Performance of cervical cytology and HPV testing for primary cervical cancer screening in Latin America: an analysis within the ESTAMPA study.

Background: Cervical cytology remains widely used as the initial tool in cervical cancer screening worldwide. WHO guidelines recommend replacing cytology with primary HPV testing to reach cervical cancer elimination goals. We assessed the performance of cytology and high-risk HPV testing to detect cervical precancer, cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) among women aged 30-64 years participating in the ESTAMPA study. Methods: Women were screened with cytology and HPV across ESTAMPA study centres in Latin America. Screen-positives were referred to colposcopy with biopsy collection and treatment as needed. Those with no evident precancer were recalled at 18-months for a second HPV test to complete disease ascertainment. Performance indicators for cytology and HPV to detect CIN3+ were estimated. Findings: 30,606 participants with available cytology and HPV results were included in the analysis. A total of 440 histologically confirmed CIN3s and 30 cancers were diagnosed. Cytology sensitivity for CIN3+ was 48.5% (95% CI: 44.0-53.0), whereas HPV testing had a sensitivity of 98.1% (95% CI: 96.3-96.7). Specificity was 96.5% (95% CI: 96.3-96.7) using cytology and 88.7% (95% CI: 88.3-89.0) with HPV. Performance estimates varied substantially by study centre for cytology (ranging from 32.1% to 87.5% for sensitivity and from 89.2% to 99.5% for specificity) while for HPV results were more consistent across sites (96.7%-100% and 83.6-90.8%, respectively). Interpretation: The limited and highly variable sensitivity of cytology strongly supports transition to the more robust and reproducible HPV-based cervical screening to ensure progress towards global cervical cancer elimination targets in Latin America. Funding: IARC/WHO, UNDP, HRP/WHO, NCI and local funders.

Trends in incidence rates of head and neck squamous cell carcinomas overall and by potential relatedness to human papillomavirus, Costa Rica 2006 to 2015.

In Costa Rica (CR), only one report on head and neck cancer (HNC) incidence trends (1985-2007) has been published and no investigations on the epidemiology of potentially human papillomavirus (HPV)-related and HPV-unrelated HNCs have been done. We examined the age-standardized incidence rates (IRs) and trends of head and neck squamous cell carcinomas (HNSCC) and compared incidence trends of potentially HPV-related and HPV-unrelated HNSCCs. We obtained all available HNC cases for the period 2006-2015 from the Costa Rican National Cancer Registry of Tumors and the population estimates from the Costa Rican National Institute of Statistics and Census. The analysis was restricted to invasive HNSCCs (n = 1577). IRs and incidence rate ratios were calculated using SEER*Stat software and were age-standardized for the 2010 Costa Rican population. Joinpoint regression analysis program was used to calculate trends and annual percent changes (APCs) in rates. For all HNSCCs, the age-standardized IR was 34.0/million person-years; 95% CI 32.4, 35.8. There was a significant decline in the incidence of nasopharyngeal cancer (APC: -5.9% per year; 95% CI -10.8, -0.7) and laryngeal cancer (APC: -5.4% per year; -9.2, 1.5). The incidence trends for hypopharyngeal, oropharyngeal and oral cavity cancers each remained stable over time. HNSCCs were categorized by their potential relatedness to HPV infection. Though the APCs were not statistically significant, IRs of potentially HPV-related HNSCCs trended upward, while HPV-unrelated HNSCCs trended downward. HNSCCs are uncommon in CR and decreased over time. We observed a divergent pattern of decreasing HPV-unrelated with increasing HPV-related HNSCCs that should be further informed by HPV genotyping tumor samples.

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.

Efficacy of the bivalent HPV vaccine against HPV 16/18-associated precancer: long-term follow-up results from the Costa Rica Vaccine Trial.

BACKGROUND: Oncogenic human papillomavirus (HPV) infections cause most cases of cervical cancer. Here, we report long-term follow-up results for the Costa Rica Vaccine Trial (publicly funded and initiated before licensure of the HPV vaccines), with the aim of assessing the efficacy of the bivalent HPV vaccine for preventing HPV 16/18-associated cervical intraepithelial neoplasia grade 2 or worse (CIN2+). METHODS: Women aged 18-25 years were enrolled in a randomised, double-blind, controlled trial in Costa Rica, between June 28, 2004, and Dec 21, 2005, designed to assess the efficacy of a bivalent vaccine for the prevention of infection with HPV 16/18 and associated precancerous lesions at the cervix. Participants were randomly assigned (1:1) to receive an HPV 16/18 AS04-adjuvanted vaccine or control hepatitis A vaccine. Vaccines were administered intramuscularly in three 0·5 mL doses at 0, 1, and 6 months and participants were followed up annually for 4 years. After the blinded phase, women in the HPV vaccine group were invited to enrol in the long-term follow-up study, which extended follow-up for 7 additional years. The control group received HPV vaccine and was replaced with a new unvaccinated control group. Women were followed up every 2 years until year 11. Investigators and patients were aware of treatment allocation for the follow-up phase. At each visit, clinicians collected cervical cells from sexually active women for cytology and HPV testing. Women with abnormal cytology were referred to colposcopy, biopsy, and treatment as needed. Women with negative results at the last screening visit (year 11) exited the long-term follow-up study. The analytical cohort for vaccine efficacy included women who were HPV 16/18 DNA-negative at vaccination. The primary outcome of this analysis was defined as histopathologically confirmed CIN2+ or cervical intraepithelial neoplasia grade 3 or worse associated with HPV 16/18 cervical infection detected at colposcopy referral. We calculated vaccine efficacy by year and cumulatively. This long-term follow-up study is registered with ClinicalTrials.gov, NCT00867464. FINDINGS: 7466 women were enrolled in the Costa Rica Vaccine Trial; 3727 received the HPV vaccine and 3739 received the control vaccine. Between March 30, 2009, and July 5, 2012, 2635 women in the HPV vaccine group and 2836 women in the new unvaccinated control group were enrolled in the long-term follow-up study. 2635 women in the HPV vaccine group and 2677 women in the control group were included in the analysis cohort for years 0-4, and 2073 women from the HPV vaccine group and 2530 women from the new unvaccinated control group were included in the analysis cohort for years 7-11. Median follow-up time for the HPV group was 11·1 years (IQR 9·1-11·7), 4·6 years (4·3-5·3) for the original control group, and 6·2 years (5·5-6·9) for the new unvaccinated control group. At year 11, vaccine efficacy against incident HPV 16/18-associated CIN2+ was 100% (95% CI 89·2-100·0); 34 (1·5%) of 2233 unvaccinated women had a CIN2+ outcome compared with none of 1913 women in the HPV group. Cumulative vaccine efficacy against HPV 16/18-associated CIN2+ over the 11-year period was 97·4% (95% CI 88·0-99·6). Similar protection was observed against HPV 16/18-associated CIN3-specifically at year 11, vaccine efficacy was 100% (95% CI 78·8-100·0) and cumulative vaccine efficacy was 94·9% (73·7-99·4). During the long-term follow-up, no serious adverse events occurred that were deemed related to the HPV vaccine. The most common grade 3 or worse serious adverse events were pregnancy, puerperium, and perinatal conditions (in 255 [10%] of 2530 women in the unvaccinated control group and 201 [10%] of 2073 women in the HPV vaccine group). Four women in the unvaccinated control group and three in the HPV vaccine group died; no deaths were deemed to be related to the HPV vaccine. INTERPRETATION: The bivalent HPV vaccine has high efficacy against HPV 16/18-associated precancer for more than a decade after initial vaccination, supporting the notion that invasive cervical cancer is preventable. FUNDING: US National Cancer Institute.

Cervical cancer incidence after screening with HPV, cytology, and visual methods: 18-Year follow-up of the Guanacaste cohort.

Testing negative for human papillomavirus (HPV) predicts long-term reassurance against invasive cervical cancer (ICC). To provide realistic estimates of effectiveness for new screening programs, we studied ICC risk after a 7-year repeated multimethod screening effort. In 1993-1994, 10,049 women aged 18-97 years were enrolled into a population-based cohort study of cervical HPV in Guanacaste, Costa Rica. Women were screened at different intervals according to enrollment results. Each visit (mean 3.2, 90% attendance) included split-sample conventional, automated, and liquid-based cytology, visual inspection, cervicography, and PCR-based HPV testing. Abnormal screening led to colposcopy and excisional treatment as appropriate during the study. Referral to colposcopy for HPV in the absence of other findings was introduced only at the last visit. Population-based Costa Rica Cancer Registry linkage identified cohort women diagnosed with ICC in the 18 years following cohort enrollment. The ICC cumulative risk was 0.4% (n = 38); 18 were diagnosed with ICC after study participation. Of these, 9 were missed at the screening step (negative screening or below the referral threshold, refused screening or colposcopy), 5 attended colposcopy but were not diagnosed as CIN2+, and 4 were treated for CIN2/3 but progressed to ICC nonetheless. Decreasing age-standardized ICC rates for the 1993-2011 period were observed in Guanacaste; cohort women showed additional 31% ICC incidence reduction with apparent downstaging of cancers that occurred. ICC risk following negative HPV testing in the optimal age range 30-50 years was extremely low. Real-life screening effectiveness following introduction is lower than the potential near-complete efficacy predicted by HPV natural history.

Rationale and design of a long term follow-up study of women who did and did not receive HPV 16/18 vaccination in Guanacaste, Costa Rica.

The Costa Rica Vaccine Trial (CVT) was a randomized clinical trial conducted between 2004 and 2010, which randomized 7466 women aged 18 to 25 to receive the bivalent HPV-16/18 vaccine or control Hepatitis-A vaccine. Participants were followed for 4 years with cross-over vaccination at the study end. In 2010 the long term follow-up (LTFU) study was initiated to evaluate the 10-year impact of HPV-16/18 vaccination, determinants of the immune response, and HPV natural history in a vaccinated population. Herein, the rationale, design and methods of the LTFU study are described, which actively follows CVT participants in the HPV-arm 6 additional years at biennial intervals (3 additional study visits for 10 years of total follow-up), or more often if clinically indicated. According to the initial commitment, women in the Hepatitis-A arm were offered HPV vaccination at cross-over; they were followed 2 additional years and exited from the study. 92% of eligible CVT women accepted participation in LTFU. To provide underlying rates of HPV acquisition and cervical disease among unvaccinated women to compare with the HPV-arm during LTFU, a new unvaccinated control group (UCG) of women who are beyond the age generally recommended for routine vaccination was enrolled, and will be followed by cervical cancer screening over 6 years. To form the UCG, 5000 women were selected from a local census, of whom 2836 women (61% of eligible women) agreed to participate. Over 90% of participants complied with an interview, blood and cervical specimen collection. Evaluation of comparability between the original (Hepatitis-A arm of CVT) and new (UCG) control groups showed that women's characteristics, as well as their predicted future risk for cervical HPV acquisition, were similar, thus validating use of the UCG. LTFU is poised to comprehensively address many important questions related to long-term effects of prophylactic HPV vaccines.

Performance of self-collected cervical samples in screening for future precancer using human papillomavirus DNA testing.

BACKGROUND: Self-collected human papillomavirus (HPV) testing could reduce barriers to cervical cancer screening, with performance comparable to clinician-collected specimens. The ability of self-collected specimens to cross-sectionally and prospectively detect precursor lesions was investigated in an HPV vaccine randomized trial in Costa Rica. METHODS: In the trial, 7466 women age 18 to 25 years received an HPV16/18 or control vaccine and were followed at least annually for four years. In this secondary analysis, we included all women who provided a self-collected cervicovaginal specimen six months after enrollment (5109 women = full analytical cohort). A subset (615 women = restricted cohort) also had clinician-collected specimens at the six-month postenrollment visit. High-grade squamous intraepithelial lesion or repeat low-grade squamous intraepithelial lesion prompted colposcopic referral throughout the study. HPV testing was performed with SPF10PCR/DEIA/LiPA25. Cross-sectional and prospective sensitivity, specificity, and predictive values were estimated. RESULTS: In the full cohort, one-time HPV testing on self-collected samples detected prevalent CIN2+ with a sensitivity of 88.7% (95% confidence interval [CI] =77.0% to 95.7%) and a specificity of 68.9% (95% CI = 67.6% to 70.1%). For predicting incident CIN2+ in the subsequent four years, sensitivity was 73.9% (95% CI = 65.8% to 81.0%) and specificity 69.4% (95% CI = 68.1% to 70.7%). In the restricted cohort, for incident CIN2+, self-collected HPV was much more sensitive than cytology (80.0% vs 10.0%); relative sensitivity was 0.1 (95% CI = 0.03% to 0.5%). Furthermore, three times more women with normal baseline cytology developed incident CIN2+ than those with negative self-collected HPV. Self-collected and clinician-collected HPV testing had comparable performance. Agreement between self- and clinician-collected samples was 89.7% (kappa = 0.78, McNemar χ2 = 0.62) for carcinogenic HPV types. CONCLUSIONS: Self-collected specimens can be used for HPV-based screening, providing sensitivity and specificity comparable with clinician-collected specimens and detecting disease earlier than cytology.

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+. We considered 1,740 carcinogenic HPV infections detected by MY09/11 PCR among 2,805 women (18-91 years old, median 34) who were actively followed at 6- or 12-month intervals. We identified women with one or more type-specific HPV infections that cleared and re-appeared and further defined a subgroup of "definite clearance and re-appearance" (≥2 intervening negative results over a period of ≥1 year). We determined the absolute risk of CIN2+ among the different groups. p values are two-sided. Only 7.7% (81/1,052) of HPV-infected women had intervening negative results. Very few (3.7%, 39/1,052) had "definite clearance and re-appearance", of which 5.1% (2/39) subsequently persisted to a diagnosis of CIN2. There were zero CIN3+ lesions. Extremely few women (2/2,805 of women in our cohort) had a type-specific carcinogenic HPV infection clear, re-appear and lead to CIN2+. If confirmed, this argues against vaccination to avoid re-appearance that leads to precursor lesions and against the need of frequent HPV screening after initial negative results.

A competitive serological assay shows naturally acquired immunity to human papillomavirus infections in the Guanacaste Natural History Study.

BACKGROUND: A competitive Luminex Immunoassay (cLIA) has been developed to measure neutralizing antibodies against human papillomavirus (HPV) types 6, 11, 16 and 18. METHODS: In a cohort of 974 women from the Guanacaste Natural History Study, we studied the relationship of baseline cLIA and virus-like particle (VLP) enzyme-linked immunosorbent assay (ELISA) (HPV16 and HPV18 only) seropositivity to measures of HPV exposure, HPV DNA positivity, number of sexual partners, cytology findings, and age. We then studied immunity against subsequent infection with HPV6, 11, 16, 18 and related types over a 7-year period. RESULTS: cLIA seroprevalence varied with previous exposure; the prevalence of cLIA results positive for HPV16 and HPV18 was lower than the prevalence of positive VLP ELISA responses. cLIA and VLP ELISA positivity predicted protection from subsequent infections with concordant types. The combined odds ratio for HPV16 and HPV18 cLIA positivity was 0.41 (95% confidence interval [CI], 0.21-0.80), and the combined odds ratio for the HPV16 and HPV18 VLP ELISA positivity was 0.65 (95% CI, 0.46-0.93). Of individual types, statistical significance was only reached for HPV16 cLIA positivity (odds ratio, 0.44; 95% CI, 0.15-0.94). CONCLUSIONS: Both assays showed an association between positive results and significant protection from subsequent infections for HPV16 and HPV18 combined. cLIA seroprevalence was lower than VLP ELISA, suggesting that the assay detects a subset of antibodies following natural infection that are specifically linked to immunity against subsequent HPV infection.

A population-based prospective study of carcinogenic human papillomavirus variant lineages, viral persistence, and cervical neoplasia.

Human papillomavirus (HPV) types differ profoundly in cervical carcinogenicity. For the most carcinogenic type HPV16, variant lineages representing further evolutionary divergence also differ in cancer risk. Variants of the remaining 10 to 15 carcinogenic HPV types have not been well studied. In the first prospective, population-based study of HPV variants, we explored whether, on average, the oldest evolutionary branches within each carcinogenic type predicted different risks of >2-year viral persistence and/or precancer and cancer [cervical intraepithelial neoplasia grade 3+ (CIN3+)]. We examined the natural history of HPV variants in the 7-year, 10,049-woman Guanacaste Cohort Study, using a nested case-control design. Infections were assigned to a variant lineage determined by phylogenetic parsimony methods based on URR/E6 sequences. We used the Fisher's combination test to evaluate significance of the risk associations, cumulating evidence across types. Globally, for HPV types including HPV16, the P value was 0.01 for persistence and 0.07 for CIN3+. Excluding HPV16, the P values were 0.04 and 0.37, respectively. For HPV16, non-European viral variants were significantly more likely than European variants to cause persistence [odds ratio (OR), 2.6; P = 0.01] and CIN3+ (OR, 2.4; P = 0.004). HPV35 and HPV51 variant lineages also predicted CIN3+. HPV variants generally differ in risk of persistence. For some HPV types, especially HPV16, variant lineages differ in risk of CIN3+. The findings indicate that continued evolution of HPV types has led to even finer genetic discrimination linked to HPV natural history and cervical cancer risk. Larger viral genomic studies are warranted, especially to identify the genetic basis for HPV16's unique carcinogenicity.

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. 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 > or =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. RESULTS: Regardless 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 > or =42 years, rates were 35.9%, 30.6%, 18.1%, and 13.5%, respectively; P < .001). Among prevalent infections, persistent infections among older women (> or =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. CONCLUSIONS: The 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.

Short term persistence of human papillomavirus and risk of cervical precancer and cancer: population based cohort study.

OBJECTIVE: To evaluate the cumulative incidence of cervical intraepithelial neoplasia II or worse (grade II+) or cervical intraepithelial neoplasia grade III+ after short term persistence of prevalently detected carcinogenic human papillomavirus (HPV). DESIGN: Population based cohort study. SETTING: Guanacaste, Costa Rica. PARTICIPANTS: 2282 sexually active women actively followed after enrolment. MAIN OUTCOME MEASURES: Primary end points: three year and five year cumulative incidence of histologically confirmed cervical intraepithelial neoplasia grade II+ (n=70). Cervical specimens collected at each visit tested for more than 40 HPV genotypes. HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, and 82 were considered the primary carcinogenic genotypes. RESULTS: Women who tested positive for a carcinogenic HPV at enrolment and after about one year (9-21 months) (positive/positive) had a three year cumulative incidence of cervical intraepithelial neoplasia grade II+ of 17.0% (95% confidence interval 12.1% to 22.0%). Those who tested negative/positive (3.4%, 0.1% to 6.8%), positive/negative (1.2%, -0.2% to 2.5%), and negative/negative (0.5%, 0.1% to 0.9%) were at a significantly lower risk. There was little difference in the cumulative incidence of cervical intraepithelial neoplasia grade II+ between testing positive twice for any carcinogenic HPV genotype (same genotype or different genotypes) v testing positive twice for the same carcinogenic genotype (17.0% v 21.3%, respectively). Short term persistence of HPV 16 strongly predicted cervical intraepithelial neoplasia grade II+, with a three year cumulative incidence of 40.8% (26.4% to 55.1%). Similar patterns were observed for the five year cumulative incidence of grade II+ and for three year and five year cumulative incidence of grade III+. CONCLUSIONS: Short term persistence of a prevalently detected carcinogenic HPV infection, especially HPV 16, strongly predicts a subsequent diagnosis of cervical intraepithelial neoplasia II+ over the next few years.

Neither one-time negative screening tests nor negative colposcopy provides absolute reassurance against cervical cancer.

A population sample of 10,049 women living in Guanacaste, Costa Rica, was recruited into a natural history of human papillomavirus (HPV) and cervical neoplasia study in 1993-1994. At the enrollment visit, we applied multiple state-of-the-art cervical cancer screening methods to detect prevalent cervical cancer and to prevent subsequent cervical cancers by the timely detection and treatment of precancerous lesions. Women were screened at enrollment with 3 kinds of cytology (often reviewed by more than one pathologist), visual inspection and cervicography. Any positive screening test led to colposcopic referral and biopsy and/or excisional treatment of CIN2 or worse. We retrospectively tested stored specimens with an early HPV test (hybrid capture tube test) and for >40 HPV genotypes using a research PCR assay. We followed women typically 5-7 years and some up to 11 years. Nonetheless, 16 cases of invasive cervical cancer were diagnosed during follow-up. Six cancer cases were failures at enrollment to detect abnormalities by cytology screening; 3 of the 6 were also negative at enrollment by sensitive HPV DNA testing. Seven cancers represent failures of colposcopy to diagnose cancer or a precancerous lesion in screen-positive women. Finally, 3 cases arose despite attempted excisional treatment of precancerous lesions. Based on this evidence, we suggest that no current secondary cervical cancer prevention technologies applied once in a previously under-screened population is likely to be 100% efficacious in preventing incident diagnoses of invasive cervical cancer.

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.

CIN2 is a much less reproducible and less valid diagnosis than CIN3: results from a histological review of population-based cervical samples.

We wished to compare the relative reproducibility and validity of cervical intraepithelial neoplasia (CIN) 2 and CIN3 diagnoses. In a population-based cohort study (1993-2001) of human papillomavirus (HPV) and cervical neoplasia in Costa Rica, we compared community pathologists' diagnoses with those of the 2 independent reviewers from the United States (total, n = 357). As measures of validity, we correlated primary and review diagnoses with HPV positivity and cytological interpretations. Two review pathologists agreed with 84% and 81%, respectively, of initial diagnoses of CIN3 compared with 13% and 31% of CIN2. The CIN3 diagnoses made by review pathologists were 94% oncogenic HPV positive, compared with 72% of CIN2 diagnoses. Eighty-one percent of CIN3 diagnoses versus 61% of CIN2 were correlated with high-grade cytological interpretations. The CIN3 is a substantially more reproducible diagnosis that can be validated more frequently with HPV tests and cytological interpretations than CIN2.

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 3.6 years after initiation of sexual life. RESULTS: A total of 53.4% of women tested positive during the study for > or =1 HPV type. Very few infections persisted for >1 to 2 years. Three women had histologically confirmed CIN 3, of which 2 showed persistent HPV 16. The other had serologic evidence of HPV 31. CONCLUSIONS: HPV infection occurs frequently and clears rapidly in most young women initiating sexual intercourse. Persistent HPV 16 can cause early CIN 3. The peak age for CIN 3 will decline with the increased screening intensity and sensitivity typical of longitudinal studies.

The carcinogenicity of human papillomavirus types reflects viral evolution.

Persistent infections with carcinogenic human papillomaviruses (HPV) cause virtually all cervical cancers. Cervical HPV types (n > 40) also represent the most common sexually transmitted agents, and most infections clear in 1-2 years. The risks of persistence and neoplastic progression to cancer and its histologic precursor, cervical intraepithelial neoplasia grade 3 (CIN3), differ markedly by HPV type. To study type-specific HPV natural history, we conducted a 10,000-woman, population-based prospective study of HPV infections and CIN3/cancer in Guanacaste, Costa Rica. By studying large numbers of women, we wished to separate viral persistence from neoplastic progression. We observed a strong concordance of newly-revised HPV evolutionary groupings with the separate risks of persistence and progression to CIN3/cancer. HPV16 was uniquely likely both to persist and to cause neoplastic progression when it persisted, making it a remarkably powerful human carcinogen that merits separate clinical consideration. Specifically, 19.9% of HPV16-infected women were diagnosed with CIN3/cancer at enrollment or during the five-year follow-up. Other carcinogenic types, many related to HPV16, were not particularly persistent but could cause neoplastic progression, at lower rates than HPV16, if they did persist. Some low-risk types were persistent but, nevertheless, virtually never caused CIN3. Therefore, carcinogenicity is not strictly a function of persistence. Separately, we noted that the carcinogenic HPV types code for an E5 protein, whereas most low-risk types either lack a definable homologous E5 ORF and/or a translation start codon for E5. These results present several clear clues and research directions in our ongoing efforts to understand HPV carcinogenesis.

Trasplante de órganos: medio siglo de reflexión ética / Organ transplantation: mediun century of ethical reflection

En el presente artículo se analizan algunos de los problemas éticos que han ido planteando la donación y trasplante de órganos a lo largo de su historia, y cómo se han resuelto. Esos problemas han sido diferentes según la propia evolución de las técnicas

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. METHODS: A cohort of 10 049 randomly selected women from 18 to 97 years old from Guanacaste, a province in northwestern Costa Rica, was intensively screened in 1993-1994 and then followed up for seven years after being enrolled. A questionnaire for demographic and risk factors was administered, and a pelvic examination was performed on sexually active women at each follow-up visit in order to obtain samples for screening tests and for research purposes. The final diagnosis given at the end of the enrollment phase categorized women into several groups according to the perceived risk of their developing either high-grade precursors of cancer or cancer. These groups were followed up at different intervals according to the risk of developing > or = CIN 2. The most active follow-up (every 6-12 months) was concentrated on the women most likely to develop >or = CIN 2, based on cytology (n = 492). The remainder of the cohort was followed either annually (n = 2 574) or after five to seven years of passive follow-up (n = 3 926). All women with possibly severe lesions detected by any technique were referred to colposcopy for further evaluation and treatment, and they were also censored from the study. Lesions >or = CIN 2 served as both the censoring outcome and our surrogate for cancer risk. RESULTS: Participation during follow-up was high (near 90%). Suspected > or = CIN 2 by any screening technique censored 4.6% of women. Most of the women censored because of suspected > or = CIN 2 came from the large group perceived at entry as being at low risk of developing > or = CIN 2, but the greatest rates of progression to > or = CIN 2 were observed among women perceived at entry to be at highest risk of > or = CIN 2, based on their cytology, virology, or sexual behavior. CONCLUSIONS: The GP is the largest population-based longitudinal cohort for the study of HPV and cervical neoplasia in the world, and its results will hopefully let us soon plan future worldwide prevention strategies. Research projects such as this one require the long-term commitment of a large multidisciplinary team and ample financial resources. The intensive effort and expertise applied in all aspects of this study were key factors in its success as a model of cooperative, interdisciplinary cancer research in Latin America. Quality control played an important role at all times during the study and made it possible to adapt new diagnostic and screening technology to Guanacaste. The systematic follow-up of a population-based group of close to 10 000 women in Guanacaste should permit careful, time-dependent evaluation of factors postulated to be linked to the development of cervical cancer as well as the evaluation of clinical markers of disease progression. The study results that have already been published have validated sensitive screening techniques and have also promoted the use of more affordable screening techniques in resource-poor, developing countries. The GP has also contributed to building knowledge for the search for vaccines against HPV as part of the effort to develop an effective tool to reduce the incidence and mortality of cervical cancer worldwide.

Description of a seven-year prospective study of human papillomavirus infection and cervical neoplasia among 10 000 women in Guanacaste, Costa Rica / Descripción de un estudio prospectivo de siete años sobre la infección por el virus del papiloma humano y el cáncer cervicouterino en 10 000 mujeres de Guanacaste, Costa Rica

OBJETIVOS: El estudio de cohorte de Guanacaste, o Proyecto Epidemiológico Guanacaste, fue diseñado para investigar el papel que desempeñan la infección por el virus del papiloma humano (VPH) y sus cofactores en el desarrollo de neoplasias cervicouterinas y para evaluar nuevas tecnologías de tamizaje del cáncer del cuello de útero. La fase de seguimiento de este proyecto se diseñó para analizar por qué una pequeña parte de las mujeres infectadas por el VPH desarrollan neoplasias intraepiteliales cervicouterinas (NIC) grados 2 y 3, o cáncer (que en lo adelante se llamarán en conjunto > NIC 2, es decir, NIC 2 o peor). El propósito de este artículo es describir en detalle ese estudio prospectivo y presentar los resultados preliminares relacionados con la incidencia de neoplasias cervicouterinas. MÉTODOS: Se realizó el tamizaje intensivo de una cohorte de 10 049 mujeres de 18 a 97 años de edad seleccionadas aleatoriamente en Guanacaste, provincia del noroeste de Costa Rica, en 1993-1994 con un seguimiento ulterior de siete años. A las participantes se les aplicó un cuestionario para conocer sus características demográficas y sus factores de riesgo, y a las sexualmente activas se les realizó además un examen pélvico en cada una de las visitas de seguimiento, a fin de obtener muestras para las pruebas de tamizaje y la investigación. El diagnóstico obtenido al final de la fase de captación permitió clasificar a las mujeres en varios grupos de acuerdo con el riesgo que presentaban de desarrollar cáncer o alguno de sus precursores de alto grado. Estos grupos tuvieron seguimientos a intervalos diferentes, según su riesgo de desarrollar > NIC 2. El seguimiento más activo (cada 6-12 meses) se concentró en las mujeres con mayores probabilidades de desarrollar > NIC 2, según los resultados citológicos (n = 492). Las mujeres restantes recibieron visitas de seguimiento anualmente (n = 2 574) o después de cinco a siete años de seguimiento pasivo (n = 3 926). A todas las mujeres en quienes se detectaron lesiones que pudieran ser graves, por cualquiera de las técnicas empleadas, se les remitió a una evaluación ulterior mediante colposcopia y a tratamiento médico, y se retiraron del estudio. Las lesiones > NIC 2 se utilizaron como criterio para la salida del estudio y como indicadores indirectos del riesgo de cáncer. RESULTADOS: La participación durante la fase de seguimiento fue alta (cercana al 90%). Cualquier indicio de > NIC 2, según cualquiera de las técnicas...

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 ≥ 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. Methods. A cohort of 10 049 randomly selected women from 18 to 97 years old from Guanacaste, a province in northwestern Costa Rica, was intensively screened in 1993­1994 and then followed up for seven years after being enrolled. A questionnaire for demographic and risk factors was administered, and a pelvic examination was performed on sexually active women at each follow-up visit in order to obtain samples for screening tests and for research purposes. The final diagnosis given at the end of the enrollment phase categorized women into several groups according to the perceived risk of their developing either high-grade precursors of cancer or cancer. These groups were followed up at different intervals according to the risk of developing ≥ CIN 2. The most active follow-up (every 6­12 months) was concentrated on the women most likely to develop ≥ CIN 2, based on cytology (n = 492). The remainder of the cohort was followed either annually (n = 2 574) or after five to seven years of passive follow-up (n = 3 926). All women with possibly severe lesions detected by any technique were referred to colposcopy for further evaluation and treatment, and they were also censored from the study. Lesions ≥ CIN 2 served as both the censoring outcome and our surrogate for cancer risk. Results. Participation during follow-up was high (near 90%). Suspected ≥ CIN 2 by any screening technique censored 4.6% of women. Most of the women censored because of suspected ≥ CIN 2 came from the large group perceived at entry as being at low risk of developing ≥ CIN 2, but the greatest rates of progression to ≥ CIN 2 were observed among women perceived at entry to be at highest risk of ≥ CIN 2, based on their cytology, virology, or sexual behavior. Conclusions. The GP is the largest population-based longitudinal cohort for the study of HPV and cervical neoplasia in the world, and its results will hopefully let us soon plan future worldwide prevention strategies. Research projects such as this one require the long-term commitment of a large multidisciplinary team and ample financial resources. The intensive effort and expertise applied in all aspects of this study were key factors in its success as a model of cooperative, interdisciplinary cancer research in Latin America. Quality control played an important role at all times during the study and made it possible to adapt new diagnostic and screening technology to Guanacaste. The systematic follow-up of a population-based group of close to 10 000 women in Guanacaste should permit careful, time-dependent evaluation of factors postulated to be linked to the development of cervical cancer as well as the evaluation of clinical markers of disease progression. The study results that have already been published have validated sensitive screening techniques and have also promoted the use of more affordable screening techniques in resource-poor, developing countries. The GP has also contributed against HPV as part of the effort to develop an effective tool to reduce the incidence and mortality of cervical cancer worldwide