Practice Guidelines

ACS Releases Guidelines for HPV Vaccination



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Am Fam Physician. 2008 Mar 15;77(6):852-863.

Guideline source: American Cancer Society

Literature search described? Yes

Evidence rating system used? Yes

Published source: CA: A Cancer Journal for Clinicians, January/February 2007

Available at: http://caonline.amcancersoc.org/cgi/content/full/57/1/7

The American Cancer Society (ACS) guideline for the early detection of cervical cancer was last reviewed and updated in 2002.1 Since then, two vaccines against the most common cancer-causing types of human papillomavirus (HPV) have been developed and tested in clinical trials (i.e., quadrivalent HPV vaccine [Gardasil] and bivalent HPV vaccine [Cervarix], not yet approved by the U.S. Food and Drug Administration [FDA]).27 An expert panel was convened by the ACS to review the data on HPV vaccines and to develop recommendations for their use.8  This group worked independently from the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention, but reviewed the same data sources. Recommendations from both groups for the use of the quadrivalent HPV vaccine were published in 2007 and are summarized in Table 1.24,810 The ACIP recommendations, which the American Academy of Family Physicians endorses, apply specifically to the quadrivalent vaccine because it currently is the only FDA-approved HPV vaccine. The ACS recommendations are meant to include the quadrivalent vaccine and, pending FDA approval, the bivalent vaccine.

Table 1

Comparison of ACIP and ACS Recommendations for HPV Vaccination

ACIP recommendation* ACS recommendation*

Routine HPV vaccination with three doses of the quadrivalent vaccine (Gardasil) is recommended for girls 11 and 12 years of age9,10

Routine HPV vaccination is recommended for girls 11 and 12 years of age8

Girls as young as nine years can be vaccinated9,10

Girls as young as nine years can be vaccinated8,10

HPV vaccination is recommended for all females 13 through 26 years of age to catch up missed doses or to complete the vaccination series24,9,10

HPV vaccination is recommended for all females 13 through 18 years of age to catch up missed doses or to complete the vaccination series8,10

The quadrivalent vaccine is not licensed for use in females younger than nine years or older than 26 years9

HPV vaccination is not recommended for women older than 26 years8

The quadrivalent vaccine is not licensed for use in males9

HPV vaccination is not recommended for males8

Cervical cancer screening recommendations have not changed for women who receive HPV vaccination9

A history of abnormal Papanicolaou test results, a positive HPV test result, or genital warts does not preclude a woman from receiving HPV vaccination9

Women should be advised that there is no clear evidence of vaccine protection for women who were previously infected with HPV vaccine types24,9

The vaccine ideally should be administered before potential exposure to genital HPV because the potential benefit is likely to diminish as the number of lifetime sex partners increases24,8

Data are insufficient to recommend for or against universal vaccination of women 19 to 26 years of age in the general population†; a decision about vaccination should be based on an informed discussion between the woman and her physician regarding her risk of previous HPV exposure and potential benefit from vaccination


ACIP = Advisory Committee on Immunization Practices; ACS = American Cancer Society; HPV = human papillomavirus.

*— ACIP recommendations apply to use of the quadrivalent HPV vaccine (Gardasil) and are endorsed by the American Academy of Family Physicians. ACS recommendations apply to the use of the quadrivalent HPV vaccine and the bivalent HPV vaccine (Cervarix), pending approval by the U.S. Food and Drug Administration.

†— Insufficient evidence of benefit refers to: (1) clinical trial data indicating a limited reduction in the overall incidence of cervical intraepithelial neoplasia grades 2 and 3 in women with an average of two and not more than four lifetime sex partners; (2) the absence of data for the prevention of HPV types 16 and 18-related cervical intraepithelial neoplasia grades 2 and 3 in women with more than four lifetime sex partners; and (3) the lack of cost-effectiveness analyses for vaccination in women 19 to 26 years of age.

Information from references 2 through 4, and 8 through 10.

Table 1   Comparison of ACIP and ACS Recommendations for HPV Vaccination

View Table

Table 1

Comparison of ACIP and ACS Recommendations for HPV Vaccination

ACIP recommendation* ACS recommendation*

Routine HPV vaccination with three doses of the quadrivalent vaccine (Gardasil) is recommended for girls 11 and 12 years of age9,10

Routine HPV vaccination is recommended for girls 11 and 12 years of age8

Girls as young as nine years can be vaccinated9,10

Girls as young as nine years can be vaccinated8,10

HPV vaccination is recommended for all females 13 through 26 years of age to catch up missed doses or to complete the vaccination series24,9,10

HPV vaccination is recommended for all females 13 through 18 years of age to catch up missed doses or to complete the vaccination series8,10

The quadrivalent vaccine is not licensed for use in females younger than nine years or older than 26 years9

HPV vaccination is not recommended for women older than 26 years8

The quadrivalent vaccine is not licensed for use in males9

HPV vaccination is not recommended for males8

Cervical cancer screening recommendations have not changed for women who receive HPV vaccination9

A history of abnormal Papanicolaou test results, a positive HPV test result, or genital warts does not preclude a woman from receiving HPV vaccination9

Women should be advised that there is no clear evidence of vaccine protection for women who were previously infected with HPV vaccine types24,9

The vaccine ideally should be administered before potential exposure to genital HPV because the potential benefit is likely to diminish as the number of lifetime sex partners increases24,8

Data are insufficient to recommend for or against universal vaccination of women 19 to 26 years of age in the general population†; a decision about vaccination should be based on an informed discussion between the woman and her physician regarding her risk of previous HPV exposure and potential benefit from vaccination


ACIP = Advisory Committee on Immunization Practices; ACS = American Cancer Society; HPV = human papillomavirus.

*— ACIP recommendations apply to use of the quadrivalent HPV vaccine (Gardasil) and are endorsed by the American Academy of Family Physicians. ACS recommendations apply to the use of the quadrivalent HPV vaccine and the bivalent HPV vaccine (Cervarix), pending approval by the U.S. Food and Drug Administration.

†— Insufficient evidence of benefit refers to: (1) clinical trial data indicating a limited reduction in the overall incidence of cervical intraepithelial neoplasia grades 2 and 3 in women with an average of two and not more than four lifetime sex partners; (2) the absence of data for the prevention of HPV types 16 and 18-related cervical intraepithelial neoplasia grades 2 and 3 in women with more than four lifetime sex partners; and (3) the lack of cost-effectiveness analyses for vaccination in women 19 to 26 years of age.

Information from references 2 through 4, and 8 through 10.

HPV-related disease includes genital warts; recurrent respiratory papillomatosis; cytologic abnormalities; and cervical, vaginal, and vulvar cancers and their associated precursor lesions. In addition, HPV is causal in a significant percentage of anal, penile, and head and neck cancers.11,12 Virtually all cervical cancers are causally related to persistent HPV infection13; HPV types 16 and 18 account for 70 percent of cervical cancers14 and 50 percent of cervical intraepithelial neoplasia grades 2 and 3 (CIN 2/3) lesions.15 Most HPV infections are transient and resolve or become undetectable within two years.1618 However, when HPV infection persists, the stepwise development of invasive cancer takes an average of 20 years.19

Genital HPV is transmitted primarily by skin-to-skin contact, usually through vaginal or anal intercourse, although intromission is not necessary. The risk of transmission by digital-genital and genital-oral contact appears likely but has not been well studied.20 Infection is common within a few years after first sexual intercourse, with almost three fourths of new infections occurring in women 15 to 25 years of age.17,21 An estimated 80 percent of sexually active men and women acquire a genital HPV infection at some point in their lifetime.22

Although cytologic screening has resulted in marked decreases in cervical cancer incidence and mortality (74 and 75 percent decreases, respectively), racial and ethnic disparities remain in incidence, mortality, and survival.23 HPV DNA testing for the presence of high-risk HPV types is indicated in two cervical screening scenarios: in conjunction with cervical cytology screening in women 30 years and older,1,24,25 and for the triage of abnormal Papanicolaou (Pap) test results read as atypical squamous cells of undetermined significance in women 21 years and older.26,27

Secondary recommendations for HPV vaccination are summarized in Table 2.8,9

Table 2

Secondary Recommendations for HPV Vaccination

General recommendations and precautions

HPV testing before vaccination is not recommended8,9

HPV vaccine can be given to women with minor acute illnesses (e.g., diarrhea, respiratory tract illnesses with or without fever) but should not be given until recovery from a moderate or severe illness9

The second most common adverse event reported after HPV vaccination is vasovagal syncope, which is common in persons 10 to 18 years of age who receive any vaccine; observation of patients for 15 minutes after vaccine administration is advised9

The use of noncomprehensive visits (e.g., those for minor illness or sports physical examinations) and alternative vaccination sites for adolescents who are unable to access comprehensive preventive care is encouraged8

Immunocompromised patients

HPV vaccine can be given to women who are immunocompromised by disease or medications, but the immune response and vaccine effectiveness may be reduced9

Pregnant and lactating patients

Pregnant women should not receive the HPV vaccine; if a woman becomes pregnant after initiation but before completion of the three-dose vaccine regimen, administration of the remaining doses should be delayed until after completion of the pregnancy9

If a vaccine dose is administered during pregnancy, no intervention isneeded9; a registry is available for pregnant patients who are vaccinated with the quadrivalent HPV vaccine (Gardasil)

Lactating women can be vaccinated9


HPV = human papillomavirus.

Information from references 8 and 9.

Table 2   Secondary Recommendations for HPV Vaccination

View Table

Table 2

Secondary Recommendations for HPV Vaccination

General recommendations and precautions

HPV testing before vaccination is not recommended8,9

HPV vaccine can be given to women with minor acute illnesses (e.g., diarrhea, respiratory tract illnesses with or without fever) but should not be given until recovery from a moderate or severe illness9

The second most common adverse event reported after HPV vaccination is vasovagal syncope, which is common in persons 10 to 18 years of age who receive any vaccine; observation of patients for 15 minutes after vaccine administration is advised9

The use of noncomprehensive visits (e.g., those for minor illness or sports physical examinations) and alternative vaccination sites for adolescents who are unable to access comprehensive preventive care is encouraged8

Immunocompromised patients

HPV vaccine can be given to women who are immunocompromised by disease or medications, but the immune response and vaccine effectiveness may be reduced9

Pregnant and lactating patients

Pregnant women should not receive the HPV vaccine; if a woman becomes pregnant after initiation but before completion of the three-dose vaccine regimen, administration of the remaining doses should be delayed until after completion of the pregnancy9

If a vaccine dose is administered during pregnancy, no intervention isneeded9; a registry is available for pregnant patients who are vaccinated with the quadrivalent HPV vaccine (Gardasil)

Lactating women can be vaccinated9


HPV = human papillomavirus.

Information from references 8 and 9.

Rationale and Evidence for Vaccination

Two prophylactic HPV vaccines have been developed that elicit strong and sustained immunity to HPV types 16 and 18 in clinical trials27,9,28; one of the vaccines also protects against two low-risk HPV types that are associated with 90 percent of cases of genital warts.3,4 Clinical trials showed that these vaccines are 75 to 100 percent effective in preventing persistent type-specific HPV 16 or 18 infection and 90 to 100 percent effective in preventing CIN 2/3, the accepted disease end point for cervical cancer, in patients who adhered to the study protocol.27,28

Few safety issues were observed during the trials, and most adverse effects were mild or moderate. The most common injection site reactions were pain, redness, and swelling, with severe intensity being reported more often in vaccine recipients than in placebo recipients.24,8,9 The most common systemic adverse effects were fever, headache, and nausea; these effects were reported by a similar proportion of vaccine and placebo recipients (69 percent). No deaths secondary to vaccine were reported. Although the quadrivalent HPV vaccine is classified as FDA pregnancy category B, ACIP does not recommend that it be given during pregnancy.9 However, ACIP has noted that the quadrivalent HPV vaccine is safe for breast-feeding women.

Because HPV is often acquired soon after the onset of sexual intercourse,20,21 routine vaccination before or shortly after first intercourse (i.e., at 11 or 12 years of age) is important to achieve optimal effectiveness. In the United States, 24 percent of girls report being sexually active by 15 years of age,29 and 7 percent of high school students (male and female) report that they had intercourse before 13 years of age.30 The risk of exposure to carcinogenic and noncarcinogenic HPV types increases with the number of lifetime sex partners.20,21 National survey data have shown that approximately 50 percent of women older than 19 years of age have had four or more sex partners.31 Because women with more than four lifetime sex partners were excluded from the quadrivalent vaccine trials and those with more than six lifetime partners were excluded from the bivalent vaccine trials, the ACS concluded that there is insufficient evidence from the general population to recommend for or against vaccination of women 19 to 26 years of age, and no evidence for women older than 26 years.8 Women 19 to 26 years of age who have been sexually active should be counseled that the vaccine may not protect them from all of the vaccine HPV types.8

The quadrivalent vaccine has demonstrated robust immune responses in adolescents (male and female) between nine and 15 years of age.10

Anticipated Impact of HPV Vaccination

Because HPV 6, 11, 16, and 18 are associated with approximately 40 percent of histologically confirmed CIN, vaccination is expected to lead to reductions in abnormal Pap test results, colposcopy referrals, cervical biopsies, and excisional procedures.15 Decreases in the number of surgical procedures will also reduce procedure-associated complications.32 There is insufficient evidence to alter screening recommendations.8 Women who receive the HPV vaccine should continue to follow current Pap screening guidelines.2,3,8,9

It is hoped that HPV vaccination will decrease existing disparities in cervical cancer incidence, mortality, and morbidity. In particular, provision of free HPV vaccines to all eligible girls up to 18 years of age under the federal Vaccines for Children Program is expected to benefit many medically underserved girls who may not receive regular screening as they get older. Similar racial and ethnic disparities in acute hepatitis B infections among children younger than 19 years were virtually eliminated in the United States between 1990 and 2004 after universal hepatitis B vaccination was recommended.33

Vaccine Implementation and Administration

The HPV vaccine can be given during the preadolescent health care visit at age 11 or 12 years, in addition to the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Boostrix, Adacel) and quadrivalent meningococcal conjugate vaccine (Menactra). This visit also gives physicians a platform to ensure compliance with other recommended vaccinations and to provide health guidance. Reminder systems can be used to ensure completion of the three-dose HPV vaccine series.

Address correspondence to Martin C. Mahoney, MD, PhD, at martin.mahoney@roswellpark.org. Reprints are not available from the authors.

Author disclosure: Dr. Cox is a member of the data and safety monitoring board for the Merck quadrivalent HPV vaccine trials. Dr. Mahoney is a member of the advisory board and speakers bureau for Merck & Co. Inc. Dr. Moscicki is a member of the speakers bureaus for Merck & Co. Inc. and GlaxoSmithKline.

REFERENCES

1. Saslow D, Runowicz CD, Solomon D, et al. American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin. 2002;52(6):342–362.

2. Paavonen J, Jenkins D, Bosch FX, et al., for the HPV PATRICIA Study Group. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 2007;369(9580):2161–2170.

3. FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007;356(19):1915–1927.

4. Garland SM, Hernandez-Avila M, Wheeler CM, et al., for the Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007;356(19):1928–1943.

5. Harper DM, Franco EL, Wheeler C, et al., for the GlaxoSmithKline HPV Vaccine Study Group. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet. 2004;364(9447):1757–1765.

6. Harper DM, Franco EL, Wheeler CM, et al., for the HPV Vaccine Study group. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet. 2006;367(9518):1247–1255.

7. Mao C, Koutsky LA, Ault KA, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial [published correction appears in Obstet Gynecol. 2006;107(6):1425]. Obstet Gynecol. 2006;107(1):18–27.

8. Saslow D, Castle PE, Cox JT, et al., for the Gynecologic Cancer Advisory Group. American Cancer Society Guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin. 2007;57(1):7–28.

9. Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER, for the Centers for Disease Control and Prevention. Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56(RR-2):1–24.

10. Block SL, Nolan T, Sattler C, et al., for the Protocol 016 Study Group. Comparison of the immunogenicity and reactogenicity of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in male and female adolescents and young adult women. Pediatrics. 2006;118(5):2135–2145.

11. Mahoney MC. Protecting our patients from HPV and HPV-related diseases: the role of vaccines. J Fam Pract. 2006;suppl:10–17.

12. D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356(19):1944–1956.

13. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189(1):12–19.

14. Muñoz N, Bosch FX, de Sanjosé S, et al., for the International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348(6):518–527.

15. Clifford GM, Smith JS, Aguado T, Franceschi S. Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: a meta-analysis. Br J Cancer. 2003;89(1):101–105.

16. Woodman CB, Collins S, Winter H, et al. Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study. Lancet. 2001;357(9271):1831–1836.

17. Winer RL, Kiviat NB, Hughes JP, et al. Development and duration of human papillomavirus lesions, after initial infection. J Infect Dis. 2005;191(5):731–738.

18. Moscicki AB, Shiboski S, Hills NK, et al. Regression of low-grade squamous intraepithelial lesions in young women. Lancet. 2004;364(9446):1678–1683.

19. Schiffman M, Castle PE. The promise of global cervical-cancer prevention. N Engl J Med. 2005;353(20):2101–2104.

20. Burchell AN, Winer RL, de Sanjosé S, Franco EL. Chapter 6: Epidemiology and transmission dynamics of genital HPV infection. Vaccine. 2006;24(suppl 3):S52–S61.

21. Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students [published correction appears in Am J Epidemiol. 2003;157(9):858]. Am J Epidemiol. 2003;157(3):218–226.

22. Myers ER, McCrory DC, Nanda K, Bastian L, Matchar DB. Mathematical model for the natural history of human papillomavirus infection and cervical carcinogenesis. Am J Epidemiol. 2000;151(12):1158–1171.

23. Kitchener HC, Castle PE, Cox JT. Chapter 7: Achievements and limitations of cervical cytology screening. Vaccine. 2006;24(suppl 3):S63–S70.

24. American College of Obstetrics and Gynecology. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 61, April 2005. Human papillomavirus. Obstet Gynecol. 2005;105(4):905–918.

25. Wright TC Jr, Schiffman M, Solomon D, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol. 2004;103(2):304–309.

26. Wright TC Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ, for the ASCCP-Sponsored Consensus Conference. 2001 Consensus guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287(16):2120–2129.

27. Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D, for the 2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference. 2006 Consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol. 2007;197(4):346–355.

28. Villa LL, Costa RL, Petta CA, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer. 2006;95(11):1459–1466.

29. Abma JC, Martinez GM, Mosher WD, Dawson BS. Teenagers in the United States: sexual activity, contraceptive use, and childbearing, 2002. Vital Health Stat 23. 2004;(24):1–48.

30. Grunbaum JA, Kann L, Kinchen S, et al. Youth risk behavior surveillance—United States, 2003 [published corrections appear in MMWR Morb Mortal Wkly Rep. 2004;53(24):536 and MMWR Morb Mortal Wkly Rep. 2005;54(24):608]. MMWR Surveill Summ. 2004;53(2):1–96.

31. Mosher WD, Chandra A, Jones J. Sexual behavior and selected health measures: men and women 15–44 years of age, United States, 2002. Adv Data. 2005;(362):1–55.

32. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet. 2006;367(9509):489–498.

33. Mast EE, Margolis HS, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents [published corrections appear in MMWR Morb Mortal Wkly Rep. 2006; 55(6):158–159 and MMWR Morb Mortal Wkly Rep. 2007;56(48):1267]. MMWR Recomm Rep. 2005;54(RR-16):1–31.



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