To the Editor: In their editorial about the availability ofa quadrivalent vaccine against human papillomavirus (HPV) (Gardasil,Merck) that was reported on by Garland et al.1 and by the FemalesUnited to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE)II Study Group2 (May 10 issue), Sawaya and Smith-McCune3 raiseconcerns regarding the adequacy of cervical dysplasia as anefficacy end point, disease due to HPV types not associatedwith the vaccine, the lower efficacy of the vaccine among womenwho were previously infected with HPV than among those who hadnever been infected, and the need for continued Papanicolaouscreening after vaccination. The approval by the Food and DrugAdministration (FDA) of the quadrivalent HPV vaccine reliedon the end points of moderate or severe cervical dysplasia (grade2 or 3 cervical intraepithelial neoplasia [CIN 2/3]) or adenocarcinomain situ, or end points reflecting more severe disease, becausethese histopathological findings represent precursor lesionsfor cervical cancer, and a diagnosis of CIN 2/3 with colposcopyresults in treatment by means of excision or ablation.4 TheFDA-approved label clearly informs health care providers ofthe other concerns: Gardasil "does not prevent infection withthe HPV types not contained in the vaccine"; it "reduced theoverall rate of CIN 2/3 or AIS [adenocarcinoma in situ] causedby vaccine or non-vaccine HPV types by 12.2% (95% CI [confidenceinterval]: –3.2%, 25.3%)" in women, regardless of theirbaseline HPV status; there is "no clear evidence of protectionfrom disease caused by HPV types for which subjects were PCR[polymerase chain reaction] positive and/or seropositive atbaseline"; and women receiving "Gardasil should continue toundergo cervical cancer screening per standard of care."5
Nancy B. Miller, M.D. Gopa Raychaudhuri, Ph.D. Joseph G. Toerner, M.D., M.P.H. Food and Drug Administration Rockville, MD 20850
References
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. [Free Full Text]
The FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915-1927. [Free Full Text]
Sawaya GF, Smith-McCune K. HPV vaccination -- more answers, more questions. N Engl J Med 2007;356:1991-1993. [Free Full Text]
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][Medline]
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 indeveloping countries, Agosti and Goldie (May 10 issue)1 suggestthat "ideal" cervical-cancer prevention programs for developingcountries should include HPV vaccination. This suggestion willremain premature until long-term follow-up data exclude thepossibility that HPV vaccination may be ineffective for theprevention of invasive cervical carcinoma. Because it is uncertainwhen such data will become available, it is essential in themeantime for developing countries to allocate their limitedresources toward screening, rather than vaccination.
Cytologic screening is feasible anywhere cervical screeningis appropriate and is the only preventive option currently availablefor public-sector control of cervical cancer in developing countries.2Past and current failures of cervical-cancer prevention effortsin developed and developing countries are attributable not tofactors specific to cytologic testing, but rather to lapsesof political will and quality management — to which allpreventive interventions, including vaccines, are vulnerable.2
Eric J. Suba, M.D. Kaiser Permanente Medical Center South San Francisco, CA 94080 eric.suba{at}kp.org
Stephen S. Raab, M.D. University of Pittsburgh Medical Center Pittsburgh, PA 15232
for the Viet/American Cervical Cancer Prevention Project
References
Agosti JM, Goldie SJ. Introducing HPV vaccine in developing countries -- key challenges and issues. N Engl J Med 2007;356:1908-1910. [Free Full Text]
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]
Drs. Garland and Koutsky reply: Miller and colleagues discussthe widely accepted concept that CIN 2/3 and adenocarcinomain situ are precancerous cervical lesions. In HPV-vaccine trials,such lesions serve as surrogate end points for cervical cancerbecause follow-up without treatment is not an ethical option1,2and appropriate excisional or ablative treatment usually preventsprogression to invasion. Moreover, the World Health Organizationendorses these end points for the assessment of prophylacticvaccine efficacy.3 Since rates of progression are lower forCIN 2 than for CIN 3 and adenocarcinoma in situ,4 it is noteworthythat a combined analysis of the data from the HPV-6/11/16/18and HPV-16 vaccine trials showed significant, high-level efficacy(97%) for prevention of the separate HPV-16/18–relatedend points of CIN 2, CIN 3, and adenocarcinoma in situ amongwomen who did not have infection with HPV-16/18 on day 1.5
Suzanne G. Garland, M.D. University of Melbourne Parkville, VIC 3052, Australia
Laura A. Koutsky, Ph.D. University of Washington Seattle, WA 98195
References
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. [Free Full Text]
The FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915-1927. [Free Full Text]
Pagliusi SR, Teresa Aguado A. Efficacy and other milestones for human papillomavirus vaccine introduction. Vaccine 2004;23:569-578. [CrossRef][Web of Science][Medline]
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][Medline]
The FUTURE II Study Group. Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet 2007;369:1861-1868. [CrossRef][Web of Science][Medline]
The editorialists reply: The FDA-approved label provided animportant first look at evidence in support of vaccine efficacyand safety; recently published interim analyses from these ongoingphase 3 trials provided a second look. Our editorial raisedadditional unanswered questions beyond the concerns addressedby Miller et al., including overall vaccine efficacy in womenunexposed to relevant vaccine HPV types, effect on cytologicabnormalities, and effect on disease caused by HPV types notincluded in the vaccine. The last question is particularly important,in light of the surprising report of vulvar cancer in a 22-year-oldtrial participant who received the vaccine1; vulvar cancer israre (overall incidence, 2.2 cases per 100,000 persons) andoccurs at a median age of 68 years in the United States.2 Thisfinding and the cited unanswered questions argue for a cautiousapproach to vaccination policy until trials have been completedand fully reported.
George F. Sawaya, M.D. Karen Smith-McCune, M.D., Ph.D. University of California at San Francisco San Francisco, CA 94118
References
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][Medline]
Drs. Agosti and Goldie reply: 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 inthe past decade to develop feasible options for cervical-cancerscreening in low-resource settings continues to build. The Billand Melinda Gates Foundation provided $55.6 million to the Alliancefor Cervical Cancer Prevention to promote screening and $13million toward the development of low-cost HPV DNA tests andother tests. We believe it is inequitable to exclude women indeveloping 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 screeningand vaccination is likely to prevent the greatest number ofdeaths from cervical cancer. However, countries will make theirown decisions about the best strategic approach to cervical-cancerprevention, accounting for local epidemiologic factors and diseaseburden,2 competing priorities, and the cost-effectiveness, affordability,and feasibility of vaccination programs targeting adolescentsand the screening of adult women. We urge that attention begiven to real-world solutions for preventing death from cervicalcancer in women living in poverty.
Jan M. Agosti, M.D. Bill and Melinda Gates Foundation Seattle, WA 98102
Sue J. Goldie, M.D., M.P.H. Harvard School of Public Health Boston, MA 02115
References
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][Medline]
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.)
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 
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