provided by the vaccine.
The quadrivalent vaccine will face competition from a second HPV vaccine to be marketed by GlaxoSmithKline. Cervarix is a bivalent vaccine that targets HPV types 16 and 18.5 The bivalent vaccine also protects against HPV types 45 and 31, which are the third and fourth most common cancer-causing strains, respectively. HPV types 16, 18, 31, and 45 produce ~80% of cervical cancer cases throughout the world.
The manufacturer of Cervarix is planning a phase 3, head-to-head trial against Gardasil. The study will enroll approximately 1000 women in the United States, divided into the following age ranges: 18 to 26, 27 to 35, and 36 to 45. The primary end point will be immune responses in the youngest group, and the secondary end points will focus on the women >26 years old.6
The introduction of the HPV vaccine allows pharmacists to continue to expand their practice as vaccination providers for adults and adolescents. It will be important for pharmacists to educate patients about the vaccine schedule and to remind them to continue with their routine Pap tests. Smoking cessation is another area in which pharmacists can counsel patients, because smoking has been linked with increased susceptibility to HPV infections and progression to cervical cancer.7 Finally, pharmacists must stress to patients that the vaccine cannot treat any current HPV infection. Providing sound patient education will increase patient knowledge about HPV and its consequences and will encourage patient acceptance of the HPV vaccine.
Dr. Thune is an infectious diseases resident and visiting faculty member at Midwestern University, College of Pharmacy?Glendale, Ariz.
1. Saslow D, Castle PE, Cox JT, et al. American Cancer Society Guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA: Cancer J Clin. 2007;57:7-28.
2. Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007 23;56(RR-2):1-24.
3. Human Papillomavirus: HPV Information for Clinicians. Centers for Disease Control and Prevention. November 2006.
4. Gardasil prescribing information. Whitehouse Station, NJ: Merck; 2007.
5. GlaxoSmithKline Web site. Available at: www.gsk.com. Accessed March 27, 2007.
6. GlaxoSmithKline press release. January 19, 2007.
7. Gunnell AS, Tran TN, Torrang A, et al. Synergy between cigarette smoking and human papillomavirus type 16 in cervical cancer in situ development. Cancer Epidemiol Biomarkers Prev. 2006;15(11):2141-2147.
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