Correspondence
Human Papillomavirus Vaccine
N Engl J Med 2007; 357:1154-1156September 13, 2007
- Article
To the Editor:
In their editorial about the availability of a quadrivalent vaccine against human papillomavirus (HPV) (Gardasil, Merck) that was reported on by Garland et al.1 and by the Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) II Study Group2 (May 10 issue), Sawaya and Smith-McCune3 raise concerns regarding the adequacy of cervical dysplasia as an efficacy end point, disease due to HPV types not associated with the vaccine, the lower efficacy of the vaccine among women who were previously infected with HPV than among those who had never been infected, and the need for continued Papanicolaou screening after vaccination. The approval by the Food and Drug Administration (FDA) of the quadrivalent HPV vaccine relied on the end points of moderate or severe cervical dysplasia (grade 2 or 3 cervical intraepithelial neoplasia [CIN 2/3]) or adenocarcinoma in situ, or end points reflecting more severe disease, because these histopathological findings represent precursor lesions for cervical cancer, and a diagnosis of CIN 2/3 with colposcopy results in treatment by means of excision or ablation.4 The FDA-approved label clearly informs health care providers of the other concerns: Gardasil “does not prevent infection with the HPV types not contained in the vaccine”; it “reduced the overall rate of CIN 2/3 or AIS [adenocarcinoma in situ] caused by vaccine or non-vaccine HPV types by 12.2% (95% CI [confidence interval]: −3.2%, 25.3%)” in women, regardless of their baseline HPV status; there is “no clear evidence of protection from disease caused by HPV types for which subjects were PCR [polymerase chain reaction] positive and/or seropositive at baseline”; and women receiving “Gardasil should continue to undergo cervical cancer screening per standard of care.”5
5 ReferencesNancy B. Miller, M.D.
Gopa Raychaudhuri, Ph.D.
Joseph G. Toerner, M.D., M.P.H.
Food and Drug Administration, Rockville, MD 208501
Garland SM ,Hernandez-Avila M ,Wheeler CM , et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007;356:1928-1943
Full Text | Web of Science | Medline2
The FUTURE II Study Group
Full Text | Web of Science | Medline3
Sawaya GF ,Smith-McCune K . HPV vaccination -- more answers, more questions. N Engl J Med 2007;356:1991-1993
Full Text | Web of Science | Medline4
Wright TC Jr ,Cox JT ,Massad LS , et al. 2001 Consensus guidelines for the management of women with cervical intraepithelial neoplasia. Am J Obstet Gynecol 2003;189:295-304
CrossRef | Web of Science | Medline5
Gardasil [quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine]. Whitehouse Station, NJ: Merck, 2006 (package insert). (Accessed August 23, 2007, at http://www.fda.gov/cber/label/hpvmer040307LB.pdf.)
To the Editor:
In their article on introducing HPV vaccine in developing countries, Agosti and Goldie (May 10 issue)1 suggest that “ideal” cervical-cancer prevention programs for developing countries should include HPV vaccination. This suggestion will remain premature until long-term follow-up data exclude the possibility that HPV vaccination may be ineffective for the prevention of invasive cervical carcinoma. Because it is uncertain when such data will become available, it is essential in the meantime for developing countries to allocate their limited resources toward screening, rather than vaccination.
Cytologic screening is feasible anywhere cervical screening is appropriate and is the only preventive option currently available for public-sector control of cervical cancer in developing countries.2 Past and current failures of cervical-cancer prevention efforts in developed and developing countries are attributable not to factors specific to cytologic testing, but rather to lapses of political will and quality management — to which all preventive interventions, including vaccines, are vulnerable.2
2 ReferencesEric J. Suba, M.D.
Kaiser Permanente Medical Center, South San Francisco, CA 94080
eric.suba@kp. org Stephen S. Raab, M.D.
University of Pittsburgh Medical Center, Pittsburgh, PA 15232for the Viet/American Cervical Cancer Prevention Project
1
Agosti JM ,Goldie SJ . Introducing HPV vaccine in developing countries -- key challenges and issues. N Engl J Med 2007;356:1908-1910
Full Text | Web of Science | Medline2
Suba EJ ,Donnelly AD ,Furia LM ,Huynh ML ,Raab SS . Cervical cancer prevention for all the world's women: genuine promise resides in skilled quality management rather than novel screening approaches. Diagn Cytopathol 2007;35:187-191
CrossRef | Web of Science | Medline
Author/Editor Response
Miller and colleagues discuss the widely accepted concept that CIN 2/3 and adenocarcinoma in situ are precancerous cervical lesions. In HPV-vaccine trials, such lesions serve as surrogate end points for cervical cancer because follow-up without treatment is not an ethical option1,2 and appropriate excisional or ablative treatment usually prevents progression to invasion. Moreover, the World Health Organization endorses these end points for the assessment of prophylactic vaccine efficacy.3 Since rates of progression are lower for CIN 2 than for CIN 3 and adenocarcinoma in situ,4 it is noteworthy that a combined analysis of the data from the HPV-6/11/16/18 and HPV-16 vaccine trials showed significant, high-level efficacy (≥97%) for prevention of the separate HPV-16/18–related end points of CIN 2, CIN 3, and adenocarcinoma in situ among women who did not have infection with HPV-16/18 on day 1.5
5 ReferencesSuzanne G. Garland, M.D.
University of Melbourne, Parkville, VIC 3052, AustraliaLaura A. Koutsky, Ph.D.
University of Washington, Seattle, WA 981951
Garland SM ,Hernandez-Avila M ,Wheeler CM , et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007;356:1928-1943
Full Text | Web of Science | Medline2
The FUTURE II Study Group
Full Text | Web of Science | Medline3
Pagliusi SR ,Teresa Aguado A . Efficacy and other milestones for human papillomavirus vaccine introduction. Vaccine 2004;23:569-578
CrossRef | Web of Science | Medline4
Wright TC Jr ,Cox JT ,Massad LS , et al. 2001 Consensus guidelines for the management of women with cervical intraepithelial neoplasia. Am J Obstet Gynecol 2003;189:295-304
CrossRef | Web of Science | Medline5
The FUTURE II Study Group
CrossRef | Web of Science | Medline
Author/Editor Response
The FDA-approved label provided an important first look at evidence in support of vaccine efficacy and safety; recently published interim analyses from these ongoing phase 3 trials provided a second look. Our editorial raised additional unanswered questions beyond the concerns addressed by Miller et al., including overall vaccine efficacy in women unexposed to relevant vaccine HPV types, effect on cytologic abnormalities, and effect on disease caused by HPV types not included in the vaccine. The last question is particularly important, in light of the surprising report of vulvar cancer in a 22-year-old trial participant who received the vaccine1; vulvar cancer is rare (overall incidence, 2.2 cases per 100,000 persons) and occurs at a median age of 68 years in the United States.2 This finding and the cited unanswered questions argue for a cautious approach to vaccination policy until trials have been completed and fully reported.
2 ReferencesGeorge F. Sawaya, M.D.
Karen Smith-McCune, M.D., Ph.D.
University of California at San Francisco, San Francisco, CA 941181
Joura EA ,Leodolter S ,Hernandez-Avila M , et al. Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials. Lancet 2007;369:1693-1702
CrossRef | Web of Science | Medline2
Cancer of the vulva. Bethesda, MD: National Cancer Institute, 2007. (Accessed August 23, 2007, at http://seer.cancer.gov/statfacts/html/vulva.html.)
Author/Editor Response
As we noted, the need for long-term follow-up data are important, which Suba and Raab emphasize. Furthermore, it is imperative that momentum behind efforts in the past decade to develop feasible options for cervical-cancer screening in low-resource settings continues to build. The Bill and Melinda Gates Foundation provided $55.6 million to the Alliance for Cervical Cancer Prevention to promote screening and $13 million toward the development of low-cost HPV DNA tests and other tests. We believe it is inequitable to exclude women in developing countries from the potential benefits of vaccination, new technology, and screening approaches that appear to be promising.1
We emphasized that an integrated approach that includes screening and vaccination is likely to prevent the greatest number of deaths from cervical cancer. However, countries will make their own decisions about the best strategic approach to cervical-cancer prevention, accounting for local epidemiologic factors and disease burden,2 competing priorities, and the cost-effectiveness, affordability, and feasibility of vaccination programs targeting adolescents and the screening of adult women. We urge that attention be given to real-world solutions for preventing death from cervical cancer in women living in poverty.
2 ReferencesJan M. Agosti, M.D.
Bill and Melinda Gates Foundation, Seattle, WA 98102Sue J. Goldie, M.D., M.P.H.
Harvard School of Public Health, Boston, MA 021151
Sankaranarayanan R ,Esmy PO ,Rajkumar R , et al. Effect of visual screening on cervical cancer incidence and mortality in Tamil Nadu, India: a cluster-randomized trial. Lancet 2007;370:398-406
CrossRef | Web of Science | Medline2
World Health Organization. WHO/ICO (Institut Català d'Oncologia) Information Centre on HPV and cervical cancer. (Accessed August 23, 2007, at http://www.who.int/hpvcentre.)
