Journals A-Z ? New England Journal of Medicine ? 361(3) July 2009 ? HPV Vaccination for the Prevention of Cervical
HPV Vaccination for the Prevention of Cervical Intraepithelial Neoplasia
Kahn, Jessica A. M.D., M.P.H.
From the Division of Adolescent Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati.
Dr. Kahn reports being coprincipal investigator in a clinical trial of HPV vaccination that is funded by the National Institutes
of Health; Merck is providing immunogenicity testing and vaccine, but no salary or other support, for this trial. No other
potential conflict of interest relevant to this article was reported.
I thank Susanne Wells, Ph.D., for her helpful comments.
This Journal feature begins with a case vignette that includes a therapeutic
recommendation. A discussion of the clinical problem and the mechanism of benefit of
this form of therapy follows. Major clinical studies, the clinical use of this therapy, and
potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are
presented. The article ends with the author's clinical recommendations.
A sexually active 18-year-old woman presents to her internist for an annual
examination. During the review of her family history, she notes that her mother
recently received a diagnosis of “pre-cervical cancer” and underwent a loop
electrosurgical excision procedure. The patient's mother has advised her to get the
“cervical-cancer shot.” Should this patient receive a human papillomavirus (HPV)
vaccine, and how effective would vaccination be in preventing cervical cancer?
The Clinical Problem
Genital HPV infection is usually acquired through sexual contact and is extremely
common. In a nationally representative study of women in the United States, 25% of
persons between the ages of 14 and 19 years and 45% of persons between the ages of 20
and 24 years were HPV-positive.1 It is estimated that more than 80% of both men and
women in the United States will be infected with HPV at some point in their lives.2 HPV
is often acquired within months after the first sexual intercourse: in a study of
university women who had recently had sexual intercourse for the first time and
reported having only one partner, almost 30% became HPV-positive within 1 year.3
Although HPV infection is usually asymptomatic, anogenital warts or cancers or other
HPV-associated cancers develop in a subgroup of infected women and men. The clinical
outcome of greatest significance for public health is cervical cancer. Globally, cervical
cancer is the second most frequent cancer among women; each year, approximately
490,000 women receive this diagnosis and 270,000 die from cervical cancer.4
In the United States, the implementation of cytologic screening programs with the
Papanicolaou (Pap) test has led to a decrease in rates of cervical cancer, since
screening identifies precancerous cervical lesions that can be treated before they
The New England Journal of Medicine
Issue: Volume 361(3), 16 July 2009, p 271–278
Copyright: Copyright © 2009 Massachusetts Medical Society. All rights reserved.
Publication Type: [Clinical Therapeutics]
Página 1 de 14 Ovid: HPV Vaccination for the Prevention of Cervical Intraepithelial Neoplasia.
progress to cancer. Despite such screening, in 2008, approximately 11,000 women
in the United States received a diagnosis of cervical cancer and 3900 died from the
disease.5 The direct medical costs associated with the prevention and treatment of
HPV-related anogenital warts and cervical disease in the United States are estimated to
be $4.0 billion annually,6 and productivity losses due to deaths from cervical cancer are
estimated to be $1.3 billion annually.7
Pathophysiological Features and Effect of Therapy
HPVs are double-stranded DNA viruses that infect cutaneous or mucosal epithelial
surfaces. The genome of the virus encodes two nucleocapsid proteins (L1 and L2) and at
least six early proteins (E1, E2, and E4 through E7) that allow for replication of viral
DNA and the assembly of viral particles.8 More than 130 HPV genotypes have been
cloned from clinical lesions, and classification is based on genetic similarities in the L1
nucleocapsid protein DNA sequence.910
Approximately 30 to 40 HPV genotypes infect the mucosa of the genital tract and
are categorized as low-risk or high-risk according to their clinical sequelae: low-risk
types are associated primarily with benign anogenital warts, and high-risk types are
associated primarily with anogenital cancers. Two low-risk types, HPV type 6 (HPV-6)
and HPV type 11 (HPV-11), cause more than 90% of anogenital warts and recurrent
respiratory papillomatosis.11 Infection with high-risk HPV types causes virtually 100% of
cervical cancers, approximately 90% of anal cancers, 50% of vulvar, vaginal, and penile
cancers, and 12% of oropharyngeal cancers.121314 HPV type 16 (HPV-16), HPV type 18
(HPV-18), or both cause approximately 70% of cervical cancers, whereas types 16, 18,
45, 31, 33, 52, 58, and 35 cause approximately 95% of cervical cancers.1516 HPV-16 and
HPV-18 cause approximately 50% of cervical-cancer precursors.17
The HPV life cycle occurs only in keratinocytes undergoing differentiation (Figure
1). In most cases, infection occurs without malignant transformation. In such cases, the
viral DNA is maintained separately from the host DNA as an episome. In the subgroup of
HPV infections leading to malignant transformation, the viral DNA is often integrated
into the host genome during progression of the cancer. Carcinogenesis is associated with
the expression of proteins E6 and E7, which inactivate tumor suppressors p53 and
retinoblastoma protein (pRb), respectively.19
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50. Schwarz TF, Dubin GO. An AS04-containing human papillomavirus (HPV) 16/18
vaccine for prevention of cervical cancer is immunogenic and well-tolerated in women
15-55 years old. Proc Am Soc Clin Oncol 2006;24:1008. [Context Link]
51. Luna J, Saah AJ, Hood S, Bautista OM, Barr E. Safety, efficacy, and immunogenicity
of quadrivalent HPV vaccine (Gardasil) in women aged 24-45. Presented at the 24th
International Papillomavirus Conference, Beijing, November 3-9 2007. [Context Link]
52. Palefsky JM, Gillison ML, Strickler HD. Chapter 16: HPV vaccines in
immunocompromised women and men. Vaccine 2006;24:Suppl 3:S3/140-S3/146.
53. Myers E, Huh WK, Wright JD, Smith JS. The current and future role of screening in
the era of HPV vaccination. Gynecol Oncol 2008;109:2 Suppl:S31-S39. [Context Link]
54. Kiviat NB, Hawes SE, Feng Q. Screening for cervical cancer in the era of the HPV
vaccine — the urgent need for both new screening guidelines and new biomarkers. J
Natl Cancer Inst 2008;100:290-1. Buy Now Bibliographic Links [Context Link]
55. Heideman DA, Snijders PJ, Berkhof J, Verheijen RH, Helmerhorst TJ, Meijer CJ.
Vaccination against HPV: indications for women and the impact on the cervical
screening programme. BJOG 2008;115:938-46. Buy Now Bibliographic Links [Context
56. Brewer NT, Cuite CL, Herrington JE, Weinstein ND. Risk compensation and
vaccination: can getting vaccinated cause people to engage in risky behaviors? Ann
Behav Med 2007;34:95-9. Bibliographic Links [Context Link]
57. Friedman LS, Kahn J, Middleman AB, Rosenthal SL, Zimet GD. Human papillomavirus
(HPV) vaccine: a position statement of the Society for Adolescent Medicine. J Adolesc
Health 2006;39:620. Bibliographic Links [Context Link]
58. 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. Full Text Bibliographic Links [Context Link]
59. Koulova A, Tsui J, Irwin K, Van Damme P, Biellik R, Aguado MT. Country
recommendations on the inclusion of HPV vaccines in national immunization
programmes among high-income countries, June 2006-January 2008. Vaccine
2008;26:6529-41. Bibliographic Links [Context Link]
60. Human papillomavirus vaccines: WHO position paper. Wkly Epidemiol Rec
2009;84:118-31. Full Text Bibliographic Links [Context Link]
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61. Kollar LM, Kahn JA. Education about human papillomavirus and human
papillomavirus vaccines in adolescents. Curr Opin Obstet Gynecol 2008;20:479-83. Ovid
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