Correspondence
A Human Papillomavirus Type 16 Vaccine
N Engl J Med 2003; 348:1402-1405April 3, 2003
- Article
To the Editor:
Koutsky et al. (Nov. 21 issue)1 report the results of a primary efficacy analysis in a controlled trial of human papillomavirus type 16 (HPV-16) vaccine that includes less than two thirds of all randomized study subjects. To better ascertain the comparability of the two study groups, we are interested in knowing the balance of other risk factors for cervical cancer, such as socioeconomic status, seropositivity for the human immunodeficiency virus (HIV), and use of oral contraceptives. In addition, the investigators excluded a substantial high-risk group (those who reported more than five male sex partners during their lifetime) but included a low-risk group (virgins). Inclusion of the high-risk group would serve to enhance the generalizability of the results.
This study evaluated persistent HPV-16 infection as a surrogate end point for cervical cancer, and the vaccine's long-term efficacy in preventing persistent HPV-16 infection and cervical cancer remains to be seen. It would also be worthwhile to know the efficacy of the vaccine in preventing other important outcomes such as anogenital warts and anal carcinoma.
1 ReferencesMurali K. Duggirala, M.D.
Maria-Teresa Cuddihy, M.D., M.P.H.
Mayo Clinic, Rochester, MN 55905
duggirala.murali@mayo. edu 1
Koutsky LA ,Ault KA ,Wheeler CM , et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002;347:1645-1651
Full Text | Web of Science | Medline
To the Editor:
The effectiveness of the HPV-16 vaccine as immunotherapy for existing infection is not clear. Although we concede that this was not the goal of the study, there appears to be an ideal opportunity to address this issue by the very nature of the study design. There remained 859 ineligible women who received the vaccine or placebo, the majority of whom presumably were initially positive for HPV-16. The report by Koutsky et al. does not mention the outcome for these women. This group is of special interest because it represents a true high-risk population. The authors state, “This exclusion [from the analysis] was made because there are no data showing that vaccines based on papillomavirus-virus-like particles provide postinfection protection against either persistent infection or lesions.” Although we agree that this was a reason to exclude these patients from the primary analysis, it would seem that the authors now have data to address the issue of postinfection protection.
Jonathan E. Tammela, M.D.
Shashikant Lele, M.D.
Kunle Odunsi, M.D., Ph.D.
Roswell Park Cancer Institute, Buffalo, NY 14263
jonathan.tammela@roswellpark. org To the Editor:
The article by Koutsky et al. and the article by Stanberry et al. in the same issue1 report promising evaluations of vaccines against HPV and herpes simplex virus (HSV) infections, both of which are common infections with sometimes harmful sequelae. These reports suggest a need to consider vaccine-delivery strategies. If they become available, vaccines against these infections should be administered before the onset of sexual activity. Although vaccination of adolescents at a pediatric visit may be the most efficient strategy for delivering these vaccines, pediatricians may be reluctant to vaccinate girls against a sexually acquired infection. Vaccination at gynecologic visits might be a complementary approach, allowing for “catch-up” and broader coverage of the at-risk population, and gynecologists may be important advocates for these vaccines, since they bear the burden of current prevention and treatment regimens.
For many women, obstetrician-gynecologists serve as the only routine health care contact. Since vaccination is not traditional in this setting, we surveyed 1063 members of the American College of Obstetricians and Gynecologists in 2001 about vaccine practices.2 Over 90 percent of the respondents said they would be very likely or likely to offer an HPV or HSV vaccine, should one become available. This level of interest was much higher than that for some other vaccines currently under development.
2 ReferencesStephanie J. Schrag, D.Phil.
Anne Schuchat, M.D.
Centers for Disease Control and Prevention, Atlanta, GA 30333
zha6@cdc.gov Jay Schulkin, Ph.D.
American College of Obstetricians and Gynecologists, Washington, DC 200241
Stanberry LR ,Spruance SL ,Cunningham AL , et al. Glycoprotein-D-adjuvant vaccine to prevent genital herpes. N Engl J Med 2002;347:1652-1661
Full Text | Web of Science | Medline2
Schrag SJ, Fiore AE, Gonik B, et al. Vaccination and perinatal infection prevention practices among obstetrician-gynecologists. Obstet Gynecol (in press).
To the Editor:
Koutsky and colleagues present astounding data on the impressive effectiveness of an HPV vaccine in specifically inhibiting the development of persistent HPV infection in women. The median follow-up of the subjects in the study was 17 months. Within this short period, the investigators also noted strong protection against the development of cervical intraepithelial neoplasias. This result is surprising, given the long and multistep process of carcinogenesis.1 These data suggest that HPV infection could indeed be a late event in the process of cervical cell transformation; therefore, the eradication of HPV infection could delay but may not prevent the long-term development of cervical neoplasias.
1 ReferencesCarlo B. Gambacorti, M.D.
Istituto Nazionale Tumori, 20133 Milan, Italy
carlo.gambacorti@istitutotumori. mi. it 1
zur Hausen H . Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2002;2:342-350
CrossRef | Web of Science | Medline
To the Editor:
Koutsky et al. present the results of a well-designed trial of an HPV-16 vaccine. As the researchers state, HPV-16 is present in 50 percent of cervical cancers and high-grade cervical intraepithelial neoplasias and is certainly an important risk factor, if not a contributing causative agent, in this disease process.
In the design of such a trial, it would seem that securing truly informed consent would be exceedingly difficult. Patients enrolled in the study would need to understand the risks inherent in HPV transmission and would need to know that the risk of viral infection of the cervix can probably be reduced with the use of barrier methods of contraception1 or fully eliminated with abstinence.
The World Medical Association Declaration of Helsinki states that the “well-being of the human subjects should take precedence over the interests of science and society” and that any new interventions need to be tested against a “proven prophylactic, diagnostic or therapeutic method.”2
If a prophylactic method exists that can potentially prevent HPV-16 infection, it is incumbent on the researchers to inform the study candidates of this fact properly, regardless of how it will affect the outcome of the research. It is not clear from the details of the report by Koutsky et al. whether such measures were taken.
2 ReferencesSimon S. Yoo, M.D.
S. Elizabeth Whitmore, M.D.
Johns Hopkins Medical Institutions, Baltimore, MD 21287
ewhitmor@jhmi.edu 1
Slattery ML ,Overall JC Jr ,Abbott TM ,French TK ,Robison LM ,Gardner J . Sexual activity, contraception, genital infections, and cervical cancer: support for a sexually transmitted disease hypothesis. Am J Epidemiol 1989;130:248-258
Web of Science | Medline2
World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2000;284:3043-3045
CrossRef | Web of Science
Author/Editor Response
Duggirala and Cuddihy's concern about potential imbalances between treatment groups in regard to certain risk factors for cervical cancer is unsubstantiated by our data. As was found for other risk factors, presented in Table 2 of our report, the distribution of oral-contraceptive users among the vaccine and placebo groups was similar (49.2 percent and 46.8 percent, respectively). Women with immune disorders, including HIV infection, were excluded from the trial. Although HIV testing was not routinely performed, 105 subjects were tested during follow-up, and all were negative. Since a prophylactic vaccine was tested, it was important to enroll subjects who did not have a prior HPV-16 infection. Women with more than five sex partners were excluded because an increased number of sex partners is a strong determinant of HPV infection.1,2 Although we agree that it would be worthwhile to know the efficacy of an HPV vaccine in preventing anogenital warts and anal cancer, effective prevention of anogenital warts would require protection against HPV types 6 and 11. The vaccine that Merck Research Laboratories is currently testing in phase 3 trials contains HPV types 6, 11, 16, and 18 virus-like particles.
As Tammela et al. suggest, it will be important to assess the effect of the HPV-16 vaccine on the persistence of viral DNA and the development of HPV-16–related cervical intraepithelial neoplasia among women who are positive for HPV-16 DNA at enrollment. Such analyses will be performed in about one year, when the trial has been completed and all results are unmasked.
The data presented by Schrag et al. on the willingness of obstetrician-gynecologists to implement prophylactic vaccination for sexually transmitted disease are encouraging, since this community has been a critical element in the successful implementation of Papanicolaou screening.
We know of no data to support Gambacorti's hypothesis that HPV infection could be a late event in the process of cervical cell transformation. Cervical intraepithelial neoplasia develops early after HPV-16 infection (median interval, 4 to 24 months),3,4 and invasive cervical cancer develops late (median interval, 20 to 30 years). Both the time to detection and detection itself depend on how frequently a woman is screened.
Yoo and Whitmore raise an important issue that was given careful consideration in the design of our protocol. Although condoms do not effectively prevent HPV infection,1,2 they do prevent infection with other sexually transmitted disease agents, including HIV. During study visits and through newsletters, all enrolled women were provided information on reducing the risk of sexually transmitted diseases, including information on abstinence.
4 ReferencesLaura A. Koutsky, Ph.D.
University of Washington, Seattle, WA 98103
kouts@u.washington. edu 1
Ho GYF ,Bierman R ,Beardsley L ,Chang CJ ,Burk RD . Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998;338:423-428
Full Text | Web of Science | Medline2
Winer RL ,Lee SK ,Hughes JP , et al. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol 2003;157:218-226
CrossRef | Web of Science | Medline3
Xi LF ,Carter JJ ,Galloway DA , et al. Acquisition and natural history of human papillomavirus type 16 variant infection among a cohort of female university students. Cancer Epidemiol Biomarkers Prev 2002;11:343-351
Web of Science | Medline4
Woodman CBJ ,Collins S ,Winter H , et al. Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study. Lancet 2001;357:1831-1836
CrossRef | Web of Science | Medline
Author/Editor Response
Use of vaccines to control HPV and HSV infections will require universal immunization as opposed to the targeting of “high-risk” persons.1 Since these are sexually acquired pathogens, immunizing persons before they become sexually experienced will afford the greatest benefit. Schrag et al. suggest that pediatricians may be reluctant to vaccinate girls against sexually transmitted infections. Pediatricians, however, are more accustomed to immunizing patients than are other medical specialists2 and routinely give the hepatitis B vaccine, which provides protection against an infection that can be sexually transmitted.3 A recent study showed that parents' acceptance of a variety of vaccines was not influenced by whether the disease was sexually transmitted.4 Thus, it is unlikely that pediatricians will encounter unusual resistance from parents when recommending immunization of preadolescents or adolescents against HPV and HSV. As with the hepatitis B vaccine, other medical specialists, including gynecologists, will be important in initial catch-up programs and in the future, providing a safety net for those who missed immunization at earlier ages. In order for catch-up and safety-net programs to be maximally effective, the discrepancy between the perceived responsibilities and actual practices of obstetrician-gynecologists (and other nonpediatric medical specialists) with regard to immunization will need to be addressed.2,5
5 ReferencesLawrence R. Stanberry, M.D., Ph.D.
University of Texas Medical Branch, Galveston, TX 77555-0351
l.stanberry@utmb. edu 1
Hughes JP ,Garnett GP ,Koutsky L . The theoretical population-level impact of a prophylactic human papilloma virus vaccine. Epidemiology 2002;13:631-639
CrossRef | Web of Science | Medline2
Recommended adult immunization schedule -- United States, 2002-2003. MMWR Morb Mortal Wkly Rep 2002;51:904-908
Medline3
Kollar LM ,Rosenthal SL ,Biro FM . Hepatitis B vaccine series compliance in adolescents. Pediatr Infect Dis J 1994;13:1006-1008
CrossRef | Web of Science | Medline4
Zimet GD ,Mays RM ,Sturm LA ,Ravert AA . Parental attitudes about vaccination: sexual transmissibility, efficacy, severity & behavioral prevention. J Adolesc Health 2003;32:164-164 abstract.
Web of Science5
Gonik B ,Jones T ,Contreras D ,Fasano N ,Roberts C . The obstetrician-gynecologist's role in vaccine-preventable diseases and immunization. Obstet Gynecol 2000;96:81-84
CrossRef | Web of Science | Medline
- Citing Articles (4)
Citing Articles
1
Lidia Rosi Medeiros, Daniela Dornelles Rosa, Maria Inês da Rosa, Mary Clarisse Bozzetti, Roselaine Ruviaro Zanini. (2009) Efficacy of Human Papillomavirus Vaccines. International Journal of Gynecological Cancer 19:7, 1166-1176
CrossRef2
Mary Anne Jackson, Angela Myers. (2005) Vaccines in the Pipeline. Pediatric Emergency Care 21:11, 777-783
CrossRef3
Gregory D. Zimet, Susan M. Perkins, Lynne A. Sturm, Rita M. Bair, Beth E. Juliar, Rose M. Mays. (2005) Predictors of STI vaccine acceptability among parents and their adolescent children. Journal of Adolescent Health 37:3, 179-186
CrossRef4
Joseph F. Buell, Thomas M. Beebe, Michael J. Hanaway, Mark J. Thomas, Steven M. Rudich, E. Steve Woodle. 2005. Transplant-Related Malignancies. , 1149-1164.
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