Field experience with the 8-HPV-type oncoprotein test for cervical cancer screening among HPV-positive women living with and without HIV in LMICs.

Overexpression of HPV-oncoproteins E6 and E7 is necessary for HPV-driven cervical carcinogenesis. Hence, these oncoproteins are promising disease-specific biomarkers. We assessed the technical and operational characteristics of the 8-HPV-type OncoE6/E7 Cervical Test in different laboratories using cervical samples from HPV-positive women living with (WLWH) and without HIV. The 8-HPV-type OncoE6/E7 Test (for short: "OncoE6/E7 test") was performed in 2833 HIV-negative women and 241 WLWH attending multicentric studies in Latin America (ESTAMPA study), and in Africa (CESTA study). Oncoprotein positivity were evaluated at each testing site, according to HIV status as well as type-specific agreement with HPV-DNA results. A feedback questionnaire was given to the operators performing the oncoprotein test to evaluate their impression and acceptability regarding the test. The OncoE6/E7 test revealed a high positivity rate heterogeneity across all testing sites (I2: 95.8%, p < .01) with significant lower positivity in WLWH compared to HIV-negative women (12% vs 25%, p < .01). A similar HPV-type distribution was found between HPV DNA genotyping and oncoprotein testing except for HPV31 and 33 (moderate agreement, k = 0.57). Twenty-one laboratory technicians were trained on oncoprotein testing. Despite operators' concerns about the time-consuming procedure and perceived need for moderate laboratory experience, they reported the OncoE6/E7 test as easy to perform and user-friendly for deployment in resource-limited settings. The high positivity rate variability found across studies and subjectivity in test outcome interpretation could potentially results in oncoprotein false positive/negative, and thus the need for further refinements before implementation of the oncoprotein testing in screen-triage-and-treat approaches is warranted.

Accuracy of HPV E6/E7 oncoprotein tests to detect high-grade cervical lesions: a systematic literature review and meta-analysis.

BACKGROUND: Cervical carcinogenesis is mediated by the HPV-E6 and E7 oncoproteins, considered as biomarkers usable in managing screen-positive women. METHODS: We conducted a systematic review and meta-analysis assessing the accuracy of HPV-E6/E7-oncoprotein tests to detect underlying cervical-precancer and cancer. We included studies reporting data on oncoprotein test accuracy detecting cervical intraepithelial neoplasia grade 3 or worse. Random effects logistic regression models were applied for pooling absolute and relative accuracy. RESULTS: Twenty-two studies were included. Sensitivity and specificity estimates ranged from 54.2% (95%CI: 45.2-63.0) to 69.5% (95%CI:60.8-76.9) and from 82.8% (95%CI: 50.4-95.8) to 99.1 (95%CI: 98.8-99.3), respectively in the population irrespective of HPV status. Higher sensitivity estimates ranging from 60.8% (95%CI: 49.6-70.9) to 75.5% (95%CI: 71.7-78.9) but lower specificity estimates ranging from 83.7% (95%CI: 76.1-89.3) to 92.1% (95%CI: 88.5-94.6) were observed in studies enrolling high-risk-HPV-positive women. Studies recruiting only HIV-positive women showed a pooled sensitivity of 46.9% (95%CI: 30.6-63.9) with a specificity of 98.0% (95%CI: 96.8-98.7). CONCLUSIONS: The high specificity of oncoprotein tests supports its use for triaging HPV-positive women. However, oncoprotein-negative women would not be recommended to undertake routine screening, requiring further follow-up. Large-scale and longitudinal studies are needed to further investigate the role of E6/E7-oncoprotein detection in predicting the risk of developing cervical pre-cancer and cancer.

Implementation of WHO guidelines for cervical cancer screening, diagnosis and treatment: knowledge and perceptions of health providers from Argentina.

BACKGROUND: The 2021 World Health Organization (WHO) guidelines on cervical cancer screening and treatment provide countries with evidence-based recommendations to accelerate disease elimination. However, evidence shows that health providers' adherence to screening guidelines is low. We conducted a study in Argentina to analyze health providers' knowledge and perceptions regarding the 2021 WHO Guidelines. METHODS: A qualitative study was conducted based on individual, semi-structured interviews with health providers specializing in gynecology (n = 15). The themes explored were selected and analyzed using domains and constructs of the Consolidated Framework for Implementation Research. RESULTS: Although health providers perceive WHO as a reliable institution, they do not know the 2021 guidelines, its supporting evidence, and its elaboration process. Their clinical practice is mainly guided by local recommendations developed by national professional medical associations (PMAs). For interviewees, WHO guidelines should be disseminated through health authorities and national PMAs, mainly through in-service training. Health providers had a positive assessment regarding WHO Recommendation 1 (screen, triage, and treatment for women aged 30 + with HPV-testing every 5 to 10 years) and perceived a favorable climate for its implementation. HPV-testing followed by triage was considered a low-complexity practice, enabling a better detection of HPV, a better selection of the patients who will need diagnosis and treatment, and a more efficient use of health system resources. However, they suggested adapting this recommendation by removing screening interval beyond 5 years. WHO Recommendation 2 (screen-and-treat approach with HPV-testing for women aged 30 + every 5 to 10 years) was predominantly rejected by interviewees, was considered an algorithm that did not respond to women's needs, and was not adequate for the Argentinean context. Regarding the HPV-test modality, clinician-collected tests were the preferred mode. Health providers considered that HPV self-collection should be used primarily among socially vulnerable women to increase screening coverage. CONCLUSION: WHO guidelines should be widely disseminated among health providers, especially in settings that could benefit from a screen-and-treat approach. Identifying areas of partnership and collaboration with PMAs in implementing WHO guidelines is essential.

Performance of visual inspection of the cervix with acetic acid (VIA) for triage of HPV screen-positive women: results from the ESTAMPA study.

VIA is recommended for triage of HPV-positive women attending cervical screening. In the multicentric ESTAMPA study, VIA performance for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) among HPV-positive women was evaluated. Women aged 30-64 years were screened with HPV testing and cytology and referred to colposcopy if either test was positive. At colposcopy visit, study-trained midwives/nurses/GPs performed VIA ahead of colposcopy. VIA was considered positive if acetowhite lesions were observed in or close to the transformation zone. Ablative treatment eligibility was assessed for VIA positives. Performance indicators were estimated. Three thousand one hundred and forty-two HPV-positive women were included. Sensitivity for CIN3+ was 85.9% (95% CI 81.2-89.5) among women <50 years and, although not significant, slightly lower in women 50+ (78.0%, 95% CI 65.9-86.6). Overall specificity was 58.6% (95% CI 56.7-60.5) and was significantly higher among women 50+ (70.3%, 95% CI 66.8-73.5) compared to women <50 (54.3%, 95% CI 52.1-56.5). VIA positivity was lower among women 50+ (35.2%, 95% CI 31.9-38.6) compared to women <50 (53.2, 95% CI 51.1-55.2). Overall eligibility for ablative treatment was 74.5% and did not differ by age. VIA sensitivity, specificity, and positivity, and ablative treatment eligibility varied highly by provider (ranges: 25%-95.4%, 44.9%-94.4%, 8.2%-65.3%, 0%-98.7%, respectively). VIA sensitivity for cervical precancer detection among HPV-positive women performed by trained providers was high with an important reduction in referral rates. However, scaling-up HPV screening triaged by VIA will be challenging due to the high variability of VIA performance and providers' need for training and supervision.

Cervical cancer screening by visual inspection and HPV testing in Eswatini.

In 2009, visual inspection with acetic acid (VIA) followed by cryotherapy (VIA-and-cryotherapy), was introduced into the Eswatini cervical cancer prevention programme. We present screening results of 654 women attending VIA-and-cryotherapy who participated in a sexually transmitted infections prevalence study, at which samples for HPV DNA testing and liquid-based cytology (LBC) were also collected. VIA positives (VIA+) ineligible for cryotherapy, suspected cancers and women with high-grade squamous intraepithelial or worse lesions (HSIL+) on LBC were referred for diagnosis and treatment. Women with negative VIA who were HPV positive (HPV+) and those VIA+ treated with cryotherapy were recalled for another VIA one-year later. The positivity rates of VIA, HPV, atypical squamous cells of undetermined significance or worse cytology abnormalities (LBC ASCUS+) and low-grade squamous intraepithelial or worse lesions (LBC LSIL+) were 9.7%, 42.6%, 13.2% and 5.3%, respectively. HPV testing detected 29 of 31 LSIL+ (93.6%, 95%CI: 78.6-99.2) while VIA only detected 11 (35.6%, 95%CI: 19.2-54.6). The HIV prevalence was 43% (95%CI: 39.2-46.9). HIV positives were at increased risk of being VIA+ (age-adjusted odds ratio: 2.5, 95%CI: 1.5-4.3), HPV+ (3.7, 2.6-5.3) and having LSIL+ (16.3, 4.9-54.8). The ineligibility rates for cryotherapy were 38% (24 of 63 VIA+), and 46% among HIV positives (18 of 39 VIA+). HPV testing was substantially more sensitive than VIA, thus, HPV followed by ablative treatment may be more effective. However, the high ineligibility for cryotherapy highlights the need for improving the assessment of eligibility for ablative treatment and for strengthening colposcopy, particularly in populations with high HIV prevalence.

Implementation research to accelerate scale-up of national screen and treat strategies towards the elimination of cervical cancer.

BACKGROUND: Cervical cancer is a significant public health problem, with 570,000 new cases and 300,000 deaths of women per year globally, mostly in low- and middle-income countries. In 2018 the WHO Director General made a call to action for the elimination of cervical cancer as a public health problem. MAIN BODY: New thinking on programmatic approaches to introduce emerging technologies and screening and treatment interventions of cervical precancer at scale is needed to achieve elimination goals. Implementation research (IR) is an important yet underused tool for facilitating scale-up of evidence-based screening and treatment interventions, as most research has focused on developing and evaluating new interventions. It is time for countries to define their specific IR needs to understand acceptability, feasibility, and cost-effectiveness of interventions as to design and ensure effective implementation, scale-up, and sustainability of evidence-based screening and treatment interventions. WHO convened an expert advisory group to identify priority IR questions for HPV-based screening and treatment interventions in population-based programmes. Several international organizations are supporting large scale introduction of screen-and-treat approaches in many countries, providing ideal platforms to evaluate different approaches and strategies in diverse national contexts. CONCLUSION: For reducing cervical cancer incidence and mortality, the readiness of health systems, the reach and effectiveness of new technologies and algorithms for increasing screening and treatment coverage, and the factors that support sustainability of these programmes need to be better understood. Answering these key IR questions could provide actionable guidance for countries seeking to implement the WHO Global Strategy towards cervical cancer elimination.

Cervical cancer burden in Latin America and the Caribbean: Where are we?

In May 2018, the World Health Organization (WHO) called for the elimination of cervical cancer. To monitor this initiative, we examined cervical cancer incidence and mortality in the Latin America and Caribbean (LAC) region using GLOBOCAN 2018, Cancer Incidence in Five Continents Series, and the WHO Mortality Database. We estimated the number of cases and age-standardized rates (ASRs) for cervical cancer incidence and mortality for 2018. We also presented the ASRs for recorded cervical cancer incidence from the period 2008 to 2012. We calculated annual rates and analyzed trends in cervical cancer incidence and mortality for all ages combined and for the following age groups: 0-29, 30-49, 50-64 and 65+. Finally, we calculated the estimated average annual percentage change in incidence and mortality rates for the past 10 years. In 2018, an estimated 56,000 new cervical cancer cases and 28,000 cervical cancer deaths occurred among women in LAC with great variations between subregions and countries/territories. Overall, trends in cervical cancer incidence and mortality have decreased over the past decade; however, the rates are still above the elimination threshold of 4 per 100,000 in most LAC countries/territories. Despite the encouraging trends observed, achieving the elimination of cervical cancer in the region still requests substantial political commitment and economic effort. Population-based cancer registries are critical in monitoring the elimination initiative.

Comparison of immediate colposcopy, repeat conventional cytology and hrHPV testing for the clinical management of ASC-US cytology in routine health services of Medellin, Colombia: The ASCUS-COL Trial.

In the context of opportunistic cervical cancer screening settings of low-and-middle-income countries, little is known about the benefits of high-risk human papillomavirus (hrHPV) testing on high-grade cervical abnormality detection among women with atypical squamous cells of undetermined significance (ASC-US) cytology in routine clinical practice. We compared the effectiveness of immediate colposcopy (IC), conventional cytology at 6 and 12 months (colposcopy if ≥ASC-US) (RC), and hrHPV testing (colposcopy if hrHPV-positive) (HPV) to detect cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) among women aged 20-69 years with ASC-US in routine care. Participants (n=2,661) were evenly randomized into three arms (n=882 IC, n=890 RC, n=889 HPV) to receive services by routine healthcare providers and invited to an exit visit 24 months after recruitment. Histopathology was blindly reviewed by a quality-control external panel (QC). The primary endpoint was the first QC-diagnosed CIN2+ or CIN3+ detected during three periods: enrolment (≤6 months for IC and HPV, ≤12 months for RC), follow-up (between enrolment and exit visit), and exit visit. The trial is completed. Colposcopy was done on 88%, 42%, and 52% of participants in IC, RC, and HPV. Overall, 212 CIN2+ and 52 CIN3+ cases were diagnosed. No differences were observed for CIN2+ detection (p=0.821). However, compared to IC, only HPV significantly reduced CIN3+ cases that providers were unable to detect during the 2-year routine follow-up (relative proportion 0.35, 95% CI 0.09-0.87). In this context, hrHPV testing was the most effective and efficient management strategy for women with ASC-US cytology.

Performance of an HPV 16/18 E6 oncoprotein test for detection of cervical precancer and cancer.

HPV testing is a better alternative for cervical cancer screening, but additional procedures are required for triage of HPV positive women. HPV encoded oncoproteins E6 and E7, as the main effectors of HPV carcinogenicity represent promising triage alternatives. To evaluate performance of the test, we included 155 women from a screening study and 59 from the same referral population attending colposcopy and with precancerous lesions. All were HPV-tested with HC2 and genotyped with LiPA, and cervical swabs were tested for HPV16/18 E6 oncoproteins. Histologic specimens were reviewed and adjudicated using p16 immunohistochemistry and 55 women had confirmed histologic HSIL, 31 (56.3%) associated with HPV 16/18, 23 with other HPV types and one HPV negative. Sensitivity and specificity were estimated with histologic HSIL/cancer as gold standard. E6 oncoprotein was detectable in all but one HSIL and in all cancers where HPV16/18 DNA was detected, but in none of the cases associated with other HPV types or HPV negatives. Among the few HPV16/18 DNA positive subjects initially without HSIL (n = 4) who were E6 oncoprotein positive, precancer was detected during follow-up in 2 out of 3 with available information. Estimated sensitivity for HPV16/18-related HSIL+ was 96.8% (95%CI = 83.8-99.8) and for all HSIL+ regardless of HPV type it was 56.4% (95%CI = 43.3-68.6). Specificity was 97.5% (95%CI = 93.7-99.0). E6 oncoprotein proved as a highly sensitive and specific marker for detection of HPV16/18-related HSIL lesions in this Honduran population with limited previous screening and may be useful as a triage method in screening programs, particularly in low income countries.

[Alternative HPV vaccination schedules in Latin America].

In 2008, the first HPV vaccination program in Latin America started in Panama, targeting girls aged 10-11 years with a 3-dose vaccine schedule, an initiative that was to be followed by other Latin American countries after local feasibility and population acceptability evaluations were completed. A 3-dose vaccine regimen over six months was originally chosen for HPV vaccines, copying the Hepatitis B vaccine schedule (0, 1-2, 6 months). Alternative vaccine schedules have been proposed afterwards based on: i) noninferior immunogenicity or immune response levels compared to those at which clinical efficacy has been proven (i.e., those observed in a 3-dose HPV vaccine schedule in women aged 15-26), and, ii) proven efficacy in clinical trials and/or effectiveness among women who were provided less than three doses due to a lack of adherence to a 3-dose vaccine schedule. In 2014, based on the available evidence and the potential increase in coverage by expansion of vaccination target groups, particularly in low and middle income countries (LMIC), the World Health Organization recommended a 2-dose schedule with at least a 6-month interval between doses for females up to 15 years of age and a 3-dose schedule for older women. More recently, it has been suggested that 1-dose HPV vaccination schemes may provide enough protection against HPV infection and may speed up the introduction of HPV vaccination in LMIC, where most needed.

En 2008, se inició en Panamá el primer programa de vacunación contra el virus del papiloma humano (VPH), dirigido a niñas de 10 a 11 años, utilizando un esquema de tres dosis en seis meses, iniciativa que fue adoptada por otros países de la región tras evaluar la aceptabilidad en la población y la viabilidad de llevar a cabo el programa. Inicialmente, el esquema de tres dosis para las vacunas contra el VPH se basó en el utilizado en la vacunación contra la hepatitis B (0, 1-2, 6 meses). Posteriormente, se han propuesto esquemas de vacunación alternativos, utilizando evidencia sobre: i) la inmunogenicidad o niveles de respuesta inmune no inferiores a aquéllos con los cuales la eficacia clínica de la vacuna fue probada (es decir, aquéllos observados con tres dosis en mujeres de 15 a 26 años); y ii) la eficacia demostrada en ensayos clínicos y efectividad demostrada en mujeres a quienes se vacunó con menos de tres dosis debido a falta de adherencia al esquema completo de tres dosis. En 2014, la Organización Mundial de la Salud recomendó un esquema de dos dosis con al menos seis meses de intervalo entre dosis para mujeres de hasta 15 años de edad y uno de tres dosis para mujeres mayores. La recomendación se basó en la evidencia disponible hasta entonces y a un posible aumento en cobertura mediante la ampliación de los grupos etarios a vacunarse, particularmente en países de ingresos bajos y medios (PIBMs). Más recientemente, se ha sugerido un esquema de vacunación contra el VPH de una sola dosis, el cual podría proporcionar suficiente protección contra la infección por VPH y así acelerar la introducción de la vacunación contra el VPH en PIBMs donde más se necesita.

Country-level correlates of cervical cancer mortality in Latin America and the Caribbean.

OBJECTIVE: To identify country-level correlates of geographical variations in cervical cancer (CC) mortality in Latin America and the Caribbean (LAC). MATERIALS AND METHODS: CC mortality rates for LAC countries (n=26) were examined in relation to country-specific socio-economic indicators (n=58) and Human Papilloma Virus (HPV) prevalence using linear regression models. RESULTS: High mortality at ages <5 years, low per capita total expenditure on health, and low proportion of the population with access to sanitation were identified as the best independent predictors of CC mortality (R² =77%). In the subset of countries (n=10) with HPV prevalence estimates, these socio-economic indicators together with high-risk HPV prevalence explained almost all the between-country variability in CC mortality (R² =98%). CONCLUSION: The findings suggest that continuing socioeconomic improvements in LAC countries will be associated with further reductions in CC mortality even in the absence of organised population-based screening and vaccination programmes.

Latin America and the Caribbean Code Against Cancer 1st Edition: Medical interventions including hormone replacement therapy and cancer screening.

Prostate, breast, colorectal, cervical, and lung cancers are the leading cause of cancer in Latin America and the Caribbean (LAC) accounting for nearly 50% of cancer cases and cancer deaths in the region. Following the IARC Code Against Cancer methodology, a group of Latin American experts evaluated the evidence on several medical interventions to reduce cancer incidence and mortality considering the cancer burden in the region. A recommendation to limit the use of HRT was issued based on the risk associated to develop breast, endometrial, and ovarian cancer and on growing concerns related to the over-the-counter and without prescription sales, which in turn bias estimations on current use in LAC. In alignment with WHO breast and cervical cancer initiatives, biennial screening by clinical breast examination (performed by trained health professionals) from the age of 40 years and biennial screening by mammography from the age of 50 years to 74, as well as cervical screening by HPV testing (either self-sampling or provider-sampling) every 5-10 years for women aged 30-64 years, were recommended. The steadily increasing rates of colorectal cancer in LAC also led to recommend colorectal screening by occult blood testing every two years or by endoscopic examination of the colorectum every 10 years for both men and women aged 50-74 years. After evaluating the evidence, the experts decided not to issue recommendations for prostate and lung cancer screening; while there was insufficient evidence on prostate cancer mortality reduction by prostate-specific antigen (PSA) testing, there was evidence of mortality reduction by low-dose computed tomography (LDCT) targeting high-risk individuals (mainly heavy and/or long-term smokers) but not individuals with average risk to whom recommendations of this Code are directed. Finally, the group of experts adapted the gathered evidence to develop a competency-based online microlearning program for building cancer prevention capacity of primary care health professionals.

Cervical Cancer Screening and Treatment algorithms using Human Papillomavirus testing - lessons learnt from a South African pilot randomized controlled trial.

BACKGROUND: To report quantitative and qualitative results on cervical cancer (CC) HPV-based screening and treatment algorithms, with/out triage with visual inspection after acetic acid (VIA), followed by ablative treatment (AT). METHODS: Women 30-54 years-old from Durban, South Africa were recruited, regardless of HIV status, randomized into one of two study arms and screened for HPV. VIA-triage arm: HPV-positive women were triaged using VIA, biopsied and received AT if VIA-positive and eligible; no-triage arm: eligible HPV-positive women received AT. Women ineligible for AT were referred to colposcopy. Women were asked about side effects immediately and one week after AT. Retention to screening and treatment algorithms was compared between arms. RESULTS: 350 women (275 HIV-uninfected and 75 women living with HIV, (WLWH)) were allocated to receive HPV testing with VIA-triage (n=175) or no-triage (n=175). HPV prevalence was 28% (95%CI=23-33); WLWH: 52% (95%CI=40-64) vs HIV-uninfected: 21% (95%CI=17-27) (p<0.05). Among women who underwent VIA triage with histological diagnosis, 3/17 were VIA negative with CIN2+; 14/18 were VIA positive with

Latin America and the Caribbean Code Against Cancer 1st Edition: 17 cancer prevention recommendations to the public and to policy-makers (World Code Against Cancer Framework).

Preventable risk factors are responsible of at least 40% of cases and almost 45% of all cancer deaths worldwide. Cancer is already the leading cause of death in almost half of the Latin American and the Caribbean countries constituting a public health problem. Cost-effective measures to reduce exposures through primary prevention and screening of certain types of cancers are critical in the fight against cancer but need to be tailored to the local needs and scenarios. The Latin America and the Caribbean (LAC) Code Against Cancer, 1st edition, consists of 17 evidence-based recommendations for the general public, based on the most recent solid evidence on lifestyle, environmental, occupational, and infectious risk factors, and medical interventions. Each recommendation is accompanied by recommendations for policymakers to guide governments establishing the infrastructure needed to enable the public adopting the recommendations. The LAC Code Against Cancer has been developed in a collaborative effort by a large number of experts from the region, under the umbrella strategy and authoritative methodology of the World Code Against Cancer Framework. The Code is a structured instrument ideal for cancer prevention and control that aims to raise awareness and educate the public, while building capacity and competencies to policymakers, health professionals, stakeholders, to contribute to reduce the burden of cancer in LAC.

Benefits, harms and cost-effectiveness of cervical screening, triage and treatment strategies for women in the general population.

In 2020, the World Health Organization (WHO) launched a strategy to eliminate cervical cancer as a public health problem. To support the strategy, the WHO published updated cervical screening guidelines in 2021. To inform this update, we used an established modeling platform, Policy1-Cervix, to evaluate the impact of seven primary screening scenarios across 78 low- and lower-middle-income countries (LMICs) for the general population of women. Assuming 70% coverage, we found that primary human papillomavirus (HPV) screening approaches were the most effective and cost-effective, reducing cervical cancer age-standardized mortality rates by 63-67% when offered every 5 years. Strategies involving triaging women before treatment (with 16/18 genotyping, cytology, visual inspection with acetic acid (VIA) or colposcopy) had close-to-similar effectiveness to HPV screening without triage and fewer pre-cancer treatments. Screening with VIA or cytology every 3 years was less effective and less cost-effective than HPV screening every 5 years. Furthermore, VIA generated more than double the number of pre-cancer treatments compared to HPV. In conclusion, primary HPV screening is the most effective, cost-effective and efficient cervical screening option in LMICs. These findings have directly informed WHO's updated cervical screening guidelines for the general population of women, which recommend primary HPV screening in a screen-and-treat or screen-triage-and-treat approach, starting from age 30 years with screening every 5 years or 10 years.

Performance of cervical cytology and HPV testing for primary cervical cancer screening in Latin America: an analysis within the ESTAMPA study.

Background: Cervical cytology remains widely used as the initial tool in cervical cancer screening worldwide. WHO guidelines recommend replacing cytology with primary HPV testing to reach cervical cancer elimination goals. We assessed the performance of cytology and high-risk HPV testing to detect cervical precancer, cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) among women aged 30-64 years participating in the ESTAMPA study. Methods: Women were screened with cytology and HPV across ESTAMPA study centres in Latin America. Screen-positives were referred to colposcopy with biopsy collection and treatment as needed. Those with no evident precancer were recalled at 18-months for a second HPV test to complete disease ascertainment. Performance indicators for cytology and HPV to detect CIN3+ were estimated. Findings: 30,606 participants with available cytology and HPV results were included in the analysis. A total of 440 histologically confirmed CIN3s and 30 cancers were diagnosed. Cytology sensitivity for CIN3+ was 48.5% (95% CI: 44.0-53.0), whereas HPV testing had a sensitivity of 98.1% (95% CI: 96.3-96.7). Specificity was 96.5% (95% CI: 96.3-96.7) using cytology and 88.7% (95% CI: 88.3-89.0) with HPV. Performance estimates varied substantially by study centre for cytology (ranging from 32.1% to 87.5% for sensitivity and from 89.2% to 99.5% for specificity) while for HPV results were more consistent across sites (96.7%-100% and 83.6-90.8%, respectively). Interpretation: The limited and highly variable sensitivity of cytology strongly supports transition to the more robust and reproducible HPV-based cervical screening to ensure progress towards global cervical cancer elimination targets in Latin America. Funding: IARC/WHO, UNDP, HRP/WHO, NCI and local funders.

Performance of standardised colposcopy to detect cervical precancer and cancer for triage of women testing positive for human papillomavirus: results from the ESTAMPA multicentric screening study.

BACKGROUND: Colposcopy, currently included in WHO recommendations as an option to triage human papillomavirus (HPV)-positive women, remains as the reference standard to guide both biopsy for confirmation of cervical precancer and cancer and treatment approaches. We aim to evaluate the performance of colposcopy to detect cervical precancer and cancer for triage in HPV-positive women. METHODS: This cross-sectional, multicentric screening study was conducted at 12 centres (including primary and secondary care centres, hospitals, laboratories, and universities) in Latin America (Argentina, Bolivia, Colombia, Costa Rica, Honduras, Mexico, Paraguay, Peru, and Uruguay). Eligible women were aged 30-64 years, sexually active, did not have a history of cervical cancer or treatment for cervical precancer or a hysterectomy, and were not planning to move outside of the study area. Women were screened with HPV DNA testing and cytology. HPV-positive women were referred to colposcopy using a standardised protocol, including biopsy collection of observed lesions, endocervical sampling for transformation zone (TZ) type 3, and treatment as needed. Women with initial normal colposcopy or no high-grade cervical lesions on histology (less than cervical intraepithelial neoplasia [CIN] grade 2) were recalled after 18 months for another HPV test to complete disease ascertainment; HPV-positive women were referred for a second colposcopy with biopsy and treatment as needed. Diagnostic accuracy of colposcopy was assessed by considering a positive test result when the colposcopic impression at the initial colposcopy was positive minor, positive major, or suspected cancer, and was considered negative otherwise. The main study outcome was histologically confirmed CIN3+ (defined as grade 3 or worse) detected at the initial visit or 18-month visit. FINDINGS: Between Dec 12, 2012, and Dec 3, 2021, 42 502 women were recruited, and 5985 (14·1%) tested positive for HPV. 4499 participants with complete disease ascertainment and follow-up were included in the analysis, with a median age of 40·6 years (IQR 34·7-49·9). CIN3+ was detected in 669 (14·9%) of 4499 women at the initial visit or 18-month visit (3530 [78·5%] negative or CIN1, 300 [6·7%] CIN2, 616 [13·7%] CIN3, and 53 [1·2%] cancers). Sensitivity was 91·2% (95% CI 88·9-93·2) for CIN3+, whereas specificity was 50·1% (48·5-51·8) for less than CIN2 and 47·1% (45·5-48·7) for less than CIN3. Sensitivity for CIN3+ significantly decreased in older women (93·5% [95% CI 91·3-95·3] in those aged 30-49 years vs 77·6% [68·6-85·0] in those aged 50-65 years; p<0·0001), whereas specificity for less than CIN2 significantly increased (45·7% [43·8-47·6] vs 61·8% [58·7-64·8]; p<0·0001). Sensitivity for CIN3+ was also significantly lower in women with negative cytology than in those with abnormal cytology (p<0·0001). INTERPRETATION: Colposcopy is accurate for CIN3+ detection in HPV-positive women. These results reflect ESTAMPA efforts in an 18-month follow-up strategy to maximise disease detection with an internationally validated clinical management protocol and regular training, including quality improvement practices. We showed that colposcopy can be optimised with proper standardisation to be used as triage in HPV-positive women. FUNDING: WHO; Pan American Health Organization; Union for International Cancer Control; National Cancer Institute (NCI); NCI Center for Global Health; National Agency for the Promotion of Research, Technological Development, and Innovation; NCI of Argentina and Colombia; Caja Costarricense de Seguro Social; National Council for Science and Technology of Paraguay; International Agency for Research on Cancer; and all local collaborative institutions.

Human papillomavirus genotyping using next generation sequencing (NGS) in cervical lesions: Genotypes by histologic grade and their relative proportion in multiple infections.

Sensitive and specific genotyping of human papillomaviruses (HPVs) is critical for the surveillance and monitoring of the vaccine effectiveness. Here, HPV genotypes were identified in 137 cervical samples with different histology (79 ≤CIN1 and 58 CIN3+) using Nested-PCR followed by Next-Generation sequencing (NGS) and relative proportions for each genotype in multiple infections were computed. All samples had been previously genotyped by PCR-Reverse Blotting Hybridization (PCR-RBH) thus allowing for a concordance analysis between both techniques. Multiple infections were present in 85% of ≤CIN1 cases compared to only 41% in CIN3+ cases (p<0.001). Among ≤CIN1 cases a towering genotypic diversity was observed, considering both low (LR-) and high risk (HR-) HPV genotypes; while among CIN3+, diversity was lower, HR-HPVs prevailing in most cases, especially HPV16. Furthermore, the predominance of HR-HPV genotypes in the proportions identified in each sample was higher in CIN3+ cases [(HPV16 (62.5%), followed by HPV31 and HPV58 (8.3% each)], than in ≤CIN1 cases [(HPV16 (17.7%), followed by HPV52 (14.7%) and HPV31 (10.3%)]. Agreement between PCR-RBH and NGS was higher than 90% for all genotypes (with an overall Kappa of 0.7), even though NGS identified eighty-nine positive results for HPV genotypes that had not been detected by PCR-RBH, evidencing its greater sensitivity. These results suggest that a reduction in genotypic diversity and/or an increase in the relative proportion of HR-HPVs in multiple infections can be considered as a biomarker for the potential risk of malignant progression.

Secondary Prevention of Cervical Cancer: ASCO Resource-Stratified Guideline Update.

PURPOSE: To update resource-stratified, evidence-based recommendations on secondary prevention of cervical cancer globally. METHODS: American Society of Clinical Oncology convened a multidisciplinary, multinational Expert Panel to produce recommendations reflecting four resource-tiered settings. A review of existing guidelines, formal consensus-based process, and modified ADAPTE process to adapt existing guidelines was conducted. Other experts participated in formal consensus. RESULTS: This guideline update reflects changes in evidence since the previous update. Five existing guidelines were identified and reviewed, and adapted recommendations form the evidence base. Cost-effectiveness analyses provided indirect evidence to inform consensus, which resulted in ≥ 75% agreement. RECOMMENDATIONS: Human papillomavirus (HPV) DNA testing is recommended in all resource settings; visual inspection with acetic acid may be used in basic settings. Recommended age ranges and frequencies vary by the following setting: maximal: age 25-65 years, every 5 years; enhanced: age 30-65 years, if two consecutive negative tests at 5-year intervals, then every 10 years; limited: age 30-49 years, every 10 years; basic: age 30-49 years, one to three times per lifetime. For basic settings, visual assessment is used to determine treatment eligibility; in other settings, genotyping with cytology or cytology alone is used to determine treatment. For basic settings, treatment is recommended if abnormal triage results are obtained; in other settings, abnormal triage results followed by colposcopy is recommended. For basic settings, treatment options are thermal ablation or loop electrosurgical excision procedure; for other settings, loop electrosurgical excision procedure or ablation is recommended; with a 12-month follow-up in all settings. Women who are HIV-positive should be screened with HPV testing after diagnosis, twice as many times per lifetime as the general population. Screening is recommended at 6 weeks postpartum in basic settings; in other settings, screening is recommended at 6 months. In basic settings without mass screening, infrastructure for HPV testing, diagnosis, and treatment should be developed.Additional information is available at www.asco.org/resource-stratified-guidelines.