Determinants of Acquisition and Clearance of Human Papillomavirus Infection in Previously Unexposed Young Women.

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.

Respiratory syncytial virus: challenges in diagnosis and impact on the elderly: Recommendations from a multidisciplinary panel.

Respiratory syncytial virus (RSV) is an important cause of respiratory illness. While most attention is paid to childhood infection, the RSV burden in adults ≥60 y should also be considered. In Brazil, this is generally underrecognized, where greater focus is toward other respiratory pathogens. This article presents insights from a multidisciplinary panel gathered to review epidemiologic data and current diagnostic approaches to RSV in Brazil (and their limitations) and develop communication strategies to improve knowledge and awareness. National surveillance data indicate a steady increase in cases of RSV-related severe acute respiratory illness (RSV-SARI) in those aged ≥60 y in recent years, with high fatality rates (>30%). Routine RSV testing in older individuals with respiratory symptoms is relatively low. Educational activities targeted toward health-care professionals and the general public are critical to raising awareness of the importance of RSV in older individuals, particularly as protective vaccines are now available.

Associations of dietary dark-green and deep-yellow vegetables and fruits with cervical intraepithelial neoplasia: modification by smoking.

Smoking has been positively and fruit and vegetable intake has been negatively associated with cervical cancer, the second most common cancer among women worldwide. However, a lower consumption of fruits and reduced serum carotenoids have been observed among smokers. It is not known whether the smoking effect on the risk of cervical neoplasia is modified by a low intake of fruits and vegetables. The present study examined the combined effects of tobacco smoking and diet using a validated FFQ and serum carotenoid and tocopherol levels on cervical intraepithelial neoplasia grade 3 (CIN3) risk in a hospital-based case-control study conducted in São Paulo, Brazil, between 2003 and 2005. The sample comprised 231 incident, histologically confirmed cases of CIN3 and 453 controls. A low intake ( ≤ 39 g) of dark-green and deep-yellow vegetables and fruits without tobacco smoking had a lesser effect on CIN3 (OR 1·14; 95 % CI 0·49, 2·65) than among smokers with higher intake ( ≥ 40 g; OR 1·83; 95 % CI 0·73, 4·62) after adjusting for confounders. The OR for the joint exposure of tobacco smoking and low intake of vegetables and fruits was greater (3·86; 95 % CI 1·74, 8·57; P for trend < 0·001) compared with non-smokers with higher intake after adjusting for confounding variables and human papillomavirus status. Similar results were observed for total fruit, serum total carotene (including ß-, α- and γ-carotene) and tocopherols. These findings suggest that the effect of nutritional factors on CIN3 is modified by smoking.

Prevalence of human papillomavirus infection and associated risk factors in young women in Brazil, Canada, and the United States: a multicenter cross-sectional study.

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.

Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial.

BACKGROUND: Effective vaccination against HPV 16 and HPV 18 to prevent cervical cancer will require a high level of sustained protection against infection and precancerous lesions. Our aim was to assess the long-term efficacy, immunogenicity, and safety of a bivalent HPV-16/18 L1 virus-like particle AS04 vaccine against incident and persistent infection with HPV 16 and HPV 18 and their associated cytological and histological outcomes. METHODS: We did a follow-up study of our multicentre, double-blind, randomised, placebo-controlled trial reported in 2004. We included women who originally received all three doses of bivalent HPV-16/18 virus-like particle AS04 vaccine (0.5 mL; n=393) or placebo (n=383). We assessed HPV DNA, using cervical samples, and did yearly cervical cytology assessments. We also studied the long-term immunogenicity and safety of the vaccine. FINDINGS: More than 98% seropositivity was maintained for HPV-16/18 antibodies during the extended follow-up phase. We noted significant vaccine efficacy against HPV-16 and HPV-18 endpoints: incident infection, 96.9% (95% CI 81.3-99.9); persistent infection: 6 month definition, 94.3 (63.2-99.9); 12 month definition, 100% (33.6-100). In a combined analysis of the initial efficacy and extended follow-up studies, vaccine efficacy of 100% (42.4-100) against cervical intraepithelial neoplasia (CIN) lesions associated with vaccine types. We noted broad protection against cytohistological outcomes beyond that anticipated for HPV 16/18 and protection against incident infection with HPV 45 and HPV 31. The vaccine has a good long-term safety profile. INTERPRETATION: Up to 4.5 years, the HPV-16/18 L1 virus-like particle AS04 vaccine is highly immunogenic and safe, and induces a high degree of protection against HPV-16/18 infection and associated cervical lesions. There is also evidence of cross protection.

Whole, Turret and step methods of rapid rescreening: is there any difference in performance?

We compared the performance of the Whole, Turret and Step techniques of 100% rapid rescreening (RR) in detection of false-negatives in cervical cytology. We tested RR performance with cytologists trained and among those without training. We revised 1,000 consecutive slides from women participating in an ongoing international screening trial. Two teams of experienced cytologists performed the RR techniques: one trained in RR procedures and the other not trained. The sensitivities in the trained group were Whole 46.6%, Turret 47.4% and Step 50.9%; and in the non-trained group were 38.6, 31.6 and 47.4%, respectively. The kappa coefficient showed a weak agreement between the two groups of cytologists and between the three RR techniques. The RR techniques are more valuable if used by trained cytologists. In the trained group, we did not observe significant differences between the RR techniques used, whereas in the non-trained group, the Step technique had the best sensitivity.

Incidence and duration of type-specific human papillomavirus infection in high-risk HPV-naïve women: results from the control arm of a phase II HPV-16/18 vaccine trial.

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 <21 years (RR=1.33, 95% CI 1.1 to 1.7) and women having >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.

Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial.

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.

Sustained efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine: final analysis of a long-term follow-up study up to 9.4 years post-vaccination.

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.

Sustained immunogenicity and efficacy of the HPV-16/18 AS04-adjuvanted vaccine: up to 8.4 years of follow-up.

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.

O Desempenho da colposcopia através do índice de Reid / The colposcopic performance through Reid's index

A colposcopia representa uma precisa colaboração na detecção das lesões precursoras do câncer do colo uterino. Como é baseada em interpretações subjetivas do colposcopista, esta técnica sofre as mesmas críticas que a interpretação do exame de Papanicolaou e do exame da biópsia, por problemas de baixa reprodutibilidade. O índice colposcópico de Reid (ICR) é um método objetivo que tem como finalidade estabelecer padrões de gravidade de uma lesão pré-maligna do colo uterino detectada por exame de colposcopia. O índice categoriza quatro achados colposcópicos a serem considerados: margem da lesão, reação ao ácido acético, características dos vasos e impregnação com solução de lugol. O ICR pode predizer a classificação histológica da doença cervical e permite a diferenciação entre baixo grau e alto grau da lesão cervical. Com estes parâmetros, o uso do índice permite que o examinador formule a impressão colposcópica e realize a biópsia na região mais alterada do colo uterino.

Estudo preliminar da citologia de base líquida em mulheres com alto risco para neoplasia de colo uterino / Preliminary study on liquid-base cytology in women with high risk for uterine cervix neoplasm

0 objetivo deste estudo é avaliar o desempenho da técnica que utiliza material coletado com escova (Cervex Brush©) e preservado em meio líquido à base de álcool para a confecção de preparados citológicos do colo uterino. Este foi um estudo descritivo em 150 mulheres encaminhadas para os Ambulatórios de Patologia Cervical do Hospital Maternidade Leonor Mendes de Barros e do Centro de Atenção Integral à Saúde da Mulher, no período de junho a dezembro de 2001. Os critérios de inclusão foram mulheres com exame citológico prévio alterado ou teste positivo para HIV ou pesquisa biomolecular e/ou sorológica positiva para HPV, e ainda qualquer condição clínica suspeita para neoplasia do colo uterino. Foram excluídas as mulheres com diagnóstico de carcinoma invasor e as submetidas a cirurgias do colo uterino. A qualidade dos esfregaços foi considerada satisfatória em 90 por cento, satisfatória mas limitada em 9,3 por cento e insatisfatória em 0,7 por cento. As células endocervicais estavam presentes em 90 por cento dos casos. Dos casos com diagnóstico citológico de normal/inflamatório que foram biopsiados, cerca de 94 por cento foram concordantes com o exame histológico, ou seja, não apresentaram lesões para os diagnósticos citológicos de LIE-BG (NIC 1/HPV), 33 por cento foram compatíveis com exame histológico. O diagnóstico citológico de lesão intraepitelial de alto grau foi concordante em 100 por cento dos casos com o exame histológico. Esse estudo preliminar apresenta dados que estimulam a realização de projetos de grande abrangência, a fim de avaliarmos o real impacto da citologia de base líquida em nosso meio.