Low risk of type-specific carcinogenic HPV re-appearance with subsequent cervical intraepithelial neoplasia grade 2/3.

Carcinogenic human papillomavirus (HPV) infections are very common after sexual debut and nearly all become undetectable ("clear") within a few years. Following clearance, the long-term risks of type-specific HPV re-appearance and subsequent risk of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) are not well defined. In the 7-year, population-based cohort study in Guanacaste, Costa Rica, we studied how often type-specific carcinogenic HPV infections re-appeared after clearance and how often re-appearance led to CIN2+.

Long-term risk of recurrent cervical human papillomavirus infection and precancer and cancer following excisional treatment.

Risk of recurrent CIN2+ (including cervical intraepithelial neoplasia grade 2 [CIN2], CIN3, carcinoma and in situ, adenocarcinoma in situ or cancer) remains elevated for years following treatment. The role of long-term post-treatment human papillomavirus (HPV) presence on subsequent risk of CIN2+ was evaluated in the 10,049-women Guanacaste cohort. Six hundred eighty-one women were referred to colposcopy because of high-grade cytology, positive cervicography and/or suspicion of cancer based on visual assessment; 486 were judged to require treatment.

Alterations of T-cell surface markers in older women with persistent human papillomavirus infection.

We previously reported decreased lymphocyte proliferative responses among older women with persistent human papillomavirus (HPV) infection. To characterize the phenotype of peripheral lymphocytes associated with persistent HPV infection, we evaluated the expression of different cell surface markers in peripheral blood mononuclear cells (PBMCs) from a case-control study within a 10,049 woman population-based cohort study in Guanacaste, Costa Rica. Women in the cohort aged 46-74 and with HPV results at their 5th year anniversary visit were considered, and all women (n = 87) with persistent HPV infections, all women (n = 196) with transient HPV infections and a random sample of HPV DNA-negative women (n = 261) frequency-matched to cases on age were selected for this study.

Longitudinal study of human papillomavirus persistence and cervical intraepithelial neoplasia grade 2/3: critical role of duration of infection.

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.

Methods: At 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.

Common genetic variants and risk for HPV persistence and progression to cervical cancer.

HPV infrequently persists and progresses to cervical cancer. We examined host genetic factors hypothesized to play a role in determining which subset of individuals infected with oncogenic human papillomavirus (HPV) have persistent infection and further develop cervical pre-cancer/cancer compared to the majority of infected individuals who will clear infection.We evaluated 7140 tag single nucleotide polymorphisms (SNPs) from 305 candidate genes hypothesized to be involved in DNA repair, viral infection and cell entry in 416 cervical intraepithelial neoplasia 3 (CIN3)/cancer cases, 356 HPV persistent women (median: 25 months), and 425 random controls (RC) from the 10,049 women Guanacaste Costa Rica Natural History study.

Common genetic variation in TP53 and risk of human papillomavirus persistence and progression to CIN3/cancer revisited.

Driven by findings that human papillomavirus (HPV)-induced degradation of p53 differs by a TP53 polymorphism at codon 72 (Pro72Arg), past studies of TP53 genetic variants and cervical cancer have focused on this nonsynonymous polymorphism, with mixed results. We analyzed common single nucleotide polymorphisms (SNP) across the TP53 locus in a population-based nested case-control study in Guanacaste, Costa Rica. We evaluated 11 SNPs, including Pro72Arg (rs1042522), among 1,281 women: 465 with cervical intraepithelial neoplasia grade 3/cancer (CIN3+), 380 with HPV persistence (median, 25 months), and 436 random population controls.

Common variants in immune and DNA repair genes and risk for human papillomavirus persistence and progression to cervical cancer.

Background: We examined host genetic factors to identify those more common in individuals whose human papillomavirus (HPV) infections were most likely to persist and progress to cervical intraepithelial neoplasia grade 3 (CIN3) and cancer.

Methods: We genotyped 92 single-nucleotide polymorphisms (SNPs) from 49 candidate immune response and DNA repair genes obtained from 469 women with CIN3 or cancer, 390 women with persistent HPV infections (median duration, 25 months), and 452 random control subjects from the 10,049-woman Guanacaste Costa Rica Natural History Study. We calculated odds ratios and 95% confidence intervals (CIs) for the association of SNP and haplotypes in women with CIN3 or cancer and HPV persistence, compared with random control subjects.

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.

Epidemiology of genital Chlamydia trachomatis infection among young women in Costa Rica.

Objective: To investigate Chlamydia trachomatis (Ct) epidemiology among 5829 women 18 to 25 years old, in Costa Rica.

Methods: Data are from a community-based human papillomavirus 16/18 vaccine trial. Before randomization, eligible women who reported previous sexual activity were interviewed and tested for Ct DNA by Hybrid Capture 2 and polymerase chain reaction-based genotyping.

High load for most high risk human papillomavirus genotypes is associated with prevalent cervical cancer precursors but only HPV16 load predicts the development of incident disease.

Cervicovaginal human papillomavirus (HPV) viral load has been purported as a potential marker for the detection of high-grade cervical intraepithelial neoplasia or cancer (>/=CIN2). To examine disease association with type-specific viral load for the full-range of anogenital HPV infections, we conducted cross-sectional and prospective analyses of approximately 2,000 HPV-infected women from a 10,000-woman population-based study in Guanacaste, Costa Rica with 7 years of follow-up. Cervical specimens were tested for >40 HPV types using a MY09/MY11 L1 consensus primer PCR method with type-specific dot blot hybridization and PCR signal intensity as a measure of viral load.

Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial.

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.

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.

The objective of this analysis was to compare the performance characteristics of two human papillomavirus (HPV) DNA detections assays, the Hybrid Capture 2 assay (HC2) and the SPF(10) assay, for the detection of carcinogenic HPV. Data are from the enrollment visits of women who participated in the randomized, double-blind, placebo-controlled phase III HPV16/18 Vaccine Trial in Guanacaste, Costa Rica. We compared the results of HC2 and SPF(10) testing of cervical specimens.

The natural history of human papillomavirus infection and cervical intraepithelial neoplasia among young women in the Guanacaste cohort shortly after initiation of sexual life.

Objective: Cross-sectional analyses of our 10,000-woman, population-based Guanacaste cohort suggest a lag of > or =10 years between the peak of human papillomavirus (HPV) infection and the later peak of cervical intraepithelial neoplasia grade 3 (CIN 3). We wanted to explore early HPV natural history and CIN 3 prospectively.

Study Design: As part of the Guanacaste cohort, we followed 206 initially virginal women aged 18 to 26 semiannually for a median of 3.

Persistent human papillomavirus infection is associated with a generalized decrease in immune responsiveness in older women.

The development of cervical cancer and its precursors are linked to persistent infection with oncogenic types of human papillomavirus (HPV). Host immune responses seem to be determinants of risk for this disease. However, little is known about the immunologic determinants of HPV persistence.

Right-sided ectocervical lesions may be associated with false-negative cytology among women with histologic cervical intraepithelial neoplasia 2 or 3.

Background: The association between the location of an ectocervical lesion and the sensibility of cytologic screening has not been adequately evaluated.

Methods: We evaluated the proportion of false-negative cytologic interpretations using three independent cytologic interpretations (conventional, PapNet, and ThinPrep) according to lesion location in 111 women with histologic cervical intraepithelial neoplasia 2 or 3 of a population-based study of cervical neoplasia conducted in Guanacaste, Costa Rica. Semiquantitative measures of human papillomavirus viral load were also considered.

Relationships of human papillomavirus type, qualitative viral load, and age with cytologic abnormality.

Persistent cervical infections with carcinogenic human papillomaviruses (HPV) cause virtually all cervical cancer. Cytologic abnormalities are the manifestations of HPV infections used to identify women at risk. To compare the potential of the full range of anogenital HPV genotypes to induce cytopathic effects, we examined the influences of HPV type, viral load, and age on cytopathology among 1,222 women having a single HPV type at enrollment into a 10,000-woman population-based study in Costa Rica.

Age-related changes of the cervix influence human papillomavirus type distribution.

Approximately 15 human papillomavirus (HPV) types cause virtually all cervical cancer whereas other HPV types are unrelated to cancer. We were interested in whether some noncarcinogenic types differ from carcinogenic in their affinity for the cervical transformation zone, where nearly all HPV-induced cancers occur. To examine this possibility, we tested cervical specimens from 8,374 women without cervical precancer and cancer participating in a population-based study in Guanacaste for >40 HPV types using PCR.

Performance of direct visual inspection of the cervix with acetic acid and magnification in a previously screened population.

Objective: To assess the screening performance of direct visual inspection with acetic acid and x2 magnification (VIAM) in a previously screened population, as performed by experienced gynecologic nurses with minimal training in VIAM.

Patients And Methods: Performance of VIAM was evaluated in 2,080 women from a population-based cohort in Guanacaste, Costa Rica, 5 years after they had negative enrollment results of conventional and liquid-based cytologic analysis, cervigram, and human papillomavirus DNA by Hybrid Capture Tube Test (Digene Corporation, Gaithersburg, MD). The VIAM results were compared with repeat conventional Pap smears, liquid-based cytologic examinations, and cervicography, with adjudication of differences by reference to MY09/MY11 L1 consensus primer polymerase chain reaction detection of oncogenic human papillomavirus DNA.

A prospective study of age trends in cervical human papillomavirus acquisition and persistence in Guanacaste, Costa Rica.

Background: Cross-sectional human papillomavirus (HPV) DNA prevalence peaks at young ages, reflecting sexual acquisition and typically rapid clearance. In some populations, HPV prevalence demonstrates a second peak in older women. Longitudinal data may help to explain this second peak.

Epidemiologic profile of type-specific human papillomavirus infection and cervical neoplasia in Guanacaste, Costa Rica.

Background: Detailed epidemiologic studies of cervical type-specific human papillomavirus (HPV) infection in large populations are scarce.

Methods: We recruited a population-based cohort in Guanacaste, Costa Rica. Participants were interviewed, screened for cervical neoplasia, and tested for >40 HPV types by use of MY09/11 L1 consensus primer polymerase chain reaction.

PCR testing of pooled longitudinally collected cervical specimens of women to increase the efficiency of studying human papillomavirus infection.

In large active cohort studies of women investigating human papillomavirus (HPV) and cervical neoplasia, many women will be HPV-negative at all time points and testing of all their cervical specimens is an inefficient use of laboratory resources. The aim of this pilot study was to evaluate whether pooling cervical specimens from the same woman might provide a useful pretest of specimens from women unlikely to have high-grade cervical neoplasia or significant HPV exposure. We selected women (n = 187) participating in the Guanacaste Project for whom we already had HPV testing data on all their specimens from multiple visits (median = 8 visits), who were HPV DNA-negative at enrollment and at their 5- to 7-year exit from the cohort, and had no evidence of high-grade cervical neoplasia.

Validation of p16INK4a as a marker of oncogenic human papillomavirus infection in cervical biopsies from a population-based cohort in Costa Rica.

Due to the high prevalence of cancer-associated types of human papillomavirus (HPV) and the poorly reproducible histologic classification of low-grade lesions, identifying infected women at highest risk for cancer prior to neoplastic progression remains a challenge. We therefore explored the utility of p16INK4a immunostaining as a potential diagnostic and prognostic biomarker for cervical neoplasia using paraffin-embedded tissue blocks (punch biopsies and loop electrosurgical excision procedures) obtained from women referred to colposcopy during the enrollment phase of the Guanacaste Project (1993 to 1994). All blocks from 292 women selected by HPV status (HPV negative, nononcogenic HPV positive, or oncogenic HPV positive) and representing the diagnostic spectrum of the population [normal to precancer: cervical intraepithelial neoplasia (CIN) 3] were immunostained for p16INK4a using the p16INK4a research kit based on the monoclonal antibody clone E6H4 (MTM Laboratories, Heidelberg, Germany).

A population-based study of vaginal human papillomavirus infection in hysterectomized women.

We compared point prevalences and determinants of human papillomavirus (HPV) DNA detection by testing enrollment vaginal specimens from hysterectomized women (n=569) and enrollment cervical specimens from nonhysterectomized women (n=6098) >or=30 years old, using MY09/MY11 L1 consensus-primer polymerase chain reaction. The subjects were participating in a population-based cohort study (n=10,049) in Guanacaste, Costa Rica, that was initiated in 1993. Non-cancer-associated HPV types, especially types 61, 71, and 72, were detected more frequently in the vaginal specimens from hysterectomized women (23.

Description of a seven-year prospective study of human papillomavirus infection and cervical neoplasia among 10000 women in Guanacaste, Costa Rica,

Objective: The Guanacaste study ("Guanacaste Project," or GP), was designed to investigate the role of human papillomavirus (HPV) infection and its cofactors in the development of cervical neoplasia and to evaluate new cervical cancer screening technologies. The follow-up phase of the GP was designed to study why a small proportion of women infected with HPV develop cervical intraepithelial neoplasia grade 2 (CIN 2), CIN 3, or cancer (these three together are globally referred to as > or = CIN 2, that is, CIN 2 or worse). The purpose of this article is to describe this prospective study in detail and to present the preliminary findings regarding the incidence of cervical neoplasia.

Comparison of ophthalmic sponges for measurements of immune markers from cervical secretions.

Measurements of cervical immunity are important for evaluating immune responses to infections of the cervix and to vaccines for preventing those infections. Three ophthalmic sponges, Weck-Cel, Ultracell, and Merocel, were loaded in vitro with interleukin-1 beta (IL-1 beta), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-15, IL-18, gamma interferon (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), immunoglobulin A (IgA), or IgG, and sponges were extracted and evaluated for total recovery by enzyme-linked immunosorbent assay (ELISA). There was excellent (>75%) recovery for all immune markers from all three devices except for IL-6, which was poorly recovered (<60%) for all sponge types, IFN-gamma, which was poorly recovered from both Weck-Cel and Ultracell sponges but was completely recovered from Merocel sponges, and IL-4, which was poorly recovered from Weck-Cel sponges but was completely recovered from Ultracell or Merocel sponges.