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OBJECTIVE: To detect factors related to overtreatment with the "Screen-and-treat" approach (S&T) in women with suspicious cervical precancerous lesions. STUDY DESIGN: A retrospective observational study of 524 women with high-grade squamous intraepithelial lesions (HSIL) or more severe (HSIL+) in cytology, treated by the Large Loop Excision of the Transformation Zone (LLETZ): 161 without a previous biopsy (S&T group) and 363 with a previous biopsy (biopsy group) from January 2017 to July 2020. The main outcome was a diagnosis of LLETZ: negative (negative or low-grade squamous intraepithlelial lesion LSIL) or HSIL+. A negative diagnosis was interpreted as "overtreatment." Results were analyzed as a function of the S&T approach (whether previous biopsy or not). Variables were obtained from medical records, and were compared with Chi-square or Fisher's exact test (p, p-value), to estimate the chances of a logistic regression analysis (Odds Ratio, OR, or admitting a Confidence Interval (CI) of 95 %). RESULTS: No differences were observed in groups regarding menopausal status, smoking, hormonal contraceptive use, colposcopy findings, LLETZ diagnosis, and recurrence. Comparing biopsy vs S&T groups, the frequency of women over 40 years was 28.4 % vs 39.7 % (p = 0.011), and transformation zone type 3 was 12.2 vs 26.8 % (p < 0.001), respectively. In women managed by S&T, when compared to a LLETZ diagnosis, an HSIL+ result was more frequent in women presenting with TZ 1 (93.1 % TZ1 vs 78.5 % TZ2 vs 73.8 % TZ3, p = 0.008) and in women with abnormal colposcopy (92.9 % abnormal vs 38.1 % negative, p < 0.001). Multiple regression analysis found that women with negative colposcopic findings presented a higher risk for negative LLETZ diagnosis (LSIL/Negative final histology) (18.6; 6.18-56.02). CONCLUSIONS: No difference was observed in the LLETZ diagnosis in women who did or did not use the S&T approach: it was adequate for women referred by cytological HSIL along with high-grade colposcopic findings.
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Displasia do Colo do Útero , Neoplasias do Colo do Útero , Gravidez , Feminino , Humanos , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/patologia , Displasia do Colo do Útero/diagnóstico , Colo do Útero/patologia , Colposcopia/métodos , BiópsiaRESUMO
Objectives: To evaluate the outcomes of conservative management in young women with high-grade squamous intraepithelial lesion (HSIL). Methods: A retrospective cohort study included women younger than 30 years referred with HSIL (cytology or biopsy) managed conservatively from 2012 to 2019, in Campinas/Brazil. Regression was the outcome when no evidence of HSIL was observed in at least two consecutive follow-ups. Kaplan-Meyer method was used to determine regression probabilities. Other tests were chi-square or Fisher, Mann-Whitney and COX regression. Results: During the study period, 89 patients were included. No progression to microinvasive or invasive cancer was observed. Sixty-one (69%) patients were younger than 25 years, and 28 (31%) were aged 25-30 years. Spontaneous regression was seen in 64 (72%) and persistence in 25 (28%) of the overall sample. The average time to regression was 15.4 months (standard deviation [SD] = 7.7), and the follow-up time was 31.6 months (SD 19.0). Age, parity, first sexual intercourse, smoking, hormonal contraception, and colposcopy impression were not different among women with regression or persistence. Regression probabilities were, respectively, 28.9%, 60.2%, and 78.1% after 12, 18, and 24 months. Most of the events happened between 12 and 18 months of follow-up. Conclusions: Conservative management in women younger than 30 years was safe: spontaneous regression was observed in 72% of all women younger than 30 with HSIL managed conservatively. No clinical variable was relevant, influencing regression. In 2 years the regression probability was 78%.
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OBJECTIVE: This paper searches an ideal cone height for stage definition and safe treatment of cervical microinvasive squamous carcinoma stage IA1 (MIC IA1), avoiding excessive cervix resection, favoring a future pregnancy. METHODS: A retrospective study was performed involving 562 women with MIC IA1, from 1985 to 2013, evaluating cone margin involvement, depth of stromal invasion, lymph vascular invasion, conization height, and residual uterine disease (RD). High-grade squamous lesions or worse detection was considered recurrence. Univariate and multivariate regression analyses were performed, including age, conization technique (CKC, cold-knife, or ETZ, excision of transformation zone), and pathological results. Conization height to provide negative margins and the risk of residual disease were analyzed. RESULTS: Conization was indicated by biopsy CIN2/3 in 293 cases. Definitive treatments were hysterectomy (69.8%), CKC (20.5%), and ETZ (9.7%). Recurrence rate was 5.5%, more frequent in older women (p = 0.030), and less frequent in the hysterectomy group (p = 0.023). Age ≥40 years, ETZ and conization height are independent risk factors for margin involvement. For ages <40 years, 10 mm cone height was associated with 68.6% Negative Predictive Value (NPV) for positive margins, while for 15 mm and 25 mm, the NPV was 75.8% and 96.2%, respectively. With negative margins, the NPV for RD varied from 85.7-92.3% for up to 24 mm cone height and 100% from 25 mm. CONCLUSION: Conization 10 mm height for women <40 years provided adequate staging for almost 70%, with 10% of RD and few recurrences. A personalized cone height and staging associated with conservative treatment are recommended.
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Carcinoma de Células Escamosas/terapia , Recidiva Local de Neoplasia/terapia , Displasia do Colo do Útero/terapia , Neoplasias do Colo do Útero/terapia , Adulto , Idoso , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/patologia , Conização/métodos , Tratamento Conservador , Feminino , Humanos , Histerectomia , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasia Residual/diagnóstico , Neoplasia Residual/patologia , Fatores de Risco , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/patologia , Adulto Jovem , Displasia do Colo do Útero/epidemiologia , Displasia do Colo do Útero/patologiaRESUMO
In 2018, WHO called for global action to eliminate cervical cancer. The complexity of the processes involved in terms of prevention is often underestimated. Low- and middle-income countries do not have a robust healthcare framework to ensure high-quality programs. The present article discusses how fragile healthcare systems are barriers to eliminating cervical cancer, and also reports the experience of a Brazilian prevention program. The article considers how cervical cancer can be interpreted as an indicator of inequality: how women's attitudes and access to care determine an early or late diagnosis, and how strategies combining vaccine and DNA-HPV tests are crucial. New vaccine schemes, the critical analysis of local data, strengthening communication, managing sentinel events, and integrating vaccination and screening data for the health information system are some of the key activities to sustainable improvement in both access and quality of care.
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Disparidades em Assistência à Saúde , Infecções por Papillomavirus/epidemiologia , Vacinas contra Papillomavirus , Displasia do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Vacinação , Brasil/epidemiologia , Atenção à Saúde/normas , Países em Desenvolvimento , Feminino , Humanos , Programas de Rastreamento , Infecções por Papillomavirus/prevenção & controle , Neoplasias do Colo do Útero/prevenção & controle , Displasia do Colo do Útero/prevenção & controleRESUMO
OBJECTIVE: To evaluate the indication and performance of systematic lymphadenectomy (SL) in Stage I endometrioid endometrial carcinoma (EEC), at intermediate risk (FIGO IAG2/G3, IBG1/G2) on recurrence, disease-free survival (DFS) and survival. STUDY DESIGN: 194 women underwent hysterectomies by laparotomy, with SL (n = 95) or without SL (n = 99) between 1990 and 2014 was evaluated. Diagnosis period, age, BMI, comorbidities, stage, and adjuvant radiotherapy were analyzed. DFS and cancer-specific survival were analyzed by Kaplan-Meier and log-rank test, and recurrences by Cox regression. RESULTS: SL was performed in 93% (41/44) of women managed before 1998 and decreasing after that (p < 0.001). SL was also more frequent if BMI under 35.0 kg/m2 (p < 0.001) and in women without comorbidities (p = 0.017). Distribution of age, stage and postoperative radiotherapy were not different between groups. There were 14 recurrences (7.4%), concentrated in the SL group (12 cases) and associated with Stage IAG3 (35.7%, p = 0.009). Longitudinal evaluation exhibited 95% of 5-year cancer-specific survival rate for non-SL group vs. 88% for the SL group (p = 0.039), and DFS rate was 97% for the non-SL group vs. 85% for the SL group (p = 0.004). Cox regression analyses exhibited Stage IAG3 (HR 6.48, IC95% 1.88-22.39; p = 0.003) associated with less DFS. CONCLUSION: SL in surgical staging of EEC at intermediate risk presented no benefits regarding recurrences, DFS, and cancer-specific survival rate when compared to patients not submitted to complete surgical staging. Stage IAG3 had poor prognosis regardless treatment modality. Our results provide further evidence to support the current trend to avoid SL in the surgical approach to selected women.
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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.
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Colo do Útero/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/epidemiologia , Adolescente , Adulto , Brasil , Canadá , Estudos de Coortes , Método Duplo-Cego , Feminino , Genótipo , Humanos , Incidência , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Prevalência , Fatores de Risco , Comportamento Sexual/estatística & dados numéricos , Parceiros Sexuais , Estados Unidos , Adulto JovemRESUMO
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+.
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Adjuvantes Imunológicos , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Displasia do Colo do Útero/etiologia , Displasia do Colo do Útero/patologia , Adolescente , Adulto , Feminino , Humanos , Gradação de Tumores , Recidiva Local de Neoplasia , Avaliação de Resultados em Cuidados de Saúde , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Vacinação , Adulto Jovem , Displasia do Colo do Útero/cirurgiaRESUMO
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 (15-25â 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 6.3â years. Cervicovaginal samples were self-collected at 3-month intervals for up to 27â 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 1â year compared with 32.3% for LR-HPV types. The risk of acquiring any HPV infection was higher among women aged <21â 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.
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Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Adolescente , Adulto , DNA Viral/análise , Método Duplo-Cego , Feminino , Humanos , Incidência , Papillomaviridae/isolamento & purificação , Fatores de Risco , Parceiros Sexuais , Fatores de Tempo , Neoplasias do Colo do Útero/prevenção & controle , Adulto JovemRESUMO
BACKGROUND: Matrix metalloproteinases (MMP) are important enzymes in the tumor microenvironment associated with progression of cervical intraepithelial neoplasia (CIN) toward squamous cell carcinoma (SCC) of the cervix. However, the role of MMPs in the inflammatory process associated with Chlamydia trachomatis infection concomitant with the carcinogenic process driven by HPV has not yet been addressed. In the present study, we analyzed the state of the MMP-9-RECK axis in cervical carcinogenesis. METHODS: The levels of MMP-9 and RECK expression were analyzed by immunocytochemistry in liquid-based cytology samples from 136 women with high-grade cervical lesions (CIN2/CIN3) and cervical SCC diagnosed by LLETZ, and in 196 women without cervical neoplasia or CIN1. Real-time qPCR was performed to analyze expression of MMP-9 and RECK in 15 cervical samples. The presence of HPV-DNA and other genital pathogens was evaluated by PCR. RESULTS: We found a higher expression of MMP-9 [OR, 4.2; 95% confidence interval (CI), 2.2-7.8] and lower expression of RECK (OR, 0.4; 95% CI, 0.2-0.7) in women with CIN2/CIN3/SCC when compared with women from the control group (no neoplasia/CIN1). A statistically significant association was also found between MMP-9/RECK imbalance and infection by alpha-9 HPV and C. trachomatis. The prevalence of C. trachomatis infection was significantly higher in women with high-grade cervical disease (OR, 3.7; 95% CI, 1.3-11.3). CONCLUSIONS: MMP-9/RECK imbalance in cervical smears is significantly associated with high-grade cervical diseases and infection by alpha-9 HPV and C. trachomatis. IMPACT: MMP-9/RECK imbalance during cervical inflammation induced by C. trachomatis might play a role in HPV-mediated cervical carcinogenesis.
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Infecções por Chlamydia/genética , Proteínas Ligadas por GPI/genética , Regulação Neoplásica da Expressão Gênica , Metaloproteinase 9 da Matriz/genética , Infecções por Papillomavirus/genética , Neoplasias do Colo do Útero/genética , Cervicite Uterina/genética , Adulto , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virologia , Colo do Útero/metabolismo , Colo do Útero/patologia , Infecções por Chlamydia/metabolismo , Infecções por Chlamydia/patologia , Chlamydia trachomatis/genética , Estudos Transversais , DNA Bacteriano/genética , DNA de Neoplasias/genética , DNA Viral/genética , Feminino , Proteínas Ligadas por GPI/biossíntese , Regulação Bacteriana da Expressão Gênica , Genótipo , Papillomavirus Humano 16/genética , Humanos , Imuno-Histoquímica , Metaloproteinase 9 da Matriz/biossíntese , Teste de Papanicolaou , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologia , Cervicite Uterina/metabolismo , Cervicite Uterina/microbiologia , Esfregaço VaginalRESUMO
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 (22â327 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).
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Adjuvantes Imunológicos/administração & dosagem , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Displasia do Colo do Útero/prevenção & controle , Displasia do Colo do Útero/virologia , Adolescente , Adulto , Fatores Etários , Costa Rica , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/imunologia , Papillomavirus Humano 18/isolamento & purificação , Humanos , Medição de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Vacinação/métodos , Adulto JovemRESUMO
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.).
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Hidróxido de Alumínio/administração & dosagem , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Lipídeo A/análogos & derivados , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Lesões Pré-Cancerosas/prevenção & controle , Neoplasias do Colo do Útero/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Adulto , Animais , Anticorpos Antivirais/sangue , DNA Viral/análise , DNA Viral/isolamento & purificação , Método Duplo-Cego , Feminino , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/isolamento & purificação , Humanos , Lipídeo A/administração & dosagem , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/administração & dosagem , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/virologia , Resultado do Tratamento , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Adulto JovemRESUMO
The efficacy of the human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against cervical infections with HPV in the Papilloma Trial against Cancer in Young Adults (PATRICIA) was evaluated using a combination of the broad-spectrum L1-based SPF10 PCR-DNA enzyme immunoassay (DEIA)/line probe assay (LiPA25) 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 SPF10 PCR-DEIA/LiPA25 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.).
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Lipídeo A/análogos & derivados , Papillomaviridae/classificação , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/imunologia , Adolescente , Adulto , DNA Viral/genética , Feminino , Genótipo , Humanos , Lipídeo A/administração & dosagem , Papillomaviridae/genética , Infecções por Papillomavirus/prevenção & controle , Reação em Cadeia da Polimerase , Resultado do Tratamento , Adulto JovemRESUMO
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.
Assuntos
Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/efeitos adversos , Vacinas contra Papillomavirus/imunologia , Neoplasias do Colo do Útero/prevenção & controle , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Brasil , DNA Viral/análise , DNA Viral/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Histocitoquímica , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/isolamento & purificação , Humanos , Testes de Neutralização , Vacinas contra Papillomavirus/administração & dosagem , Resultado do Tratamento , Esfregaço Vaginal , Adulto JovemRESUMO
BACKGROUND: We examined risk of newly detected human papillomavirus (HPV) infection and cervical abnormalities in relation to HPV type 16/18 antibody levels at enrollment in PATRICIA (Papilloma Trial Against Cancer in Young Adults; NCT00122681). METHODS: Using Poisson regression, we compared risk of newly detected infection and cervical abnormalities associated with HPV-16/18 between seronegative vs seropositive women (15-25 years) in the control arm (DNA negative at baseline for the corresponding HPV type [HPV-16: n = 8193; HPV-18: n = 8463]). RESULTS: High titers of naturally acquired HPV-16 antibodies and/or linear trend for increasing antibody levels were significantly associated with lower risk of incident and persistent infection, atypical squamous cells of undetermined significance or greater (ASCUS+), and cervical intraepithelial neoplasia grades 1/2 or greater (CIN1+, CIN2+). For HPV-18, although seropositivity was associated with lower risk of ASCUS+ and CIN1+, no association between naturally acquired antibodies and infection was demonstrated. Naturally acquired HPV-16 antibody levels of 371 (95% confidence interval [CI], 242-794), 204 (95% CI, 129-480), and 480 (95% CI, 250-5756) EU/mL were associated with 90% reduction of incident infection, 6-month persistent infection, and ASCUS+, respectively. CONCLUSIONS: Naturally acquired antibodies to HPV-16, and to a lesser extent HPV-18, are associated with some reduced risk of subsequent infection and cervical abnormalities associated with the same HPV type.
Assuntos
Anticorpos Antivirais/imunologia , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Papillomaviridae/imunologia , Infecções por Papillomavirus/diagnóstico , Adolescente , Adulto , DNA Viral/genética , Método Duplo-Cego , Feminino , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Papillomaviridae/genética , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Fatores de Risco , Neoplasias do Colo do Útero/etiologia , Neoplasias do Colo do Útero/virologia , Adulto Jovem , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/virologiaRESUMO
BACKGROUND: More information is needed about time between sexual initiation and human papillomavirus (HPV) infection and development of cervical precancer. METHODS: The objectives were to investigate the time between first sexual activity and detection of first cervical HPV infection or development of first cervical intraepithelial neoplasia (CIN), and associated factors in women from the double-blind, multinational, 4-year PATRICIA trial. PATRICIA enroled women aged 15-25 years with no more than 6 lifetime sexual partners. Women were randomized 1:1 to the HPV-16/18 AS04-adjuvanted vaccine or to control, but only women from the control arm who began sexual intercourse during the study or within 6 months before enrolment, and had no HPV infection detected before the recorded date of their first sexual intercourse, were included in the present analysis. The time between onset of sexual activity and detection of the first cervical HPV infection or development of the first CIN lesion was analyzed using Kaplan-Meier and univariate and multivariable Cox proportional-hazards models. RESULTS: A total of 9337 women were enroled in the control arm of PATRICIA of whom 982 fulfilled the required inclusion criteria for analysis. A cumulative total of 28%, 44%, and 62% of the subjects had HPV infection within 12, 24, and 48 months, respectively. The overall incidence rate was 27.08 per 100 person-years. The most common oncogenic types associated with 6-month persistent infection were HPV-16 (incidence rate: 2.74 per 100 person-years), HPV-51 (2.70), HPV-52 (1.66), HPV-66 (1.14), and HPV-18 (1.09). Increased infection risk was associated with more lifetime sexual partners, being single, Chlamydia trachomatis history, and duration of hormone use. CIN1+ and CIN2+ lesions were most commonly associated with HPV-16, with an overall incidence rate of 1.87 and 1.07 per 100 person-years, respectively. Previous cervical HPV infection was most strongly associated with CIN development. CONCLUSIONS: More than 25% of women were infected with HPV within 1 year of beginning sexual activity. Without underestimating the value of vaccination at older ages, our findings emphasize its importance before sexual initiation. TRIAL REGISTRATION: clinicaltrials.gov: NCT00122681 .
Assuntos
Infecções por Papillomavirus/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Comportamento Sexual/estatística & dados numéricos , Displasia do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Adolescente , Adulto , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Fatores de Risco , Parceiros Sexuais , Espanha/epidemiologia , Fatores de Tempo , Adulto JovemRESUMO
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.
Assuntos
Alphapapillomavirus , Colo do Útero/virologia , Infecções por Papillomavirus/metabolismo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologia , Adolescente , Adulto , Colo do Útero/metabolismo , Colo do Útero/patologia , Método Duplo-Cego , Feminino , Humanos , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/patologia , Fatores de Risco , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/patologiaRESUMO
BACKGROUND: Public Health England has reported a decrease of up to 20.8% in new diagnoses of external genital warts (GWs) among women aged <19 years since the national vaccination program with the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine began in 2008. A post hoc analysis of the phase III PATRICIA (PApilloma TRIal against Cancer In young Adults) trial (NCT00122681) was performed to ascertain whether protection against low-risk HPV types was apparent. METHODS: Vaccine efficacy (VE) at 48 months was assessed against 6-month persistent infection (6MPI) with low-risk HPV types in the total vaccinated cohort (TVC) and in the TVC naive (for 25 HPV types tested) populations. RESULTS: In the TVC naive cohort, VE against 6MPI (95% confidence interval) was 34.5% (11.3 to 51.8) for HPV-6/11, 34.9% (9.1 to 53.7) for HPV-6, 30.3% (-45.0 to 67.5) for HPV-11, and 49.5% (21.0 to 68.3) for HPV-74. CONCLUSIONS: The HPV-16/18 AS04-adjuvanted vaccine appears to have moderate efficacy against persistent infections with a number of low-risk HPV types (HPV-6/11/74), which are responsible for the majority of external GWs, and recently, antibody and cell-mediated immune response to HPV-6/11 have been observed. These findings may help to explain the decrease in external GW diagnoses seen in England.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Condiloma Acuminado/prevenção & controle , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Lipídeo A/análogos & derivados , Vacinação , Ensaios Clínicos Fase III como Assunto , Condiloma Acuminado/epidemiologia , Condiloma Acuminado/imunologia , Método Duplo-Cego , Feminino , Papillomavirus Humano 6/imunologia , Humanos , Incidência , Achados Incidentais , Lipídeo A/administração & dosagem , Estudos Multicêntricos como Assunto , Vacinas contra Papillomavirus , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
OBJECTIVE: We 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. METHODS: Women 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. RESULTS: 16782 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 <15 years at first sexual intercourse, higher number of sexual partners during the past 12 months, longer duration of hormonal contraception and history of sexually transmitted infection (STI). For cervical abnormalities, only history of STI (excluding Chlamydia trachomatis) remained significant in the multivariable analysis after adjusting for HPV infection. CONCLUSIONS: Women reporting 3+ sexual partners in the past 12 months had the highest risk of HPV infection at baseline. HPV infection was the main risk factor for cervical abnormalities, and history of STIs excluding Chlamydia trachomatis increased risk to a lesser extent. Although behavioral factors can influence risk, all sexually active women are susceptible to HPV infection.
Assuntos
Colo do Útero/patologia , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/etiologia , Doenças do Colo do Útero/epidemiologia , Doenças do Colo do Útero/etiologia , Neoplasias do Colo do Útero/prevenção & controle , Adolescente , Adulto , Colo do Útero/virologia , Feminino , Humanos , Modelos Logísticos , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus , Prevalência , Fatores de Risco , Doenças do Colo do Útero/prevenção & controle , Doenças do Colo do Útero/virologia , Vacinação , Adulto JovemRESUMO
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.
Assuntos
Anticorpos Antivirais/sangue , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/imunologia , Neoplasias do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/virologia , Adolescente , Adulto , Brasil , Canadá , Feminino , Seguimentos , Humanos , Placebos/administração & dosagem , Gravidez , Fatores de Tempo , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: Cervical intraepithelial neoplasia grade 2 or greater (CIN2+) is the surrogate endpoint used in licensure trials of human papillomavirus (HPV) vaccines. Vaccine efficacy against CIN3+, the immediate precursor to invasive cervical cancer, is more difficult to measure because of its lower incidence, but provides the most stringent evidence of potential cancer prevention. We report vaccine efficacy against CIN3+ and adenocarcinoma in situ (AIS) in the end-of-study analysis of 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 receive an HPV-16/18 AS04-adjuvanted 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 patients and study investigators were masked to allocated vaccine. The primary endpoint of PATRICIA has been reported previously. In the present end-of-study analysis, we focus on CIN3+ and AIS in the populations of most clinical interest, the total vaccinated cohort (TVC) and the TVC-naive. The TVC comprised all women who received at least one vaccine dose, approximating catch-up populations and including sexually active women (vaccine n=9319; control=9325). The TVC-naive comprised women with no evidence of oncogenic HPV infection at baseline, approximating early adolescent HPV exposure (vaccine n=5824; control=5820). This study is registered with ClinicalTrials.gov, number NCT00122681. FINDINGS: Vaccine efficacy against CIN3+ associated with HPV-16/18 was 100% (95% CI 85·5-100) in the TVC-naive and 45·7% (22·9-62·2) in the TVC. Vaccine efficacy against all CIN3+ (irrespective of HPV type in the lesion and including lesions with no HPV DNA detected) was 93·2% (78·9-98·7) in the TVC-naive and 45·6% (28·8-58·7) in the TVC. In the TVC-naive, vaccine efficacy against all CIN3+ was higher than 90% in all age groups. In the TVC, vaccine efficacy against all CIN3+ and CIN3+ associated with HPV-16/18 was highest in the 15-17 year age group and progressively decreased in the 18-20 year and 21-25 year age groups. Vaccine efficacy against all AIS was 100% (31·0-100) and 76·9% (16·0-95·8) in the TVC-naive and TVC, respectively. Serious adverse events occurred in 835 (9·0%) and 829 (8·9%) women in the vaccine and control groups, respectively; only ten events (0·1%) and five events (0·1%), respectively, were considered to be related to vaccination. INTERPRETATION: PATRICIA end-of-study results show excellent vaccine efficacy against CIN3+ and AIS irrespective of HPV DNA in the lesion. Population-based vaccination that incorporates the HPV-16/18 vaccine and high coverage of early adolescents might have the potential to substantially reduce the incidence of cervical cancer. FUNDING: GlaxoSmithKline Biologicals.