Francesca Holme 1, * Sharon Kapambwe 2 Ashrafun Nessa 3 Partha Basu 4 Raul Murillo 5,6 Jose Jeronimo 1. Abstract 1 INTRODUCTION SUPPLEMENT ARTICLE

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1 DOI: /ijgo SUPPLEMENT ARTICLE Scaling up proven innovative cervical cancer screening strategies: Challenges and opportunities in implementation at the population level in low- and lower- middle- income countries Francesca Holme 1, * Sharon Kapambwe 2 Ashrafun Nessa 3 Partha Basu 4 Raul Murillo 5,6 Jose Jeronimo 1 1 PATH, Seattle, WA, USA 2 Ministry of Health of Zambia and Centre for Infectious Disease Research in Zambia, Lusaka, Zambia 3 Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh 4 International Agency for Research on Cancer, Lyon, France 5 Centro Javeriano de Oncologia, Hospital Universitario San Ignacio, Bogota, Colombia 6 Faculty of Medicine, Pontificia Universidad Javeriana, Bogota, Colombia *Correspondence Francesca Holme, PATH, Seattle, WA, USA. fholme@path.org Abstract The problem of cervical cancer in low-and lower-middle-income countries (LLMICs) is both urgent and important, and calls for governments to move beyond pilot testing to population-based screening approaches as quickly as possible. Experiences from Zambia, Bangladesh, Guatemala, Honduras, and Nicaragua, where scale-up of evidence-based screening strategies is taking place, may help other countries plan for large-scale implementation. These countries selected screening modalities recommended by the WHO that are within budgetary constraints, improve access for women, and reduce health system bottlenecks. In addition, some common elements such as political will and government investment have facilitated action in these diverse settings. There are several challenges for continued scale-up in these countries, including maintaining trained personnel, overcoming limited follow-up and treatment capacity, and implementing quality assurance measures. Countries considering scale-up should assess their readiness and conduct careful planning, taking into consideration potential obstacles. International organizations can catalyze action by helping governments overcome initial barriers to scale-up. KEYWORDS Cervical cancer; HPV test; Low- and lower-middle income countries; Scale-up; Screening; Visual inspection with acetic acid 1 INTRODUCTION With 85% of the more than half a million new cases of cervical cancer each year occurring in low-resource countries, 1 it is clear that swift action is needed at the population level to halt this preventable disease among the world s most vulnerable groups. Experts worldwide agree that the best available evidence supports visual inspection with acetic acid (VIA) and human papillomavirus (HPV) testing as primary screening methods for cervical precancer in low-resource settings, depending on available resources and local context. The WHO recognizes screening and treatment of precancerous lesions to prevent cervical cancer as one of the best buys for noncommunicable disease control, based on feasibility and cost-effectiveness. 2 However, few low- and lower-middle-income countries (LLMICs) are taking these strategies from pilot program to scale at the population level where they could have a significant impact on disease rates. Therefore, it This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics Int J Gynecol Obstet 2017;138 (Suppl. 1):63 68 wileyonlinelibrary.com/journal/ijgo 63

2 64 Holme meet AL is important to share lessons learned from countries where scale-up is underway so that other countries can assess their own readiness to scale-up, determine which strategy would be most suitable for their settings, and learn from previous experiences in order to plan for similar facilitators and barriers to population-based implementation. In this article, we discuss current status and progress of efforts to scale-up cervical cancer screening in five countries in three regions of the world, remaining challenges, and recommendations for decision makers contemplating population-level implementation. In this article we focus on the scaling-up process rather than outcomes of these programs, which deserve further attention in future reports. 2 CURRENT STATUS AND PROGRESS OF SCALE- UP EFFORTS Although pilot or investigational screening programs have taken place in several LLMICs, to our knowledge, none have grown into population-based screening programs with full nationwide coverage of the target population. 3,4 However, there are some countries in which governments have begun moving toward scale-up. The governments of Zambia and Bangladesh are undertaking large-scale screening efforts using VIA. In Zambia, which has a population of 14.5 million, scale-up efforts began in 2006; currently, there are more than 60 operational VIA clinics throughout the country, where approximately women are screened annually. 5 In Bangladesh (population million), concerted scale-up efforts also began in ,7 Today, 375 VIA centers are operational throughout the country; in 2015, more than women were screened. Both countries have plans to expand these efforts. Beginning in 2015, the governments of Guatemala, Nicaragua, and Honduras (with populations of 15.5 million, 6.1 million, and 8.1 million, respectively) began scaling- up screening using HPV testing, starting in three to four provinces per country. In 2016, the Guatemalan health system screened women with HPV testing; in Honduras and Nicaragua, and women were screened, respectively, involving between 75 and 220 health facilities. In all of these countries, future expansion to additional provinces and healthcare facilities is planned. Table 1 provides an overview of the characteristics of the screening programs in these five countries. Some common tools and strategies emerge across these five countries where governments have expanded their screening efforts. The countries selected screening tests supported by WHO in their 2013 guidelines that are within budgetary reach for their public health systems and improve access for women in a variety of settings, and they chose follow-up and treatment algorithms that reduce healthcare system bottlenecks. 8 In Zambia, VIA screening aided by digital cervicography is carried out by nurses in basic health facilities, thereby improving access for women in remote communities. A positive VIA result is followed by immediate treatment with cryotherapy for women with suitable lesions. This screen-and-treat model reduces the number of clinic visits required per woman. In Bangladesh, VIA is offered in primary, secondary, and tertiary level health service settings for ease of access; VIA-positive cases are then referred for colposcopy and treatment, usually with thermal coagulation if eligible, or if not, with the loop electrosurgical excision procedure (LEEP). The majority of colposcopy clinics practice a see-and-treat protocol with simultaneous collection of biopsy material to be processed later. In Central America, governments are implementing HPV testing using a low-cost assay. HPV testing enables women to collect their own vaginal samples in a variety of settings, thus improving access to, and uptake of, screening. Studies have shown increased screening participation rates with the inclusion of a self-sampling strategy HPV-positive women are followed up with a triage test (VIA or Papanicolaou [Pap]); a positive triage test result is followed immediately with cryotherapy treatment if the lesion is suitable, thus minimizing the resources and clinic visits required. Another common factor enabling scale-up in all five countries was a pilot phase supported in part by nonprofit or international organizations in collaboration with government entities. Pilot program design and duration varied across countries and included planning activities and initial implementation in a limited number of sites. In Zambia, women were screened in 15 primary care clinics during a 2-year pilot. With support from cooperating partners such as the United States President s Emergency Plan for AIDS Relief and United States Centers for Disease Control and Prevention, the government leveraged existing HIV care services to offer screening that targeted, but was not limited to, HIV-positive populations. 12 In Bangladesh, a UNFPA-supported pilot phase took place in government facilities in 16 districts, where more than women were screened with VIA over the course of one year. 6,13 In each of the Central American countries mentioned above, a 12-to 16-month planning and pilot phase took place with technical assistance from PATH, including a situational assessment and implementation of HPV testing for approximately women per country by selected government facilities, during which additional systems strengthening activities were also conducted. Initial HPV test kits were donated to the countries by PATH, contingent on the governments committing to set aside funds in their national budgets to purchase future HPV test kits. In all five countries, lessons reported from the pilot phase were critical for informing further planning and decision making for government-led scale-up. Not every LLMIC is currently ready to undertake scale-up efforts. Within countries, there may be wide variations in readiness by province, due to geographical factors or access to health infrastructure. Although the five countries we consider here vary widely in terms of these characteristics, as well as population density, culture, and other situational elements, all were able to begin the scale-up process by building on local, context-specific health system strengths, including existing resources and personnel. In Zambia, the cervical cancer prevention program successfully leveraged existing HIV, reproductive health, and maternal and child health program infrastructure for cervical cancer screening activities. In Bangladesh, the cervical cancer screening program was developed within existing government facilities at the primary, secondary, and tertiary levels in a rolling fashion by training healthcare providers at each VIA and colposcopy facility. In the three Central American countries, governments selected follow-up and treatment algorithms that took advantage of existing VIA and Pap capacity.

3 Holme meet AL 65 TABLE 1 Characteristics of country screening programs. Country Year pilot project initiated Year program scale- up began Screening policy and protocol Bangladesh Cervical and Breast Cancer Screening Program: Standard & Guidelines(2005) Guatemala National Guidelines for Screening and Treatment of Precancerous Lesions for the Prevention of Cervical Cancer (2014) Honduras Protocol for Screening and Treatment of Precancerous Lesions for Cervical Cancer Prevention (2015) Nicaragua Norm and Protocol for Cervical Cancer Prevention and Control (not yet published) Zambia Visual Inspection with Acetic Acid (VIA) and Cryotherapy: A Reference Manual for Trainers and Health Care Providers (2015) Screening test used Target age Management algorithm for screenpositive women Health information system capabilities VIA 30 years VIA+ women referred for colposcopy and treated immediately Electronic template recently introduced; generates key system indicators; does not yet enable tracking of women HPV DNA years Varies by health facility: HPV screen-and-treat, using VIA to determine treatment eligibility only HPV+ VIA+ women treated; HPV+ VIA women rescreened in 1 year HPV+ Pap ASCUS+ women referred for colposcopy and treatment; HPV+ normal Pap rescreened in 1 year Electronic; generates key system indicators; limited functionality for HPV DNA years HPV+ VIA+ women treated; HPV+ VIA women rescreened in 1 year Electronic template recently introduced; generates key system indicators; limited functionality for HPV DNA years Varies by health facility: HPV+ VIA+ women treated; HPV+ VIA women rescreened in 1 year HPV+ Pap ASCUS+ women referred for colposcopy and treatment; HPV+ normal Pap rescreened in 1 year Electronic; generates key system indicators; enables VIA aided by digital cervicography years VIA+ women treated immediately Electronic; generates key system indicators; enables Institution responsible for program coordination Ministry of Health and Family Welfare, Bangabandhu Sheikh Mujib Medical University and UNFPA Ministry of Public Health and Social Assistance Secretary of Health Ministry of Health Ministry of Health

4 66 Holme meet AL Another necessary component of readiness to begin scaling-up is political will, as evidenced by some degree of government investment in cervical cancer prevention. The nature of that investment varies according to local budgetary capacity, and helps determine both the organization of the screening program and the screening test to be used. In Zambia, political will has been generated over time by champions both internal and external to the Ministry of Health; these leaders found a key ally in the First Lady s office, which has incorporated cervical cancer prevention into its top priorities. Zambia now has designated personnel in the Ministry of Health in charge of cervical cancer prevention, with the authority to oversee screening efforts across the country. In Bangladesh, government commitment has grown slowly over time. Initial expansion was led by the collaborative efforts of the government, Bangabandhu Sheikh Mujib Medical University, and UNFPA. The external partners ensured that government personnel and facilities were the ultimate stewards of their efforts, and the government has assumed increasing responsibility for the cervical cancer screening program. In Central America, governments were investing in cervical cancer screening prior to HPV test introduction (primarily using Pap), but these investments were not generating the intended benefit for their target populations. In each country, Ministry of Health and other key leaders worked together to revise local screening and treatment guidelines, incorporating newer, more effective evidence- based approaches. These discussions laid both the political and policy groundwork to enable introduction of HPV testing. 3 REMAINING CHALLENGES AND PRIORITIES FOR SCALE- UP Several common challenges remain for continued scale-up in these countries, and similar obstacles may be encountered in other LLMICs. First, training and maintaining a cadre of personnel who can carry out screening and treatment activities is a significant challenge. In Zambia, high staff attrition has been an obstacle to scale-up; reasons include transfer to health facilities where screening services are not yet available, and staff pursuing further education. Even where screening is available, personnel are often reallocated when demand is high for other services in the same health facility. In Bangladesh, the challenge of retaining a trained cohort of personnel who can perform VIA has been largely overcome because the government implemented a training system to fill vacancies created by personnel transfer and retirement. However, overall scarcity of nurses and competing demands on their time continue to present challenges. In Central America, training healthcare personnel to offer HPV self-sampling has proved to be relatively easy; nurses aides and community volunteers can be trained quickly to teach self-sampling. The larger challenge is training and retaining providers to perform VIA triage after HPV testing and to perform cryotherapy for screen-positive women. Frequent personnel reassignment presents an obstacle in all three Central American countries. A second, closely related issue is ensuring adequate follow-up and treatment for screen-positive women; this requires both a functional health information system to track screen-positive women through to treatment completion and consistent treatment availability. Zambia has implemented a largely electronic health information system that allows the government to track screen-positive women via mobile phone, enabling more effective follow-up. The government of Bangladesh currently tracks monthly performance data from VIA clinics and colposcopy centers and an electronic template has recently been introduced, but records are not yet linked to specific women to enable tracking. In Central America, governments are at varying stages of implementation of electronic recordkeeping systems. The Nicaraguan electronic health information system is the most nimble in tracking women. Still, all three countries continue to rely on paper forms for some tracking, and this requires periodic manual revision. Treatment capacity has also been a challenge as these countries scale up their screening efforts. Cryotherapy is the primary treatment option for most women in Zambia and Central America, but procuring the gas required for freezing is a significant obstacle. In Zambia, nitrous oxide gas is imported from South Africa, but this is expensive and requires constant management of bureaucratic procurement processes. In Central America, gas typically is procured at the local health facility level, where competing demands on cash flow often diminish available funds. Within both of these contexts, the low quality of carbon dioxide gas damages equipment. The Guatemalan government has procured and is in the process of introducing thermal coagulation devices which need only electricity in select sites to overcome this barrier. In Bangladesh, the government has been using thermal coagulation in select centers, avoiding the need for gas. Access to LEEP and other advanced treatments is also a challenge for scale-up in all five countries. In all of the countries, LEEP equipment and surgical loops are costly and must be imported, and most countries face a shortage of colposcopists who can provide advanced treatments. An additional challenge in all of the countries considered here is monitoring and improving the quality of screening and treatment services to ensure that programs ultimately have their intended impact on cervical cancer mortality rates. The main goal of quality assurance programs in government-led cervical cancer screening and treatment is to develop internal capacity for periodic and permanent monitoring of key performance indicators. Accordingly, an excessive demand for quality indicators challenges sustainability of quality assurance programs in low-income settings. A discussion of a minimum set of indicators is beyond the purpose of this paper; however, examples of good practices to collect data in this area include accreditation and reaccreditation of providers and specialists, clear definitions and reporting processes for safety incidents, incorporating quality indicator information into data systems, and screening failure analysis (in case of invasive cancer or death). Gold standard quality assurance procedures have not yet been widely established for VIA and HPV testing as frontline screening strategies in population-based programs, although leaders around the world are making strides in this area. In Zambia, the quality of VIA screening is monitored and reinforced via digital cervicography reviewed by expert physicians, and a 2014 study showed slightly improved sensitivity of this method over unaided VIA among HIV-infected women. 14 Studies in Bangladesh produced several recommendations for improvements in program reach, training of providers, and referral systems, but

5 Holme meet AL 67 continuous quality monitoring of these components has yet to be implemented routinely. 6,7 Quality assurance procedures integral to HPV testing are being developed and implemented in select locations in Central America, but in most cases these measures have not yet been uniformly adopted, often due to the absence of a technical leader with the authority to drive this work. More broadly, ministry of health officials often do not routinely use key indicators such as coverage rates, screening test positivity rates, and percentage of women completing treatment to monitor and improve overall system functioning. In many cases, limited available data and a lack of previous demand for and use of key indicators in decision making complicate these efforts. Another challenge is maintaining government coordination, commitment, and investment, including ensuring supportive organizational structures within ministries of health in the face of competing priorities. In Zambia, other noncommunicable diseases as well as infectious disease priorities compete for limited resources; in Bangladesh, obstetricians/gynecologists are often busy attending deliveries, limiting their time for cervical cancer prevention activities; and in Central America, disease outbreaks such as Zika and dengue interrupt screening activities. In particular, outreach strategies to encourage participation in cervical cancer screening are often viewed as low-priority activities within the context of health emergencies and thus sometimes suffer owing to limited resources. Political changes that inevitably accompany routine elections can also disrupt ongoing screening and treatment activities as ministry of health priorities shift. In all five countries, ongoing budgetary commitment is required to maintain and further expand screening efforts. Cost-effectiveness of a given screening method is often less important for budgetary decision making than the line-item costs for delivering screening and treatment services. Still, the screening programs in these five LLMICs would provide an excellent opportunity to perform cost-effectiveness analyses of various screening algorithms in real program settings. The trade-off between high compliance to treatment achieved through the screen-and-treat approach and the over-treatment inherent in this strategy should be carefully evaluated in the context of both VIA and HPV test-based screening. 4 RECOMMENDATIONS The problem of cervical cancer in LLMICs is both urgent and important. To address the issue, governments must begin to move beyond pilot testing and opportunistic efforts to implementing large-scale, population-based approaches where possible. This will not be immediately feasible in every country or province, but it should start in settings with proven readiness. Cervical cancer prevention advocates should first assess their country s readiness to scale-up. Even when immediate scale-up is not possible, decision makers should consider the local context and political environment and lay the groundwork within ministries of health to secure long-term involvement and commitment. This may take the form of developing new national guidelines or cancer prevention plans in order to involve key stakeholders in the decision-making process. Decision makers should determine which evidence-based strategy is within reach for their public system that will reduce bottlenecks to treatment and streamline points of contact for women. Countries where scale-up is possible in the near future should undertake careful planning for program rollout, including a pilot period. International and donor organizations can help governments overcome initial barriers to scale-up, such as providing context-specific technical support for policy development, personnel training, improved information systems, resource planning, and financial modeling. They also can continue to support governments in building greater follow-up and treatment capacity and implementing quality assurance strategies. These entities should prioritize supporting governments that demonstrate political commitment and other basic conditions necessary to scale up new screening and treatment strategies. Countries should also be encouraged to publish results of program monitoring and evaluation efforts so that the effectiveness of large-scale VIA- and HPV-based screening programs in LLMICs is documented and available for other countries considering these strategies. AUTHOR CONTRIBUTIONS FH led content development and writing of the article, including content on Central America. SK provided conceptual input, wrote content on Zambia, and edited article drafts. AN provided conceptual input, wrote content on Bangladesh, and edited article drafts. PB and RM provided conceptual input, wrote content, and edited article drafts. JJ provided conceptual input and edited article drafts. ACKNOWLEDGMENTS On behalf of PATH and our collaborating partners in Central America, Francesca Holme and Jose Jeronimo are grateful to the Ministries of Health of Guatemala, Honduras, and Nicaragua. We would like to acknowledge the Bill & Melinda Gates Foundation and the Union for International Cancer Control for their support of scale-up of cervical cancer screening efforts in Central America. PATH s work in cervical cancer prevention is funded in part by the Bill & Melinda Gates Foundation (OPP ). The findings and conclusions contained within this publication are those of the authors and do not necessarily reflect positions or policies of the Bill & Melinda Gates Foundation. Ashrafun Nessa is grateful to the Ministry of Health and Family Welfare of Bangladesh for collaboration with Bangabandhu Sheikh Mujib Medical University in developing the Cervical and Breast Cancer Screening Program, and to the UNFPA and WHO in Bangladesh and the International Agency for Research on Cancer for their valuable technical support and active cooperation. Sharon Kapambwe is grateful to the Zambia Ministry of Health, the Centre for Infectious Disease Research in Zambia, and all cooperating partners working on the cervical cancer screening program for their valuable technical support and active cooperation. CONFLICTS OF INTEREST FH, SK, AN, PB, and RM have no conflicts of interest to declare. JJ was the co-owner and Deputy Manager of Onco Prev International,

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