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Lifetime number of sex partners, marital status, and history of sexually transmitted disease were associated with human papillomavirus (HPV) acquisition among women without prior exposure to HPV infection, with no observed differences in risk determinants patterns for HPV infections by length of follow-up. Supplemental digital content is available in the text., Background Global variation in human papillomavirus (HPV) prevalence and persistence may be explained by differences in risk factors, such as sexual activity, oral contraceptive use, and behavioral factors. We evaluated determinants of acquisition and clearance of HPV infection among young women previously unexposed to HPV. Methods Five hundred thirty-four women aged 15 to 25 years who were cytology and HPV DNA negative, and seronegative for anti-HPV-16/18 antibodies, were recruited (July 2000–September 2001) from study centers in Brazil, the United States, and Canada (NCT00689741/NCT00120848). They were followed up for 76 months. Cervical samples were HPV genotyped via polymerase chain reaction. We used multivariable (forward stepwise, P = 0.15) Cox proportional hazards regression to estimate rate ratios (RR) and 95% confidence intervals (CI), separately according to length of follow-up time. Results On short-term follow-up (0–27 months), 257 (48%; 8535.80 person-months; incidence rate = 30.11; 95% CI, 26.64–34.02) incident HPV infections were detected. Marital status, lifetime number of sex partners, history of any sexually transmitted disease, and occasional use of oral contraceptives were strongly associated with acquisition of any HPV. Having 2 or more lifetime sex partners (RR, 2.03; 95% CI, 1.37–3.02) and a history of any sexually transmitted disease (RR, 1.98; 95% CI, 1.19–3.29) were the most important determinants of high-risk HPV (hrHPV) incidence. During the entire follow-up (0–76 months), an increased hrHPV clearance was found among women in North America (RR, 1.38; 95% CI, 1.08–1.78) and black women (RR, 1.64; 95% CI, 1.04–2.60). Greater number of lifetime partners was associated with reduced clearance rates for any HPV (RR, 0.65; 95% CI, 0.43–0.98). Conclusions We identified variation in risk of HPV acquisition and clearance among women unexposed to HPV at baseline.

Objective To analyze the acceptability, safety, and effectiveness of thermocoagulation for the treatment of histologically proven cervical intraepithelial neoplasia grade 2–3 (CIN2–3) lesions. Methods In a retrospective study, data were obtained for women treated for CIN2–3 lesions by thermocoagulation at the Hospital de Clinicas de Porto Alegre, Brazil, between March 6, 2012, and October 29, 2013, and followed up after 1 year. The proportions of women with no evidence of disease, adverse effects, or complications were determined. Results Among 52 women included, 44 (85%) had no evidence of disease 1 year after thermocoagulation. The rate of no disease at follow-up was similar for women treated for CIN2 (17/20 [85%]) and CIN3 (27/32 [84%]). No serious adverse effects or complications requiring hospitalization were observed during the follow-up period. Conclusion Thermocoagulation is useful in the management of ectocervical CIN and should be integrated into public health services for management of cervical cancer.

Summary 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).

The efficacy of the human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against cervical infections with HPV in the Pa pilloma Tri al against C ancer i n Young A dults (PATRICIA) was evaluated using a combination of the broad-spectrum L1-based SPF 10 PCR-DNA enzyme immunoassay (DEIA)/line probe assay (LiPA 25 ) system with type-specific PCRs for HPV-16 and -18. Broad-spectrum PCR assays may underestimate the presence of HPV genotypes present at relatively low concentrations in multiple infections, due to competition between genotypes. Therefore, samples were retrospectively reanalyzed using a testing algorithm incorporating the SPF 10 PCR-DEIA/LiPA 25 plus a novel E6-based multiplex type-specific PCR and reverse hybridization assay (MPTS12 RHA), which permits detection of a panel of nine oncogenic HPV genotypes (types 16, 18, 31, 33, 35, 45, 52, 58, and 59). For the vaccine against HPV types 16 and 18, there was no major impact on estimates of vaccine efficacy (VE) for incident or 6-month or 12-month persistent infections when the MPTS12 RHA was included in the testing algorithm versus estimates with the protocol-specified algorithm. However, the alternative testing algorithm showed greater sensitivity than the protocol-specified algorithm for detection of some nonvaccine oncogenic HPV types. More cases were gained in the control group than in the vaccine group, leading to higher point estimates of VE for 6-month and 12-month persistent infections for the nonvaccine oncogenic types included in the MPTS12 RHA assay (types 31, 33, 35, 45, 52, 58, and 59). This post hoc analysis indicates that the per-protocol testing algorithm used in PATRICIA underestimated the VE against some nonvaccine oncogenic HPV types and that the choice of the HPV DNA testing methodology is important for the evaluation of VE in clinical trials. (This study has been registered at ClinicalTrials.gov under registration no. NCT00122681.)

HPV-023 (NCT00518336; ClinicalTrial.gov) is a long-term follow-up of an initial double-blind, randomized (1:1), placebo-controlled study (HPV-001, NCT00689741) evaluating the efficacy against human papillomavirus (HPV)-16/18 infection and associated cyto-histopathological abnormalities, persistence of immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine. Among the women, aged 15–25 years, enrolled in HPV-001 and who participated in the follow-up study HPV-007 (NCT00120848), a subset of 437 women from five Brazilian centers participated in this 36-month long-term follow-up (HPV-023) for a total of 113 months (9.4 years). During HPV-023, anti-HPV-16/18 antibodies were measured annually by enzyme-linked immunosorbent assay (ELISA) and pseudovirion-based neutralisation assay (PBNA). Cervical samples were tested for HPV DNA every 6 months, and cyto-pathological examinations were performed annually. During HPV-023, no new HPV-16/18-associated infections and cyto-histopathological abnormalities occurred in the vaccine group. Vaccine efficacy (VE) against HPV-16/18 incident infection was 100% (95%CI: 66.1, 100). Over the 113 months (9.4 years), VE was 95.6% (86.2, 99.1; 3/50 cases in vaccine and placebo groups, respectively) against incident infection, 100% (84·1, 100; 0/21) against 6-month persistent infection (PI); 100% (61·4, 100; 0/10) against 12-month PI; 97·1% (82.5, 99.9; 1/30) against ≥ ASC-US; 95·0% (68.0, 99.9; 1/18) against ≥ LSIL; 100% (45.2, 100; 0/8) against CIN1+; and 100% (–128.1, 100; 0/3) against CIN2+ associated with HPV-16/18. All vaccinees remained seropositive to HPV-16/18, with antibody titers remaining several folds above natural infection levels, as measured by ELISA and PBNA. There were no safety concerns. To date, these data represent the longest follow-up reported for a licensed HPV vaccine.

We evaluated the efficacy of the human papillomavirus (HPV)−16/18 AS04‐adjuvanted vaccine in preventing HPV‐related disease after surgery for cervical lesions in a post‐hoc analysis of the PApilloma TRIal against Cancer In young Adults (PATRICIA; NCT00122681). Healthy women aged 15–25 years were randomized (1:1) to receive vaccine or control at months 0, 1 and 6 and followed for 4 years. Women were enrolled regardless of their baseline HPV DNA status, HPV‐16/18 serostatus, or cytology, but excluded if they had previous or planned colposcopy. The primary and secondary endpoints of PATRICIA have been reported previously; the present post‐hoc analysis evaluated efficacy in a subset of women who underwent an excisional procedure for cervical lesions after vaccination. The main outcome was the incidence of subsequent HPV‐related cervical intraepithelial neoplasia grade 2 or greater (CIN2+) 60 days or more post‐surgery. Other outcomes included the incidence of HPV‐related CIN1+, and vulvar or vaginal intraepithelial neoplasia (VIN/VaIN) 60 days or more post‐surgery. Of the total vaccinated cohort of 18,644 women (vaccine = 9,319; control = 9,325), 454 (vaccine = 190, control = 264) underwent an excisional procedure during the trial. Efficacy 60 days or more post‐surgery for a first lesion, irrespective of HPV DNA results, was 88.2% (95% CI: 14.8, 99.7) against CIN2+ and 42.6% (−21.1, 74.1) against CIN1+. No VIN was reported and one woman in each group had VaIN2+ 60 days or more post‐surgery. Women who undergo surgical therapy for cervical lesions after vaccination with the HPV‐16/18 vaccine may continue to benefit from vaccination, with a reduced risk of developing subsequent CIN2+., What's new? Persistent infection with oncogenic human papillomavirus (HPV) is a pre‐requisite for cervical cancer, with women who have already undergone treatment for related cervical lesions representing a high‐risk group for the subsequent development of cervical cancer. To date, HPV vaccination is not thought to alter the course of disease in women with prevalent type‐specific infections or pre‐existing lesions at the time of vaccination. This post‐hoc analysis of a randomized controlled trial however shows that women who undergo surgery for cervical lesions after receiving the HPV‐16/18 AS04‐adjuvanted vaccine may continue to benefit from vaccination, with a reduced risk of developing subsequent high‐grade cervical disease.

ObjectiveWe evaluated baseline data from the PApilloma TRIal against Cancer In young Adults (PATRICIA; NCT00122681) on the association between behavioral risk factors and HPV infection and cervical abnormalities.MethodsWomen completed behavioral questionnaires at baseline. Prevalence of HPV infection and cervical abnormalities (detected by cytological or histological procedures) and association with behavioral risk factors were analyzed by univariate and stepwise multivariable logistic regressions.Results16782 women completed questionnaires. Among 16748 women with data for HPV infection, 4059 (24.2%) were infected with any HPV type. Among 16757 women with data for cytological abnormalities, 1626 (9.7%) had a cytological abnormality, of whom 1170 (72.0%) were infected with at least one oncogenic HPV type including HPV-16 (22.7%) and HPV-18 (9.3%). Multivariable analysis (adjusted for age and region, N=14404) showed a significant association between infection with any HPV type and not living with a partner, smoking, age

In the Phase III PATRICIA study (NCT00122681), the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix(®), GlaxoSmithKline Biologicals) was highly efficacious against HPV-16/18 infections and precancerous lesions in women HPV-16/18 deoxyribose nucleic acid (DNA) negative and seronegative at baseline. We present further data on vaccine efficacy (VE) against HPV-16/18 in the total vaccinated cohort including women who may have been exposed to HPV-16/18 infection before vaccination. In women with no evidence of current or previous HPV-16/18 infection (DNA negative and seronegative), VE was 90.3% (96.1% confidence interval: 87.3-92.6) against 6-month persistent infection (PI), 91.9% (84.6-96.2) against cervical intraepithelial neoplasia (CIN)1+ and 94.6% (86.3-98.4) against CIN2+ [97.7% (91.1-99.8) when using the HPV type assignment algorithm (TAA)]. In women HPV-16/18 DNA negative but with serological evidence of previous HPV-16/18 infection (seropositive), VE was 72.3% (53.0-84.5) against 6-month PI, 67.2% (10.9-89.9) against CIN1+, and 68.8% (-28.3-95.0) against CIN2+ [88.5% (10.8-99.8) when using TAA]. In women with no evidence of current HPV-16/18 infection (DNA negative), regardless of their baseline HPV-16/18 serological status, VE was 88.7% (85.7-91.1) against 6-month PI, 89.1% (81.6-94.0) against CIN1+ and 92.4% (84.0-97.0) against CIN2+ [97.0% (90.6-99.5) when using TAA]. In women who were DNA positive for one vaccine type, the vaccine was efficacious against the other vaccine type. The vaccine did not impact the outcome of HPV-16/18 infections present at the time of vaccination. Vaccination was generally well tolerated regardless of the woman's HPV-16/18 DNA or serological status at entry.

To determine the prevalence of cervical human papillomavirus (HPV) infection and risk factors in young women from Brazil, Canada, and the USA. Cross-sectional study in 3204 healthy women, aged 15 to 25 years. Cervical samples were collected for cytology and for HPV DNA detection (SPF 10-LiPA 25 system). Serum samples were collected for the measurement of HPV-16 and HPV-18 antibodies by enzyme-linked immunosorbent assay. Risk factors were obtained through a questionnaire. Overall, 26.6% of women had DNA detected for at least 1 HPV type. The prevalence for oncogenic HPV types was 21.7% (25% in Brazil, 16.9% in Canada, and 19.1% in the USA). HPV-16 was the most prevalent oncogenic type (5.2%). The next most common oncogenic HPV types were 51 (3.3%), 52 (3.3%), 31 (2.9%), 66 (2.3%), and 39 (2.0%). Multiple oncogenic types were detected in one-third of the infections. The prevalence of HPV-16 and/or HPV-18 infections detected by DNA and/or enzyme-linked immunosorbent assay was 24.8%. The majority of women (85%) had a normal cervical cytology. Sexual behavior was the main determinant for HPV-16/18 infections and squamous intraepithelial lesions. The prevalence of HPV oncogenic infections was high and linked to sexual behavior. Strategies to reduce the burden of oncogenic HPV infection, such as prophylactic vaccination programs, are likely to impact the burden of disease due to cervical precancer and cancer.

The performance of cervical cancer (CC) screening can be improved by combining Pap smear with human papillomavirus (HPV) testing or visual methods, addressing local demographic, clinical and economic characteristics., The NIS Cohort study was supported by the INCO-CopernicusProgramoftheEuropeanCommission(Contract No. ERB IC15-CT98 – 0321), and the LAMSstudy by the European Commission, INCO-DEV Program(Contract# ICA4-CT-2001 – 10013). We express specialthanks to the former Digene Corp. for providing theHybrid Capture analyser, samplers and the test kits at ourdisposal. We express our thanks to all women who partici-pated in these two cohort studies. Finally, all the membersof the NIS and LAMS Study research groups are acknowl-edged for their invaluable contribution to these studies.

We report efficacy and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine up to 7.3 years post-vaccination. The study was conducted in a population (N=433) of women enrolled in Brazilian centres from an initial placebo-controlled study. Women were aged 15-25 years at first vaccination. During the most recent year of follow-up, approximately 7 years after initial vaccination, no cases of infection or cytohistological lesions associated with HPV-16/18 were observed in the vaccinees. Vaccine efficacy (95% confidence interval) up to 7.3 years was 94.5% (82.9, 98.9) for incident infection, 100% (55.7, 100) for 12-month persistent infection and 100% (-129.8, 100) for cervical intraepithelial neoplasia grade 2+. Antibody titres for total IgG and neutralising antibodies remained several folds above natural infection levels and >or=96% of women were seropositive. Vaccine safety was similar to placebo. This is the longest follow-up study for a licensed cervical cancer vaccine.

Our objective was to assess whether neutrophil gelatinase-associated lipocalin (NGAL)/lipocalin 2 (LCN2) expression in cervical human papillomavirus (HPV) lesions has implications on the outcome of HPV infections or disease progression. Cervical biopsy specimens from 225 women in the Latin American Screening study were analyzed for NGAL/LCN2 expression using immunohistochemical analysis, to assess associations with cervical intraepithelial neoplasia (CIN) grade, high-risk HPV, and in predicting outcomes of high-risk (HR)-HPV infections. Expression of NGAL/LCN2 increased with lesion grade (odds ratio [OR], 3.86; 95% confidence interval [CI], 1.53-9.71; P = .001). Up-regulation was also related to HR-HPV detection (OR, 2.21; 95% CI, 1.15-4.24; P = .016) and showed a linear relationship to HR-HPV load (P = .002). NGAL/LCN2 expression was of no value in predicting the outcomes of HR-HPV infections or the surrogate end points (incident CIN 1+ and CIN 2+) of progressive disease. Because the SV40 large T antigen is a powerful up-regulator of this lipocalin, up-regulation of NGAL/LCN2 in CIN is probably induced by HR-HPV E6 oncoprotein, most likely by eliminating its normal transcription repression exerted by wild-type p53., This study is part of the Latin American Screening Study and was funded by the European Commission, INCO-DEV contract ICA4-CT-2001-10013.

Protease inhibitor serpin-B2 (plasminogen activator inhibitor-2 [PAI-2]) protects pRb from degradation in human papillomavirus (HPV)-18+ HeLa cells. Our objective was to assess whether the pRb-mediated HPV-suppressive effect of PAI-2 in cancer cell lines has implications in the outcome of HPV infections. Cervical biopsy specimens from 225 women were analyzed for PAI-2 expression to assess its value as a predictor of cervical intraepithelial neoplasia (CIN) grade, high-risk (HR) HPV at baseline, outcomes of HR-HPV infections, and the development of incident CIN. PAI-2 expression increased in parallel with lesion grade. Nuclear PAI-2 expression was significantly related to HR-HPV detection and had a linear relationship with HR-HPV load. PAI-2 expression was of no value in predicting the outcomes of HR-HPV infections. The same was true for PAI-2 as a predictor of surrogate end points (incident CIN 1+, CIN 2+) of progressive disease. PAI-2 expression is up-regulated on transition from CIN 2 to CIN 3. The HR-HPV suppressive effects of PAI-2 were not related to more favorable outcomes of HR-HPV infections or lower risk of disease progression to CIN., Supported by the European Commission, INCO-DEV Programme (contract ICA4-CT-2001-10013).

Prophylactic human papillomavirus (HPV) vaccines have to provide sustained protection. We assessed efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years.Women aged 15-25 years, with normal cervical cytology, who were HPV-16/18 seronegative and oncogenic HPV DNA-negative (14 types) at screening participated in a double-blind, randomised, placebo-controlled initial study (n=1113; 560 vaccine group vs 553 placebo group) and follow-up study (n=776; 393 vs 383). 27 sites in three countries participated in the follow-up study. Cervical samples were tested every 6 months for HPV DNA. Management of abnormal cytologies was prespecified, and HPV-16/18 antibody titres were assessed. The primary objective was to assess long-term vaccine efficacy in the prevention of incident cervical infection with HPV 16 or HPV 18, or both. We report the analyses up to 6.4 years of this follow-up study and combined with the initial study. For the primary endpoint, the efficacy analysis was done in the according-to-protocol (ATP) cohort; the analysis of cervical intraepithelial neoplasia grade 2 and above (CIN2+) was done in the total vaccinated cohort (TVC). The study is registered with ClinicalTrials.gov, number NCT00120848.For the combined analysis of the initial and follow-up studies, the ATP efficacy cohort included 465 women in the vaccine group and 454 in the placebo group; the TVC included 560 women in the vaccine group and 553 in the placebo group. Vaccine efficacy against incident infection with HPV 16/18 was 95.3% (95% CI 87.4-98.7) and against 12-month persistent infection was 100% (81.8-100). Vaccine efficacy against CIN2+ was 100% (51.3-100) for lesions associated with HPV-16/18 and 71.9% (20.6-91.9) for lesions independent of HPV DNA. Antibody concentrations by ELISA remained 12-fold or more higher than after natural infection (both antigens). Safety outcomes were similar between groups: during the follow-up study, 30 (8%) participants reported a serious adverse event in the vaccine group versus 37 (10%) in the placebo group. None was judged related or possibly related to vaccination, and no deaths occurred.Our findings show excellent long-term efficacy, high and sustained immunogenicity, and favourable safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years.GlaxoSmithKline Biologicals (Belgium).

Background: The purpose of this study was to assess the effect of smoking on the prevalence and incidence of high-risk human papillomavirus (hr-HPV) infection and cervical intraepithelial neoplasia (CIN) in a large sample of Latin American women. Methods: The study examines baseline data on over 12,000 women included in the Latin American Screening Study (Brazil and Argentina), and over 1000 women followed-up for a period of 36 months. Three groups were formed: never smokers, current, and past smokers. The prevalence of hr-HPV infection and CIN were compared between the study groups. In the prospective analysis, women were controlled at 6-month intervals to assess the cumulative risk of incident hr-HPV infection, smear abnormalities, and CIN. Results: A higher prevalence (21.7%) of hr-HPV infection was found among current smokers as compared to never smokers (16.5%) or past smokers (13.5%). Being current smoker was significantly (P, Supported by the INCO-DEV Program of the European Commission (Project No. ICA4-CT-2001-10013).

Drug abuse (addiction) has been listed among the risk factors for human papillomavirus (HPV) infections, but no case-control studies exist to rule out sexual behaviour and other potential confounders. The aim of this study is to evaluate the role of drug addiction as an independent predictor of HR-HPV infections and (cervical intraepithelial neoplasia) CIN2+ in an age-matched case-control (1:4) study nested within the prospective Latin American Screening (LAMS) study cohort. All 109 women in the LAMS cohort (n=12,114) reporting drug abuse/addiction were matched with four controls (n = 436) of non-abusers strictly by age. Conditional logistic regression analysis was used to estimate the co-variates of drug abuse, and the whole series (n=545) was analysed for predictors of HR-HPV and CIN2+ using univariate and multivariate regression models. Oncogenic HPV infections were significantly (P=0.019) more prevalent among abusers (37.7%) than in controls (21.9%), but there was no difference in high-grade squamous intraepithelial lesions (P=0.180) or CIN2+ lesions (P=0.201). In multivariate conditional logistic regression, number of lifetime sexual partners (P=0.0001), ever smokers (P=0.0001), non-use of OCs (P=0.013), ever having sexually transmitted diseases (STD) (P=0.041) and no previous Pap smear (P=0.027) were independent co-variates of drug addiction. Drug abuse was not an independent risk factor of high-risk (HR)-HPV infection, which was significantly predicted by (1) age below 30 years (P=0.045), (2) more than five lifetime sexual partners (P=0.046) and (3) being current smoker (P=0.0001). In multivariate model, only HR-HPV infection was an independent risk factor of CIN2+ (P=0.031), with adjusted OR=11.33 (95% CI 1.25-102.50). These data indicate that drug addiction is not an independent risk factor of either HR-HPV infections or CIN2+, but the increased prevalence of HR-HPV infections is explained by the high-risk sexual behaviour and smoking habits of these women., European Commission (LAMS denotes Latin American Screening study funded by European Commission), INCO-DEV Programme (Contract No. ICA4-CT-2001-10013). The generous contribution of DIGENE Inc. (USA) donating the HCII tests at our disposal is gratefully acknowledged

To evaluate the population of macrophages during the cervical malignant transformation and its influence in CIN outcome.Biopsies from 26 normal cervix, 28 low-grade (LSIL), 30 high grade squamous intraepithelial lesions (HSIL) and 28 squamous cell carcinomas (SCC) were stained by HE to assess inflammation and by immunohistochemistry with anti-CD68 to detect macrophages. The macrophage count was corrected for the epithelial and stromal compartments using appropriate software. Clinical and prospective follow-up data were also available.We identified that macrophage count increased linearly with disease progression (median count per case at x200 magnification: normal, 5.1; LSIL, 5.5; HSIL, 9.9; SCC, 14.5; P0.001), that inflammation also increased (moderate-intense inflammation present in 25%, 46.1%, 58.4% and 89.3% of normal, LSIL, HSIL and SCC, respectively; P0.001) and that macrophage count was independently associated with the lesion grade (P0.001). Moreover, macrophages showed an increasing migration into the epithelium along with the progression of CIN to invasive cancer. Of the 24 LSIL cases with information available, followed-up for 805+/-140 days, 16 regressed, 6 persisted and 2 progressed. Age, high-risk HPV or inflammation were not risk factors for persistent/progressed LSIL in our cohort. However, LSIL that persisted or progressed showed a higher macrophage count (median of 10.8) than lesions that regressed (7; P=0.031).The study on macrophages offers a potential approach for cervical cancer treatment, since macrophages are closely related to progression of CIN, and can be used as an applicable marker of such a risk.

We report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ((HPV-16/18) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults (PATRICIA). The total vaccinated cohort (TVC) included all randomized participants who received at least one vaccine dose (vaccine, n = 9,319; control, n = 9,325) at months 0, 1, and/or 6. The TVC-naive (vaccine, n = 5,822; control, n = 5,819) had no evidence of high-risk HPV infection at baseline, approximating adolescent girls targeted by most HPV vaccination programs. Mean follow-up was approximately 39 months after the first vaccine dose in each cohort. At baseline, 26% of women in the TVC had evidence of past and/or current HPV-16/18 infection. HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds. In the TVC, vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or greater (CIN1+), CIN2+, and CIN3+ associated with HPV-16/18 was 55.5% (96.1% confidence interval [CI], 43.2, 65.3), 52.8% (37.5, 64.7), and 33.6% (−1.1, 56.9). VE against CIN1+, CIN2+, and CIN3+ irrespective of HPV DNA was 21.7% (10.7, 31.4), 30.4% (16.4, 42.1), and 33.4% (9.1, 51.5) and was consistently significant only in 15- to 17-year-old women (27.4% [10.8, 40.9], 41.8% [22.3, 56.7], and 55.8% [19.2, 76.9]). In the TVC-naive, VE against CIN1+, CIN2+, and CIN3+ associated with HPV-16/18 was 96.5% (89.0, 99.4), 98.4% (90.4, 100), and 100% (64.7, 100), and irrespective of HPV DNA it was 50.1% (35.9, 61.4), 70.2% (54.7, 80.9), and 87.0% (54.9, 97.7). VE against 12-month persistent infection with HPV-16/18 was 89.9% (84.0, 94.0), and that against HPV-31/33/45/51 was 49.0% (34.7, 60.3). In conclusion, vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities, and catch-up vaccination up to 18 years of age is most likely effective. (This study has been registered at ClinicalTrials.gov under registration no. NCT001226810.)

To explore the predictors of intermediate endpoints of cervical cancer in 500 women living in Porto Alegre.Five hundred randomly selected women (mean age 20.3 years, range 15-25) were screened using PCR detecting 25 HPV types (HPV6, 11, 16, 18, 31, 33, 34, 35, 39, 40, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 70, and 74). Women were interviewed and serum samples were analysed for antibodies to HPV16 and HPV18 VLPs. Regression models were constructed to analyse predictive factors for (a) HPV PCR status, (b) HPV16-seropositivity, (c) HPV18-seropositivity, and (d) SIL in the PAP smear, used as intermediate endpoints of cervical cancer.Specific HPV types were identified in 137 (27.4%) of the 157 (31.4%) PCR-positive women. PAP test result was the most powerful independent predictor of HPV status in PCR (p = 0.0001), followed by the sexual activity started (p = 0.001) (adjusted OR 34.075, 95% CI: 4.650-249.715). PAP test SIL was independently predicted only by the HPV PCR status (p = 0.0001) (OR 7.561, 95% CI: 2.787-20.514). HPV16 and HPV18 serostatus were the most significant predictors of each other (p=0.0001), and the life-time number of sexual partners was more significant (p=0.001) predictor of HPV16 than HPV18 serostatus (p = 0.049).These data are useful in evaluating the exposure status of the women to the risk factors of cervical cancer in south of Brazil.

Objective To evaluate the performance of the conventional Pap test and liquid-based cytology (LBC) in an ongoing multicenter trial testing optional screening tools (cytolosy, screening colposcopy, visual inspection with acetic acid, visual inspection with Lugol's Iodine, cervicography and Hybrid Capture II [HCII] (Digene Brazil, Sno Paulo, Brazil) conventional and self-sampling), for cervical cancer in Brazil and Argentina. Study Design A cohort of 12,107 women attending four clinics (Campinas, Sao Paulo, Porto Alegre, Buenos Aires) were randomized into the 8 diagnostic arms. Women testing positive with any of the tests were referred for colposcopy, and cervical biopsies were used as the gold standard to assess performance characteristics of the diagnostic tests. Conventional Pap smears were sampled by all clinics (n=10,240), and LBC (Autocyte® PREP, [TriPath Imaging, Burlington, North Carolina, U.S.A.], n = 320, and DNA-Citoliq® [Digene Brazil], n=1,346) was performed by 1 of the clinics. Results Conventional Pap smears showed no squamous intraepithelial lesions (normal) in 8,946 (87.4%) and I.BC in 1.373 (82.4%). Using high grade squamous intraepithelial lesions (HSIL) as the cutoff, Pap smears predicted high grade (cervical intraepithelial neoplasia [CIN] 3) with OR 63.0 (95% CI, 36.90-107.70), standard error (SE) 59%. SP 97.8%, positive predictive value (PPV) 68.1% and negative predictive value (NPV) 96.7%. The same figures for Autocyte® PREP were: OR 9.0 (95% CI, 2.43-33.24), sensitivity (SE) 33.3%, specificity (SP) 100%, PPV 100% and negative PV (NPV) 88.8%. DNA-Citoliq® detected CIN 3 as follows: OR 11.8 (95% CI 2.60-53.26), SE 40.0%, SP 94.6%, PPV 40.0% and NPV 94.6%. Lowering the cut-off to low grade squamous intraepithelial lesions increased SE and NPV but compromised SP and PPV. The detection rates for high grade lesions after an atypical squamous cells of undetermined significance diagnosis were similar with the 3 techniques. Conclusion In our settings, the 3 methods of cervical cytology were slightly different in performance. The conventional Pap smear had the highest SE, while.Autocyte® PREP had 100% SP and PPV in detecting CIN 3 with the HSIL cutoff. All 3 tests had lower SE but higher SP as compared to HCII.

Summary Background Vaccination against the most common oncogenic human papillomavirus (HPV) types, HPV-16 and HPV-18, could prevent development of up to 70% of cervical cancers worldwide. We did a randomised, double-blind, controlled trial to assess the efficacy, safety, and immunogenicity of a bivalent HPV-16/18 L1 virus-like particle vaccine for the prevention of incident and persistent infection with these two virus types, associated cervical cytological abnormalities, and precancerous lesions. Methods We randomised 1113 women between 15–25 years of age to receive three doses of either the vaccine formulated with AS04 adjuvant or placebo on a 0 month, 1 month, and 6 month schedule in North America and Brazil. Women were assessed for HPV infection by cervical cytology and self-obtained cervicovaginal samples for up to 27 months, and for vaccine safety and immunogenicity. Findings In the according-to-protocol analyses, vaccine efficacy was 91·6% (95% CI 64·5–98·0) against incident infection and 100% against persistent infection (47·0–100) with HPV-16/18. In the intention-to-treat analyses, vaccine efficacy was 95·1% (63·5–99·3) against persistent cervical infection with HPV-16/18 and 92·9% (70·0–98·3) against cytological abnormalities associated with HPV-16/18 infection. The vaccine was generally safe, well tolerated, and highly immunogenic. Interpretation The bivalent HPV vaccine was efficacious in prevention of incident and persistent cervical infections with HPV-16 and HPV-18, and associated cytological abnormalities and lesions. Vaccination against such infections could substantially reduce incidence of cervical cancer.

(See the editorial commentary by Franceschi and Baussano on pages 507–9.) Human papillomavirus (HPV) types 16 and 18 cause approximately 70% of invasive cervical cancer worldwide [1]. Two prophylactic vaccines against HPV infection are available and have been shown to prevent persistent HPV infection and precancerous cervical abnormalities associated with HPV-16/18 [2–6]. Approximately 50%–70% of women develop serum antibodies after naturally acquired infection with HPV-16 or HPV-18 [7–13]. Naturally acquired antibodies can remain detectable for at least 4–5 years, albeit at much lower levels than those induced by vaccination [14]. Whereas some studies have not shown an immune protection role for naturally acquired antibodies [15–18], others have shown that they may provide protection against future infection [19–21]. Underpowering of studies and differences in methodology may explain these discrepancies. In addition, the levels of naturally acquired antibodies that may provide protection have not yet been established. Vaccine efficacy data from the Papilloma Trial Against Cancer in Young Adults (PATRICIA) of the HPV-16/18 AS04-adjuvanted vaccine (Cervarix®) have been reported previously [3, 22–24]. The intensive follow-up of the control arm of large vaccine trials provides an opportunity to evaluate the natural history of HPV infection, including the impact of naturally induced antibodies on infection and cervical abnormalities. The present paper describes an analysis of the risk of newly detected HPV infection and development of cervical abnormalities according to the baseline level of naturally acquired antibodies to HPV-16 or HPV-18 in women from the control group of PATRICIA over a 4-year follow-up.

Objective. This study was conducted to test the performance characteristics of cervical cancer screening by visual inspection of the cervix with acetic acid and iodine solution. Methods. A total of 100 women were screened for cervical cancer by Pap smear and naked eye inspection of the cervix after application of acetic acid and iodine solution. Results. Comparing visual inspection to the Pap test, a sensitivity of 85.7%, specificity of 78.5%, and concordance of 79% (p < .0011) was established. Comparing the Pap test with colposcopy, the corresponding figures were 42.9%, 92.3%, and 66.6% (p < .077), respectively. Visual inspection compared to colposcopy showed corresponding figures of 100%, 7.7%, and 55.5% (p = .48), respectively. Colposcopy and biopsy had an agreement of 100%. Conclusions. Visual inspection with acetic acid and iodine solution proved to be a reasonable method of screening for cervical cancer precursors.

This double-blind, multicenter, randomized, placebo-controlled study was conducted to assess the efficacy of a bivalent human papillomavirus (HPV)-16/18 L1 virus-like particle vaccine in preventing cervical infection withHPV-16/18. The study participants were recruited among healthy women aged 15 to 25 years from 32 healthcare facilities in Brazil, Canada, and the United States. A total of 1113 women enrolled in the study. Enrollees had 6 or fewer lifetime sexual partners, no history of cervical abnormality, and were negative for high-risk HPV types. The subjects were randomized to receive placebo injections or the vaccine that contained 20 μg each of HPV-16 and HPV-18 virus-like particles. Women received 1 0.5-mL dose of vaccine or placebo at enrollment, 1 month, and 6 months. Cervical smears were taken at 6, 12, and 18 months. In addition, participants collected self-administered cervicovaginal samples at enrollment, 6 months, and every 3 months thereafter. Serologic testing for immunogenicity was performed at 0, 1, 6, 12, and 18 months. The women kept a diary of symptoms for 1 week after each injection, and symptoms were evaluated by telephone interview 1 month after each injection. Outcome results at 27 months were available for 81 women in the vaccine group and 59 in the placebo group. Study subject data were analyzed in two different cohorts. One analysis was performed including women who received all 3 injections and who had complete follow-up data. They comprised the 'according-to-protocol' cohort (ATP). Another analysis was performed using data from the 'intention-to-treat' cohort (ITT), which consisted of all enrolled participants who had at least one dose of vaccine or placebo and had any data available for analysis. There were 560 subjects randomized to receive vaccine and 553 randomized to receive placebo. The average age was 20 years. The two groups had similar patterns of risk factors for HPV infection. There were no cases of persistent HPV-16/18 among ATP women who received the vaccine. The vaccine was 100% effective against HPV-16, HPV-18, and HPV-16/18 (P < 0.0001). The effectiveness against HPV-18 infection was not significant until 27 months. In comparison, 13 (2.1%) women in the ATP group who received placebo developed a persistent HPV-16 infection, 4 (0.6%) had persistent HPV-18, and 16 (2.6%) had persistent HPV-16/18. In the ITT cohort, there were 4 women in the vaccine group who were positive for persistent HPV-16 (0.5%: efficacy 84.5%, P < 0.0001), 1 positive for persistent HPV-18 (0.1%: efficacy 91.1%, P = 0.003) and 4 with HPV-16/18 (0.5%: efficacy 87.5%, P

To assess the prediction potential of a 5-biomarker panel for detecting high-risk human papillomavirus (HR-HPV) infections and/or cervical intraepithelial neoplasia (CIN) progression. Five biomarkers, lipocalin, plasminogen activator inhibitor-2, p300, interleukin-10, and stratifin, were assessed in cervical biopsies from 225 women of the Latin American Screening Study. Competing-risks regression models were constructed to assess their predictive power for (i) HR-HPV outcomes (negative, transient, or persistent infection) and (ii) CIN outcomes (no progression, incident CIN1, CIN2, or CIN3). p300, LCN2, stratifin were significantly associated with prevalent HR-HPV but lost their significance in multivariate analysis. In the multivariate model, only p300 was an independent predictor of CIN3 (odds ratio=2.63; 95% confidence interval, 1.05-6.61; P=0.039). In univariate competing-risks regression, lipocalin predicted permanent HR-HPV-negative status, but in the multivariate model, IL-10 emerged as a independent predictor of HPV-negative status (subhazard ratio=4.04; 95% confidence interval, 1.81-9.01; P=0.001). The clinical value of the panel in predicting longitudinal outcomes of HR-HPV infection and/or incident CIN is limited., Supported by the European Commission, INCO-DEV Programme (Contract# ICA4-CT-2001-10013).

Summary Background We evaluated the efficacy of the human papillomavirus HPV-16/18 AS04-adjuvanted vaccine against non-vaccine oncogenic HPV types in the end-of-study analysis after 4 years of follow-up in PATRICIA (PApilloma TRIal against Cancer In young Adults). Methods Healthy women aged 15–25 years with no more than six lifetime sexual partners were included in PATRICIA irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to HPV-16/18 vaccine or a control hepatitis A vaccine, via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The study was double-blind. The primary endpoint of PATRICIA has been reported previously; the present analysis evaluates cross-protective vaccine efficacy against non-vaccine oncogenic HPV types in the end-of-study analysis. Analyses were done for three cohorts: the according-to-protocol cohort for efficacy (ATP-E; vaccine n=8067, control n=8047), total vaccinated HPV-naive cohort (TVC-naive; no evidence of infection with 14 oncogenic HPV types at baseline, approximating young adolescents before sexual debut; vaccine n=5824, control n=5820), and the total vaccinated cohort (TVC; all women who received at least one vaccine dose, approximating catch-up populations that include sexually active women; vaccine n=9319, control=9325). Vaccine efficacy was evaluated against 6-month persistent infection, cervical intraepithelial neoplasia grade 2 or greater (CIN2+) associated with 12 non-vaccine HPV types (individually or as composite endpoints), and CIN3+ associated with the composite of 12 non-vaccine HPV types. This study is registered with ClinicalTrials.gov, number NCT00122681. Findings Consistent vaccine efficacy against persistent infection and CIN2+ (with or without HPV-16/18 co-infection) was seen across cohorts for HPV-33, HPV-31, HPV-45, and HPV-51. In the most conservative analysis of vaccine efficacy against CIN2+, where all cases co-infected with HPV-16/18 were removed, vaccine efficacy was noted for HPV-33 in all cohorts, and for HPV-31 in the ATP-E and TVC-naive. Vaccine efficacy against CIN2+ associated with the composite of 12 non-vaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), with or without HPV-16/18 co-infection, was 46·8% (95% CI 30·7–59·4) in the ATP-E, 56·2% (37·2–69·9) in the TVC-naive, and 34·2% (20·4–45·8) in the TVC. Corresponding values for CIN3+ were 73·8% (48·3–87·9), 91·4% (65·0–99·0), and 47·5% (22·8–64·8). Interpretation Data from the end-of-study analysis of PATRICIA show cross-protective efficacy of the HPV-16/18 vaccine against four oncogenic non-vaccine HPV types—HPV-33, HPV-31, HPV-45, and HPV-51—in different trial cohorts representing diverse groups of women. Funding GlaxoSmithKline Biologicals.

BACKGROUND: The control arm of PATRICIA (PApilloma TRIal against Cancer In young Adults, NCT00122681) was used to investigate the risk of progression from cervical HPV infection to cervical intraepithelial neoplasia (CIN) or clearance of infection, and associated determinants. METHODS AND FINDINGS: Women aged 15-25 years were enrolled. A 6-month persistent HPV infection (6MPI) was defined as detection of the same HPV type at two consecutive evaluations over 6 months and clearance as ≥2 type-specific HPV negative samples taken at two consecutive intervals of approximately 6 months following a positive sample. The primary endpoint was CIN grade 2 or greater (CIN2+) associated with the same HPV type as a 6MPI. Secondary endpoints were CIN1+/CIN3+ associated with the same HPV type as a 6MPI; CIN1+/CIN2+/CIN3+ associated with an infection of any duration; and clearance of infection. The analyses included 4825 women with 16,785 infections (3363 women with 6902 6MPIs). Risk of developing a CIN1+/CIN2+/CIN3+ associated with same HPV type as a 6MPI varied with HPV type and was significantly higher for oncogenic versus non-oncogenic types. Hazard ratios for development of CIN2+ were 10.44 (95% CI: 6.96-15.65), 9.65 (5.97-15.60), 5.68 (3.50-9.21), 5.38 (2.87-10.06) and 3.87 (2.38-6.30) for HPV-16, HPV-33, HPV-31, HPV-45 and HPV-18, respectively. HPV-16 or HPV-33 6MPIs had ~25-fold higher risk for progression to CIN3+. Previous or concomitant HPV infection or CIN1+ associated with a different HPV type increased risk. Of the different oncogenic HPV types, HPV-16 and HPV-31 infections were least likely to clear. CONCLUSIONS: Cervical infections with oncogenic HPV types increased the risk of CIN2+ and CIN3+. Previous or concomitant infection or CIN1+ also increased the risk. HPV-16 and HPV-33 have by far the highest risk of progression to CIN3+, and HPV-16 and HPV-31 have the lowest chance of clearance. ispartof: PLoS One vol:8 issue:11 ispartof: location:United States status: published

Objectives Persistence of human papillomaviruses (HPVs) is necessary for cervical carcinogenesis. We evaluated incidence and duration of type-specific HPV infections and the influence of age and number of sexual partners. Methods Data were obtained from 553 women (15–25 years), who were seronegative and DNA-negative for high-risk HPV (HR-HPV) types and were enrolled in the placebo arm of a randomised trial of the HPV-16/18 vaccine (NCT00689741/NCT00120848). They were followed for 6.3 years. Cervicovaginal samples were self-collected at 3-month intervals for up to 27 months, and cervical samples were collected by clinicians at 6-month intervals until study end. Samples were tested for HPV types using a broad-spectrum PCR assay. Incidence rate ratios (RRs) and 95% CIs were used to estimate the association among age, sexual habits and HPV acquisition. Results Incidence rates (95% CI) using cervical samples were 11.8 (10.4 to 13.4) and 5.6 (4.7 to 6.6) per 1000 women-months for HR-HPVs and low-risk HPVs (LR-HPVs), respectively. Equivalent rates in combined cervicovaginal and cervical samples were 17.2 (15.4 to 19.2) and 6.9 (5.9 to 8.0), respectively. 54 per cent of HR-HPV types from combined cervicovaginal and cervical samples persisted for 1 year compared with 32.3% for LR-HPV types. The risk of acquiring any HPV infection was higher among women aged 1 sexual partner (RR=1.83, 95% CI 1.4 to 2.4) at baseline. Conclusions HR-HPV infections were more common and lasted longer on average than LR-HPV infections. HPV acquisition was more common in younger women with multiple sexual partners. Trial registration number NCT00689741, NCT00120848; Post-results.

We sought to evaluate the performance of diagnostic tools to establish an affordable setting for early detection of cervical cancer in developing countries. We compared the performance of different screening tests and their feasibility in a cohort of over 12,000 women: conventional Pap smear, liquid-based cytology, visual inspection with acetic acid (VIA), visual inspection with Iodine solution (VILI), cervicography, screening colposcopy, and high-risk human papillomavirus (HPV) testing (HR-HPV) collected by physician and by self-sampling. HR-HPV assay collected by the physician has the highest sensitivity (80 %), but high unnecessary referrals to colposcopy (15.1 %). HR-HPV test in self-sampling had a markedly lower (57.1 %) sensitivity. VIA, VILI, and cervicography had a poor sensitivity (47.4, 55, and 28.6 %, respectively). Colposcopy presented with sensitivity of 100 % in detecting CIN2+, but the lowest specificity (66.9 %). Co-testing with VIA and VILI Pap test increased the sensitivity of stand-alone Pap test from 71.6 to 87.1 % and 71.6 to 95 %, respectively, but with high number of unnecessary colposcopies. Co-testing with HR-HPV importantly increased the sensitivity of Pap test (to 86 %), but with high number of unnecessary colposcopies (17.5 %). Molecular tests adjunct to Pap test seems a realistic option to improve the detection of high-grade lesions in population-based screening programs., European Commission, INCO-DEV Programme (contract# ICA4-CT-2001-10013). The generous contribution of DIGENE Corporation (USA) donating the HCII tests at our disposal is gratefully acknowledged.

Prophylactic human papillomavirus (HPV) vaccines are now available and vaccination programs are being widely implemented, targeting adolescent girls prior to sexual debut. Since the risk of HPV exposure persists throughout a woman's sexual life, the duration of protection provided by vaccination is critical to the overall vaccine effectiveness. We report the long-term efficacy and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine (Cervarix (®) ) up to 8.4 y after the first vaccine dose. In an initial placebo-controlled study performed in US, Canada and Brazil, women aged 15-25 y with normal cervical cytology, HPV-16/18 seronegative by ELISA, DNA-negative for 14 oncogenic HPV types by PCR, received either the HPV-16/18 vaccine or placebo (n = 1,113). Subjects were followed up to 6.4 y after the first dose (n = 776). We report an additional 2-y follow-up for women enrolled from the Brazilian centers from the initial study (n = 436). During the current follow-up study (HPV-023, NCT00518336), no new infection or lesions associated with HPV-16/18 occurred in the vaccine group. Vaccine efficacy over the entire follow-up (up to 8.4 y) was 95.1% (84.6, 99.0) for incident infection, 100% (79.8, 100) for 6-mo persistent infection, 100% (56.1, 100) for 12-mo persistent infection and 100% (0, 100) for CIN2+ associated with HPV-16/18. All women in the vaccine group remained seropositive to both HPV-16/18, with antibody titers for total and neutralizing antibodies remaining several-folds above natural infection levels. The safety profile was clinically acceptable for both vaccine and control groups. This is, to date, the longest follow-up study for a licensed cervical cancer vaccine.

Introdução: O câncer cervical é uma neoplasia maligna com possibilidade de prevenção. Rastreamento adequado pode reduzir morbimortalidade. Objetivo: Verificar a evolução clínica em pacientes com citopatológico de colo uterino com atipias em células escamosas de origem indeterminada (ASC-US ). Método: Coorte retrospectiva em pacientes com ASC-US do Ambulatório de Ginecologia do Hospital de Clínicas de Porto Alegre. Acompanhamento por 3 anos e seguimento com citologia e/ou histologia. Análise: Statistical Package for Social Sciences (dados descritivos e associações). Variáveis quantitativas com distribuição simétrica: média e desvio-padrão. Variáveis qualitativas: percentuais; aprovação do Grupo de Pesquisa e Pós-graduação do Hospital de Clínicas de Porto Alegre (07-286). Resultados: Amostra de 320 casos. Média de idade das pacientes: 41,3 anos. Não houve associação com tabagismo e ASC-US , lesão intraepitelial escamosa de baixo grau (LSIL) ou lesão intraepitelial escamosa de alto grau (HSIL) (22,8 versus 20,5%; odds ratio = 0,87; intervalo de confiança de 95% 0,38-1,99; p=0,751). Das pacientes com ASC-US , 87,2% fizeram colposcopia imediata; 104 resultaram em alterações menores e quatro em maiores à colposcopia, embora 85 pacientes tenham realizado biópsias. A histologia mostrou: 7,5% de neoplasia intraepitelial 1; 2,1%, neoplasia intraepitelial 2/3; e 0,9%, carcinoma. Um total de 12,5% fez algum tipo de tratamento cirúrgico, sendo este excisão eletrocirúrgica com alça até histerectomia. Ao final do estudo, 77,5% tiveram citopatológico normal como desfecho; 20,3% tiveram ASC-US persistente ou LSIL; 1,3%, HSIL; e 0,9%, carcinoma. Conclusões: O percentual de citopatológicos com ASC-US era esperado e foi adequado. A maioria dos exames teve um acompanhamento citológico normal, mas tivemos um número muito elevado de biópsias em pacientes com colposcopias com alterações menores. A taxa de evolução para lesões de alto grau e câncer não foi desprezível, alertando para necessidade de acompanhamento na presença de ASC-US . Background: Cervical cancer is a preventable malignant neoplasia. Adequate screening may reduce mortality and morbidity. Aims: To investigate the clinical outcome in patients with pap smears showing atypical squamous cells of undetermined origin (ASC-US ). Methods: Retrospective cohort study involving patients with ASC-US seen at the Gynecology Outpatient Clinic of Hospital de Clínicas de Porto Alegre. Three-year follow-up and monitoring based on cytological or histological tests. Analysis: Statistical Package for the Social Sciences (descriptive data and associations). Quantitative variables with symmetric distribution: mean and standard deviation. Qualitative variables: percentage; approval of the Research and Graduate Study Program of Hospital de Clínicas de Porto Alegre (07-286). Results: Our sample included 320 cases. Patients’ mean age: 41.3 years. There was no association with smoking and ASC-US , low squamous intraepithelial lesion (LSIL), or high squamous intraepithelial lesion (HSIL) (22.8 versus 20.5%, odds ratio = 0.87, 95% confidence interval 0.38-1.99, p = 0.751). Of the patients with ASC-US , 87.2% had immediate colposcopy, 104 had minor changes and four had major changes on colposcopy, although 85 patients underwent biopsies. Histology showed: 7.5% of intraepithelial neoplasia 1; 2.1% of intraepithelial neoplasia 2/3; and 0.9% of carcinoma. A total of 12.5% patients underwent surgical treatment consisting of loop electrosurgical excision procedure followed by hysterectomy. At the end of the study, 77.5% had normal pap smear; 20.3% had persistent ASC-US or LSIL; 1.3% had HSIL; and 0.9% had carcinoma. Conclusions: The percentage of pap smears with ASC-US was expected and adequate. Most tests had normal results during the follow-up, but there was a very large number of biopsies in patients with minor changes on colposcopy. The rate of progression to high-grade lesions and cancer was not negligible, prompting the need for monitoring the presence of ASC-US.

AIMS: To evaluate the role of hormonal contraceptives as a risk factor of high-risk human papillomavirus (HR-HPV), cervical intraepithelial lesions (CIN) and cervical cancer in our multi-center population-based LAMS (Latin American Screening) study. METHODS: A cohort study with >12,000 women from Brazil and Argentina using logistic regression to analyze the covariates of hormonal contraception (HOC - oral, injections, patches, implants, vaginal ring and progesterone intrauterine system) use followed by multivariate modeling for predictors of HR-HPV and CIN2+. RESULTS: HR-HPV infection was a consistent risk factor of high-grade CIN in all three groups of women. The length of HOC use was not significantly related to high-grade squamous intraepithelial lesions (HSIL)+ Pap (p = 0.069), LSIL+ Pap (p = 0.781) or ASCUS+ (p = 0.231). The same was true with the length of HOC use and histology CIN3+ (p = 0.115) and CIN2+ (p = 0.515). Frequently, HOC users have previously shown more HPV-related lesions, as well as lower HPV prevalence if they were current smokers. But HOC use and time of usage were not independent risk factors of either HR-HPV infection or high-grade CIN using multiple logistic regressions. CONCLUSIONS: No evidence was found for an association between the use of HOC with an increased risk for HR-HPV infection or high-grade CIN in this cohort., This study is a part of the ongoing LAMS (Latin American Screening) study, entitled: Improving Health Systems Towards Equality-Based Control of Cervical Cancer in Latin America, and is supported by the INCO-DEV Program of the European Commission (Project No. ICA4-CT-2001-10013). The generous contribution of Digene Corporation (USA) who donated the HCII tests at our disposal is gratefully acknowledged.

To evaluate the role of the expression of the transcription factor p300 as an independent predictor of high-risk human papillomavirus (HR-HPV) infections and outcome of the cervical disease.Cervical biopsy samples taken at enrolment from 225 women of the Latin American Screening study cohort were analyzed for p300 using immunohistochemistry to assess its value as predictor of (a) cervical intraepithelial neoplasia (CIN) grade, and (b) HR-HPV at baseline, as well as (c) outcomes of HR-HPV infections, and (d) development of incident CIN as surrogate endpoints of progressive disease.There was a significant linear trend in increasing upregulation (=pattern shift) of p300 (P=0.0001) in parallel with increasing grade of CIN. When dichotomized (normal/moderately increase vs. strong-intense), upregulated p300 expression predicted CIN3+ with odds ratio=4.16 (95% confidence interval: 1.95-8.86) (P=0.0001) and CIN2+ with odds ratio=3.48 (95% confidence interval: 1.86-6.48) (P=0.0001). p300 was upregulated more often in HR-HPV+ lesions than in those remaining negative. Semiquantitative viral loads were also directly related to upregulation of p300 (P=0.036), but p300 was not a significant predictor of disease progression to either CIN1+ or CIN2+.p300 expression was upregulated in CIN lesions and related to detection and viral load of HR-HPV but not to their outcome or to incident CIN., This study has been supported by the European Commission, INCO-DEV Programme (Contract ICA4-CT-2001-10013).

To assess whether the potentially high-risk (HR) human papillomavirus (HPV)-related up-regulation of 14-3-3sigma (stratifin) has implications in the outcome of HPV infections or cervical intraepithelial neoplasia (CIN) lesions, cervical biopsy specimens from 225 women in the Latin American Screening Study were analyzed for 14-3-3sigma expression using immunohistochemical analysis. We assessed its associations with CIN grade and HR HPV at baseline and value in predicting outcomes of HR-HPV infections and the development of incident CIN 1+ and CIN 2+. Expression of 14-3-3sigma increased in parallel with the lesion grade. Up-regulation was also significantly related to HR-HPV detection (P = .004; odds ratio, 2.71; 95% confidence interval, 1.37-5.35) and showed a linear relationship to HR-HPV loads (P = .003). 14-3-3sigma expression was of no value in predicting the outcomes (incident, persistent, clearance) of HR-HPV infections or incident CIN 1+ and CIN 2+. 14-3-3sigma is not inactivated in cervical carcinoma and CIN but is up-regulated on transition from CIN 2 to CIN 3. Its normal functions in controlling G(1)/S and G(2)/M checkpoints are being bypassed by HR HPV., LAMS, Latin American Screening Study, funded by European Commission, INCO-DEV contract ICA4-CT-2001-10013.

Bypassing the local immunological defense reactions in the cervix is one of the prerequisites for human papillomaviruses (HPV) infections to progress to intraepithelial neoplasia (CIN). The role of potent immunosuppressive cytokines, e.g., interleukin-10 (IL-10), depressing these local virus-specific immunological responses is incompletely studied. To assess, whether IL-10 expression in cervical HPV lesions has any implications in the outcome of HPV infections or disease progression to CIN. Baseline cervical biopsies from 225 women of the LAMS study sub-cohort were analyzed for IL-10 expression using immunohistochemistry, to assess its associations with CIN grade, and high-risk HPV (HR-HPV) at baseline, as well as in predicting outcomes of HR-HPV infections, and development of incident CIN1+ and CIN2+ in this longitudinal setting. Expression of IL-10 in cervical lesions was up-regulated most often in high-grade CIN, and IL-10 over-expression retained its value as independent predictor of CIN2+ (odds ratio (OR) = 4.92) and CIN3+ (OR = 7.51) also in multivariate model, including HR-HPV and several known covariates of IL-10 expression. Up-regulation was not related to HR-HPV detection, and showed no relationship to HR-HPV viral loads. Using longitudinal predictive indicators (SE, SP, PPV, NPV), IL-10 expression was of no value in predicting (1) the outcomes of HR-HPV infections, or (2) the surrogate endpoints (incident CIN1+, CIN2+) of progressive disease. IL-10 over-expression (along with HR-HPV) was one of the independent covariates of CIN2/3. This immunosuppressive cytokine might play an important role in creating a microenvironment that favors progressive cervical disease and immune evasion by HR-HPV., European Commission, INCO-DEV Programme (Contract# ICA4-CT-2001-10013). The generous contribution of former DIGENE Inc. (USA) donating the HC2 tests at our disposal is gratefully acknowledged.

New end points are needed in future human papillomavirus (HPV) vaccine efficacy studies that accurately predict disease progression. Background: New end points are needed in future human papillomavirus (HPV) vaccine efficacy studies that accurately predict disease progression. Objectives: Potential intermediate end points were analyzed in the combined New Independent States of the Former Soviet Union (NIS) and the Latin American Screening (LAMS) study cohorts. Study Design and Methods: Data files of 2 international screening trials, the NIS (n = 3187) and the LAMS (n = 12,114) study cohorts, were combined, and a subcohort of 1865 (n = 854 and n = 1011 for the NIS and the LAMS, respectively) women prospectively followed up for 19.7 (median, 22.2) months was analyzed for different intermediate end-point markers of disease progression to squamous intraepithelial lesion (SIL), cervical intraepithelial neoplasia grade 1 and higher (CIN1+), and CIN grade 2 and higher (CIN2+) as terminal events. Results: Altogether, 131 (7.0%), 90 (4.8%), and 39 (2.1%) cases progressed to SIL, CIN1+, and CIN2+, respectively, progression times being equal in the NIS (11.9, 16.8, and 19.6 months) and LAMS (13.6, 14.1, and 15.4 months) cohorts (P = 0.931, P = 0.335, and P = 0.535). The 2 most powerful end-point markers of disease progression to CIN2+ were high-grade squamous intraepithelial lesions based on Papanicolaou test results at 6-month (odds ratio [OR] = 47.1; 95% confidence interval [CI], 17.3-128.7) and 12-month (OR = 21.5; 95% CI, 5.1-90.8) follow-up visits, with longitudinal positive and negative predictive values of 42.1% and 98.0% (6 months) and 33.3% and 97.7% (12 months). Of the virological end points, more than 6 months of persistent high-risk HPV (HR-HPV) was the most powerful predictor of progression to CIN1+ (OR = 18.6; 95% CI, 2.5-136.5), with longitudinal positive and negative predictive values of 10.3% and 99.4%, respectively. No additional benefit was obtained using more than 12 months of persistent HR-HPV end point. Conclusions: High-grade squamous intraepithelial lesion based on a Papanicolaou test results at 6- or 12-month follow-up visits was the most powerful end point, either considering cytological end points alone or in comparison to any of the virological end points. Of the virological end points, more than 6-month HR-HPV persistence criteria give the most powerful estimate of a progressive disease.

To examine the effect of smoking on the incidence of low- and high-grade cervical intraepithelial neoplasia (CIN) in women with a baseline Pap smear of atypical squamous cells (ASC) or a low-grade squamous intraepithelial lesion (LSIL). Objective. To examine the effect of smoking on the incidence of low‐ and high‐grade cervical intraepithelial neoplasia (CIN) in women with a baseline Pap smear of atypical squamous cells (ASC) or a low‐grade squamous intraepithelial lesion (LSIL). Design. Prospective study in which a cohort of women with normal colposcopy and ASC/LSIL at baseline were followed at 6‐month intervals of up to 36 months. Women were grouped in post‐hoc analysis according to their smoking behavior: never (or past) smokers and current smokers. Setting. This report was based on data from the Latin American Screening Study, conducted in São Paulo, Campinas, Porto Alegre (Brazil) and Buenos Aires (Argentina). Population. A subset of 150 women derived from a cohort of 1,011 women. Methods. Multivariate Cox analysis and Kaplan–Meier curves were used. Main outcome measures. Low‐ and high‐grade CIN during follow‐up. Results. The only factor related to an increased risk of developing CIN was the positive high‐risk (hr) HPV status (hazard ratio (HR) = 3.42; 95% CI: 1.11–9.43). A total of 21 cases of incident CIN were detected during follow‐up. Of these, 11 appeared in the group of 67 smokers and 10 among the 83 non‐smoker women (log‐rank, p = 0.33). Smoking status was not associated with the risk of developing CIN (HR = 0.73; 95% CI: 0.40–1.33). However, when restricting the analysis to high‐grade CIN only (11 cases), the probability of developing the disease was significantly higher among smokers (p = 0.04). Conclusions. Smoking contributes additional risk for developing high‐grade CIN in women with ASC or LSIL cytology but normal colposcopy., LAMS (Latin American Screening) study, entitled: Improving health systems towards equality‐based control of cervical cancer in Latin America, and supported by the Inco‐Dev Program of the European Commission (Project No. ICA4‐CT‐2001‐10013). The contribution of Digene Inc. (USA)

To describe the expression of vascular endothelial growth factor (VEGF), proto-oncogene macrophage colony-stimulating factor receptor (c-fms) and cyclooxygenase-2 (COX-2) in cervical carcinogenesis and to analyze the correlation of VEGF with c-fms and COX-2 expression.In this study, 26 cases of benign cervix, 28 low-grade cervical intraepithelial neoplasia (CIN; CIN 1), 30 high-grade CIN (CIN 2/3) and 28 squamous cervical carcinomas (SCC) were examined by immunohistochemistry (IHC) and analysis was performed separately for epithelium and stroma.Positive epithelial expressions in normal cervix, low-grade CIN, high-grade CIN and SCC were, respectively: VEGF - 11.5%, 39.3%, 53.3% and 75% (P0.001); c-fms - 0%, 10.7%, 40% and 67.9% (P0.001); COX-2 - 7.7%, 39.3%, 80% and 100% (P0.001). Stromal VEGF expression was higher than epithelial expression in all CIN grades and was also associated with the lesion grade, while c-fms and COX-2 stromal expression was weak. VEGF expression was statistically correlated to c-fms and COX-2 expression in high-grade CIN (P=0.020 and P=0.027, respectively) and SCC (P=0.015 and P=0.005, respectively).On the basis of our findings, these factors may participate in the development and progression of CIN lesions, with possible interaction of c-fms and COX-2 on VEGF expression, and may be potential molecular targets for studies of cervical cancer prevention and treatment.

To assess whether human papillomavirus (HPV) testing is a safe enough approach to warrant extension of the screening intervals of baseline Papanicolaou (Pap)-/HPV- women in low-income settings., European Commission, INCO-DEV Programme (Contract # ICA4-CT-2001-10013). The generous contribution from DIGENE Inc. (USA) donating the HC 2 tests

The study of biomarkers by immunohistochemistry (IHC) for cervical cancer and intraepithelial lesions is a promising field. However, manual interpretation of IHC and reproducibility of the scoring systems can be highly subjective. In this article, we present a novel and simple computer-assisted IHC interpretation method based on cyan-magenta-yellow-black (CMYK) color format, for tissues with diaminobenzidine cytoplasmatic staining counterstained with methyl green. This novel method is more easily interpreted than previous computer-assisted methods based on red-green-blue (RGB) color format and presents a strong correlation with the manual H-score. It is simple, objective, and requires only low-cost software and minimal computer skills. Briefly, a total of 67 microscopic images of cervical carcinoma, normal cervix, and negative controls were analyzed in Corel Photo Paint X3 software in CMYK and RGB color format, and compared with manual H-score IHC assessments. The clearest and best positive correlation with the H-score was obtained using the image in CMYK color format and crude values of magenta color (Spearman correlation coefficient=0.84; agreement of 93.33%, P, Supported in part by grant 0629/05-7 from the Foundation for the Coordination of Higher Education and Graduate Training (CAPES), Brazil, and in part by grant 05-154 from Hospital de Clínicas de Porto Alegre Research Incentive Fund (HCPA-FIPE), Brazil

Background The aim of this interim analysis of a large, international phase III study was to assess the efficacy of an AS04 adjuvanted L1 virus-like-particle prophylactic candidate vaccine against infection with human papillomavirus (HPV) types 16 and 18 in young women. Methods 18 644 women aged 1525 years were randomly assigned to receive either HPV16/18 vaccine (n=9319) or hepatitis A vaccine (n=9325) at 0, 1, and 6 months. Of these women, 88 were excluded because of high-grade cytology and 31 for missing cytology results. Thus, 9258 women received the HPV16/18 vaccine and 9267 received the control vaccine in the total vaccinated cohort for efficacy, which included women who had prevalent oncogenic HPV infections, often with several HPV types, as well as low-grade cytological abnormalities at study entry and who received at least one vaccine dose. We assessed cervical cytology and subsequent biopsy for 14 oncogenic HPV types by PCR. The primary endpointvaccine efficacy against cervical intraepithelial neoplasia (CIN) 2+ associated with HPV16 or HPV18was assessed in women who were seronegative and DNA negative for the corresponding vaccine type at baseline (month 0) and allowed inclusion of lesions with several oncogenic HPV types. This interim event-defined analysis was triggered when at least 23 cases of CIN2+ with HPV16 or HPV18 DNA in the lesion were detected in the total vaccinated cohort for efficacy. Analyses were done on a modified intention-to-treat basis. This trial is registered with the US National Institutes of Health clinical trial registry, number NCT00122681. Findings Mean length of follow-up for women in the primary analysis for efficacy at the time of the interim analysis was 14·8 (SD 4·9) months. Two cases of CIN2+ associated with HPV16 or HPV18 DNA were seen in the HPV16/18 vaccine group; 21 were recorded in the control group. Of the 23 cases, 14 (two in the HPV16/18 vaccine group, 12 in the control group) contained several oncogenic HPV types. Vaccine efficacy against CIN2+ containing HPV16/18 DNA was 90·4% (97·9% CI 53·499·3; p