Estimating human papillomavirus vaccine efficacy from a single-arm trial: proof-of-principle in the Costa Rica Vaccine Trial.

BACKGROUND: The World Health Organization recommends a 1- or 2-dose human papillomavirus (HPV) vaccination schedule for females aged 9 to 20 years. Studies confirming the efficacy of a single dose and vaccine modifications are needed, but randomized controlled trials are costly and face logistical and ethical challenges. We propose a resource-efficient single-arm trial design that uses untargeted and unaffected HPV types as controls. METHODS: We estimated HPV vaccine efficacy (VE) from a single arm by comparing 2 ratios: the ratio of the rate of persistent incident infection with vaccine-targeted HPV 16 and 18 (HPV 16/18) and cross-protected types HPV 31, 33, and 45 (HPV 31/33/45) to vaccine-unaffected types HPV 35, 39, 51, 52, 56, 58, 59, and 66 (HPV 35/39/51/52/56/58/59/66) vs the ratio of prevalence of these types at the time of trial enrollment. We compare VE estimates using only data from the bivalent HPV 16/18 vaccine arm of the Costa Rica Vaccine Trial with published VE estimates that used both the vaccine and control arms. RESULTS: Our single-arm approach among 3727 women yielded VE estimates against persistent HPV 16/18 infections similar to published 2-arm estimates from the trial (according-to-protocol cohort: 91.0% , 95% CI = 82.9% to 95.3% [single-arm] vs 90.9% , 95% CI = 82.0% to 95.9% [2-arm]; intention-to-treat cohort: 41.7%, 95% CI = 32.4% to 49.8% [single-arm] vs 49.0% , 95% CI = 38.1% to 58.1% [2-arm]). VE estimates were also similar in analytic subgroups (number of doses received; baseline HPV serology status). CONCLUSIONS: We demonstrate that a single-arm design yields valid VE estimates with similar precision to a randomized controlled trial. Single-arm studies can reduce the sample size and costs of future HPV vaccine trials while avoiding concerns related to unvaccinated control groups. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00128661.

Performance of Cervical Screening a Decade Following HPV Vaccination: The Costa Rica Vaccine Trial.

BACKGROUND: We investigated the impact of human papillomavirus (HPV) vaccination on the performance of cytology-based and HPV-based screening for detection of cervical precancer among women vaccinated as young adults and reaching screening age. METHODS: A total of 4632 women aged 25-36 years from the Costa Rica HPV Vaccine Trial were included (2418 HPV-vaccinated as young adults and 2214 unvaccinated). We assessed the performance of cytology- and HPV-based cervical screening modalities in vaccinated and unvaccinated women to detect high-grade cervical precancers diagnosed over 4 years and the absolute risk of cumulative cervical precancers by screening results at entry. RESULTS: We detected 95 cervical intraepithelial neoplasia grade 3 or worse (52 in unvaccinated and 43 in vaccinated women). HPV16/18/31/33/45 was predominant (69%) among unvaccinated participants, and HPV35/52/58/39/51/56/59/66/68 predominated (65%) among vaccinated participants. Sensitivity and specificity of cervical screening approaches were comparable between women vaccinated as young adults and unvaccinated women. Colposcopy referral rates were lower in the vaccinated group for HPV-based screening modalities, but the positive predictive value was comparable between the 2 groups. CONCLUSIONS: Among women approaching screening ages, vaccinated as young adults, and with a history of intensive screening, the expected reduction in the positive predictive value of HPV testing, associated with dropping prevalence of HPV-associated lesions, was not observed. This is likely due to the presence of high-grade lesions associated with nonvaccine HPV types, which may be less likely to progress to cancer.

Rationale and design of a double-blind randomized non-inferiority clinical trial to evaluate one or two doses of vaccine against human papillomavirus including an epidemiologic survey to estimate vaccine efficacy: The Costa Rica ESCUDDO trial.

HPV vaccination of adolescent girls is the most effective measure to prevent cervical cancer. The World Health Organization recommends that adolescent girls receive two doses of vaccine but only a small proportion of girls from regions with the highest disease burden are vaccinated because of cost and logistical considerations. Our Costa Rica HPV Vaccine trial suggested that one dose of the bivalent HPV vaccine provides robust and lasting protection against persistent HPV infections for over a decade. Data from a post-licensure trial of the quadrivalent vaccine in India also suggested that a single dose may be effective in reducing cervical cancer risk. To formally compare one versus two doses of the bivalent and nonavalent HPV vaccines, we implemented a large, randomized, double-blind trial to investigate the non-inferiority of one compared to two vaccine doses in the prevention of new HPV16/18 infections that persist 6 or more months. Bivalent and nonavalent vaccines will be evaluated separately. The trial enrolled and randomized (1:1:1:1 to 1- and 2-dose arms of the bivalent and nonavalent vaccines) 20,330 girls 12 to 16 years old residing in Costa Rica. Trial participants are followed every 6 months for up to 5 years. We also aim to estimate vaccine efficacy by comparing the rates of 6 month persistent infection in unvaccinated women with the rates in the follow-up visits of trial participants. We included one survey of unvaccinated women at the start of the study (N = 4452) and will include another survey concomitant with follow up visits of trial participants at year 4.5 (planned N = 3000). Survey participants attend two visits 6 months appart. Herein, we present the rationale, design, and enrolled study population of the ESCUDDO trial. ClinicalTrials.gov Identifier: NCT03180034.

Project profile: a multicenter study on breast cancer in young women in Latin America (PRECAMA study).

OBJECTIVE: To describe the rationale and the methodology of a multicenter project to study the etiology of breast cancer in young Latin American women. MATERIALS AND METHODS: The International Agency for Research on Cancer has established an international collaborative population-based case-control study in four countries in Latin America: Chile, Colombia, Costa Rica, and Mexico (the PRECAMA study). Standardized methodologies were developed to collect information on reproductive variables, lifestyle, anthropometry, diet, clinical and pathological data, and biological specimens. The study will be extended to other countries in the region. CONCLUSIONS: PRECAMA is unique in its multidisciplinary approach that combines genetics, genomics, and metabolomics with lifestyle factors. Then data generated through this project will be instrumental to identify major risk factors for molecular subtypes of breast cancer in young women, which will be important for pre- vention and targeted screening programs in Latin America.

OBJETIVO: Describir la justificación y la metodología para el establecimiento de un proyecto multicéntrico sobre el cáncer de mama en mujeres jóvenes de América Latina. MATERIAL Y MÉTODOS: La Agencia Internacional para la Investigación del Cáncer (IARC) ha establecido un estudio colaborativo internacional de casos y controles con base poblacional en cuatro países de América Latina: Chile, Colombia, Costa Rica y México (el estudio PRECAMA). Se han desarrollado metodologías estandarizadas para recolectar información sobre variables reproductivas, estilos de vida, antropometría y dieta, datos clínicos y patológicos y muestras biológicas. CONCLUSIONES: PRECAMA es único en su enfoque multidisciplinario. Los datos generados a través de este proyecto serán fundamentales para identificar los principales factores de riesgo del cáncer de mama en mujeres jóvenes. Los hallazgos serán relevantes para la prevención y los programas de detección oportuna en América Latina, con beneficios clínicos inmediatos.

Project profile: a multicenter study on breast cancer in young women in Latin America (PRECAMA study) / Perfil de Proyecto: Un estudio multicéntrico sobre el cáncer de mama en mujeres jóvenes en América Latina (estudio PRECAMA)

Abstract: Objective: To describe the rationale and the methodology of a multicenter project to study the etiology of breast cancer in young Latin American women. Materials and methods: The International Agency for Research on Cancer has established an international collaborative population-based case-control study in four countries in Latin America: Chile, Colombia, Costa Rica, and Mexico (the PRECAMA study). Standardized methodologies were developed to collect information on reproductive variables, lifestyle, anthropometry, diet, clinical and pathological data, and biological specimens. The study will be extended to other countries in the region. Conclusion: PRECAMA is unique in its multidisciplinary approach that combines genetics, genomics, and metabolomics with lifestyle factors. The data generated through this project will be instrumental to identify major risk factors for molecular subtypes of breast cancer in young women, which will be important for prevention and targeted screening programs in Latin America.

Resumen: Objetivo: Describir la justificación y la metodología para el establecimiento de un proyecto multicéntrico sobre el cáncer de mama en mujeres jóvenes de América Latina. Material y métodos: La Agencia Internacional para la Investigación del Cáncer (IARC) ha establecido un estudio colaborativo internacional de casos y controles con base poblacional en cuatro países de América Latina: Chile, Colombia, Costa Rica y México (el estudio PRECAMA). Se han desarrollado metodologías estandarizadas para recolectar información sobre variables reproductivas, estilos de vida, antropometría y dieta, datos clínicos y patológicos y muestras biológicas. Conclusión: PRECAMA es único en su enfoque multidisciplinario. Los datos generados a través de este proyecto serán fundamentales para identificar los principales factores de riesgo del cáncer de mama en mujeres jóvenes. Los hallazgos serán relevantes para la prevención y los programas de detección oportuna en América Latina, con beneficios clínicos inmediatos.

Reproductive factors and molecular subtypes of breast cancer among premenopausal women in Latin America: the PRECAMA study.

Etiological differences among breast cancer (BC) subtypes have not been clearly established, especially among young women in Latin America. This study examined the relationship between reproductive factors and BC subtypes among 288 BC cases (20-45 years) and population-based matched controls in four Latin American countries. Immunohistochemistry was determined centrally. Associations between BC and reproductive factors were determined. Older age at first full-term pregnancy (FFTP) (Odds Ratio (OR) = 1.11; 95% Confidence Interval (CI), 1.04-1.19 per year), longer time between menarche and FFTP (OR = 1.12; 95%CI: 1.04-1.20 per year), and older age at last pregnancy (OR = 1.10; 95%CI, 1.02-1.19 per year) were associated with an increased risk of estrogen receptor positive (ER+) tumors (n = 122). Ever pregnant (OR = 0.35; 95%CI, 0.13-0.96), number of childbirths (OR = 0.64; 95%CI, 0.47-0.87 per child), time since last birth (OR = 0.92; 95%CI, 0.85-0.99 per year), and history of breastfeeding (OR = 0.23; 95%CI, 0.09-0.58) were inversely associated with the risk of ER+ tumor. Older age at menarche (OR = 0.63; 95%CI, 0.45-0.89 per year) and longer duration of breastfeeding (OR = 0.97; 95%CI, 0.94-1.01 per month) were inversely associated with estrogen receptor negative (ER-) tumors (n = 48). Reproductive factors may be differentially associated with BC subtypes in young Latin American women.