Efficacy and Safety of Human Papillomavirus Gardasil

Table of Contents

Introduction
Main body
Conclusion
Works cited

Introduction

Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States, and continued HPV infection can cause cervical cancer in women, anal cancer, genital cancer, and genital warts in both men and women. First epidemiological data, derived from the U.S National Health and Nutrition Examination Survey, estimated that the prevalence of human papillomavirus (HPV) infection in a representative sample of women was highest in those aged 20-24 years. (Markowitz). The prevalence, enormity of strains, difficulty in diagnosing, route of transmission, and treatment options make Human papillomavirus (HPV) pose major challenge to health care providers. Research findings suggests that vaccination can protect females from the four types of HPV, and the vaccine Gardasil has been approved by Food and Drugs Administration (FDA) for prophylaxis in 2007. The Advisory Committee on Immunization Practice (ACIP) also recommended it for immunization, and the Centers for Disease Control (CDC) decided to add Gardasil to its Vaccine for Children Program in the same year. It has attracted much criticism and debate is still ripe on the effectiveness of Gardasil. Since prophylaxis is better and effective than treatment, backing away from the most effective means of protecting a generation of women from the scourge of cervical cancer is not justifiable, and critical follow-up should be carried out to identify adverse effects of Gardasil.

Main body

Approximately 20 Million Americans are currently infected, and another 6.2 million persons are newly infected every year. (CDC, 2007 and MMWR, 2007). The prevention and treatment of anogenital warts and cervical HPV-related disease imposes an estimated burden of $4 billion or more (2004 dollars) in direct costs in the United States each year(NEJM, 2007). HPV accounts for approximately 68% of squamous cell cancer, 83% of adenocarcinomas, half of vulvar squamous cell cancers, 90% anal squamous cell cancers, 90% genital warts (condyloma), and rarely in recurrent respiratory papillomatosis (RRP). The American Cancer society estimates that in 2008, there will be: 3,460 women diagnosed with vulvar cancer; 2210 women diagnosed with vaginal and other female genital cancers, 1,250 men diagnosed with penile and other male genital cancers; and 3,050 women and 2,020 men diagnosed with anal cancer. (Genital HPV Infection CDC Fact Sheet).

More than 100 different HPV types have been isolated so far, of which types 6 and 11 are termed low-risk types as they cause low-grade cervical cell changes, genital warts, and recurrent respiratory papillomatosis. High-risk types, including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 73, and 82 can cause high-grade cervical cell abnormalities, and these high-risk types are detected in 99% cervical cancer cases. Initial infection of HPV virus is in the basal layer of epithelium, and differentiating epithelial cells remain in an active cell cycle, which become thick, sometimes exophytic, epithelial lesion, and by integrating into the host chromosome produce virion. Genital warts can be single or multiple bumps appearing on the vulva, in and around the vagina or anus, on the cervix, on the penis, scortum, groin, or thigh. Cervical cancer and other less common HPV-related cancers may not have signs or symptoms until they are advanced. Human papillomavirus infection is primarily transmitted by sexual activity; multiple sex partners, and partners sexual behavior, as well as transmission from mother to a newborn baby are associated with genital HPV transmission. Though HPV symptoms are brief, and approximately 90% of the infection may clear within 2 years, persistent infection with high-risk types (particularly HPV 16) is major risk factor for cervical cancer.

Since HPV cannot be cultured, and the assays differ in their sensitivity and type specificity, only the Digene Hyrbid Capture 2(HC2) High-Risk HPV DNA Test is approved by the U.S Food and Drug Administration for clinical use. In the trials of quadrivalent HPV vaccine, to specifically detect the L1, E6 and E7 gene for each HPV type, multiplex assays were used (MMWR, 2007).

Treatment for HPV infection is directed at its associated lesions, and various local approaches like cryotherapy, electrocautery, laser therapy, surgical excision, or topical pharmacologic agents are applied according to symptom. Existing limited data shows that available therapies for HPV-related lesions might reduce but probably do not eliminate infectiousness (MMWR, 2007)

Research findings suggests that vaccination can protect females from the four types of HPV, and the vaccine is recommended for 11 and 12 year-old girls and also for girls and women age 13 through 26 who have not yet been vaccinated or completed the vaccine series.

The quadrivalent human papillomavirus (HPV) vaccine types 6, 11, 16, 18 GARDASIL was licensed by the U.S Food and Drug Administration on June 8, 2006 for prevention of vaccine HPV-type-related cervical cancer, cervical cancer precursors, vaginal and vulvar cancer precursors, and anogenital warts. The Advisory Committee on Immunization Practice (ACIP) on the use of a quadrivalent HPV vaccine recommends its use for vaccination among females aged 9-26 years in the United States. (MMWR, 2007). The vaccine Gardasil is manufactured by Merck and Co., Inc., Whitehouse Station, New Jersey. Another vaccine Cervarix developed by GlaxoSmithKline for use against HPV is expecting approval of FDA. The L1 major capsid protein of quadrivalent HPV is the antigen used for vaccination, and it contains no thimerosal and antibiotics. The vaccine should be stored at 2 to 8 degrees Celsius and not frozen. The vaccine is administered intramuscularly, preferably in the deltoid muscle, as three separate 0.5 ml. doses, of which second and third dose should be administered 2 months and 6 months respectively after the first dose.

Gardasil was tested in over 11,000 women in the United States and around the world to ascertain its efficacy, before inclusion under immunization program. Randomized, double-blind, placebo-controlled clinical studies to evaluate efficacy of monovalent and quadrivalent vaccines were conducted in three phases among females aged 16 to 26, of which two phase III efficacy studies of quadrivalent HPV vaccine were international studies. It was found that the quadrivalent HPV vaccine has a high efficacy for prevention of four types of vaccine HPV related persistent infection, but the vaccine does not protect against disease caused by nonvaccine HPV type. Though studies to ascertain duration of protection of vaccination is still underway, combined analysis of all participants through year 3 and a subset through 60 months found that the efficacy against persistent infection of disease was 95.8%. Vaccine related serious adverse events occurred <0.1% of persons (NEJM, 2007).

The recommendation of Advisory Committee on Immunization Practices (ACIP) that all girls 11 and 12 years of age receive HPV vaccine and the Centers for Disease Control (CDC) decision to add Gardasil to its Vaccine for Children Program have attracted multiple response (Charo). Though CDCs Vaccine for Children Program provides free immunization to impoverished or underserved children, high cost of Gardasil may withhold parental consent. As of April 27, 2007 legislation has been defeated in New Mexico, Mississippi, Kentucky, and West Virginia, and only Texas and Virginia have enacted law mandating HPV vaccination. But Texas law is under litigation.

Political and legislative maneuvering is ripe to forestall the creation of mandated HPV vaccination program even it includes some form of parental opt-out. It has been settled law that states may require people to be vaccinated and earlier federal and state court decisions have consistently upheld vaccination mandates for children. However, it is viewed that mandatory HPV vaccination is an example of state paternalism aimed at protecting the vaccine rather than community protection. It is also argued that mandatory HPV vaccination will have a disinhibiting effect and thus encourage sexual activity among teens who might otherwise have remained abstinent. (Charo). Instead of focusing on the high cost of the vaccine that poses a genuine obstacle to stakeholders concern is on the perceived interference in family life and sexual mores. (Examining the FDAs HPV Vaccine Records), a conservative, non-partisan educational foundation, on perusal of FDA records, including Mercks final report before the approval of the vaccine Gardasil among other things, points out that: Gardasil is not 100% effective against all HPVs; It cannot cure pre-existing HPV; Gardasil is marketed as a vaccine that prevents cancer, but it & has not been evaluated for the potential to cause carcinogenicity or genotoxicity; While Gardasil is the most expensive vaccine ever to be recommended by the FDA, its long-term effective ness is unknown and could be as brief as only two to three years; and Gardasil is still in the testing stages and will not be fully evaluated for safety until September, 2009. It opines that now, almost two years later, it looks like the FDA may have approved Gardasil too quickly (Examining the FDAs HPV Vaccine Records).

As per reports of Vaccine Adverse Event Reporting System (VAERS), as of June 30, 2008, there have been 9,749 reports of adverse events following Gardasil vaccination. Of these 94% were classified as reports of non-serious events, and 6% as serious events. (Information from FDA and CDC on Gardasil and its Safety). Non-serious events comprise fainting, pain at the injection site, headache, nausea, and fever. Watching the injected person carefully for 15 minutes after vaccination and keeping seated could help prevent fainting and related fall injury. The serious outcomes reported to VAERS up to end June 2008 in persons after receiving Gardasil was 20 deaths, which had no common pattern and investigations established the cause of death by factors other than vaccine related. Neurological disorder (Guillain-Barre Syndrome GBS), and blood clots (Thromboembolic disorder) are other serious adverse occurrences reported, which are not conclusively linked with Gardasil.

Based on various considerations and cost effectiveness, the recommended age for vaccination is 11-12 years, though female aged 13-26 years also can benefit from vaccination. Quadrivalent HPV vaccine is not licensed for use among females aged <9 years or those aged >26 years. The vaccine is not recommended for use in pregnancy, and for persons with a history of immediate hypersensitivity to yeast or to any vaccine component. But, HBV vaccine could be administered to lactating mothers, persons with minor acute illness, and immunocompromised persons, as well as simultaneously with other vaccines.

Conclusion

The controversy on mandatory HPV vaccination with Gardasil may be presumed as corporate war between Merck and GlaxoSmithKline, because HPV vaccine Cervarix of GlaxoSmithKline is expecting FDA approval, and likely to be introduced in market. Since prophylaxis is better and effective than treatment, backing away from the most effective means of protecting a generation of women from the scourge of cervical cancer is not justifiable. (Charo). Condom use and a monogamous relationship are considered as the strategy most likely to prevent future genital HPV infection. Even though routine reporting of HPV does not exist in the United States, and many aspects of the natural history, including the role and duration of naturally acquired immunity after infection, and cumulative risk for HPV infection are not yet fully understood, prophylaxis against this silent killer will be the best approach of prevention.