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BACKGROUND: Despite surgical and pharmacological interventions, endometriosis can recur. Reliable information regarding risk of recurrence following a first diagnosis is scant. The aim of this study was to examine clinical and survey data in the setting of disease recurrence to identify predictors of risk of endometriosis recurrence. METHODS: This observational study reviewed data from 794 patients having surgery for pelvic pain or endometriosis. Patients were stratified into two analytic groups based on self-reported or surgically confirmed recurrent endometriosis. Statistical analyses included univariate, followed by multivariate logistic regression to identify risk factors of recurrence, with least absolute shrinkage and selection operator (Lasso) regularisation. Risk-calibrated Supersparse Linear Integer Models (RiskSLIM) and survival analyses (with Lasso) were undertaken to identify predictive features of recurrence. RESULTS: Several significant features were repeatedly identified in association with recurrence, including adhesions, high rASRM score, deep disease, bowel lesions, adenomyosis, emergency room attendance for pelvic pain, younger age at menarche, higher gravidity, high blood pressure and older age. In the surgically confirmed group, with a score of 5, the RiskSLIM method was able to predict the risk of recurrence (compared to a single diagnosis) at 95.3% and included adenomyosis and adhesions in the model. Survival analysis further highlighted bowel lesions, adhesions and adenomyosis. CONCLUSIONS: Following an initial diagnosis of endometriosis, clinical decision-making regarding disease management should take into consideration the presence of bowel lesions, adhesions and adenomyosis, which increase the risk of endometriosis recurrence.
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Endometriose , Recidiva , Humanos , Endometriose/diagnóstico , Endometriose/cirurgia , Feminino , Adulto , Fatores de Risco , Pessoa de Meia-Idade , Adulto JovemRESUMO
Global methylation analysis of gene promoters is promising for detection of high-grade squamous intraepithelial lesions or worse (HSIL+) in high-risk human papillomavirus (hrHPV)-positive women. However, diagnostic performance of methylation data at individual CpG-sites is limited. We explored methylation for predicting HSIL+ in self- and clinician-collected samples from Papua New Guinea. Methylation of EPB41L3 (1-6 CpG-sites), hTERT (1-10 CpG-sites) and FAM19A4 (1-5 CpG-sites) was assessed through pyrosequencing from 44 HPV+ samples (4 cancers, 19 HSIL, 4 low-grade squamous intraepithelial lesions (LSIL), 17 normal). New primers were designed for FAM19A4 directed to the first exon region not explored previously. In clinician-collected samples, methylation at CpG-sites 4 and 5 of EPB41L3 were the best HSIL predictors (AUC >0.83) and CpG-site 4 for cancer (0.925). Combination of EPB41L3 sites 2/4 plus FAM19A4 site 1 were the best HSIL+ markers [100% sensitivity, 63.2% specificity]. Methylation at CpG-site 5 of FAM19A4 was the best HSIL predictor (0.67) in self-collected samples, and CpG-sites 1 and 3 of FAM19A4 for cancer (0.77). Combined, FAM19A4 site 1 plus HPV 16/18 detection yielded sensitivity of 82.6% and specificity of 61.9%. In conclusion, methylation at individual CpG-sites of EPB41L3 and FAM19A4 outperformed global analysis and improved HSIL+ detection, warranting further investigation.
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OBJECTIVE: WHO recommends human papillomavirus (HPV) testing for cervical screening, with triage of high-risk HPV (hrHPV) positive women. However, there are limitations to effective triage for low-resource, high-burden settings, such as Papua New Guinea. In this exploratory study, we assessed the performance of host methylation as triage tools for predicting high-grade squamous intraepithelial lesions (HSIL) in self-collected and clinician-collected samples. DESIGN: Exploratory observational study. SETTING: Provincial hospital, same-day cervical screen-and-treat trial, Papua New Guinea. PARTICIPANTS: 44 hrHPV+women, with paired self/clinician-collected samples (4 squamous cell carcinomas (SCC), 19 HSIL, 4 low-grade squamous intraepithelial lesions, 17 normal). PRIMARY AND SECONDARY OUTCOME MEASURES: Methylation levels of CADM1, MAL and miR124-2 analysed by methylation-specific PCRs against the clinical endpoint of HSIL or SCC (HSIL+) measured using liquid-based-cytology/p16-Ki67 stain. RESULTS: In clinician-collected samples, MAL and miR124-2 methylation levels were significantly higher with increasing grade of disease (p=0.0046 and p<0.0015, respectively). miR124-2 was the best predictor of HSIL (area under the curve, AUC 0.819) while MAL of SCC (AUC 0.856). In self-collected samples, MAL best predicted HSIL (AUC 0.595) while miR124-2 SCC (AUC 0.812). Combined miR124-2/MAL methylation yielded sensitivity and specificity for HSIL+ of 90.5% (95% CI 69.6% to 98.8%) and 70% (95% CI 45.7% to 88.1%), respectively, in clinician-collected samples, and 81.8% (95% CI 59.7% to 94.8%) and 47.6% (95% CI 25.7% to 70.2%), respectively, in self-collected samples. miR124-2/MAL plus HPV16/HPV18 improved sensitivity for HSIL+ (95.2%, 95% CI 76.2% to 99.9%) but decreased specificity (55.0%, 95% CI 31.5% to 76.9%). CONCLUSION: miR124-2/MAL methylation is a potential triage strategy for the detection of HSIL/SCC in low-income and middle-income country.
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Molécula 1 de Adesão Celular , Metilação de DNA , Detecção Precoce de Câncer , MicroRNAs , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina , Infecções por Papillomavirus , Triagem , Neoplasias do Colo do Útero , Humanos , Feminino , MicroRNAs/genética , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Papua Nova Guiné , Detecção Precoce de Câncer/métodos , Molécula 1 de Adesão Celular/genética , Adulto , Triagem/métodos , Pessoa de Meia-Idade , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/genética , Infecções por Papillomavirus/diagnóstico , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/diagnóstico , Manejo de Espécimes/métodos , Adulto Jovem , Sensibilidade e Especificidade , Esfregaço VaginalRESUMO
The efficiency of PCR-based diagnostic assays can be impacted by the quality of DNA template, and anal samples can be particularly problematic due to the presence of faecal contaminants. Here, we compared the Quick-DNA Viral Kit (Zymo, Zymo Research, CA) and MagNA Pure 96 DNA and Viral NA Small Volume Kit (MP96, Roche) for use of the Seegene Anyplex II HPV28 assay (Anyplex28, Seegene) with anal samples. A total of 94 anal samples extracted using the MP96 and Zymo kits were tested via the Anyplex28, which detects high-risk human papillomavirus (HR-HPV, Panel A) and low-risk (LR-HPV, Panel B) HPV types. Testing the HR-HPV types (Panel A), 86 (91.5%) MP96 and 84 (89.4%) Zymo samples were deemed assessable. Overall agreement between the two methods was 87/94 (92.6%, 95% CI: 85.3-97.0) with the Kappa value of 0.678 (0.5-0.9). Of the 87 assessable samples, 50 (57.5%) were concordant, 34 (39.1%) partially concordant, and 10 (11.5%)discordant. In conclusion, the Anyplex28 produces comparable HPV genotyping results when using DNA extracts from either of these two methods.
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DNA Viral , Papillomaviridae , Infecções por Papillomavirus , Humanos , DNA Viral/genética , DNA Viral/isolamento & purificação , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Papillomaviridae/classificação , Reação em Cadeia da Polimerase/métodos , Canal Anal/virologia , Kit de Reagentes para DiagnósticoRESUMO
CONTEXT.: Detection of human papillomavirus (HPV) in formalin-fixed, paraffin-embedded (FFPE) tissues may identify the cause of lesions and has value for the development of new diagnostic assays and epidemiologic studies. Seegene Anyplex II assays are widely used for HPV screening, but their performance using FFPE samples has not been fully explored. OBJECTIVE.: To validate Anyplex II HPV HR Detection (Anyplex II, Seegene) using FFPE samples. DESIGN.: We used 248 stored DNA extracts from cervical cancer FFPE samples collected during 2005-2015 that tested HPV positive using the RHA kit HPV SPF10-LiPA25, v1 (SPF10, Labo Biomedical Products) HPV genotyping assay, manufacturer-validated for FFPE samples. RESULTS.: Of the selected 248 samples, 243 were used in our analysis. Consistent with SPF10 genotyping results, Anyplex II detected all 12 oncogenic types and had an overall HPV detection rate of 86.4% (210 of 243 samples). Anyplex II and SPF10 showed very high agreement for the detection of the 2 most important oncogenic genotypes: HPV 16 (219 of 226; 96.9%; 95% CI, 93.7-98.75) and HPV 18 (221 of 226; 97.8%; 95% CI, 94.9-99.3). CONCLUSIONS.: Overall results showed that both platforms produced comparable HPV genotyping results, indicating the suitability of Anyplex II for FFPE samples. The Anyplex II assay has the added convenience of being an efficient, single-well semiquantitative polymerase chain reaction assay. Further optimization of Anyplex II may enhance its performance using FFPE samples by improving the detection limit.
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Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Papillomavirus Humano , Infecções por Papillomavirus/diagnóstico , Inclusão em Parafina/métodos , Papillomaviridae/genética , Genótipo , DNA Viral/genética , DNA Viral/análise , FormaldeídoRESUMO
IMPORTANCE: The quantity of the human papillomavirus (HPV) is associated with disease outcome. We designed an accurate and precise digital PCR assay for quantitating HPV in anal samples, a sample type that is typically problematic due to the presence of PCR inhibitors.
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Papillomavirus Humano 16 , Infecções por Papillomavirus , Humanos , Papillomavirus Humano 16/genética , Infecções por Papillomavirus/diagnóstico , Canal Anal , Reação em Cadeia da Polimerase , Papillomaviridae/genéticaRESUMO
BACKGROUND: The transition of Australia's National Cervical Screening Program from cytology to a molecular test for human papillomavirus (HPV) (locally referred to as the 'Renewal'), including a longer five-year interval and older age at commencement, significantly impacted all sectors of program delivery. The Renewal had major implications for the roles and requirements of pathology laboratories providing services for the Program. This study aimed to understand the early impacts of the Renewal and its implementation on the pathology sector. METHODS: Semi-structured qualitative interviews were conducted with key stakeholders (N = 49) involved in the STakeholder Opinions of Renewal Implementation and Experiences Study (STORIES), 11-20 months after the program transition. A subset of interviews (N = 24) that discussed the pathology sector were analysed using inductive thematic analysis. RESULTS: Four overarching themes were identified: implementation enablers, challenges, missed opportunities, and possible improvements. Participants believed that the decision to transition to primary HPV screening was highly acceptable and evidence-based, but faced challenges due to impacts on laboratory infrastructure, resources, staffing, and finances. These challenges were compounded by unfamiliarity with new information technology (IT) systems and the new National Cancer Screening Register ('Register') not being fully functional by the date of the program transition. The limited availability of self-collection and lack of standardised fields in pathology forms were identified as missed opportunities to improve equity in the Program. To improve implementation processes, participants suggested increased pathology sector involvement in planning was needed, along with more timely and transparent communication from the Government, and clearer clinical management guidelines. CONCLUSION: The transition to primary HPV screening had a significant and multifaceted impact on the Australian pathology sector reflecting the magnitude and complexity of the Renewal. Strategies to support the pathology sector through effective change management, clear, timely, and transparent communication, as well as adequate funding sources will be critical for other countries planning to transition cervical screening programs.
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Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/prevenção & controle , Detecção Precoce de Câncer , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/prevenção & controle , Austrália , Programas de RastreamentoRESUMO
The COVID-19 pandemic has exacerbated the existing challenges to achieving the WHO target of eliminating cervical cancer as a public health problem by working towards the target of fewer than four cases per 100 000 women. We reviewed the literature to identify potential recovery strategies to support cervical cancer prevention programs in lower-and middle-income countries (LMICs) following COVID-19 disruptions and the extent to which strategies have been implemented. Utilising the WHO health systems framework, we mapped these recovery strategies against the six building blocks to examine their reach across the health system. Most recovery strategies were focused on service delivery, while leadership and governance played a pivotal role in the continuity of cervical cancer prevention programs during the pandemic. Leadership and governance were the drivers for outcomes in the building blocks of health information systems, financing and critical support in operationalising service delivery strategies. In the aftermath of the COVID-19 pandemic with strained health resources and economies, stakeholders would significantly influence the coverage and sustainability of cervical cancer prevention programs. The support from multisectoral stakeholders would accelerate the recovery of cervical cancer prevention programs. To achieve the WHO target by 2030, we call for future studies to understand the barriers and facilitators from the perspectives of stakeholders in order to support the decision-making processes and information required to implement recovery strategies in LMICs.
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Cervical cancer is the fourth most common malignancy in women of reproductive age globally. The burden of this disease is highest in low-income and middle-income countries, especially among women living with HIV. In 2018, WHO launched a global strategy to accelerate cervical cancer elimination through rapid scale-up of prophylactic vaccination, cervical screening, and treatment of precancers and cancers. This initiative was key in raising a call for action to address the stark global disparities in cervical cancer burden. However, achieving elimination of cervical cancer among women with HIV requires consideration of biological and social issues affecting this population. This Position Paper shows specific challenges and uncertainties on the way to cervical cancer elimination for women living with HIV and highlights the scarcity of evidence for the effect of interventions in this population. We argue that reaching equity of outcomes for women with HIV will require substantial advances in approaches to HPV vaccination and improved understanding of the long-term effectiveness of HPV vaccines in settings with high HIV burden cervical cancer, just as HIV, is affected by social and structural factors such as poverty, stigma, and gender discrimination, that place the elimination strategy at risk. Global efforts must, therefore, be galvanised to ensure women living with HIV have optimised interventions, given their substantial risk of this preventable malignancy.
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Infecções por HIV , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/prevenção & controle , Detecção Precoce de Câncer , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/prevenção & controle , PobrezaRESUMO
In this study, we aimed to document stakeholders' experiences of implementing Australia's renewed National Cervical Screening Program. In December 2017, the program changed from 2nd yearly cytology for 20-69 year olds to 5 yearly human papillomavirus (HPV) screening for women 25-74 years. We undertook semi-structured interviews with key stakeholders including government, program administrators, register staff, clinicians and health care workers, non-government organisations, professional bodies, and pathology laboratories from across Australia between Nov 2018 - Aug 2019. Response rate to emailed invitations was 49/85 (58%). We used Proctor et al's (2011) implementation outcomes framework to guide our questions and thematic analysis. We found that stakeholders were evenly divided over whether implementation was successful. There was strong support for change, but concern over aspects of the implementation. There was some frustration related to the delayed start, timeliness of communication and education, shortcomings in change management, lack of inclusion of Aboriginal and Torres Strait Islander people in planning and implementation, failure to make self-collection widely available, and delays in the National Cancer Screening Register. Barriers centred around a perceived failure to appreciate the enormity of the change and register build, and consequent failure to resource, project manage and communicate effectively. Facilitators included the good will and dedication of stakeholders, strong evidence base for change and the support of jurisdictions during the delay. We documented substantial implementation challenges, offering learnings for other countries transitioning to HPV screening. Sufficient planning, significant and transparent engagement and communication with stakeholders, and change management are critical.
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BACKGROUND: Gay and bisexual men (GBM) are at increased risk of human papillomavirus (HPV)-associated anal high-grade squamous intraepithelial lesions (HSILs). Understanding the fractions of HSILs attributable to HPV genotypes is important to inform potential impacts of screening and vaccination strategies. However, multiple infections are common, making attribution of causative types difficult. Algorithms developed for predicting HSIL-causative genotype fractions have never been compared with a reference standard in GBM. METHOD: Samples were from the Study of the Prevention of Anal Cancer. Baseline HPV genotypes detected in anal swab samples (160 participants) were compared with HPV genotypes in anal HSILs (222 lesions) determined by laser capture microdissection (LCM). Five algorithms were compared: proportional, hierarchical, maximum, minimum, and maximum likelihood estimation. RESULTS: All algorithms predicted HPV-16 as the most common HSIL-causative genotype, and proportions differed from LCM detection (37.8%) by algorithm (with differences of -6.1%, +20.9%, -20.4%, +2.9%, and +2.2% respectively). Fractions predicted using the proportional method showed a strong positive correlation with LCM, overall (R = 0.73 and P = .002), and by human immunodeficiency virus (HIV) status (HIV positive, R = 0.74 and P = .001; HIV-negative, R = 0.68 and P = .005). CONCLUSIONS: Algorithms produced a range of inaccurate estimates of HSIL attribution, with the proportional algorithm performing best. The high occurrence of multiple HPV infections means that these algorithms may be of limited use in GBM.
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Neoplasias do Ânus , Infecções por HIV , Soropositividade para HIV , Infecções por Papillomavirus , Lesões Intraepiteliais Escamosas , Masculino , Humanos , Papillomavirus Humano , Homossexualidade Masculina , Infecções por Papillomavirus/epidemiologia , Genótipo , Neoplasias do Ânus/diagnóstico , Papillomaviridae/genética , Infecções por HIV/complicaçõesRESUMO
In Australia's HPV-based cervical screening program, we previously showed that risk of histological high-grade abnormality at 1 year post screening decreased with age in women with oncogenic HPV. In this study, we followed 878 HPV16/18 positive women aged 55 years and over for up to 3 years post screening test, to determine the proportion with histological high-grade abnormality (HGA, incorporating high-grade squamous intraepithelial abnormality (HSIL), adenocarcinoma in situ (AIS), squamous cell carcinoma (SCC) and adenocarcinoma) and to correlate risk of HGA with liquid-based cytology result and with prior screening history. HGA was detected in 7.8% at 1 year and 10.0% at 3 years, with no significant difference (P = .136), despite the number of women with follow-up information significantly increasing from 82.9% to 91.0% (P < .0001). The proportion of HPV16/18 positive women with HGA at 3 years was highest in those with an HSIL cytology result (79.0%) and lowest in those with negative cytology (6.2%). Women with an adequate screening history had fewer HGA than such women with inadequate prior screening (6.6% vs 16.0%, P = .001) or with a history of an abnormality (6.6% vs 14.4%, P = .001). HPV16/18 infection in women over 55 years may have a different natural history from that in younger women, in whom HGA are more common after HPV16/18 detection. In HPV-based cervical screening programs, management algorithms for screen-detected abnormalities based on risk stratification should include factors such as age, screening history and index cytology result, so that women receive appropriate investigation and follow-up.
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Infecções por Papillomavirus , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Feminino , Humanos , Idoso , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/patologia , Papillomavirus Humano 16 , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/patologia , Detecção Precoce de Câncer , Papillomavirus Humano 18 , PapillomaviridaeRESUMO
BACKGROUND: In December 2017, the Australian National Cervical Screening Program transitioned from 2-yearly cytology-based to 5-yearly human papillomavirus (HPV)-based cervical screening, including a vaginal self-collection option. Until July 2022, this option was restricted to under- or never-screened people aged 30 years and older who refused a speculum exam. We investigated the perspectives and experiences of stakeholders involved in, or affected by, the initial implementation of the restricted self-collection pathway. METHODS: Semi-structured interviews were conducted with 49 stakeholders as part of the STakeholder Opinions of Renewal Implementation and Experiences Study. All interviews were audio recorded and transcribed. Data were thematically analysed and coded to the Conceptual Framework for Implementation Outcomes. RESULTS: Stakeholders viewed the introduction of self-collection as an exciting opportunity to provide under-screened people with an alternative to a speculum examination. Adoption in clinical practice, however, was impacted by a lack of clear communication and promotion to providers, and the limited number of laboratories accredited to process self-collected samples. Primary care providers tasked with communicating and offering self-collection described confusion about the availability, participant eligibility, pathology processes, and clinical management processes for self-collection. Regulatory delay in developing an agreed protocol to approve laboratory processing of self-collected swabs, and consequently initially having one laboratory nationally accredited to process samples, led to missed opportunities and misinformation regarding the pathway's availability. CONCLUSIONS: Whilst the introduction of self-collection was welcomed, clear communication from Government regarding setbacks in implementation and how to overcome these in practice were needed. As Australia moves to a policy of providing everyone eligible for screening the choice of self-collection, wider promotion to providers and eligible people, clarity around pathology processes and the scaling up of test availability, as well as timely education and communication of clinical management practice guidelines, are needed to ensure smoother program delivery in the future. Other countries implementing self-collection policies can learn from the implementation challenges faced by Australia.
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Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/diagnóstico , Detecção Precoce de Câncer/métodos , Austrália , Programas de Rastreamento/métodos , Pesquisa Qualitativa , Infecções por Papillomavirus/diagnósticoRESUMO
OBJECTIVE: Anal cancer is preceded by high-risk human papillomavirus (HRHPV) infection, predominantly HPV16. No HPV assay is licenced for use in anal screening. We aimed to determine the sensitivity and specificity of four anal canal swab HPV assays to predict high-grade squamous epithelial lesions (HSIL). METHODS: In a cohort of Australian HIV-positive and negative gay and bisexual men, we compared the sensitivity and specificity of detection of 13 anal HRHPV genotypes by Linear Array (LA), Cobas 4800, EuroArray, and Anyplex II HPV28 (+ and ++ cut offs), compared their ability to predict prevalent anal HSIL, and compared anal canal HRHPV detection with HRHPV isolated from HSIL using laser capture microdissection (LCM). RESULTS: A total of 475 participants had baseline results available for all four assays (166, 35.0% HIV positive), and 169 participants had a diagnosis of cytological and/or histological HSIL. The HPV16 and any HRHPV detection were highest with Anyplex II HPV28 (+) (156, 32.8% 95% CI 28.6-37.2 and 359, 75.6%, 95% CI 71.5-79.4, respectively). For detection of concurrent HSIL and HPV16, the assay sensitivity was similar, ranging from 49.1%, 95% CI 41.4-56.9 (Anyplex II HPV28 ++) to 55.0%, 95% CI 47.2-62.7 (Anyplex II HPV28 +). For concurrent HSIL and any HRHPV detection, EuroArray was more specific than Anyplex II HPV28 (+) (45.9% 95% CI 40.2-51.7 vs 36.7%, 95% CI 31.3-42.4, p = 0.021) and had comparable specificity with Anyplex II HPV28 (++) (45.9% vs 47.2%, 95% CI 41.5-53.0, p = 0.75). All assays had high sensitivities for predicting HPV16 detected on LCM (92.5-97.5%). Anyplex II HPV28 and EuroArray were significantly more sensitive than LA for lesions caused by non-HPV16 HRHPV types on LCM. DISCUSSION: Anyplex II HPV28 and EuroArray detected more non-16 HRHPV genotypes than LA. Increasing the Anyplex II HPV28 cutoff improved specificity without compromising sensitivity for detection of concurrent HSIL.
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Alphapapillomavirus , Infecções por Papillomavirus , Masculino , Humanos , Papillomaviridae/genética , Canal Anal , Austrália , Papillomavirus Humano 16RESUMO
Human papillomavirus (HPV) is detected in up to 96% of anal squamous cell cancers, where screening programs needed. However, the best methodology is still undetermined. Host DNA methylation markers CADM1, MAL and miR124 have been identified in cervical disease, but not anal disease. Anal swabs varying by disease grade were assessed for DNA methylation of CADM1, MAL and miR124-2. Each marker was compared across disease grades, stratified by HPV and HIV status. Receiver operating characteristic curves identified the predictive value of significant gene candidates. CADM1 methylation was significantly higher in high-grade squamous intraepithelial lesions (HSIL) compared with low-grade (LSIL) (p = 0.005) or normal (p < 0.001) samples with 67.2% correctly identified as HSIL. MAL methylation was significantly (p = 0.002) increased in HSIL compared with LSIL in HIV positive participants with 79.8% correctly indicated as HSIL. Gene miR124-2, showed no difference between disease grades. Biomarkers with established diagnostic value in cervical disease have limited utility in the prediction of anal disease, with CADM1 identified as a marker with screening potential in a gay and bisexual men (GBM) population and MAL in HIV positive GBM population. New markers specific to the anal mucosa are required to improve triage of high-risk individuals.
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Alphapapillomavirus , Neoplasias do Ânus , Infecções por HIV , Infecções por Papillomavirus , Lesões Intraepiteliais Escamosas , Neoplasias do Colo do Útero , Neoplasias do Ânus/diagnóstico , Neoplasias do Ânus/genética , Biomarcadores , Molécula 1 de Adesão Celular/genética , Metilação de DNA/genética , Feminino , Infecções por HIV/genética , Humanos , Masculino , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/genética , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/genética , Neoplasias do Colo do Útero/patologiaRESUMO
Background: Substantial declines in genital warts have been observed in countries with quadrivalent/nonavalent human papillomavirus (q/n HPV) vaccination programmes, with Australia showing the most pronounced and long-term reductions. No study has assessed progress towards elimination of genital warts in a nation-wide sample of patients, and migrants' contribution to population-level control of genital warts. We assessed Australia's progress towards genital warts elimination by examining trends in diagnoses in Australian- and overseas-born patients of sexual health clinics (SHCs) across Australia. Methods: A cross-sectional trend analysis of new genital warts diagnoses among first-time patients of 34 SHCs, between 2004 and 2018, was performed. Rate ratios (RR) were calculated using Poisson regression models, for comparing trends in proportions of new genital warts diagnoses in Australian- and overseas-born patients during the pre-vaccination era (2004-2007) and the vaccination era (2008-2018), and by 2018 relative to 2004-2007. Findings: A total of 439,957 new patients (Australian-born: 230,230; overseas-born: 209,727) were seen at SHCs, 6â¢4% were diagnosed with genital warts (Australian-born: 7â¢1%; overseas-born: 5â¢6%). By 2018, there had been a 64% reduction in the proportion of all SHC patients with a genital warts diagnosis relative to 2004-2007 (RR: 0â¢36, 95% CI: 0â¢35-0â¢38). The decline was more pronounced at 72% (RR: 0â¢28, 95% CI: 0 â¢27-0â¢30) among Australian-born patients, with the greatest reduction in women and men aged <21 years, at 98% (RR: 0â¢02, 95% CI: 0â¢01-0â¢03) and 92% (RR: 0â¢08, 95% CI: 0â¢06-0â¢11), respectively. By 2018, there was a 49% reduction in the proportion of overseas-born patients diagnosed with genital warts (RR: 0â¢51, 95% CI:0â¢48-0â¢54), and a 21% reduction in overseas-born patients from countries with no or bivalent HPV (bHPV) vaccination programme (RR: 0â¢79, 95% CI: 0â¢71-0â¢90). Interpretation: The substantial reductions in Australian-born people is a testament to the efficacy of quadrivalent (qHPV) and nonavalent (nHPV) vaccines and the high and wide-spread vaccination coverage in Australia. However, population-wide elimination of genital warts in Australia is dependent on other countries initiating or expanding their own HPV vaccination programmes. Funding: The Australian Government Department of Health and Seqirus Australia.
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BACKGROUND: In Australia, the government-funded human papillomavirus (HPV) vaccination programme was introduced in April, 2007, for girls and young women, and in February, 2013, for boys. As of Dec 31, 2018, all Australian-born female individuals younger than 38 years and male individuals younger than 21 years have been eligible for the free quadrivalent or nonavalent HPV vaccine. We aimed to examine the trends in genital wart diagnoses among Australian-born female and heterosexual male individuals who attended sexual health clinics throughout Australia before and after the introduction of the gender-neutral HPV vaccination programme in February, 2013. METHODS: We did a serial cross-sectional analysis of genital wart diagnoses among Australian-born female and heterosexual male individuals attending a national surveillance network of 35 clinics between Jan 1, 2004, and Dec 31, 2018. We calculated prevalence ratios of genital warts, using log-binomial regression models, for the female-only vaccination period (July 1, 2007, to Feb 28, 2013), gender-neutral vaccination period (March 1, 2013, to Dec 31, 2018), and the whole vaccination period (July 1, 2007, to Dec 31, 2018) compared with the pre-vaccination period (Jan 1, 2004, to June 30, 2007). FINDINGS: We included 121 038 men and 116 341 women in the analysis. Overall, we observed a 58% reduction (prevalence ratio 0·42, 95% CI 0·40-0·44) in genital wart diagnoses in female individuals and a 45% reduction (0·55, 0·53-0·57) in genital wart diagnoses in heterosexual male individuals after the introduction of the vaccination programme in 2007. The largest reduction in genital warts was observed in younger individuals, and there was a decreasing magnitude of reduction with increasing age (80%, 72%, 61%, 41%, and 16% reductions in female individuals aged 15-20 years, 21-25 years, 26-30 years, 31-35 years, and ≥36 years, respectively; 70%, 61%, 49%, 37%, and 29% reductions in male individuals aged 15-20 years, 21-25 years, 26-30 years, 31-35 years, and ≥36 years, respectively). Significant reductions observed in female individuals (0·32, 0·28-0·36) and male individuals (0·51, 0·43-0·61) aged 15-20 years in the female-only vaccination period were followed by a more substantial reduction in female individuals (0·07, 0·06-0·09) and male individuals (0·11, 0·08-0·15) aged 15-20 years in the gender-neutral vaccination period. INTERPRETATION: The national gender-neutral HPV vaccination programme has led to substantial and ongoing reduction in genital warts among Australian female and heterosexual male individuals, with a marked reduction in young individuals who received the vaccine at school. FUNDING: Seqirus Australia and the Australian Government Department of Health.
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Condiloma Acuminado/epidemiologia , Condiloma Acuminado/prevenção & controle , Programas de Imunização/métodos , Vacinas contra Papillomavirus/administração & dosagem , Adolescente , Adulto , Austrália/epidemiologia , Estudos Transversais , Feminino , Heterossexualidade , Humanos , Masculino , Prevalência , Vigilância de Evento Sentinela , Adulto JovemRESUMO
BACKGROUND: In Australia, high and widespread uptake of the quadrivalent human papillomavirus (HPV) vaccine has led to substantial population-level reductions in the prevalence of quadrivalent vaccine targeted HPV genotypes 6/11/16/18 in women aged ≤ 35 years. We assessed risk factors for HPV detection among 18-35 year old women, 9-12 years after vaccine program introduction. METHODS: Women attending health services between 2015 and 2018 provided a self-collected vaginal specimen for HPV genotyping (Roche Linear Array) and completed a questionnaire. HPV vaccination status was validated against the National Register. Adjusted odds ratios (aORs) and 95% confidence intervals (CI) were calculated for factors associated with HPV detection. RESULTS: Among 1564 women (median age 24 years; IQR 21-27 years), Register-confirmed ≥ 1-dose vaccine coverage was highest at 69.3% and 68.1% among women aged 18-21 and 22-24 years respectively, decreasing to 42.9% among those aged 30-35 years. Overall prevalence of quadrivalent vaccine-targeted HPV types was very low (2.0%; 95% CI: 1.4-2.8%) and influenced only by vaccination status (5.5% among unvaccinated compared with 0.7% among vaccinated women; aOR = 0.13 (95% CI: 0.05-0.30)). Prevalence of remaining HPV types, at 40.4% (95% CI: 38.0-42.9%), was influenced by established risk factors for HPV infection; younger age-group (p-trend < 0.001), more recent (p < 0.001) and lifetime sexual partners (p-trend < 0.001), but not vaccination status. Prevalence of HPV31/33/45, which shared risk factors with that of non-vaccine targeted HPV types, was also lower among vaccinated (4%) compared with unvaccinated (7%) women (aOR = 0.51; 95% CI: 0.29-0.89), indicative of cross-protection. CONCLUSION: Vaccination has changed the epidemiology of HPV infection in Australian women, having markedly reduced the prevalence of vaccine-targeted types, including amongst women with known risk factors for infection. Vaccinated women appear to be benefiting from modest cross-protection against types 31/33/45 afforded by the quadrivalent HPV vaccine. These results reinforce the importance of HPV vaccination.
Assuntos
Alphapapillomavirus , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Adolescente , Adulto , Austrália/epidemiologia , Feminino , Humanos , Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/prevenção & controle , Prevalência , Fatores de Risco , Vacinação , Adulto JovemRESUMO
BACKGROUND: Anal infection with high-risk human papillomavirus (HPV) genotypes 16 and 18 and anal cancer are overrepresented in men who have sex with men (MSM). This study investigated HPV prevalence in young MSM before and after the implementation of a school-based quadrivalent HPV (genotypes 6, 11, 16, and 18) vaccination programme for boys in Australia in 2013. METHODS: In this repeated cross-sectional study, MSM aged 16-20 years were recruited from two successive birth cohorts via sexual health clinics and the community in Melbourne, Australia. The first cohort was before the implementation of gender-neutral vaccination (HYPER1 study, done in 2010-12, NCT01422356), and the second was the post-vaccination cohort (HYPER2 study, done in 2017-18, NCT03000933). Men who self-identified as being same-sex attracted were enrolled, and those recruited via the HYPER2 study had to be resident in Australia since 2013 to ensure eligibility. Study procedures were done in the Melbourne Sexual Health Centre. A clinician-collected anal swab and self-collected penile swab and oral rinse were tested for 28 HPV genotypes, and data on demographics and sexual health practices were collected via questionnaires. Only assessable samples were included in the analyses. We compared anatomical site-specific prevalence of HPV genotypes between cohorts by calculating the prevalence ratio, adjusting for age, circumcision, and sex with women. Herd protection was also assessed, by calculating the adjusted prevalence ratios by vaccination status. FINDINGS: 400 MSM, 200 per cohort, were included in the study. In both cohorts, the median number of lifetime male partners was ten (IQR 5-25). The prevalence of any anal quadrivalent vaccine-preventable HPV genotype was higher in the pre-vaccination cohort (54 [28%] of 193) than in the post-vaccination cohort (14 [7%] of 193; adjusted prevalence ratio [PR] 0·24, 95% CI 0·14-0·42), largely driven by decreases in HPV6, followed by HPV11, 16, and 18. Nevertheless, there was also a significant reduction in anal HPV16 and 18 in the post-vaccination cohort from the pre-vaccination cohort (0·31, 0·14-0·68). The prevalence of any penile quadrivalent vaccine-preventable HPV genotype was also higher in the pre-vaccination cohort (21 [12%] of 177) than in the post-vaccination cohort (11 [6%] of 179; 0·48, 0·24-0·97), driven by decreases in HPV 6 and 11, but not by 16 and 18. The prevalence of any oral quadrivalent vaccine-preventable HPV genotype was higher in the pre-vaccination cohort (seven [4%] of 200) than in the post-vaccination cohort (one [1%] of 199; 0·10, 0·01-0·97); there were no cases of oral HPV6 or 11 detected in HYPER2. Comparing the pre-vaccinated cohort with the 149 confirmed vaccinated men from HYPER2 showed a reduction in any quadrivalent vaccine-preventable HPV genotype for anal (0·09, 0·03-0·25) and penile (0·18, 0·05-0·59) infection but not for oral infection (0·17, 0·03-1·08). INTERPRETATION: A reduction in anal, penile, and oral quadrivalent vaccine-targeted genotypes occurred in young MSM following the implementation of a school-based gender-neutral HPV vaccination programme. The fall in anal HPV16 and 18 may lead to a reduction in the incidence of anal cancer. FUNDING: Merck and the Australian Government Department of Health.
Assuntos
Alphapapillomavirus/imunologia , Homossexualidade Masculina/estatística & dados numéricos , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Adolescente , Alphapapillomavirus/classificação , Alphapapillomavirus/genética , Alphapapillomavirus/isolamento & purificação , Austrália/epidemiologia , Estudos de Coortes , Estudos Transversais , Genótipo , Humanos , Masculino , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia , Vacinação , Adulto JovemRESUMO
In order to achieve the global elimination of cervical cancer as a public health problem, close surveillance of progress in public health and clinical activities and outcomes across the three pillars of vaccination, screening and treatment will be required. Surveillance should ideally occur within an integrated system that is planned, funded, and regularly evaluated to ensure it is providing timely, accurate and relevant feedback for action. In this paper, we conceptualise the main public health surveillance objectives as process and outcome measures in each of the three pillars. Process measures include coverage/participation measures for vaccination, screening and treatment alongside the ongoing assessment of the quality and reach of these programs and activities. Outcome measures related to the natural history of human papillomavirus (HPV) infection include HPV infection prevalence, precursor cervical lesions and cervical cancers (including stage at diagnosis, cancer incidence and mortality). These outcome measures can be used for monitoring the effectiveness of the three core activities in the short, medium and long term to assess whether these interventions are effectively reducing their occurrence. We discuss possible methods for the surveillance of these measures in the context of country capacity, drawing from examples in Australia, the USA and in low and middle income countries.