Rationale and design of a community-based double-blind randomized clinical trial of an HPV 16 and 18 vaccine in Guanacaste, Costa Rica.

We report the rationale, design, methods and details of participation of a community-based, double-blind, randomized clinical trial of an HPV 16 and 18 vaccine conducted in two provinces of Costa Rica to investigate the efficacy and population impact of the vaccine in the prevention of cervical cancer precursors. More than 24,000 women between 18 and 25 years of age were invited to participate and pre-screened for eligibility, with recruitment of 7466 women (30% of those pre-screened, 59% of those eligible) who were randomized to receive 3 doses of the HPV vaccine or hepatitis A vaccine as control. A complex protocol of data and specimen collection was applied, including an interview, pelvic exam for sexually active women, blood for serology and cell-mediated immunity, cervical secretions for local immunity and cells for HPV, Chlamydia trachomatis and gonorrhea testing. Eighty percent of the women received three doses, 12.4% two doses and 7.4% one dose. At visits, compliance with data and specimen collection was close to 100%. Baseline characteristics and age-specific prevalence of HPV and cervical neoplasia are reported. Overall prevalence of HPV was high (50%), with 8.3% of women having HPV 16 and 3.2% HPV 18. LSIL was detected in 12.7% of women at baseline and HSIL in 1.9%. Prevalence of Chlamydia was 14.2%. There was very good agreement in HPV detection between clinician-collected and self- collected specimens (89.4% agreement for all types, kappa 0.59). Follow up will continue with yearly or more frequent examinations for at least 4 years for each participant.

[1]  D. Lowy,et al.  Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. , 2007, JAMA.

[2]  F. Bray,et al.  Chapter 2: The burden of HPV-related cancers. , 2006, Vaccine.

[3]  L. Mango,et al.  Design and methods of a population-based natural history study of cervical neoplasia in a rural province of Costa Rica: the Guanacaste Project. , 1997, Revista panamericana de salud publica = Pan American journal of public health.

[4]  S. Franceschi,et al.  Variations in the age‐specific curves of human papillomavirus prevalence in women worldwide , 2006, International journal of cancer.

[5]  Michael Quinn,et al.  Chapter 8: Screening for cervical cancer in developing countries. , 2006, Vaccine.

[6]  S. Wacholder,et al.  Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. , 2008, Journal of the National Cancer Institute.

[7]  Jose Jeronimo,et al.  Human papillomavirus and cervical cancer , 2007, The Lancet.

[8]  H. Lawson,et al.  Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). , 2007, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[9]  X. Castellsagué,et al.  An update of prophylactic human papillomavirus L1 virus-like particle vaccine clinical trial results. , 2008, Vaccine.

[10]  M. Plummer,et al.  Population-Based Study of Human Papillomavirus Infection and Cervical Neoplasia in Rural Costa Rica , 2000 .

[11]  W. Quint,et al.  Technical Advance Novel Short-Fragment PCR Assay for Highly Sensitive Broad-Spectrum Detection of Anogenital Human Papillomaviruses , 1998 .

[12]  D M Parkin,et al.  International trends in incidence of cervical cancer: II. Squamous‐cell carcinoma , 2000, International journal of cancer.

[13]  M. Lehtinen,et al.  Introducing human papillomavirus vaccines—questions remain , 2008, Annals medicus.

[14]  Diane Solomon,et al.  2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. , 2007, American journal of obstetrics and gynecology.

[15]  S. Wacholder,et al.  Epidemiology of Genital Chlamydia trachomatis Infection Among Young Women in Costa Rica , 2008, Sexually transmitted diseases.

[16]  M. Sherman,et al.  An association of cervical inflammation with high-grade cervical neoplasia in women infected with oncogenic human papillomavirus (HPV). , 2001, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[17]  S. Wacholder,et al.  HPV co-factors related to the development of cervical cancer: results from a population-based study in Costa Rica , 2001, British Journal of Cancer.

[18]  W. Quint,et al.  Comparison of the SPF10-LiPA System to the Hybrid Capture 2 Assay for Detection of Carcinogenic Human Papillomavirus Genotypes among 5,683 Young Women in Guanacaste, Costa Rica , 2007, Journal of Clinical Microbiology.

[19]  S Wacholder,et al.  HPV DNA testing in cervical cancer screening: results from women in a high-risk province of Costa Rica. , 2000, JAMA.

[20]  Guillermo Marshall,et al.  A comparison of single and combined visual, cytologic, and virologic tests as screening strategies in a region at high risk of cervical cancer. , 2003, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[21]  C. Wheeler,et al.  Sustained efficacy up to 4·5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial , 2006, The Lancet.

[22]  Henry C Kitchener,et al.  Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial , 2007, The Lancet.

[23]  J. Berzofsky,et al.  Persistent human papillomavirus infection is associated with a generalized decrease in immune responsiveness in older women. , 2006, Cancer research.

[24]  Allan Hildesheim,et al.  Description of a seven-year prospective study of human papillomavirus infection and cervical neoplasia among 10000 women in Guanacaste, Costa Rica,. , 2004, Revista panamericana de salud publica = Pan American journal of public health.

[25]  Wim Quint,et al.  Development and Clinical Evaluation of a Highly Sensitive PCR-Reverse Hybridization Line Probe Assay for Detection and Identification of Anogenital Human Papillomavirus , 1999, Journal of Clinical Microbiology.

[26]  C. Wheeler,et al.  A comparison of a prototype PCR assay and hybrid capture 2 for detection of carcinogenic human papillomavirus DNA in women with equivocal or mildly abnormal papanicolaou smears. , 2005, American journal of clinical pathology.

[27]  C. Wheeler,et al.  A controlled trial of a human papillomavirus type 16 vaccine. , 2002, The New England journal of medicine.

[28]  H. Hollema,et al.  Comprehensive study of several general and type-specific primer pairs for detection of human papillomavirus DNA by PCR in paraffin-embedded cervical carcinomas , 1996, Journal of clinical microbiology.

[29]  K. Straif,et al.  Carcinogenicity of human papillomaviruses. , 2005, The Lancet. Oncology.

[30]  C. Wheeler,et al.  Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. , 2006, Vaccine.

[31]  S. Wacholder,et al.  Epidemiologic profile of type-specific human papillomavirus infection and cervical neoplasia in Guanacaste, Costa Rica. , 2005, The Journal of infectious diseases.

[32]  W. Quint,et al.  Highly Effective Detection of Human Papillomavirus 16 and 18 DNA by a Testing Algorithm Combining Broad-Spectrum and Type-Specific PCR , 2006, Journal of Clinical Microbiology.