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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

JAMA. 2007;298:743-753.

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 increases the rate of viral clearance in women already infected with HPV.

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

Participants  A total of 2189 women aged 18 to 25 years who were recruited between June 2004 and December 2005. Participants were positive for HPV DNA at enrollment, 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 control hepatitis A vaccine (n = 1101) over 6 months.

Main Outcome Measures  Presence of HPV DNA was determined in cervical specimins by a molecular hybridization assay using chemiluminescence with HPV RNA probes and by polymerase chain reaction using SPF10 primers and a line probe assay detection system before vaccination and by polymerase chain reaction after vaccination. We compared rates of type-specific viral clearance using generalized estimating equations 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 interval, –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 (vaccine 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 categories, among women receiving all vaccine doses, among women with single infections, or among women stratified by the following entry variables: HPV-16/18 serology, cytologic results, HPV DNA viral load, time since sexual debut, Chlamydia trachomatis or Neisseria gonorrhoeae infection, hormonal contraceptive use, or smoking.

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

Trial Registration  clinicaltrials.gov Identifier: NCT00128661

Author Affiliations: Division of Cancer Epidemiology and Genetics (Drs Hildesheim and Wacholder), Division of Cancer Prevention and Control (Dr Solomon), and Center for Cancer Research (Drs Schiller and Lowy), National Cancer Institute, Bethesda, Maryland; Proyecto Epidemiológico Guanacaste, Fundación INCIENSA, San José, Costa Rica (Drs Herrero, Rodriguez, Bratti, and Gonzalez and Mss Porras and Jimenez); and GlaxoSmithKline Biologicals, King of Prussia, Pennsylvania (Dr Dubin).

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