ACIP Recommends Quadrivalent HPV Vaccine
News Author: Laurie Barclay, MD
CME Author: Penny Murata, MD
March 23, 2007 — The Advisory Committee on Immunization Practices (ACIP) recommends quadrivalent human papillomavirus (HPV) vaccine for girls and women aged 9 to 26 years, according to guidelines published in the March 12 Early Release issue of the Morbidity and Mortality Weekly Report.
"Genital HPV is the most common sexually transmitted infection in the United States; an estimated 6.2 million persons are newly infected every year," write Lauri E. Markowitz, MD, from the National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention (proposed), and colleagues. "Although the majority of infections cause no clinical symptoms and are self-limited, persistent infection with oncogenic types can cause cervical cancer in women.... Cervical cancer rates have decreased in the United States because of widespread use of Papanicolaou testing, which can detect precancerous lesions of the cervix before they develop into cancer; nevertheless, during 2007, an estimated 11,100 new cases will be diagnosed and approximately 3,700 women will die from cervical cancer."
The guidelines represent the first ACIP statement on the use of a quadrivalent HPV vaccine licensed by the US Food and Drug Administration on June 8, 2006. This report reviews the epidemiology of HPV and associated diseases, the licensed HPV vaccine, and recommendations for vaccination among girls and women aged 9 to 26 years in the United States.
The licensed HPV vaccine is composed of HPV L1, the major capsid protein of HPV. The quadrivalent HPV vaccine is a mixture of 4 HPV type-specific noninfectious virus-like particles prepared from the L1 proteins of HPV 6, 11, 16, and 18 combined with an aluminum adjuvant.
In clinical trials, the vaccine was highly effective in preventing persistent HPV infection, cervical cancer precursor lesions, vaginal and vulvar cancer precursor lesions, and genital warts caused by HPV types 6, 11, 16, or 18 among girls and women who had not already been infected with the respective HPV type. Although there is no evidence of protection against disease caused by HPV types with which girls and women are infected at the time of vaccination, girls and women infected with one or more vaccine HPV types before vaccination would be protected against disease caused by the other vaccine HPV types.
In clinical trials, systemic clinical adverse events were reported by a similar proportion of HPV vaccine and placebo recipients, and the maximum intensity rating of systemic clinical adverse events was mild or moderate. Vaccine-related serious adverse events occurred in less than 0.1% of persons, and included bronchospasm, gastroenteritis, headache/hypertension, vaginal hemorrhage, and injection site pain/movement impairment.
In the overall safety evaluation, 10 persons in the group that received quadrivalent HPV vaccine and 7 persons in the placebo group died during the course of the trials, but none of the deaths were considered to be vaccine related.
Quadrivalent HPV vaccine is not recommended for use in pregnancy.
Quadrivalent HPV vaccine is available as a sterile suspension for injection in a single-dose vial or a prefilled syringe, and it is administered intramuscularly as 3 separate 0.5-mL doses. The second dose should be administered 2 months after the first dose and the third dose 6 months after the first dose.
The recommended age for vaccination of girls is 11 to 12 years during the established young adolescent healthcare visit at age 11 to 12 years as recommended by several professional organizations when other vaccines are also recommended.
The HPV vaccine can be given as young as age 9 years, and catch-up vaccination is recommended for teens and women aged 13 to 26 years who were not previously vaccinated. It is not possible for a clinician to assess the extent to which sexually active persons would benefit from vaccination, and the risk for HPV infection might continue as long as persons are sexually active. At any age, Papanicolaou testing and screening for HPV DNA or HPV antibody are not recommended before vaccination.
The guidelines caution that vaccination is not a substitute for routine cervical cancer screening and girls and women who have received vaccination should have cervical cancer screening according to the recommended protocol.
After reviewing available data on the epidemiology and natural history of HPV, vaccine acceptability, and sexual behavior in the United States, the ACIP also considered economic and cost-effectiveness analyses presented during meetings in June 2005, October 2005, and February 2006. The ACIP HPV vaccine workgroup developed recommendation options based on the above, as well as on expert opinion of the workgroup members.
The final recommendations were presented to ACIP at the June 2006 ACIP meeting and approved at the June 2006 meeting. The guidelines also recommend long-term follow-up studies to determine duration of protection. Additional data available in the near future from clinical trials and any new information on epidemiology of HPV will be reviewed by ACIP as they become available, and recommendations will be updated as needed.
"The recommendation for routine vaccination of females aged 11 to 12 years is based on several considerations, including studies suggesting that quadrivalent HPV vaccine among adolescents will be safe and effective; high antibody titers achieved after vaccination at age 11 - 12 years; data on HPV epidemiology and age of sexual debut in the United States; and the high probability of HPV acquisition within several years of sexual debut," the authors write. "Ideally, HPV vaccine should be administered before sexual debut, and duration of protection should extend for many years, providing protection when exposure through sexual activity might occur. The vaccine has been demonstrated to provide protection for at least 5 years without evidence of waning protection."
Morbid Mortal Wkly Rep Early Release. 2007;56:1-24.
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr56e312a1.htm
Clinical Context
The most common sexually transmitted infection in the United States is genital HPV. In the January-February 2004 issue of the Perspectives on Sexual and Reproductive Health, Weinstock and colleagues noted that the US annual HPV incidence is about 6.2 million for persons aged 14 to 44 years, with 74% occurring in ages 15 to 24 years. According to the US Cancer Statistics Working Group, in 2003, the incidence of cervical cancer in the United States was 8.1 per 100,000 or about 11,820 cases. In the February 6, 2003, issue of The New England Journal of Medicine, Munoz and colleagues reported that persistent infection with high-risk HPV types was associated with cervical cancer, low- and high-grade cervical cancer precursors, and anogenital cancer. HPV types 16 and 18 cause about 70% of cervical cancers, according to Bosch and de Sanjose in the 2003 issue of the Journal of the National Cancer Institute: Monographs.
Persistent infection with low-risk HPV types 6 and 11 has been linked to benign or low-grade cervical cancer cell changes, genital warts, and respiratory papillomatosis. A quadrivalent HPV vaccine was licensed in the United States in June 2006 for girls and women aged 9 to 26 years to prevent HPV type 6-, 11-, 16-, and 18-related cervical cancer, precursors to cervical cancer and vaginal and vulvar cancer, and anogenital warts.
In 2004, the ACIP HPV vaccine workgroup started to review published and unpublished data from HPV vaccine clinical trials, HPV epidemiology, vaccine acceptability, and sexual behavior. ACIP approved the final recommendations in June 2006. Subsequent modifications were made after the Centers for Disease Control and Prevention review. This is the first ACIP statement to summarize HPV epidemiology, the HPV quadrivalent vaccine licensed for use in the United States, and HPV vaccine recommendations for use in girls and women aged 9 to 26 years.
Study Highlights
* Genital HPV infection is usually transmitted by sexual intercourse with greater risk linked to increased number of sex partners.
* In the United States, 3.7% of girls reported sexual activity by age 13 years and 24% by age 15 years.
* Most significant risk factor for cervical cancer precursors and cervical cancer is persistent infection with high-risk HPV types, especially type 16.
* HPV is also associated with most vaginal intraepithelial neoplasias III (VaIN III) and vaginal cancers (especially type 16), 76% vulvar intraepithelial neoplasia (VIN) and 42% vulvar carcinoma (types 16 or 18), 90% anal squamous cell cancer, all anogenital warts (90% from types 6 and 11), and juvenile onset recurrent respiratory papillomatosis.
* HPV-related lesion treatments do not appear to affect infectiousness.
* HPV prevention methods include abstinence, monogamy with uninfected partner, and possibly condom use, but not routine HPV infection surveillance or partner treatment.
* Each 0.5-mL dose contains 20 µg of HPV 6 L1 protein, 40 µg of HPV 11 L1 protein, 40 µg of HPV 16 L1 protein, 20 µg of HPV 18 L1 protein, and 225 µg of amorphous aluminum hydroxyphosphate sulfate and also includes sodium chloride, L-histidine, polysorbate 80, sodium borate, and water.
* Vaccine efficacy is 89.5% for persistent HPV 6, 11, 16, or 18 infection; 100% for HPV 16- or 18-related cervical intraepithelial neoplasia (CIN) 2/3; 95.2% to 100% for any grade CIN; 98.9% for HPV-6, 11-, 16-, or 18-related external genital warts; and 100% for HPV 16- or 18-related VIN 2/3 or VaIN 2/3.
* If HPV vaccine-type is seropositive or HPV DNA is positive, efficacy for CIN 2/3 prevention was unclear.
* Women who received at least 1 vaccine dose and any follow-up showed efficacy of 39% for type 16- or 18-related CIN 2/3 or adenocarcinoma in situ; 46.4% for any vaccine type-related CIN; 69.1% for vaccine type-related VIN 2/3 and VaIN 2/3; and 68.5% for vaccine type-related genital warts.
* Seropositivity for all ages was 99% for HPV types 6, 11, 16, and 18.
* Serious adverse events were similar for vaccine and placebo groups (< 0.1%); 10 deaths in vaccine group were not vaccine related.
* Most common local adverse event in vaccinated subjects was pain (84%).
* The second most common adverse event from the vaccine was syncope according to the Vaccine Adverse Event Reporting System; observation for 15 minutes postvaccination should be considered.
* Special situations:
o Vaccine is not effective for existing HPV infection, cervical lesions, or genital warts.
o Breast-fed infants of 500 women who received vaccine during lactation had no events.
o Immunosuppressed girls and women can receive vaccine but might have decreased immune response and efficacy.
o Vaccine is not recommended during pregnancy, but no intervention is necessary if received (Category B classification); 1244 vaccinated women who became pregnant had no increase in spontaneous loss or congenital anomalies.
* Contraindications include moderate or severe illnesses and history of immediate hypersensitivity to yeast or any vaccine component.
* Second and third doses should be given 2 months (minimum 4 weeks) and 6 months (minimum 12 weeks) after first dose; interrupted vaccine series does not need to be restarted.
* Papanicolaou test and HPV DNA or HPV antibody testing are not needed prior to vaccination.
* Vaccine can be administered with other age-appropriate vaccines, but only data for hepatitis B vaccine exist.
* Cervical cancer screening should continue in vaccinated patients.
* HPV vaccine is not licensed for girls younger than 9 years or women older than 26 years or for boys and men.
Pearls for Practice
* Quadrivalent HPV vaccine is highly efficacious in the prevention of persistent HPV infection, cervical cancer precursor lesions, vaginal and vulvar cancer precursor lesions, and genital warts due to HPV types 6, 11, 16, or 18 in girls and women who are not infected. The most common local adverse event is pain.
* Three-dose series of the quadrivalent HPV vaccine is recommended routinely for girls and women aged 11 to 12 years, but can be given to those aged 9 to 26 years; girls and women who have received vaccination should continue to undergo recommended cervical cancer screening.
1. Which of the following statements about quadrivalent HPV vaccine is most accurate? (Required for credit)
The most common local adverse event is erythema
It is effective in prevention of cervical cancer precursor lesions
It is effective in prevention of cervical cancer precursor lesions but not genital warts
It is effective in prevention of vaginal and vulvar cancer precursor lesions but not cervical cancer precursor lesions
It is effective in prevention of genital warts but not vaginal and vulvar cancer precursor lesions
2. An 11-year-old girl receives her first quadrivalent HPV vaccine today. Which of the following statements is most accurate? (Required for credit)
The second dose of HPV vaccine is due in 6 months
If she misses the next scheduled dose, she will need to restart the vaccine series
After she receives all 3 doses, she will not need cervical cancer screening in the future
Her 9-year-old sister could receive the vaccine today
Medscape Medical News 2007. ©2007 Medscape
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