RESUMO
Among women aged 27-45 years, the quadrivalent human papillomavirus (qHPV; HPV6/11/16/18) vaccine was generally well tolerated, efficacious, and immunogenic in the placebo-controlled FUTURE III study (NCT00090220; n = 3253). The qHPV vaccine was also generally well tolerated and highly immunogenic in men aged 27-45 years who participated in the single-cohort mid-adult male (MAM) study (NCT01432574; n = 150). Here, we report results of a long-term follow up (LTFU) extension of FUTURE III with up to 10 years follow-up. To understand the relevance of the mid-adult women LTFU study in the context of mid-adult men vaccination, we report results from post-hoc, cross-study immunogenicity analyses conducted to compare immunogenicity (geometric mean titers; GMTs) at 1-month post-qHPV vaccine dose 3 in women and men aged 27-45 years versus women and men aged 16-26 years from prior efficacy studies. The qHPV vaccine demonstrated durable protection against the combined endpoint of HPV6/11/16/18-related high-grade cervical dysplasia and genital warts up to 10 years (median 8.9) post-dose 3 and sustained HPV6/11/16/18 antibody responses through approximately 10 years in women aged 27-45 years. Efficacy of qHPV vaccine in men aged 27-45 years was inferred based on the cross-study analysis of qHPV vaccine immunogenicity demonstrating non-inferior HPV6/11/16/18 antibody responses in men aged 27-45 years versus 16-26 years. In conclusion, durable effectiveness of the qHPV vaccine was demonstrated in women 27-45 years of age, and vaccine efficacy was inferred in men 27-45 years of age based on the serological results.
Assuntos
Infecções por Papillomavirus , Vacinas contra Papillomavirus , Adulto , Anticorpos Antivirais , Estudos Clínicos como Assunto , Feminino , Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18 , Humanos , Imunogenicidade da Vacina , Masculino , Pessoa de Meia-Idade , Papillomaviridae , Infecções por Papillomavirus/prevenção & controle , Vacinas CombinadasRESUMO
BACKGROUND: We investigated the impact of human papillomavirus (HPV) vaccination on the performance of cytology-based and HPV-based screening for detection of cervical precancer among women vaccinated as young adults and reaching screening age. METHODS: A total of 4632 women aged 25-36 years from the Costa Rica HPV Vaccine Trial were included (2418 HPV-vaccinated as young adults and 2214 unvaccinated). We assessed the performance of cytology- and HPV-based cervical screening modalities in vaccinated and unvaccinated women to detect high-grade cervical precancers diagnosed over 4 years and the absolute risk of cumulative cervical precancers by screening results at entry. RESULTS: We detected 95 cervical intraepithelial neoplasia grade 3 or worse (52 in unvaccinated and 43 in vaccinated women). HPV16/18/31/33/45 was predominant (69%) among unvaccinated participants, and HPV35/52/58/39/51/56/59/66/68 predominated (65%) among vaccinated participants. Sensitivity and specificity of cervical screening approaches were comparable between women vaccinated as young adults and unvaccinated women. Colposcopy referral rates were lower in the vaccinated group for HPV-based screening modalities, but the positive predictive value was comparable between the 2 groups. CONCLUSIONS: Among women approaching screening ages, vaccinated as young adults, and with a history of intensive screening, the expected reduction in the positive predictive value of HPV testing, associated with dropping prevalence of HPV-associated lesions, was not observed. This is likely due to the presence of high-grade lesions associated with nonvaccine HPV types, which may be less likely to progress to cancer.
Assuntos
Infecções por Papillomavirus , Vacinas contra Papillomavirus , Neoplasias do Colo do Útero , Costa Rica/epidemiologia , Detecção Precoce de Câncer/métodos , Feminino , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Humanos , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/prevenção & controle , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/prevenção & controle , Vacinação , Adulto JovemRESUMO
BACKGROUND: Oncogenic human papillomavirus (HPV) infections cause most cases of cervical cancer. Here, we report long-term follow-up results for the Costa Rica Vaccine Trial (publicly funded and initiated before licensure of the HPV vaccines), with the aim of assessing the efficacy of the bivalent HPV vaccine for preventing HPV 16/18-associated cervical intraepithelial neoplasia grade 2 or worse (CIN2+). METHODS: Women aged 18-25 years were enrolled in a randomised, double-blind, controlled trial in Costa Rica, between June 28, 2004, and Dec 21, 2005, designed to assess the efficacy of a bivalent vaccine for the prevention of infection with HPV 16/18 and associated precancerous lesions at the cervix. Participants were randomly assigned (1:1) to receive an HPV 16/18 AS04-adjuvanted vaccine or control hepatitis A vaccine. Vaccines were administered intramuscularly in three 0·5 mL doses at 0, 1, and 6 months and participants were followed up annually for 4 years. After the blinded phase, women in the HPV vaccine group were invited to enrol in the long-term follow-up study, which extended follow-up for 7 additional years. The control group received HPV vaccine and was replaced with a new unvaccinated control group. Women were followed up every 2 years until year 11. Investigators and patients were aware of treatment allocation for the follow-up phase. At each visit, clinicians collected cervical cells from sexually active women for cytology and HPV testing. Women with abnormal cytology were referred to colposcopy, biopsy, and treatment as needed. Women with negative results at the last screening visit (year 11) exited the long-term follow-up study. The analytical cohort for vaccine efficacy included women who were HPV 16/18 DNA-negative at vaccination. The primary outcome of this analysis was defined as histopathologically confirmed CIN2+ or cervical intraepithelial neoplasia grade 3 or worse associated with HPV 16/18 cervical infection detected at colposcopy referral. We calculated vaccine efficacy by year and cumulatively. This long-term follow-up study is registered with ClinicalTrials.gov, NCT00867464. FINDINGS: 7466 women were enrolled in the Costa Rica Vaccine Trial; 3727 received the HPV vaccine and 3739 received the control vaccine. Between March 30, 2009, and July 5, 2012, 2635 women in the HPV vaccine group and 2836 women in the new unvaccinated control group were enrolled in the long-term follow-up study. 2635 women in the HPV vaccine group and 2677 women in the control group were included in the analysis cohort for years 0-4, and 2073 women from the HPV vaccine group and 2530 women from the new unvaccinated control group were included in the analysis cohort for years 7-11. Median follow-up time for the HPV group was 11·1 years (IQR 9·1-11·7), 4·6 years (4·3-5·3) for the original control group, and 6·2 years (5·5-6·9) for the new unvaccinated control group. At year 11, vaccine efficacy against incident HPV 16/18-associated CIN2+ was 100% (95% CI 89·2-100·0); 34 (1·5%) of 2233 unvaccinated women had a CIN2+ outcome compared with none of 1913 women in the HPV group. Cumulative vaccine efficacy against HPV 16/18-associated CIN2+ over the 11-year period was 97·4% (95% CI 88·0-99·6). Similar protection was observed against HPV 16/18-associated CIN3-specifically at year 11, vaccine efficacy was 100% (95% CI 78·8-100·0) and cumulative vaccine efficacy was 94·9% (73·7-99·4). During the long-term follow-up, no serious adverse events occurred that were deemed related to the HPV vaccine. The most common grade 3 or worse serious adverse events were pregnancy, puerperium, and perinatal conditions (in 255 [10%] of 2530 women in the unvaccinated control group and 201 [10%] of 2073 women in the HPV vaccine group). Four women in the unvaccinated control group and three in the HPV vaccine group died; no deaths were deemed to be related to the HPV vaccine. INTERPRETATION: The bivalent HPV vaccine has high efficacy against HPV 16/18-associated precancer for more than a decade after initial vaccination, supporting the notion that invasive cervical cancer is preventable. FUNDING: US National Cancer Institute.
Assuntos
Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Displasia do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/prevenção & controle , Vacinas Combinadas/administração & dosagem , Adolescente , Adulto , Costa Rica , Método Duplo-Cego , Feminino , Humanos , Imunização , Gradação de Tumores , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Vacinas Combinadas/efeitos adversos , Adulto Jovem , Displasia do Colo do Útero/patologia , Displasia do Colo do Útero/virologiaRESUMO
Nearly 90% of cervical cancer cases and deaths occur in low- and middle-income countries that lack comprehensive national HPV immunization and cervical cancer screening programs. In these settings, it is difficult to implement screening programs due to a lack of infrastructure and shortage of trained personnel. Screening programs based on visual inspection with acetic acid (VIA) have been successfully implemented in some low-resource settings. However, VIA has poor specificity and up to 90% of patients receiving treatment based on a positive VIA exam are over-treated. A number of studies have suggested that high-resolution cervical imaging to visualize nuclear morphology in vivo can improve specificity by better distinguishing precancerous and benign lesions. To enable high-resolution imaging in low-resource settings, we developed a portable, low-cost, high-resolution microendoscope that uses a mobile phone to detect and display images of cervical epithelium in vivo with subcellular resolution. The device was fabricated for less than $2,000 using commercially available optical components including filters, an LED and triplet lenses assembled in a 3D-printed opto-mechanical mount. We show that the mobile high-resolution microendoscope achieves similar resolution and signal-to-background ratio as previously reported high-resolution microendoscope systems using traditional cameras and computers to detect and display images. Finally, we demonstrate the ability of the mobile high-resolution microendoscope to image normal and precancerous squamous epithelium of the cervix in vivo in a gynecological referral clinic in Barretos, Brazil.
Assuntos
Telefone Celular , Colposcopia/métodos , Microscopia Intravital/métodos , Displasia do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/prevenção & controle , Brasil , Colo do Útero/diagnóstico por imagem , Colo do Útero/patologia , Colposcopia/economia , Colposcopia/instrumentação , Países em Desenvolvimento , Desenho de Equipamento , Estudos de Viabilidade , Feminino , Células HeLa , Recursos em Saúde/provisão & distribuição , Humanos , Processamento de Imagem Assistida por Computador/instrumentação , Processamento de Imagem Assistida por Computador/métodos , Microscopia Intravital/economia , Microscopia Intravital/instrumentação , Programas de Rastreamento/economia , Programas de Rastreamento/instrumentação , Programas de Rastreamento/métodos , Aplicativos Móveis , Exame Físico/economia , Exame Físico/instrumentação , Exame Físico/métodos , Impressão Tridimensional , Sensibilidade e Especificidade , Displasia do Colo do Útero/patologia , Neoplasias do Colo do Útero/patologiaRESUMO
Cervical cancer is the third leading cause of cancer-related death among women in low-to-middle income countries. Pap testing and pathological services are difficult to implement under these settings. Alternative techniques for the diagnosis of cervical precancer in these settings are needed to reduce the burden of the disease. The objective of this study was to evaluate the diagnostic accuracy of a low-cost, high-resolution microendoscope imaging system in identifying precancerous lesions of the cervix in vivo. A retrospective study of 59 patients undergoing colposcopy for an abnormal Pap test was performed at Hospital de Câncer de Barretos in Brazil. All patients underwent colposcopy as per standard of care, and acetowhite lesions were recorded. High-resolution microendoscopy (HRME) images were obtained from one colposcopically normal region and from all lesions observed on colposcopy. Biopsies of abnormal areas were obtained and reviewed by three independent, blinded pathologists and compared with HRME findings. The mean nuclear area and the median nuclear eccentricity were calculated from HRME images acquired from each site. A diagnostic algorithm to distinguish histopathologically diagnosed cervical intraepithelial neoplasias of grade 2 or more severe lesions (high grade) from less severe lesions (low grade) was developed using these parameters. A test of trend was used to analyze the relationship between HRME positivity and severity of histopathogical diagnosis. Fisher's exact test was used to analyze differences in HRME positivity between high-grade and low-grade lesions. Evaluable images were obtained from 108 of 143 discrete sites. Of these, 71 sites were colposcopically normal or low grade according to histopathology and 37 were diagnosed as high grade on the basis of histopathology. Using the mean nuclear area and the median nuclear eccentricity, HRME images from 59 colposcopically abnormal sites were classified as high grade or low grade with 92% sensitivity and 77% specificity compared with histopathological findings. Increasing HRME positivity showed a significant trend with increasing severity of diagnosis (Ptrend<0.001). We found a strong association (P<0.001) between HRME positivity and a histopathological diagnosis of cervical intraepithelial neoplasia of grade 2 or higher. HRME demonstrated an accurate in-situ diagnosis of high-grade dysplasia. In low-resource settings in which colposcopy and histopathology services are severely limited or unavailable, HRME may provide a low-cost, accurate method for diagnosis of cervical precancer without the need for biopsy, allowing for a single 'screen-and-treat' approach.
Assuntos
Colposcopia/economia , Recursos em Saúde/economia , Área Carente de Assistência Médica , Sistemas Automatizados de Assistência Junto ao Leito/economia , Displasia do Colo do Útero/economia , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Colposcopia/normas , Feminino , Tecnologia de Fibra Óptica/economia , Tecnologia de Fibra Óptica/normas , Recursos em Saúde/normas , Humanos , Histeroscopia/economia , Histeroscopia/normas , Microscopia de Fluorescência/economia , Microscopia de Fluorescência/normas , Pessoa de Meia-Idade , Projetos Piloto , Sistemas Automatizados de Assistência Junto ao Leito/normas , Estudos Retrospectivos , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Human papillomavirus (HPV) causes two types of external genital lesions (EGLs) in men: genital warts (condyloma) and penile intraepithelial neoplasia (PeIN). OBJECTIVE: The purpose of this study was to describe genital HPV progression to a histopathologically confirmed HPV-related EGL. DESIGN, SETTING, AND PARTICIPANTS: A prospective analysis nested within the HPV Infection in Men (HIM) study was conducted among 3033 men. At each visit, visually distinct EGLs were biopsied; the biopsy specimens were subjected to pathologic evaluation and categorized by pathologic diagnoses. Genital swabs and biopsies were used to identify HPV types using the Linear Array genotyping method for swabs and INNO-LiPA for biopsy specimens. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: EGL incidence was determined among 1788 HPV-positive men, and cumulative incidence rates at 6, 12, and 24 mo were estimated. The proportion of HPV infections that progressed to EGL was also calculated, along with median time to EGL development. RESULTS AND LIMITATIONS: Among 1788 HPV-positive men, 92 developed an incident EGL during follow-up (9 PeIN and 86 condyloma). During the first 12 mo of follow-up, 16% of men with a genital HPV 6 infection developed an HPV 6-positive condyloma, and 22% of genital HPV 11 infections progressed to an HPV 11-positive condyloma. During the first 12 mo of follow-up, 0.5% of men with a genital HPV 16 infection developed an HPV 16-positive PeIN. Although we expected PeIN to be a rare event, the sample size for PeIN (n=10) limited the types of analyses that could be performed. CONCLUSIONS: Most EGLs develop following infection with HPV 6, 11, or 16, all of which could be prevented with the 4-valent HPV vaccine. PATIENT SUMMARY: In this study, we looked at genital human papillomavirus (HPV) infections that can cause lesions in men. The HPV that we detected within the lesions could be prevented by a vaccine.
Assuntos
Carcinoma in Situ/epidemiologia , Condiloma Acuminado/epidemiologia , Papillomavirus Humano 11/isolamento & purificação , Papillomavirus Humano 16/isolamento & purificação , Neoplasias Penianas/epidemiologia , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Carcinoma in Situ/patologia , Carcinoma in Situ/virologia , Condiloma Acuminado/patologia , Condiloma Acuminado/virologia , Progressão da Doença , Seguimentos , Genótipo , Papillomavirus Humano 11/genética , Papillomavirus Humano 16/genética , Papillomavirus Humano 6/genética , Papillomavirus Humano 6/isolamento & purificação , Humanos , Incidência , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Neoplasias Penianas/patologia , Neoplasias Penianas/virologia , Prevalência , Estudos Prospectivos , Estados Unidos/epidemiologia , Adulto JovemRESUMO
The Costa Rica Vaccine Trial (CVT) was a randomized clinical trial conducted between 2004 and 2010, which randomized 7466 women aged 18 to 25 to receive the bivalent HPV-16/18 vaccine or control Hepatitis-A vaccine. Participants were followed for 4 years with cross-over vaccination at the study end. In 2010 the long term follow-up (LTFU) study was initiated to evaluate the 10-year impact of HPV-16/18 vaccination, determinants of the immune response, and HPV natural history in a vaccinated population. Herein, the rationale, design and methods of the LTFU study are described, which actively follows CVT participants in the HPV-arm 6 additional years at biennial intervals (3 additional study visits for 10 years of total follow-up), or more often if clinically indicated. According to the initial commitment, women in the Hepatitis-A arm were offered HPV vaccination at cross-over; they were followed 2 additional years and exited from the study. 92% of eligible CVT women accepted participation in LTFU. To provide underlying rates of HPV acquisition and cervical disease among unvaccinated women to compare with the HPV-arm during LTFU, a new unvaccinated control group (UCG) of women who are beyond the age generally recommended for routine vaccination was enrolled, and will be followed by cervical cancer screening over 6 years. To form the UCG, 5000 women were selected from a local census, of whom 2836 women (61% of eligible women) agreed to participate. Over 90% of participants complied with an interview, blood and cervical specimen collection. Evaluation of comparability between the original (Hepatitis-A arm of CVT) and new (UCG) control groups showed that women's characteristics, as well as their predicted future risk for cervical HPV acquisition, were similar, thus validating use of the UCG. LTFU is poised to comprehensively address many important questions related to long-term effects of prophylactic HPV vaccines.
Assuntos
Papillomavirus Humano 18/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus , Neoplasias do Colo do Útero/prevenção & controle , Adulto , Costa Rica/epidemiologia , Estudos Cross-Over , Detecção Precoce de Câncer , Feminino , Seguimentos , Vacinas contra Hepatite A/administração & dosagem , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/isolamento & purificação , Humanos , Infecções por Papillomavirus/epidemiologia , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/efeitos adversos , Vacinas contra Papillomavirus/imunologia , Projetos de Pesquisa , Fatores de Tempo , Doenças do Colo do Útero/epidemiologia , Doenças do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/epidemiologia , Vacinação , Adulto Jovem , Displasia do Colo do Útero/epidemiologia , Displasia do Colo do Útero/prevenção & controleRESUMO
A histologic pattern-based system of risk stratification for endocervical adenocarcinoma has been recently proposed on the basis of tumor-stroma interface and lymph-vascular invasion. The key utility of the system lies in separating cases with very low risk for nodal metastases (pattern A) from those with higher risk (patterns B and C), which may alter the treatment approach. In this study, we determine the reproducibility of applying this system among gynecologic pathologists from 2 institutions using blinded review of 49 adenocarcinomas from 2003 to 2013. κ values and pairwise differences are calculated for the proposed 3-tier system (patterns A, B, and C) as well as a modified version comparing pattern A versus patterns B and C combined (2-tier system). Consensus diagnosis for the 3-tier system is reached in 50% of cases, with majority of κ values indicating fair to almost perfect agreement (range, 0.24 to 0.84). When condensed to 2 tiers, consensus is reached in 81.3% of cases with κ values showing modest improvement (range, 0.33 to 0.92). Pairwise difference analysis reveals diagnosis trends for specific pathologists on the 3-tier system that decrease with 2 tiers. Interpretive variability may be of practical significance in application of the proposed 3-tier pattern-based approach to endocervical adenocarcinoma. Additional studies with larger patient cohorts are needed to confirm the negligible risk for lymph node involvement seen in pattern A patients and to further evaluate the applicability of this new classification system.
Assuntos
Adenocarcinoma/patologia , Neoplasias do Colo do Útero/patologia , Adenocarcinoma/classificação , Adenocarcinoma/metabolismo , Biópsia , Consenso , Feminino , Humanos , Metástase Linfática , Variações Dependentes do Observador , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Estados Unidos , Neoplasias do Colo do Útero/classificaçãoRESUMO
Cervical carcinoma is the most common cancer among Belizean women; however, data regarding the frequency of human papillomavirus (HPV) genotypes and their association with cervical cancer are nonexistent. We therefore included HPV genotyping as part of a week-long cervical cancer screening campaign conducted in Belize City in 2007. Conventional Papanicolaou smears with Hybrid Capture (HC) 2 HPV testing were performed on 463 women. All HC2-positive samples were genotyped using a developmental GP5+/GP6+ polymerase chain reaction-coupled Luminex assay for 2 low-risk and 18 high-risk HPV types. The prevalence of high-risk HPV was 15.6% in the total population, 10.1% in those with normal cytologic findings, and 93.3% in women with a high-grade squamous intraepithelial lesion. Of patients with HPV infections, 35% had multiple types (5.4% of the total group). Of all women and of women with normal cytologic findings, 5.2% and 2.8%, respectively, had HPV16 or 18. For all women, HPV16, 18, 56, and 52 were present in decreasing order of frequency. HPV11 was present in only one patient, and none had HPV6. HPV16 was found in 47% of high-grade squamous epithelial lesions; however, no case of HSIL had HPV18 or 45. HPV35 and HPV58 were the next most common types in high-grade squamous intraepithelial lesion, each occurring in 20% of cases of high-grade squamous intraepithelial lesion, followed by HPV31 in 13.3%. Although women younger than 25 years old were underrepresented, these data suggest that the HPV profile of this cohort of Belizean women differs somewhat from that in the region. In addition, these data are of importance with regard to the development of HPV vaccines that will be used in less developed countries, where care should be taken not to implement vaccination at the cost of basic screening and diagnostic services.
Assuntos
Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Displasia do Colo do Útero/virologia , Adulto , Belize/epidemiologia , Feminino , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/isolamento & purificação , Humanos , Teste de Papanicolaou , Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/genética , Vacinas contra Papillomavirus , Prevalência , Esfregaço VaginalRESUMO
Human papillomavirus (HPV) infection causes cervical cancer and genital warts. Young women (1106) were randomized to receive one of three formulations of a quadrivalent HPV (Types 6/11/16/18) L1 virus-like particle (VLP) vaccine or one of two placebo formulations. The goal was to assess vaccine safety and immunogenicity in baseline HPV 6/11/16 or 18-naïve and previously infected subjects. All three formulations were highly immunogenic. At Month 2 (postdose 1), among women with vaccine-type antibodies at baseline, vaccine-induced anti-HPV responses were approximately 12- to 26-fold higher than those observed in baseline-naïve women, suggesting an anamnestic response. Following an initial, similar sized decline, anti-HPV responses plateaued and remained stable through end-of-study (3.0 years). No vaccine-related serious adverse experiences were reported.