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Safaeian M.,U.S. National Cancer Institute | Rodriguez A.C.,Proyecto Epidemiologico Guanacaste
American Journal of Epidemiology | Year: 2014

Prophylactic human papillomavirus (HPV) vaccination with 3 doses of either of 2 commercially available vaccines is highly efficacious in preventing infections with the most carcinogenic types of HPV (HPV 16 and HPV 18) at the cervix and other anatomical sites at which HPV-related cancers develop. Concern has been raised that eradicating the most virulent HPV types, 16 and 18, could result in 1 or more of the types that are not targeted by the vaccine occupying the ecological niche created by the elimination of these types, referred to as type replacement. In this issue of the Journal, Yang et al. (Am J Epidemiol. 2014;180(11):1066-1075) report on concurrent infections with multiple HPV types in unvaccinated women who underwent cervical screening in New Mexico (December 2007-April 2009) to identify possible interactions between HPV types, which if present could suggest the possibility of type replacement. Consistent with previous reports, they show minimal type-specific interactions among women with normal cytology, which they consider an indication that type replacement of HPV 16/18 is unlikely to be an issue in the general population postvaccination. Type replacement may be of less concern with the introduction of multivalent vaccines that include most of the carcinogenic HPV types; continued surveillance postvaccination should improve our understanding of the impact of HPV vaccination on type distribution and screening performance. © 2014 Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US. Source

Vaccarella S.,IARC | Franceschi S.,IARC | Snijders P.J.F.,VU University Amsterdam | Herrero R.,Proyecto Epidemiologico Guanacaste | And 2 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2010

To understand viral interactions and the cross-reactivity of natural or vaccine-induced responses, we investigated whether multiple human papillomavirus (HPV) infections, particularly certain combinations of types, have the tendency to cluster together. Cervical cell samples were collected from women in the framework of the IARC HPV Prevalence Surveys.Women with a cytology diagnosis of high-grade squamous intraepithelial lesion or worse were excluded, leaving 13,961 women for this analysis. HPV DNA was assessed using a general GP5+/6+ primer-mediated PCR. HPV genotyping was done using enzyme immunoassay or reverse line blot analysis. Logistic regression with type-specific HPV positivity as an outcome was used, adjusted for age, study area, and lifetime number of sexual partners.Woman-level random effects were added to represent unobservable risk factors common to all HPV types. The observed-to-expected ratio was 1.20 (95% credible interval, 1.14-1.26) for infection with two HPV types and 1.02 (95% credible interval, 0.91-1.12) for three for more types, with the best possible adjustment. Among combinations of specific HPV types, the tendency to cluster increased with the genetic similarity of the L1 region. High observed-to-expected ratios were found for closely homologous types, including HPV33/58, 18/45, 33/35, and 31/35. The excess of multiple infections, however, was clearly evident only when enzyme immunoassay, and not reverse line blot, was used as the genotyping method. The different results by genotyping method suggest that the apparent clustering of HPV infections was an artifact of the measurement process. Further investigation is required to evaluate other widely used HPV detection methods. ©2010 AACR. Source

Kreimer A.R.,U.S. National Institutes of Health | Struyf F.,GSK Vaccines | Del Rosario-Raymundo M.R.,San Pablo Colleges Medical Center | Hildesheim A.,U.S. National Institutes of Health | And 8 more authors.
The Lancet Oncology | Year: 2015

Background: There is some evidence to suggest that one or two doses of the HPV vaccine provides similar protection to the three-dose regimen. The main aim of the study was to ascertain HPV-16/18 vaccine efficacy in both full and naive cohorts and to explore protection conferred against non-vaccine HPV types, by number of doses received. Methods: Summary data from the Costa Rica Vaccine Trial (CVT; NCT00128661) and ~the PATRICIA trial (. NCT001226810), two phase 3, double-blind, randomised controlled clinical trials of the HPV-16/18 AS04-adjuvanted vaccine in young women, were combined in a post-hoc analysis (GlaxoSmithKline [GSK] e-track number 202142) to investigate the efficacy of fewer than three doses of the HPV-16/18 vaccine after 4 years of follow-up. Women were randomly assigned to receive three doses of the HPV-16/18 vaccine or to a control vaccine; yet, some received fewer doses. After exclusion of women with less than 12 months of follow-up or those who were HPV-16/18 DNA-positive at enrolment (for the HPV-16/18 endpoint), we calculated vaccine efficacy against one-time detection of incident HPV infections after three, two, and one dose(s). The primary study endpoint was one-time detection of first incident HPV-16/18 infections accumulated during the follow-up phase. Findings: We assessed vaccine efficacy against incident HPV-16/18 infection in the modified total vaccinated cohort (22 327 received three doses, 1185 two doses, 543 one dose). Vaccine efficacy against incident HPV-16/18 infections for three doses was 77·0% (95% CI 74·7-79·1), two doses was 76·0% (62·0-85·3), and one dose was 85·7% (70·7-93·7). Vaccine efficacy against incident HPV-31/33/45 infections for three doses was 59·7% (56·0-63·0), two doses was 37·7% (12·4-55·9), and one dose was 36·6% (-5·4 to 62·2). Vaccine efficacy against incident HPV-16/18 infection for two-dose women who received their second dose at 1 month was 75·3% (54·2-87·5) and 82·6% (42·3-96·1) for those who received the second dose at 6 months (CVT data only). Vaccine efficacy against HPV-31/33/45 for two-dose women who received their second dose at 6 months (68·1%, 27·0-87·0; CVT data only), but not those receiving it at one month (10·1%, -42·0 to 43·3), was similar to the three-dose group. Interpretation: 4 years after vaccination of women aged 15-25 years, one and two doses of the HPV-16/18 vaccine seem to protect against cervical HPV-16/18 infections, similar to the protection provided by the three-dose schedule. Two doses separated by 6 months additionally provided some cross-protection. These data argue for a direct assessment of one-dose efficacy of the HPV-16/18 vaccine. Funding: US National Cancer Institute, National Institutes of Health Office of Research on Women's Health, and Ministry of Health of Costa Rica (CVT); GlaxoSmithKline Biologicals SA (PATRICIA). © 2015 Elsevier Ltd. Source

Rodriguez A.C.,Proyecto Epidemiologico Guanacaste | Herrero R.,Proyecto Epidemiologico Guanacaste | Bratti C.,Proyecto Epidemiologico Guanacaste | Solomon D.,U.S. National Cancer Institute | And 6 more authors.
Journal of the National Cancer Institute | Year: 2010

Background The natural history of human papillomavirus (HPV) infections in older women is critical for preventive strategies, including vaccination and screening intervals, but is poorly understood. In a 7-year population-based cohort study in Guanacaste, Costa Rica, we examined whether women's age and the duration of carcinogenic HPV infections influenced subsequent persistence of infection and risk of cervical intraepithelial neoplasia grade 2 (CIN 2) or worse disease.MethodsAt enrollment, of the 9466 participants eligible for pelvic examination, 9175 were screened for cervical neoplasia using multiple methods; those with CIN 2 or worse disease were censored and treated. Participants at low risk of CIN 2 or worse (n = 6029) were rescreened at 5-7 years (passively followed), whereas higher-risk participants (n = 2115) and subsets of low-risk women (n = 540) and initially sexually inactive women (n = 410) were rescreened annually or semiannually (actively followed) for up to 7 years. HPV testing was done using a polymerase chain reaction-based method. We determined, by four age groups (18-25, 26-33, 34-41, and ≥42 years), the proportion of prevalent infections (found at baseline) and newly detected infections (first found during follow-up) that persisted at successive 1-year time points and calculated absolute risks of CIN 2 and CIN grade 3 (CIN 3) or worse during follow-up. P values are two-sided.ResultsRegardless of the woman's age, newly detected infections were associated with very low absolute risks of persistence, CIN 2, or worse disease. For newly detected infections, the rate of progression to CIN 2+ (or CIN 3+), after 3 years of follow-up, was not higher for women aged 34 years and older than for younger women. Moreover, rates of newly detected infections declined sharply with age (in the actively followed group, at ages 18-25, 26-33, 34-41, and ≥42 years, rates were 35.9%, 30.6%, 18.1%, and 13.5%, respectively; P <. 001). Among prevalent infections, persistent infections among older women (≥42 years) was higher than that among younger age groups or new infections at any age (P <. 01 for comparison of eight groups). Most (66 of 85) CIN 2 or worse detected during follow-up was associated with prevalent infections. Only a small subset (25 of 1128) of prevalent infections persisted throughout follow-up without apparent CIN 2 or worse.ConclusionsThe rate of new infections declines with age, and new infections typically do not progress to CIN 2 or worse disease in older women; thus, overall potential benefit of prophylactic vaccination or frequent HPV screening to prevent or detect new carcinogenic HPV infections at older ages is low. Source

Mirabello L.,U.S. National Cancer Institute | Sun C.,Yeshiva University | Ghosh A.,U.S. National Cancer Institute | Rodriguez A.C.,Proyecto Epidemiologico Guanacaste | And 7 more authors.
Journal of the National Cancer Institute | Year: 2012

Background Previous studies have suggested an association between human papillomavirus type 16 (HPV16) genome methylation and cervical intraepithelial neoplasia grade 3 (CIN3) (ie, cervical precancer) and cancer, but the Results have been inconsistent. Methods We designed a case-control study within a large prospective cohort of women who underwent multiple screenings for cervical cancer in Guanacaste, Costa Rica. Diagnostic specimens were collected at the time of CIN3 diagnosis (n = 30 case subjects) and persistent HPV16 infection (persistence; n = 35 case subjects), prediagnostic specimens at the first HPV16-positive screening visit (n = 20 CIN3 case subjects; n = 35 persistence case subjects), and control specimens from women with infection clearance within 2 years (n = 34 control subjects). DNA extracted from specimens (cervical cells) was analyzed for methylation levels at 67 CpG sites throughout the HPV16 genome using pyrosequencing. Benjamini-Hochberg method was used to account for multiple testing. Associations between methylation levels and risk of CIN3 or persistence were assessed using logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs).Results Increased methylation in diagnostic vs control specimens at nine CpG sites, three in each L1, L2, and E2/E4 genomic regions, was associated with an increased risk of CIN3 (third tertile [high] vs first and second tertiles combined [low], OR = 3.29 [95% CI = 1.16 to 9.34] to 11.12 [95% CI = 2.29 to 76.80]) and persistence. High methylation at three of these CpG sites was associated with a much higher risk when combined compared with low methylation at these sites (OR = 52, 95% CI = 4.0 to 670). In prediagnostic vs control specimens, increased methylation at a CpG site (nucleotide position 4261) in L2 was associated with an increased risk of CIN3. Conclusion In this HPV16-infected cohort, increased methylation of CpG sites within the HPV16 genome before diagnosis and at the time of diagnosis was associated with cervical precancer. © 2012 Oxford University Press. Source

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