Transformation Zone Assessment Using Visual Inspection With Acetic Acid Before and After Thermal Ablation: Implications for Follow-Up.

PURPOSE: Thermal ablation (TA) has become the conventional method for treatment of precancerous cervical lesions in low-resource settings. After TA, both the squamocolumnar junction (SCJ) and the transformation zone (TZ) may be subject to change. Our aim was to evaluate SCJ and TZ variability after TA. METHODS: Study data were collected in a large prospective trial of a cervical cancer screening campaign in Cameroon. For each patient, two sets of cervical photos (native and with acetic acid) were taken before and 6-12 months after TA. The SCJ and TZ were evaluated independently by three observers according to the WHO nomenclature. When discordances were observed between the type of TZ and SCJ selected by each observer, a corrected TZ was established on the basis of the SCJ categorization. Interobserver agreement for TZ interpretation was evaluated using Cohen's kappa coefficient for agreement between two observers and Fleiss' kappa between three observers. RESULTS: Fifty consecutive participants were included in the analysis. Seventy-six percent were interpreted as TZ1-2, and 24% as TZ3 before TA. In 56% of cases, the entire SCJ could not be entirely visualized after TA, thus being recategorized as TZ3. Interobserver agreement was fair for diagnosis before TA (Kappa coefficient, 0.34; 95% CI, 0.27 to 0.45) and moderate for diagnosis after TA (Kappa coefficient, 0.40; 95% CI, 0.30 to 0.50). After TA, 36% progressed from TZ1-2 to TZ3, with a moderate interobserver agreement (Kappa coefficient, 0.44; 95% CI, 0.40 to 0.54). CONCLUSION: We observed a shift of the SCJ into the endocervical canal after TA. A significant proportion of participants had TZ 3 after treatment, raising the question of visual inspection with acetic acid's applicability as a first-line follow-up examination method after TA.

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.

Inter- and intra-observer agreement in the assessment of the cervical transformation zone (TZ) by visual inspection with acetic acid (VIA) and its implications for a screen and treat approach: a reliability study.

BACKGROUND: In low-resource countries, interpretation of the transformation zone (TZ) using the classification of the International Federation for Cervical Pathology and Colposcopy (IFCPC), adopted by the World Health Organization, is critical for determining if visual inspection with acetic acid (VIA) screening and thermal ablation treatment are possible. We aim to assess inter- and intra-observer agreement in TZ interpretation. METHODS: We performed a prospective multi-observer reliability study. One hundred cervical digital images of Human papillomavirus positive women (30-49 years) were consecutively selected from a Cameroonian cervical cancer screening trial. Images of the native cervix and after VIA were obtained. The images were evaluated for the TZ type at two time points (rounds one and two) by five VIA experts from four countries (Côte d'Ivoire, Cameroon, Peru, and Zambia) according to the IFCPC classification (TZ1 = ectocervical fully visible; TZ2 = endocervical fully visible; TZ3 = not fully visible). Intra- and inter-observer agreement were measured by Fleiss' kappa. RESULTS: Overall, 37.0% of images were interpreted as TZ1, 36.4% as TZ2, and 26.6% as TZ3. Global inter-observer reliability indicated fair agreement in both rounds (kappa 0.313 and 0.288). The inter-observer agreement was moderate for TZ1 interpretation (0.460), slight for TZ2 (0.153), and fair for TZ3 (0.329). Intra-observer analysis showed fair agreement for two observers (0.356 and 0.345), moderate agreement for two other (0.562 and 0.549), and one with substantial agreement (0.728). CONCLUSION: Interpretation of the TZ using the IFCPC classification, adopted by the World Health Organization, is critical for determining if VIA screening and thermal ablation treatment are possible. However, the low inter- and intra-observer agreement suggest that the reliability of the referred classification is limited in the context of VIA. It's integration in treatment recommendations should be used with caution since TZ3 interpretation could lead to an important referral rate for further evaluation. Trial registration Cantonal Ethics Board of Geneva, Switzerland: N°2017-0110. Cameroonian National Ethics Committee for Human Health Research N°2018/07/1083/CE/CNERSH/SP.

Achieving equity in cervical cancer screening in low- and middle-income countries (LMICs): Strengthening health systems using a systems thinking approach.

The World Health Organization (WHO) is leading a call to action to eliminate cervical cancer by the end of the century through global implementation of two effective evidence-based preventive interventions: HPV vaccination and cervical screening and management (CSM). Models estimate that without intervention, over the next 50 years 12.2 million new cases of cervical cancer will occur, nearly 60% of which are preventable only through CSM. Given that more than 80% of the cervical cancer occurs in low- and middle-income countries (LMICs), scaling up sustainable CSM programs in these countries is a top priority for achieving the global elimination goals. Multiple technologies have been developed and validated to meet this need. Now it is critical to identify strategies to implement these technologies into complex, adaptive health care delivery systems. As part of the coordinated cervical cancer elimination effort, we applied a systems thinking lens to reflect on our experiences with implementation of HPV-based CSM programs using the WHO health systems framework. While many common health system barriers were identified, the effectiveness of implementation strategies to address them was context dependent; often reflecting differences in stakeholder's belief in the quality of the evidence supporting a CSM algorithm, the appropriateness of the evidence and algorithm to context, and the 'implementability' of the algorithm under realistic assessments of resource availability and constraints. A structured planning process, with early and broad stakeholder engagement, will ensure that shared-decisions in CSM implementation are appropriately aligned with the culture, values, and resource realities of the setting.

Health economic evaluation of primary human papillomavirus screening in urban populations in China.

BACKGROUND: On Nov 17, 2020, WHO launched a global initiative to accelerate the elimination of cervical cancer through the implementation of HPV vaccination, cervical cancer screening and treatment for precancer and cancer. China has the largest burden of cervical cancer in the world, but only has a national cervical cancer screening program in rural areas since 2009. Here, we aimed to evaluate the effectiveness and cost-effectiveness of cervical cancer screening in urban China, using Shenzhen City as an example. METHODS: We use an extensively validated platform ('Policy1-Cervix'), calibrated to data from Shenzhen city and Guandong Province. We evaluated a range of strategies that have previously been implemented as pilot studies in China, or recommended as guidelines within China and globally, spanning primary HPV, cytology and co-testing strategies. We additionally considered alternate triaging methods, age ranges and screening intervals, resulting in 19 algorithms in total. RESULTS: Of the 19 strategies considered, the most effective approach involved primary HPV testing. At 3- to 10-yearly intervals, primary HPV testing reduced the age-standardized cancer mortality rate by 37-71 %. The most cost-effective strategy was 5-yearly primary HPV testing with partial genotyping triage for ages 25-65, discharging to 10-yearly screening for low-risk women (ICER = US$7191/QALYS using 2018 costs; willingness-to-pay threshold<1xGDP [US$9771]). This strategy gave an incidence and mortality reduction of 56 % and 63 %, respectively. This remained the most cost-effective strategy under most conditions in sensitivity analysis. CONCLUSION: Primary HPV testing would be cost-effective in Shenzhen and could more than halve cervical cancer incidence rates to 6 per 100,000 over the long term. In order to achieve rates below 4 per 100,000, the elimination threshold set by the World Health Organization, vaccination will likely also be necessary.

Multicentric study of cervical cancer screening with human papillomavirus testing and assessment of triage methods in Latin America: the ESTAMPA screening study protocol.

INTRODUCTION: Human papillomavirus (HPV) testing is replacing cytology in primary screening. Its limited specificity demands using a second (triage) test to better identify women at high-risk of cervical disease. Cytology represents the immediate triage but its low sensitivity might hamper HPV testing sensitivity, particularly in low-income and middle-income countries (LMICs), where cytology performance has been suboptimal. The ESTAMPA (EStudio multicéntrico de TAMizaje y triaje de cáncer de cuello uterino con pruebas del virus del PApiloma humano; Spanish acronym) study will: (1) evaluate the performance of different triage techniques to detect cervical precancer and (2) inform on how to implement HPV-based screening programmes in LMIC. METHODS AND ANALYSIS: Women aged 30-64 years are screened with HPV testing and Pap across 12 study centres in Latin America. Screened positives have colposcopy with biopsy and treatment of lesions. Women with no evident disease are recalled 18 months later for another HPV test; those HPV-positive undergo colposcopy with biopsy and treatment as needed. Biological specimens are collected in different visits for triage testing, which is not used for clinical management. The study outcome is histological high-grade squamous intraepithelial or worse lesions (HSIL+) under the lower anogenital squamous terminology. About 50 000 women will be screened and 500 HSIL+ cases detected (at initial and 18 months screening). Performance measures (sensitivity, specificity and predictive values) of triage techniques to detect HSIL+ will be estimated and compared with adjustment by age and study centre. ETHICS AND DISSEMINATION: The study protocol has been approved by the Ethics Committee of the International Agency for Research on Cancer (IARC), of the Pan American Health Organisation (PAHO) and by those in each participating centre. A Data and Safety Monitoring Board (DSMB) has been established to monitor progress of the study, assure participant safety, advice on scientific conduct and analysis and suggest protocol improvements. Study findings will be published in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: NCT01881659.

Development and application of a framework to estimate health care costs in China: The cervical cancer example.

OBJECTIVES: Information on healthcare costs in low-and-middle-income countries is limited. This study presents a framework to perform healthcare cost estimates for each province in China. METHODS: This study has two aims. Using cervical cancer as an example, the first aim is to use data (including micro-costing data) from one province to derive estimates for other provinces in China. This used provincial and national Chinese-language statistical reports and considered levels of service delivery, hospital-seeking behaviour, and the urban/rural population distribution. The second aim is to characterise the relationship between the reference costs estimated using the method mentioned above and two sets of cost estimates derived using simplified cost-scaling method with per capita Gross Domestic Product (GDP), and the Human Development Index (HDI). For simplified methods, regression modelling characterised the relationship between province-specific healthcare costs and macro-economic indicators, then we used the exponential fit to extrapolate costs. RESULTS: Using the reference method, the estimated costs were found to vary substantially by urban/rural regions and between provinces; the ratios of highest to lowest provincial costs were 3.5 for visual inspection with acetic acid (VIA), 4.4 for cold knife conisation (CKC) and 4.6 for stage II cancer treatment. The HDI-based scaling method generally resulted in a better fit to reference costs than the GDP method. CONCLUSIONS: These reference costs for cervical cancer can inform cost-effectiveness evaluation of cervical screening and HPV vaccination in China. HDI-based methods for cost-scaling-based on social, as well as purely economic, factors-have potential to provide more accurate estimates.

Health impact of delayed implementation of cervical cancer screening programs in India: A modeling analysis.

India has the highest burden of cervical cancer in the world. To estimate the consequences of delaying implementation of organized cervical cancer screening, we projected the avertable burden of disease under different implementation scenarios of a screening program. We used an individual-based microsimulation model of human papillomavirus (HPV) infection and cervical cancer calibrated to epidemiologic data from India to project age-specific cancer incidence and mortality reductions associated with screening (once-in-a-lifetime among women aged 30-34 years) with one-visit visual inspection with acetic acid (VIA) and one- and two-visit HPV DNA testing. We then applied these reductions to a population model to project the lifetime cervical cancer cases and deaths averted under different implementation scenarios taking place from 2017 to 2026: (1) immediate implementation of screening with currently available screening tests (one-visit VIA, two-visit HPV testing); (2) immediate implementation of screening with currently available screening tests, with a switch to point-of-care one-visit HPV testing in 5 years; and (3) 5-year delayed implementation of screening with current screening tests or point-of-care HPV testing. Immediate implementation of two-visit HPV testing with a switch to one-visit HPV testing averted 574,100 cases and 382,500 deaths over the lifetimes of 81.4 million 30- to 34-year-old women screened once between 2017 and 2026. Delayed implementation with a one-visit HPV test averted 209,300 cases and 139,100 deaths. Delaying implementation of screening programs in high-burden settings will result in substantial morbidity and mortality among women beyond the age for adolescent HPV vaccination.

Cost-Effectiveness of Cervical Cancer Screening in Women Living With HIV in South Africa: A Mathematical Modeling Study.

BACKGROUND: Women with HIV face an increased risk of human papillomavirus (HPV) acquisition and persistence, cervical intraepithelial neoplasia, and invasive cervical cancer. Our objective was to determine the cost-effectiveness of different cervical cancer screening strategies among women with HIV in South Africa. METHODS: We modified a mathematical model of HPV infection and cervical disease to reflect coinfection with HIV. The model was calibrated to epidemiologic data from HIV-infected women in South Africa. Clinical and economic data were drawn from in-country data sources. The model was used to project reductions in the lifetime risk of cervical cancer and incremental cost-effectiveness ratios (ICERs) of Pap and HPV DNA screening and management algorithms beginning at HIV diagnosis, at 1-, 2-, or 3-year intervals. Strategies with an ICER below South Africa's 2016 per capita gross domestic product (US$5270) were considered "cost-effective." RESULTS: HPV testing followed by treatment (test-and-treat) at 2-year intervals was the most effective strategy that was also cost-effective, reducing lifetime cancer risk by 56.6% with an ICER of US$3010 per year of life saved. Other cost-effective strategies included Pap (referral threshold: HSIL+) at 1-, 2-, and 3-year intervals, and HPV test-and-treat at 3-year intervals. Pap (ASCUS+), HPV testing with 16/18 genotyping, and HPV testing with Pap or visual triage of HPV-positive women were less effective and more costly than alternatives. CONCLUSIONS: Considering per capita gross domestic product as the benchmark for cost-effectiveness, HPV test-and-treat is optimal in South Africa. At lower cost-effectiveness benchmarks, Pap (HSIL+) would be optimal.

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

PURPOSE: To provide resource-stratified, evidence-based recommendations on the secondary prevention of cervical cancer globally. METHODS: ASCO convened a multidisciplinary, multinational panel of oncology, primary care, epidemiology, health economic, cancer control, public health, and patient advocacy experts to produce recommendations reflecting four resource-tiered settings. A review of existing guidelines, a formal consensus-based process, and a modified ADAPTE process to adapt existing guidelines were conducted. Other experts participated in formal consensus. RESULTS: Seven existing guidelines were identified and reviewed, and adapted recommendations form the evidence base. Four systematic reviews plus 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 by setting are as follows: maximal: ages 25 to 65, every 5 years; enhanced: ages 30 to 65, if two consecutive negative tests at 5-year intervals, then every 10 years; limited: ages 30 to 49, every 10 years; and basic: ages 30 to 49, one to three times per lifetime. For basic settings, visual assessment is recommended as triage; in other settings, genotyping and/or cytology are recommended. For basic settings, treatment is recommended if abnormal triage results are present; in other settings, colposcopy is recommended for abnormal triage results. For basic settings, treatment options are cryotherapy or loop electrosurgical excision procedure; for other settings, loop electrosurgical excision procedure (or ablation) is recommended. Twelve-month post-treatment follow-up is recommended in all settings. Women who are HIV positive should be screened with HPV testing after diagnosis and screened 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 can be found at www.asco.org/rs-cervical-cancer-secondary-prev-guideline and www.asco.org/guidelineswiki.It is the view of of ASCO that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement, but not replace, local guidelines.

Estimating the value of point-of-care HPV testing in three low- and middle-income countries: a modeling study.

BACKGROUND: Where resources are available, the World Health Organization recommends cervical cancer screening with human papillomavirus (HPV) DNA testing and subsequent treatment of HPV-positive women with timely cryotherapy. Newer technologies may facilitate a same-day screen-and-treat approach, but these testing systems are generally too expensive for widespread use in low-resource settings. METHODS: To assess the value of a hypothetical point-of-care HPV test, we used a mathematical simulation model of the natural history of HPV and data from the START-UP multi-site demonstration project to estimate the health benefits and costs associated with a shift from a 2-visit approach (requiring a return visit for treatment) to 1-visit HPV testing (i.e., screen-and-treat). We estimated the incremental net monetary benefit (INMB), which represents the maximum additional lifetime cost per woman that could be incurred for a new point-of-care HPV test to be cost-effective, depending on expected loss to follow-up between visits (LTFU) in a given setting. RESULTS: For screening three times in a lifetime at 100% coverage of the target population, when LTFU was 10%, the INMB of the 1-visit relative to the 2-visit approach was I$13 in India, I$36 in Nicaragua, and I$17 in Uganda. If LTFU was 30% or greater, the INMB values for the 1-visit approach in all countries was equivalent to or exceeded total lifetime costs associated with screening three times in a lifetime. At a LTFU level of 70%, the INMB of the 1-visit approach was I$127 in India, I$399 in Nicaragua, and I$121 in Uganda. CONCLUSIONS: These findings indicate that point-of-care technology for cervical cancer screening may be worthy of high investment if linkage to treatment can be assured, particularly in settings where LTFU is high.

Resource-stratified implementation of a community-based breast cancer management programme in Peru.

Breast cancer incidence and mortality rates continue to rise in Peru, with related deaths projected to increase from 1208 in 2012, to 2054 in 2030. Despite improvements in national cancer control plans, various barriers to positive breast cancer outcomes remain. Multiorganisational stakeholder collaboration is needed for the development of functional, sustainable early diagnosis, treatment and supportive care programmes with the potential to achieve measurable outcomes. In 2011, PATH, the Peruvian Ministry of Health, the National Cancer Institute in Lima, and the Regional Cancer Institute in Trujillo collaborated to establish the Community-based Program for Breast Health, the aim of which was to improve breast health-care delivery in Peru. A four-step, resource-stratified implementation strategy was used to establish an effective community-based triage programme and a practical early diagnosis scheme within existing multilevel health-care infrastructure. The phased implementation model was initially developed by the Breast Cancer Initiative 2·5: a group of health and non-governmental organisations who collaborate to improve breast cancer outcomes. To date, the Community-based Program for Breast Health has successfully implemented steps 1, 2, and 3 of the Breast Cancer Initiative 2·5 model in Peru, with reports of increased awareness of breast cancer among women, improved capacity for early diagnosis among health workers, and the creation of stronger and more functional linkages between the primary levels (ie, local or community) and higher levels (ie, district, region, and national) of health care. The Community-based Program for Breast Health is a successful example of stakeholder and collaborator involvement-both internal and external to Peru-in the design and implementation of resource-appropriate interventions to increase breast health-care capacity in a middle-income Latin American country.

Evidence-based policy choices for efficient and equitable cervical cancer screening programs in low-resource settings.

Women in developing countries disproportionately bear the burden of cervical cancer. The availability of prophylactic vaccines against human papillomavirus (HPV) types 16 and 18, which cause approximately 70% of cervical cancers, provides reason for optimism as roll-out begins with support from Gavi, the Vaccine Alliance. However, for the hundreds of millions of women beyond the target age for HPV vaccination, cervical cancer screening to detect and treat precancerous lesions remains the only form of prevention. Here we describe the challenges that confront screening programs in low-resource settings, including (1) optimizing screening test effectiveness; (2) achieving high screening coverage of the target population; and (3) managing screen-positive women. For each of these challenges, we summarize the tradeoffs between resource utilization and programmatic attributes. We then highlight opportunities for efficient and equitable programming, with supporting evidence from recent mathematical modeling analyses informed by data from the PATH demonstration projects in India, Nicaragua, and Uganda.

The Cost-Effectiveness of Visual Triage of Human Papillomavirus-Positive Women in Three Low- and Middle-Income Countries.

Background: World Health Organization guidelines support human papillomavirus (HPV) testing alone (followed by treatment with cryotherapy) or in conjunction with visual inspection with acetic acid (VIA) triage testing. Our objective was to determine the cost-effectiveness of VIA triage for HPV-positive women in low-resource settings.Methods: We calibrated mathematical simulation models of HPV infection and cervical cancer to epidemiologic data from India, Nicaragua, and Uganda. Using cost and test performance data from the START-UP demonstration projects, we assumed screening took place either once or three times in a lifetime between ages 30 and 40 years. Strategies included (i) HPV alone, followed by cryotherapy for all eligible HPV-positive women; and (ii) HPV testing with VIA triage for HPV-positive women, followed by cryotherapy for eligible women who were also VIA-positive (HPV-VIA). Model outcomes included lifetime risk of cervical cancer and incremental cost-effectiveness ratios (ICERs; international dollars/year of life saved).Results: In all three countries, HPV alone was more effective than HPV-VIA. In Nicaragua and Uganda, HPV alone was also less costly than HPV-VIA; ICERs associated with screening three times in a lifetime (HPV alone) were below per capita GDP. In India, both HPV alone and HPV-VIA had ICERs below per capita GDP.Conclusions: VIA triage of HPV-positive women is not likely to be cost-effective in settings with high cervical cancer burden. HPV alone followed by treatment may achieve greater health benefits and value for public health dollars.Impact: This study provides early evidence on the cost-effectiveness of HPV testing followed by VIA triage versus an HPV screen-and-treat strategy. Cancer Epidemiol Biomarkers Prev; 26(10); 1500-10. ©2017 AACR.

Cost-effectiveness of HPV-based cervical cancer screening in the public health system in Nicaragua.

OBJECTIVES: To evaluate the cost-effectiveness of human papillomavirus (HPV) DNA testing (versus Papanicolaou (Pap)-based screening) for cervical cancer screening in Nicaragua. DESIGN: A previously developed Monte Carlo simulation model of the natural history of HPV infection and cervical cancer was calibrated to epidemiological data from Nicaragua. Cost data inputs were derived using a micro-costing approach in Carazo, Chontales and Chinandega departments; test performance data were from a demonstration project in Masaya department. SETTING: Nicaragua's public health sector facilities. PARTICIPANTS: Women aged 30-59 years. INTERVENTIONS: Screening strategies included (1) Pap testing every 3 years, with referral to colposcopy for women with an atypical squamous cells of undetermined significance or worse result ('Pap'); (2) HPV testing every 5 years, with referral to cryotherapy for HPV-positive eligible women (HPV cryotherapy or 'HPV-Cryo'); (3) HPV testing every 5 years, with referral to triage with visual inspection with acetic acid (VIA) for HPV-positive women ('HPV-VIA'); and (4) HPV testing every 5 years, with referral to Pap testing for HPV-positive women ('HPV-Pap'). OUTCOME MEASURES: Reduction in lifetime risk of cancer and incremental cost-effectiveness ratios (ICER; 2015 US$ per year of life saved (YLS)). RESULTS: HPV-based screening strategies were more effective than Pap testing. HPV-Cryo was the least costly and most effective strategy, reducing lifetime cancer risk by 29.5% and outperforming HPV-VIA, HPV-Pap and Pap only, which reduced cancer risk by 19.4%, 12.2% and 10.8%, respectively. With an ICER of US$320/YLS, HPV-Cryo every 5 years would be very cost-effective using a threshold based on Nicaragua's per capita gross domestic product of US$2090. Findings were robust across sensitivity analyses on test performance, coverage, compliance and cost parameters. CONCLUSIONS: HPV testing is very cost-effective compared with Pap testing in Nicaragua, due to higher test sensitivity and the relatively lower number of visits required. Increasing compliance with recommended follow-up will further improve the health benefits and value for public health dollars.

Cost-effectiveness of an HPV self-collection campaign in Uganda: comparing models for delivery of cervical cancer screening in a low-income setting.

With the availability of a low-cost HPV DNA test that can be administered by either a healthcare provider or a woman herself, programme planners require information on the costs and cost-effectiveness of implementing cervical cancer screening programmes in low-resource settings under different models of healthcare delivery. Using data from the START-UP demonstration project and a micro-costing approach, we estimated the health and economic impact of once-in-a-lifetime HPV self-collection campaign relative to clinic-based provider-collection of HPV specimens in Uganda. We used an individual-based Monte Carlo simulation model of the natural history of HPV and cervical cancer to estimate lifetime health and economic outcomes associated with screening with HPV DNA testing once in a lifetime (clinic-based provider-collection vs a self-collection campaign). Test performance and cost data were obtained from the START-UP demonstration project using a micro-costing approach. Model outcomes included lifetime risk of cervical cancer, total lifetime costs (in 2011 international dollars [I$]), and life expectancy. Cost-effectiveness ratios were expressed using incremental cost-effectiveness ratios (ICERs). When both strategies achieved 75% population coverage, ICERs were below Uganda's per capita GDP (self-collection: I$80 per year of life saved [YLS]; provider-collection: I$120 per YLS). When the self-collection campaign achieved coverage gains of 15-20%, it was more effective than provider-collection, and had a lower ICER unless coverage with both strategies was 50% or less. Findings were sensitive to cryotherapy compliance among screen-positive women and relative HPV test performance. The primary limitation of this analysis is that self-collection costs are based on a hypothetical campaign but are based on unit costs from Uganda. Once-in-a-lifetime screening with HPV self-collection may be very cost-effective and reduce cervical cancer risk by > 20% if coverage is high. Demonstration projects will be needed to confirm the validity of our logistical, costing and compliance assumptions.

To expand coverage, or increase frequency: Quantifying the tradeoffs between equity and efficiency facing cervical cancer screening programs in low-resource settings.

Cervical cancer is a leading cause of cancer death worldwide, with 85% of the disease burden residing in less developed regions. To inform evidence-based decision-making as cervical cancer screening programs are planned, implemented, and scaled in low- and middle-income countries, we used cost and test performance data from the START-UP demonstration project in Uganda and a microsimulation model of HPV infection and cervical carcinogenesis to quantify the health benefits, distributional equity, cost-effectiveness, and financial impact of either (1) improving access to cervical cancer screening or (2) increasing the number of lifetime screening opportunities for women who already have access. We found that when baseline screening coverage was low (i.e., 30%), expanding coverage of screening once in a lifetime to 50% can yield comparable reductions in cancer risk to screening two or three times in a lifetime at 30% coverage, lead to greater reductions in health disparities, and cost 150 international dollars (I$) per year of life saved (YLS). At higher baseline screening coverage levels (i.e., 70%), screening three times in a lifetime yielded greater health benefits than expanding screening once in a lifetime to 90% coverage, and would have a cost-effectiveness ratio (I$590 per YLS) below Uganda's per capita GDP. Given very low baseline coverage at present, we conclude that a policy focus on increasing access for previously unscreened women appears to be more compatible with improving both equity and efficiency than a focus on increasing frequency for a small subset of women.

Effectiveness of novel, lower cost molecular human papillomavirus-based tests for cervical cancer screening in rural china.

This study examined the efficacy of the OncoE6™ Cervical Test, careHPV™ and visual inspection with acetic acid (VIA) in identifying women at risk for cervical cancer and their capability to detect incident cervical precancer and cancer at 1-year follow-up. In a population of 7,543 women living in rural China, women provided a self-collected and two clinician-collected specimens and underwent VIA. All screen positive women for any of the tests, a ∼ 10% random sample of test-negative women that underwent colposcopy at baseline, and an additional ∼ 10% random sample of test-negative women who did not undergo colposcopy at baseline (n = 3,290) were recruited. 2,904 women were rescreened 1 year later using the same tests, colposcopic referral criteria, and procedures. Sensitivities of baseline tests to detect 1-year cumulative cervical intraepithelial neoplasia Grade 3 or cancer (CIN3+) were 96.5% and 81.6% for careHPV™ on clinician-collected and self-collected specimens, respectively, and 54.4% for OncoE6™ test. The OncoE6™ test was very specific (99.1%) and had the greatest positive predictive value (PPV; 47.7%) for CIN3+. Baseline and 1-year follow-up cervical specimens testing HPV DNA positive was sensitive (88.0%) but poorly predictive (5.5-6.0%) of incident CIN2+, whereas testing repeat HPV16, 18 and 45 E6 positive identified only 24.0% of incident CIN2+ but had a predictive value of 33.3%. This study highlights the different utility of HPV DNA and E6 tests, the former as a screening and the latter as a diagnostic test, for detection of cervical precancer and cancer.

Implementation of HPV testing in Latin America.

Cervical cancer is one of the leading killers among women in Latin America, a region where most countries have not been successful in implementing population-level cytology-based screening programs. This disease is caused by persistent infection with oncogenic HPV; in recent years, more HPV tests have become available and prices have dropped significantly, making it possible for countries to adopt these technologies. Pilot programs that took place in Nicaragua, Mexico, and Argentina showed a high level of efficacy in detecting precancerous cervical lesions and good feasibility and acceptance of self-sampling. El Salvador, Guatemala, Honduras, and Nicaragua are beginning to institutionalize HPV testing at the population level. The experience from the different countries has created rich information about the barriers and requirements for implementing HPV screening at large scale in these resource-constrained countries. There are several challenges for implementation, including a need to update screening guidelines, strengthen treatment capacity, and develop a comprehensive quality assurance plan for the HPV testing. At the same time, there are several opportunities in Latin America that make the process more feasible and faster than in other regions of the world: most Latin American countries already have screening programs funded by their national governments, several countries in the region are already implementing HPV testing, and there is a regional pooled procurement mechanism that could facilitate the purchase of HPV tests at an accessible price. We envision that most countries in the region will include HPV testing in their national program within the next three to five years.