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Effect of Human Papillomavirus 16/18 L1 Viruslike Particle Vaccine Among Young Women With Preexisting Infection

A Randomized Trial

Allan Hildesheim, PhD Rolando Herrero, MD, PhD Sholom Wacholder, PhD Ana C. Rodriguez, MD Diane Solomon, MD M. Concepcion Bratti, MD John T. Schiller, PhD Paula Gonzalez, MD Gary Dubin, MD Carolina Porras, MQC Silvia E. Jimenez, MBA Douglas R. Lowy, MD

for the Costa Rican HPV Vaccine Trial Group

K N O W L E D G E T H A T I N F E C T I O N w i t h 1 o f a p p r o x i m a t e l y 1 5 o n c o g e n i c h u m a n p a p i l l o m a - v i r u s ( H P V ) t y p e s i s r e q u i r e d for the development of cervical cancer has permitted primary prevention efforts via vaccination.1 Two vaccines based on HPV L1 protein viruslike particles (VLPs) are undergoing evalu- ation in large-scale clinical trials.2-5 One vaccine (Gardasil) is a quadriva- lent HPV-16/18 cervical cancer candi- date vaccine that contains VLPs from 2 oncogenic HPV types, HPV-16 and HPV-18, and also contains VLPs from HPV types 6 and 11, which are not involved in cervical cancer pathogen- esis but are linked to benign genital warts. This vaccine has been approved

For editorial comment see p 805.

Context Viruslike particle human papillomavirus (HPV) vaccines were designed to prevent HPV infection and development of cervical precancers and cancer. Women with oncogenic HPV infections might consider vaccination as therapy.

Objective To determine whether vaccination against HPV types 16 and 18 in- creases the rate of viral clearance in women already infected with HPV.

Design and Setting Phase 3, masked, community-based randomized trial con- ducted in 2 provinces of Costa Rica.

Participants A total of 2189 women aged 18 to 25 years who were recruited be- tween June 2004 and December 2005. Participants were positive for HPV DNA at en- rollment, had at least 6 months of follow-up, and had follow-up HPV DNA results.

Intervention Participants were randomly assigned to receive 3 doses of a bivalent HPV-16/18 L1 protein viruslike particle AS04 candidate vaccine (n=1088) or a con- trol hepatitis A vaccine (n=1101) over 6 months.

Main Outcome Measures Presence of HPV DNA was determined in cervical speci- mins by a molecular hybridization assay using chemiluminescence with HPV RNA probes and by polymerase chain reaction using SPF10 primers and a line probe assay detec- tion system before vaccination and by polymerase chain reaction after vaccination. We compared rates of type-specific viral clearance using generalized estimating equa- tions methods at the 6-month visit (after 2 doses) and 12-month visit (after 3 doses) in the 2 study groups.

Results There was no evidence of increased viral clearance at 6 or 12 months in the group who received HPV vaccine compared with the control group. Clearance rates for HPV-16/18 infections at 6 months were 33.4% (82/248) in the HPV vaccine group and 31.6% (95/ 298) in the control group (vaccine efficacy for viral clearance, 2.5%; 95% confidence in- terval, −9.8% to 13.5%). Human papillomavirus 16/18 clearance rates at 12 months were 48.8% (86/177) in the HPV vaccine group and 49.8% (110/220) in the control group (vac- cine efficacy for viral clearance, −2.0%; 95% confidence interval, −24.3% to 16.3%). There was no evidence of a therapeutic effect for other oncogenic or nononcogenic HPV cat- egories, among women receiving all vaccine doses, among women with single infections, or among women stratified by the following entry variables: HPV-16/18 serology, cyto- logic results, HPV DNA viral load, time since sexual debut, Chlamydia trachomatis or Neis- seria gonorrhoeae infection, hormonal contraceptive use, or smoking.

Conclusion In women positive for HPV DNA, HPV-16/18 vaccination does not ac- celerate clearance of the virus and should not be used to treat prevalent infections.

Trial Registration clinicaltrials.gov Identifier: NCT00128661

JAMA. 2007;298(7):743-753


Author Affiliations and a complete list of the inves- tigators of the Costa Rican HPV Vaccine Trial Group appears at the end of this article. Corresponding Author: Allan Hildesheim, PhD, Division of Cancer Epidemiology and Genetics, National Cancer

Institute, 6120 Executive Blvd, Ste 550, Rockville, MD 20852 (Hildesha@exchange.nih.gov); Rolando Her- rero, MD, PhD, Proyecto Epidemiolo´ gico Guanacaste, Torre La Sabana, 300 Oeste del ICE, Piso 7, Sabana Norte, San Jose´, Costa Rica (Rherrero@amnet.co.cr).

©2007 American Medical Association. All rights reserved.

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


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