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ever, efficacy results from the present analysis caution against the benefit of vaccination to treat established infec- tions, regardless of safety profile. Given published data suggesting the overall safety of the present vaccine,3,28 a main residual question of interest is whether reactogenicity and adverse event pro- files differ by HPV infection status at the time of vaccination. Data to evaluate these questions directly will be avail- able after unblinding occurs in our and other ongoing trials.

We evaluated viral clearance at 6 and 12 months after enrollment. While the evaluation of viral clearance at 6 months had the advantage of including more than 85% of participants with preva- lent HPV infection at enrollment, it evaluated efficacy before the full series of vaccinations were administered. Con- versely, the evaluation of viral clear- ance at 12 months had the advantage of evaluating clearance rates after the full series of vaccinations were adminis- tered but included a smaller propor- tion (70%) of participants with preva- lent HPV infection at enrollment. It is reassuring to note that results were con- sistent in both approaches.

Results from our community-based study provide strong evidence that there is little, if any, therapeutic benefit from the vaccine in the population we stud- ied. Furthermore, we see no reason to believe that there is therapeutic benefit of the vaccine elsewhere because the bio- logical effect of vaccination among al- ready infected women is not expected to vary by population. We should note that while the vaccine efficacy esti- mates provided herein are accurate, the absolute clearance estimates reported within individual study groups may be too high because we excluded women referred to colposcopy from the analy- sis; infections in these women are un- doubtedly less likely to clear than in women who were not referred.

In summary, our results demon- strate that in women positive for HPV DNA, HPV-16/18 vaccination does not accelerate clearance of the virus and should not be used for purposes of treat- ing prevalent infections.

Author Affiliations: Division of Cancer Epidemiology and Genetics (Drs Hildesheim and Wacholder), Divi- sion of Cancer Prevention and Control (Dr Solomon), and Center for Cancer Research (Drs Schiller and Lowy), National Cancer Institute, Bethesda, Maryland; Proyecto Epidemiolo´ gico Guanacaste, Fundacio´ n INCIENSA, San Jose´ , Costa Rica (Drs Herrero, Rod- riguez, Bratti, and Gonzalez and Mss Porras and Jimenez); and GlaxoSmithKline Biologicals, King of Prussia, Pennsylvania (Dr Dubin). Author Contributions: Drs Hildesheim, Herrero, and Wacholder had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Hildesheim, Herrero, Wacholder, Rodriguez, Bratti, Schiller, Dubin, Lowy. Acquisition of data: Hildesheim, Herrero, Rodriguez, Solomon, Bratti, Gonzalez, Porras, Jimenez. Analysis and interpretation of data: Hildesheim, Herrero, Wacholder, Rodriguez, Solomon, Bratti, Schiller, Dubin, Lowy. Drafting of the manuscript: Hildesheim, Herrero, Schiller. Critical revision of the manuscript for important in- tellectual content: Hildesheim, Herrero, Wacholder, Rodriguez, Solomon, Bratti, Schiller, Gonzalez, Dubin, Porras, Jimenez, Lowy. Statistical analysis: Hildesheim, Wacholder. Obtained funding: Hildesheim, Herrero, Dubin, Lowy. Administrative, technical, or material support: Herrero, Solomon, Bratti, Gonzalez, Porras, Jimenez Study supervision: Hildesheim, Herrero, Solomon, Bratti, Schiller. Financial Disclosures: Drs Schiller and Lowy report that they are named inventors on US government– owned HPV vaccine patents that are licensed to GSK and Merck and are entitled to limited royalties as specified by federal law. Dr Dubin is employed by GSK Biologicals, the manufacturer of the vaccine used in this trial. No other financial disclosures were reported. Costa Rican HPV Vaccine Trial Group: Proyecto Epi- demiolo´ gico Guanacaste, Fundacio´ n INCIENSA, San Jose´, Costa Rica: Mario Alfaro (cytologist), Manuel Bar- rantes (field supervisor), M. Concepcion Bratti (co- investigator), Fernando Ca´ rdenas (general field su- pervisor), Bernal Corte´ s (specimen and repository manager), Albert Espinoza (head, coding and data en- try), Yenory Estrada (pharmacist), Paula Gonzalez (co- investigator), Diego Guille´n (pathologist), Rolando Her- rero (co–principal investigator), Silvia E. Jimenez (trial coordinator), Jorge Morales (colposcopist), Lidia Ana Morera (head study nurse), Elmer Pe´ rez (field super- visor), Carolina Porras (co-investigator), Ana Cecilia Rodriguez (co-investigator), Maricela Villegas (clinic physician); University of Costa Rica, San Jose´: En- rique Freer (director, HPV diagnostics laboratory), Jose Bonilla (head, HPV immunology laboratory), Sandra Silva (head microbiologist, HPV diagnostics labora- tory), Ivannia Atmella (microbiologist, immunology laboratory), Margarita Ramı´rez (microbiologist, im- munology laboratory); National Cancer Institute [NCI], Bethesda, Maryland: Pam Gahr (trial coordinator), Al- lan Hildesheim (co–principal investigator and NCI co– project officer), Douglas R. Lowy (HPV virologist), Mark Schiffman (medical monitor and NCI co–project offi- cer), John T. Schiller (HPV virologist), Mark Sherman (quality control pathologist), Diane Solomon (medi- cal monitor and quality control pathologist), Sholom Wacholder (statistician); Science Applications Inter- national Corporation, NCI-Frederick, Frederick, Mary- land: Ligia Pinto (head, HPV immunology labora- tory), Alfonso Garcia-Pineres (scientist, HPV immunology laboratory); Women and Infants Hospi- tal of Rhode Island, Providence: Claire Eklund (qual- ity control cytology), Martha Hutchinson (quality con- trol cytology); Delft Diagnostics Laboratory, Delft, the Netherlands: Wim Quint (HPV DNA testing), Leen-

Jan van Doorn (HPV DNA testing); Data and Safety Monitoring Board: Steven Self (chair) Luis Diego Cal- zada, Ruth Karron, Ritu Nayar, Nancy Roach; Scien- tific HPV Working Group (external): Joanna Cain (chair), Diane Davey, David DeMets, Francisco Fus- ter, Ann Gershon, Elizabeth Holly, Silvia Lara, Raphael Viscidi, Henriette Raventos, Luis Rosero-Bixby, Kris- ten Suthers. Funding/Support: The Costa Rican HPV Vaccine Trial is a long-standing collaboration between investigators in Costa Rica and the NCI. The trial is sponsored and funded by the NCI (grant N01-CP-11005), with fund- ing support from the National Institutes of Health Of- fice for Research on Women’s Health, and conducted with support from the Ministry of Health of Costa Rica. Vaccine was provided for our trial by GSK Biologicals, under a Clinical Trials Agreement with the NCI. GlaxoSmithKline also provided support for aspects of the trial associated with regulatory submission needs of the company under grant FDA BB-IND 7920. Role of the Sponsors: The NCI and Costa Rica inves- tigators are responsible for the design and conduct of the study; collection, management, analysis, and in- terpretation of the data; and preparation of the manu- script. The NCI and Costa Rica investigators make fi- nal editorial decisions on this and subsequent publications; GSK has the right to review and com- ment. Additional Contributions: We thank the women of Guanacaste and Puntarenas, Costa Rica, who partici- pated in this study. We also acknowledge the effort and dedication of the staff in Costa Rica involved in this project, including Bernardo Blanco and his team (census); Ricardo Cerdas and Ana Herna´ ndez (blood processing); Osman Lo´ pez, Johnny Matamoros, Cris- tian Montero, Rafael Thompson, and Jorge Uma ˜na (field activity coordinators); Su Yen Araya, Hazel Bar- quero, Hayleen Campos, Muriel Grijalba, Ana Cris- tina Monge, Ana Peraza, Diana Robles, Marı´a Fern- anda Sa´ enz, Dorita Vargas, and Jessica Vindas (clinic coordinators); Paola Alvarez, Dinia Angulo, Ana Live Arias, Betzaida Barrantes, Marianela Bonilla, Jessenia Chinchilla, Marianela Herrera, Andrea Interiano, Viv- iana Lorı´a, Rebeca Ocampo, Angie Ramı´rez, Libia Ri- vas, Jessenia Ruiz, Malena Salas, and Yesenia Va´ zquez (clinicians); Marta Alvarado, Ana Cristina Arroyo, Glo- riana Barrientos, Diana Dı´az, Marlen Jara, Maureen Matarrita, Marı´a Ester Molina, Elida Ordo´ ˜nez, Gina Sa´ nchez, and Siara Villegas (nurses); Arianne Cas- trillo and Vivian Lopez (education and outreach ef- fort coordinators); Karla Coronado (appointment co- ordinator); Ricardo Alfaro (quality control coordinator); Charles Sanchez and Livia Romero (document center coordinators); and Eric Alpizar and Carlos Avila (in- formation technology coordinators). We especially rec- ognize Sofia Elizondo, executive director of Funda- cio´ n INCIENSA, and her staff for administrative support. We appreciate the team from Information Manage- ment Services, Silver Spring, Maryland, responsible for the development and maintenance of the data sys- tem used in the trial and who serve as the data man- agement center for this effort, specifically the contri- butions of Julie Buckland, Jean Cyr, Laurie Rich, and John Schussler. We acknowledge the contributions made by individuals at Westat Inc, Rockville, Mary- land, who provided project development and/or moni- toring support, including Maribel Gomez, Kirk Mid- kiff, Kerrygrace Morrisey, and Susan Truitt. We acknowledge the assistance provided by Carla Chor- ley, Troy Moore, Kathi Shea, and Heather Siefers in the establishment of a specimen and vaccine reposi- tory for our trial and in their continued assistance with the handling and shipment of specimens. From GSK Biologicals, we acknowledge Anne Schuind, Kelechi Lawrence, Darrick Fu, and Bruce Innis for their con- tribution to discussions regarding trial conduct and Francis Dessy and Brigitte Colau for HPV-16/18 an- tibody testing.


JAMA, August 15, 2007—Vol 298, No. 7 (Reprinted)

©2007 American Medical Association. All rights reserved.

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