# Roles of the technical and working groups
and treatment is provided soon or, ideally, immediately after a positive screening test.
The goal of a screen-and-treat programme for cervical cancer is to reduce cervical cancer and related mortality with relatively few adverse events. The programme must include a screening test or strategy (sequence of tests) and be linked to appropriate treatments for CIN, and also provide referral for treatment of women with invasive cervical cancer. Common screening tests that are widely used include tests for human papillomavirus (HPV), cytology (Pap test), and unaided visual inspection with acetic acid (VIA). These tests can be used as a single test or in a sequence. When using a single test, a positive result indicates the need for treatment. When using a sequence of tests, women who test positive on the first test receive another test and only those who test positive on the second test are treated. Women with a positive first screening test followed by a negative second screening test are followed up. Available treatments include cryotherapy, large loop excision of the transformation zone (LEEP/ LLETZ), and cold knife conization (CKC).
This guideline provides recommendations for strategies for a screen-and-treat programme. It builds upon the existing recommendations for the use of cryotherapy to treat CIN (6,7) and on the new WHO guidelines for treatment of cervical intraepithelial neoplasia 2-3 and glandular adenocarcinoma in situ (8), which is being published concomitantly with these present guidelines. When developing the guideline, the Guideline Development Group (GDG) considered that countries currently providing screen-and-treat programmes may be uncertain about which strategy to use. Therefore, these recommendations were developed by comparing the benefits and harms of different screen-and-treat strategies.
For countries where a cervical cancer prevention and control programme already exists, these recommendations were developed to assist decision-makers to determine whether to provide a different screening test followed by a different treatment instead, or to provide a series of tests followed by an adequate treatment. For countries where such a programme does not currently exist, these recommendations can be used to determine which screening test and treatment to provide.
In addition, a decision-making framework is proposed in Annex 2 to help programme managers choose the right strategy based on the specific country or regional context. ; treatment of histologically confirmed CIN2+ (a new guideline is being published concomitantly with this present one; and strategies for screening and treatment of precancerous cervical lesions (the subject of this present guidance). In addition, there is a new awareness that when making recommendations for screen-and-treat strategies, the consequences of treating or not treating women after positive or negative screening results should also be considered. Typically, the selection of a screening test is based on its accuracy, which is determined by calculating the sensitivity and specificity of the test, and recommendations are based on that evidence. However, these data, do not address the consequences of screening and treating women. When deciding on a screenand-treat strategy, it is critical to consider the downstream consequences after treatment (for a positive test) or no treatment (for a negative test), such as cervical cancer and related mortality, recurrence of CIN2+, adverse effects of treatment (and overtreatment), and use of resources. These recommendations are based on evidence about the diagnostic accuracy of each of the screening tests, together with evidence about the benefits and harms of treatments.

# Target audience
This guideline is intended primarily for policy-makers, managers, programme officers, and other professionals in the health sector who have responsibility for choosing strategies for cervical cancer prevention, at country, regional and district levels. Individuals working in reproductive health care programmes, particularly programmes for the prevention of sexually transmitted infections (STIs) including HIV/AIDS and for family planning, at the district and primary health care levels, should also consult these guidelines to understand how recommendations are developed and why it is vitally important to select and implement evidence-based strategies to prevent cervical cancer.
This guideline provides recommendations for screen-and-treat strategies to prevent cervical cancer (Chapter 3). In addition to the recommendations, this document proposes a decision-making flowchart for choosing the best screen-and-treat strategy for a particular setting at a programme level (Annex 2); and -for use once the strategy is chosen -the screen-and-treat flowcharts for all strategies are provided, including the flowcharts specifically for women of negative or unknown HIV status (Annex 3), and those for women of HIV-positive status or of unknown HIV status in areas with areas with high endemic HIV infection (Annex 4). This document also describes the WHO methodology that was used for the development of these recommendations (Chapter 2, and Annexes 5-7), and provides GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evidence profiles 3 and evidence-to-recommendation tables 4 for each recommendation (available online: Supplemental material, Sections A and B). This document provides the scientific background and justification for the practical information found in the C4-GEP (10).
The GRADE evidence profiles summarize the evidence from the systematic reviews and the model, as well as the quality of the evidence. The 'evidence-to-recommendation tables' describe the process of going from the evidence to developing the recommendations, and explain the judgements and rationale for factors that are not part of the GRADE evidence profiles.
The methods used to develop these guidelines followed the WHO handbook for guideline development (11,12).

# Formulating questions and determining outcomes
In February 2011, the GDG met to discuss the questions and outcomes to address in the chapter on screen-and-treat strategies to appear in the updated C4-GEP, in order to incorporate new evidence. The GDG identified 15 potential questions to guide the evidence review for screening options and treatment strategies for cervical pre-cancer. The MG surveyed the GDG anonymously online using Survey Monkey 5 to prioritize the questions and determine which ones are clinically relevant or used in practice; 14 out of 17 members responded. Among the 15 questions, the GDG identified 7 that related to comparisons between standard screen-and-treat strategies and those that are NOT typically used in practice (e.g. an HPV test followed by cytology),
Survey Monkey: www.surveymonkey.com
and therefore these seven questions were excluded. The remaining eight questions were retained as the basis for the screening recommendations (see Box 1).
During this same meeting, the GDG developed a list of outcomes that should be considered when making decisions and recommendations for the screen-and-treat strategies. These outcomes were informed by the work previously conducted for the preparation of the WHO guidelines entitled Use of cryotherapy for cervical intraepithelial neoplasia (7). Following the meeting, the MG surveyed all GDG and ERG members online using Survey Monkey to identify and rank the critical outcomes for making recommendations. Participants ranked outcomes on a scale from 1 (not at all important) to 7 (critical) in terms of importance for decision-making. Thirty of the Box 1: Prioritized questions for screening options for cervical pre-cancer 1. Should an HPV test or VIA be used to screen? 2. Should an HPV test or cytology followed by colposcopy (with or without biopsy) be used to screen? 3. Should VIA or cytology followed by colposcopy (with or without biopsy) be used to screen? 4. Should an HPV test or an HPV test followed by colposcopy (with or without biopsy) be used to screen? 5. Should an HPV test followed by VIA or an HPV test as a single test be used to screen? 6. Should an HPV test followed by VIA or VIA as a single test be used to screen? 7. Should an HPV test followed by VIA or cytology followed by colposcopy (with or without biopsy) be used to screen? 8. Should an HPV test followed by VIA or an HPV test followed by colposcopy (with or without biopsy) be used to screen? 50 members surveyed provided responses and an average ranking was calculated for each outcome. Outcomes with an average ranking of 4 (important) or higher were included in the evidence review and considered when making the recommendations (see Box 2).

# Synthesis of the evidence and preparation of evidence profiles
A screen-and-treat strategy is made up of two linked parts: the screening test(s) followed by treatment of CIN. The best studies to inform screen-and-treat recommendations are randomized controlled trials in which women are randomized to receive 'screen-and-treat strategy A' or 'screen-and-treat strategy B', and health outcomes of all of the women are measured and presented (even those who had false-negative screening results and were never treated). However, few such studies have been conducted; most studies do not link the screening strategy with the treatment and the outcomes. Instead, there are studies that measure the accuracy of a test to diagnose CIN (without reporting on treatment), and there are other studies that only measure health outcomes of screen-positive women after treatment. Hence, the outcomes for women with true-negative or false-negative screening results are not measured. This is true for the literature for cervical pre-cancer screening; few studies report health outcomes of all women who were screened, including those who were treated and those who were not. For this reason, the primary evidence used to develop these screen-andtreat recommendations could not be based on evidence from randomized controlled studies. Instead, these recommendations are based on modelling health outcomes from a series of reviews of the diagnostic accuracy of the available screening tests, and a series of reviews of the effects of the various treatments for CIN.  (8). The searches were not restricted by language or study design in order not to exclude primary studies or previously published systematic reviews in this area. Reference lists of relevant studies were reviewed and the WHO GDG was contacted for additional references. 6 At least two members of the MG independently screened titles and abstracts and the full text of relevant articles, and a third investigator resolved disagreements. The MG included observational studies for diagnostic test accuracy studies considered at low risk of bias. For example, all women in the studies had to receive both screening tests that 6Details of the methods for the systematic reviews are available at the WHO website.
were being compared, and all women who tested positive or negative (or a random sample of at least 10% of the women who tested negative) had to receive the 'gold standard' diagnostic test. Studies had to include non-pregnant women aged 18 years or older who had not been treated previously for CIN. Women could be of HIV-positive or HIV-negative status or of unknown HIV status. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was used to develop the flow diagram for inclusion and exclusion of studies (Annex 6).
A list of all studies included in the reviews of diagnostic test accuracy is provided in Annex 7.
Two members of the MG independently abstracted data about patient characteristics, setting, and diagnostic test accuracy, using a pre-tested data abstraction form. Data to assess the quality of the studies was also collected with the QUADAS tool (QUality Assessment for Diagnostic Accuracy Studies) (13). We pooled the diagnostic test accuracy data using Stata 12 data analysis and statistical software.
The MG developed a mathematical model to calculate the benefits and harms of each screen-and-treat strategy compared to other screen-and-treat strategies for women of unknown HIV status and for women of HIVpositive status. CIN2+ prevalence, natural progression data, the pooled diagnostic test accuracy results, and pooled data on treatment effects and complications were all considered in the model (see Annex 7 for references used in the model). The estimates of the expected absolute effects on health-care outcomes and a summary of the model assumptions are provided transparently in the evidence profiles for women of negative or unknown HIV status and for women of HIV-positive status (see Supplemental material, Sections A and B, available online) and for women of different ages.
Two members of the MG evaluated the quality of evidence using the Grading of Recommenda-tions Assessment, Development and Evaluation (GRADE) approach (14,15) and presented the evidence and its quality in the GRADE evidence profiles. Evidence for diagnostic accuracy of the screening tests is presented in evidence profiles for diagnostic test accuracy for each recommendation (see Supplemental material, Sections A and B, generally in section 2.1 for each recommendation). The evidence from the model (i.e. outcomes after a screen-and-treat strategy) is also presented in evidence profiles (see Supplemental material, Sections A and B, generally in sections 2.2 and 2.3 for each recommendation, according to age). The quality of the evidence or confidence in the effect estimates was assessed as high moderate
, low or very low according to the GRADE criteria. Tables to facilitate decision-making for recommendations (evidence-to-recommendations tables) were produced for each recommendation. These tables include a summary of the evidence (benefits and harms), an assessment of the quality of the evidence, relevant patient values and preferences, and any implications for use of resources and feasibility (Supplemental material, Sections A and B).

# Modelling of health outcomes
A screening test with the highest diagnostic accuracy is not necessarily the test of choice in clinical practice. The decision to recommend a screening test needs to be justified by its impact on downstream patient-important health outcomes. Decision analysis is a powerful tool for evaluating a diagnostic or screening test on the basis of long-term patient-important outcomes when only intermediate outcomes -such as test sensitivity and specificityare known. When making the decision to recommend a diagnostic or screening test, a panel should consider the health outcomes downstream from the test. For example, the health risks of interventions resulting from falsepositive (FP) and false-negative (FN) findings should be compared with the health benefits associated with true-negative (TN) and truepositive (TP) findings.
To inform these recommendations, we built a mathematical model using TreeAge Pro 2012 software. In this model we calculated the proportions of TP, TN, FP and FN findings for each of the screening tests (VIA, HPV and cytology) given the pooled test-accuracy estimates and the pretest probability of having CIN in that population. We then calculated the probability of developing any of the critical outcomes for decision-making (see Box 2) based on the treatment they may receive and the pooled estimates of efficacy and potential complications of the different treatments (cryotherapy, CKC and LEEP). To calculate an overall estimate of the outcome, we added the probability of developing an outcome for each of the categories (TP, TN, FP, FN) for the same screening test and treatment option. We identified our assumptions for the models a priori. These assumptions are summarized in the Supplemental material available online, Sections A and B (below each GRADE evidence table for patient-important outcomes following different screen-and-treat strategies). We also specified a priori the sensitivity analysis we performed based on HIV status (HIV-positive compared to unknown HIV status) and different age categories.

# Development of the recommendations
In early 2012 (26-28 April), the GDG, the ERG and the MG met to discuss the recommendations. One member each from the GDG and the MG chaired the meeting, which was attended by experts from around the world, representing various public health and medical disciplines. To expand the geographical representativeness of the GDG, it was decided that the ERG -a large group with members representing many countries -would participate in the development of the recommendations during that meeting. Members of the MG presented evidence profiles and evidence-to-recommendation tables, which included evidence about the benefits and harms, values and preferences, resources and feasibility.
With regard to patient values and preferences, the GDG agreed that the evidence found could be applied across all recommendations (16)(17)(18). The evidence from qualitative studies suggests that women may fear screening and may have a high level of anxiety related to colposcopy or treatment, and may feel burdened by the need for a second visit for treatment. However, once women decide to be screened they find the screening tests and immediate treatment acceptable. Evidence from the systematic reviews demonstrated that there is a preference for more frequent screening and active management among women who have screened positive for CIN1. In addition, evidence from controlled trials showed that women find treatment by cryotherapy and LEEP acceptable, and are satisfied with a screenand-treat approach (19).
WHO has recently developed the WHO cervical cancer prevention and control costing tool (20). This tool includes two modules: one on the cost of HPV vaccination and the other on the cost of a screen-and-treat programme. The purpose of the tool is to help programme managers develop a budget for the programme. In order to develop the tool, the cost of each intervention was collected for a range of countries and the calculation tables were developed. This, in addition to the experience of the members of the ERG, was essential to the discussion of the resources needed for each of strategy.
Recommendations were made by the GDG and ERG by balancing the overall desirable and undesirable consequences of the screen-and-treat strategies, which included consideration of important outcomes, values and preferences, resources and feasibility, along with the level of certainty of that information. Members of the panel made decisions based on consensus and unanimous voting, which was not anonymous. The results of those discussions are documented in the evidence-to-recommendation tables for each recommendation, available online in Supplemental material, Sections A and B. The GDG and ERG also identified key research gaps. All the discussions and decisions took place during the April 2012 meeting and no major discord was noted.
The recommendations were assessed as 'strong' or 'conditional', in accordance with the WHO handbook for guideline development (11,12). Strong recommendations have been worded as 'we recommend' and conditional recommendations as 'we suggest'. A strong recommendation means that it was clear to the panel that the net desirable consequences of the specified strategy outweighed those of the alternative strategy. But a conditional recommendation was made when it was less clear whether the net desirable consequences of the specified strategy outweighed those of the other strategy. In this guideline, many recommendations are conditional. Table 1 provides a guide to the interpretation of the strength of the recommendations.

# Guideline review and approval process
The WHO screen-and-treat strategies to prevent cervical cancer underwent the following peer review process before and during development:  The questions formulated for the development of the guidelines were circulated among the WHO Steering Group, who also discussed them with the GDG. When the GDG and the WHO Steering Group had reached agreement on the questions, these were sent to the ERG.  The protocol for systematic reviews was circulated among the GDG. This protocol was also discussed during the ERG meeting, which was also attended by the European Guidelines Development Group in addition to the WHO Steering Group, the GDG and the MG. During that meeting the evidence that had been identified and the draft evidence profiles were discussed.  Discussions and conference calls were regularly held with the GDG to discuss the data from the literature review, the models, the estimated parameters to include in the models, and the outcomes.  The final draft guideline with the recommendations was circulated among the members of the GDG for review before WHO clearance. For patients Most individuals in this situation would want the recommended course of action, and only a small proportion would not.
Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences.
The majority of individuals in this situation would want the suggested course of action, but many would not.

# For clinicians
Most individuals should receive the intervention. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator.
Clinicians should recognize that different choices will be appropriate for each individual and that clinicians must help each individual arrive at a management decision consistent with his or her values and preferences. Decision aids may be useful to help individuals make decisions consistent with their values and preferences.

# For policymakers
The recommendation can be adopted as policy in most situations.
Policy-making will require substantial debate and involvement of various stakeholders.
To aid decision-making by programme managers, a decision-making flowchart or algorithm is provided for choosing the best screen-and-treat strategy for a particular setting at a programme level (see Annex 2). Once the strategy has been chosen, flowcharts for each strategy can be followed; these are provided in Annex 3 (negative or unknown HIV status) and Annex 4 (HIV-positive status or unknown HIV status in areas with high endemic HIV infection).
The algorithm and the flowcharts are based on the recommendations detailed in this chapter.
Important considerations that apply to all screen-and-treat recommendations

# Population targeted by the recommendations
The recommendations in this guideline apply to women 30 years of age (recommended age to start screening) and older because of their higher risk of cervical cancer. However, the magnitude of the net benefit will differ among age groups and may extend to younger and older women depending on their baseline risk of CIN2+. Priority should be given to screening women aged 30-49 years, rather than maximizing the number of screening tests in a woman's lifetime. Screening even once in a lifetime would be beneficial. Screening intervals may depend on financial, infrastructural, and other resources.
For women of HIV-positive status, or of unknown HIV status in areas with high endemic HIV infection, the following should be noted.
Although the evidence about screening and treatment to prevent cervical cancer is of lower quality for women who are HIV-positive than for women who are HIV-negative or of unknown HIV status, cervical cancer screening should be done in sexually active girls and women, as soon as a woman or a girl has tested positive for HIV.
Supplemental material, Section A (negative or unknown HIV status) and Section B
(HIV-positive status or unknown HIV status in areas with high endemic HIV infection) provide the evidence and judgements for each recommendation (this material is available online).

# Considerations for screening tests
The recommendations include strategies based on three screening tests: HPV (cut-off level 1.0 pg/ml), cytology (cut-off level ASCUS+, atypical squamous cells of undetermined significance), and VIA. VIA is appropriate to use in women whose transformation zone is visible (typically in those younger than 50). This is because once menopause occurs, the transformation zone, where most precancerous lesions occur, frequently recedes into the endocervical canal and prevents it from being fully visible.

# Considerations for treatments
For all screen-and-treat recommendations, cryotherapy is the first-choice treatment for women who have screened positive and are eligible for cryotherapy. When women have been assessed as not eligible for cryotherapy, LEEP is the alternative treatment. Eligibility for cryotherapy follows the guidance provided in the update of the C4-GEP (10): Screen-positive women are eligible for cryotherapy if the entire lesion is visible, the squamocolumnar junction is visible, and the lesion does not cover more than 75% of the ectocervix. If the lesion extends beyond the cryoprobe being used, or into the endocervical canal, the patient is not eligible for cryotherapy and LEEP is the alternative option.
Before treatment, ALL women who have screened positive with any test (but especially with an HPV test) should be visually inspected with acetic acid to determine eligibility for cryotherapy and to rule out large lesions or suspected cervical cancer. VIA should be performed by a trained provider.
Note that there is a distinction in these recommendations between (a) using VIA to determine eligibility for treatment (i.e. cryotherapy versus LEEP), and (b) using VIA as a screening test to determine whether or not to treat.
a. In the 'HPV test' screen-and-treat strategy, women who are HPV-negative are not treated. Women who are HPV-positive will all be treated, and VIA is used to determine eligibility for treatment with cryotherapy or LEEP.
b. In the 'HPV test followed by VIA' strategy, women who are HPV-negative are not treated. Women who are HPV-positive all undergo VIA, which is used in this case as a second screening test to determine treatment. Women who are HPV-positive and VIA-positive will all be treated, while women who are HPV-positive and VIA-negative will not be treated.

# Screening intervals and follow-up
Ideal screening intervals are provided below and for all screen-and-treat strategies in Annexes 3 and 4.
In women who test negative on VIA or cytology (Pap smear), the screening interval for repeat screening should be every three to five years.
In women who test negative on an HPV test, rescreening should be done after a minimum interval of five years. Women who have received treatment should receive post-treatment follow-up screening at one year to ensure effectiveness of treatment. Refer to Annex 3 for flowcharts for all strategies for women who are of negative or unknown HIV status.
In women who are of HIV-positive status or of unknown HIV status in areas with high endemic HIV infection, if the screening test is negative, the screening interval for repeat screening should be within three years. Women who have received treatment should receive post-treatment follow-up screening at one year to ensure effectiveness of treatment. Refer to Annex 4 for flowcharts for all strategies for women who are of HIV-positive status or of unknown HIV status in areas with high endemic HIV infection.

# Screen-and-treat recommendations
Recommendation 1. The expert panel recommends against the use of CKC as treatment in a screen-and-treat strategy (strong recommendation, evidence)
Remarks: The screen-and-treat strategies considered by the panel with CKC as treatment included an HPV test, VIA, or an HPV test followed by VIA as screening. Although the benefits were similar for CKC compared with cryotherapy or LEEP for all screen-and-treat strategies, the harms were greater with CKC. This recommendation applies to women regardless of HIV status. See Supplemental material, Sections A and B.
Summary of the evidence: Low-quality evidence from pooled observational studies showed that the recurrence of CIN after treatment with CKC may be 3% less than the recurrence after cryotherapy or LEEP. However, this difference did not lead to important differences in cervical cancer incidence or related mortality (risk difference of 0.08%).
In contrast, the incidence of major bleeding requiring hospitalization or blood transfusions may be greater (1/1000 treated with CKC versus 1/10 000 with cryotherapy or LEEP for most screen-and-treat strategies) and the risk of premature delivery after treatment with CKC may be greater than with cryotherapy or LEEP (Risk Ratio 3.41 versus 2.00). The increased risks of these complications apply to all treated women, regardless of whether they were correctly or incorrectly classified as having CIN2+ (i.e. including women with falsepositive results who are treated unnecessarily). These differences were similar to the benefits and harms found when modelled for women of HIV-positive status. Summary of the evidence: Low-quality to very-low-quality evidence showed that there may be fewer CIN2+ recurrences with the screen-and-treat strategy using an HPV test (3/1000 fewer), as well as fewer cervical cancers (1/10 000 fewer) and fewer deaths (6/100 000 fewer) than with a strategy using VIA for screening. These differences result from fewer missed cases of CIN2+ with the HPV test strategy compared with the VIA strategy (i.e. fewer false negatives). The difference in overtreatment may be relatively small (157 000 cases with an HPV test versus 127 000 cases with VIA out of 1 000 000 women). The number of cancers found at first-time screening may be slightly greater with VIA (7/10 000 more). There may be little to no difference in complications, such as major bleeding or infections (e.g. 1/100 000 fewer with the VIA strategy). These results are similar to the benefits and harms found when modelled for women of HIV-positive status.
Recommendation 3. The expert panel suggests a strategy of screen with an HPV test and treat with cryotherapy (or LEEP when not eligible for cryotherapy) over a strategy of screen with cytology followed by colposcopy (with or without biopsy) and treat with cryotherapy (or LEEP when not eligible) (conditional recommendation, evidence)
Remarks: The reductions in cancer and related mortality were slightly greater with an HPV test only compared to cytology followed by colposcopy. Although there may be overtreatment of populations with high HPV prevalence and consequently more harms, as well as fewer cancers seen at first-time screening with an HPV test, there are greater resources required in cytology programmes due to quality control, training, and waiting time. The addition of colposcopy also requires a second visit. However, in countries where an appropriate/high-quality screening strategy with cytology (referring women with ASCUS or greater results) followed by colposcopy already exists, either an HPV test or cytology followed by colposcopy could be used. See Supplemental material, Sections A and B.
Summary of the evidence: As there were few to no studies evaluating the diagnostic accuracy of cytology followed by colposcopy compared to an HPV test, the effects of the sequence of tests were calculated by combining diagnostic data from cytology and colposcopy, resulting in lower-quality evidence. For the strategy of cytology followed by colposcopy (with or without biopsy), we analysed data for two scenarios: (1) Women who screened positive on cytology underwent colposcopy only (i.e. treatment was based on colposcopic impression); and (2) Women who screened positive on cytology underwent colposcopy, and then women with positive colposcopy results were biopsied (i.e. treatment was based on the biopsy result). Evidence showed that there may be fewer CIN2+ recurrences with the HPV test strategy (3/1000 fewer), as well as fewer cervical cancers (1/10 000 fewer) and fewer deaths (6/100 000 fewer) than with cytology followed by colposcopy. These differences result from fewer missed cases of CIN2+ with the HPV test strategy (i.e. fewer false negatives). Overtreatment, however, may be slightly greater with an HPV test when compared with cytology followed by colposcopy without biopsy (7/100 more women) or with biopsy when indicated (10/100 more women). This may result in slightly more complications with the HPV test strategy. The number of cancers detected at first-time screening may be slightly greater with the cytology followed by colposcopy strategy (1/1000 more).
Recommendation 4. The expert panel recommends a strategy of screen with VIA and treat with cryotherapy (or LEEP when not eligible for cryotherapy) over a strategy of screen with cytology followed by colposcopy (with or without biopsy) and treat with cryotherapy (or LEEP when not eligible) (strong recommendation, evidence)
Remarks: The benefits and harms of the two screen-and-treat strategies are similar, but there are fewer harms with cytology followed by colposcopy with biopsy when indicated. Despite overtreatment with VIA and fewer cancers detected at first-time screening, more resources are required for cytology programmes with colposcopy (with or without biopsy) due to quality control, training, and waiting time, as well as a second visit. The recommendation for VIA over cytology followed by colposcopy can be applied in countries that are currently considering either strategy, or countries that currently have both strategies available. This recommendation applies to women regardless of HIV status. See Supplemental material, Sections A and B.
Summary of the evidence: As there were few to no studies evaluating the diagnostic accuracy of cytology followed by colposcopy compared to VIA, the effects of the sequence of tests were calculated by combining diagnostic data from cytology and colposcopy, resulting in lower-quality evidence. For the strategy of cytology followed by colposcopy (with or without biopsy), we analysed data for two scenarios: (1) Women who screened positive on cytology underwent colposcopy only (i.e. treatment was based on colposcopic impression); and ( 2) Women who screened positive on cytology underwent colposcopy, and then women with positive colposcopy results were biopsied (i.e. treatment was based on the biopsy result). Evidence showed that there may be little or no difference in CIN2+ recurrence, cervical cancers, and related mortality between the strategies. Overtreatment, however, may be slightly greater with VIA compared to cytology followed by colposcopy without biopsy (11/100 more women) or with biopsy when indicated (18/100 more women). This may result in slightly greater harm with the VIA strategy. The number of cancers detected at first-time screening may be slightly greater with the cytology followed by colposcopy strategy (2/1000 more) compared with the VIA strategy.
Recommendation 5. The expert panel suggests a strategy of screen with an HPV test and treat with cryotherapy (or LEEP when not eligible for cryotherapy) over a strategy of screen with an HPV test followed by colposcopy (with or without biopsy) and treat with cryotherapy (or LEEP when not eligible) (conditional recommendation, evidence)
Remarks: The reductions in cancer and related mortality with either strategy outweigh the harms and costs of no screening, and were similar between the two strategies. Although overtreatment and, consequently, harms are reduced with the addition of colposcopy (with or without biopsy), there are more resource implications with colposcopy due to increased training of providers, quality control, waiting time, and the potential for more women to be lost to follow-up. The addition of colposcopy to an HPV test would also require a second visit. In countries without an existing screening strategy, an HPV test followed by colposcopy is not recommended. This recommendation applies to women regardless of HIV status. See Supplemental material, Sections A and B.
Summary of the evidence: As there were few to no studies evaluating the diagnostic accuracy of an HPV test followed by colposcopy, the effects of the sequence of tests were calculated by combining diagnostic data from the individual tests, resulting in lower-quality evidence. For the strategy of an HPV test followed by colposcopy (with or without biopsy), we analysed data for two scenarios:
(1) Women who screened positive on HPV testing underwent colposcopy only (i.e. treatment was based on colposcopic impression); and (2) Women who screened positive on HPV testing underwent colposcopy, and then women with positive colposcopy results were biopsied (i.e. treatment was based on the biopsy result). Evidence showed that there may be little to no difference in CIN2+ recurrence, cervical cancers, and related mortality between the strategies. Overtreatment, however, may be slightly greater with an HPV test only compared with an HPV test followed by colposcopy without biopsy (5/100 more women) or with biopsy when indicated (12/100 more women). This may result in slightly greater harm with an HPV-test-only strategy. The number of cancers detected at first-time screening may be slightly greater with an HPV test followed by colposcopy strategy (1/1000 more) than with an HPV test only.
Recommendation 6. The expert panel suggests either a strategy of screen with an HPV test followed by VIA and treat with cryotherapy (or LEEP when not eligible for cryotherapy) or a strategy of screen with an HPV test and treat with cryotherapy (or LEEP when not eligible) (conditional recommendation, evidence)
Remarks: The reductions in cancer and related mortality were greater with an HPV test used as a single screening test than with an HPV test followed by VIA, and this reduction was even greater in women of HIV-positive status.
However, there may be overtreatment, and thus potentially greater harms with screen-and-treat when using an HPV test as a single test. There is also some uncertainty about the effects of an HPV test followed by VIA and how VIA performs after a positive HPV test because there was no direct evidence about this strategy. There is also the potential for additional resources that are required to refer women for VIA testing after a positive HPV test, the need for a second visit to perform VIA, and increased training to perform both tests. For these reasons, the recommendation is for either an HPV test followed by VIA or an HPV test only, and it is conditional. It is to be noted that benefits are more pronounced compared to harm in women of HIV-positive status when using an HPV test only. See Supplemental material, Sections A and B.
Summary of the evidence: As there were no studies evaluating the diagnostic accuracy of an HPV test followed by VIA, the effects were calculated by combining diagnostic data from an HPV test only with data for VIA only, resulting in lower-quality evidence. This evidence showed that there may be slightly greater CIN2+ recurrences with an HPV test followed by VIA (4/1000 more), as well as more cervical cancers (1/10 000 more) and more deaths (7/100 000 more) than with an HPV test only. The difference was due to a slightly higher rate of missed cases of CIN 2+ with an HPV test followed by VIA than with an HPV test only (6/1000 more). The number of cancers detected at first-time screening may be slightly greater with an HPV test followed by VIA (7/10 000 more), and there may be fewer women treated unnecessarily (1/10 fewer) due to the lower false-positive rate with an HPV test followed by VIA. If fewer women are treated unnecessarily, this may result in lower resource use and fewer complications with an HPV test followed by VIA.
However, these results were more pronounced when modelled for women of HIV-positive status. There may be greater differences in benefits and harms. The evidence for women of HIV-positive status showed that there is likely to be an even greater rate of CIN2+ recurrences with an HPV test followed by VIA (22/1000 more), as well as more cervical cancers (17/10 000 more) and more deaths (12/100 000 more) than with HPV only. However, there may be fewer women treated unnecessarily (1/10 fewer) when using the screening strategy of an HPV test followed by VIA, resulting in fewer resources for unnecessary treatment and fewer complications.
Recommendation 7. The expert panel suggests a strategy of screen with an HPV test followed by VIA and treat with cryotherapy (or LEEP when not eligible for cryotherapy) over a strategy of screen with VIA and treat with cryotherapy (or LEEP when not eligible) (conditional recommendation, evidence)
Remarks: The reductions in cancer and related mortality with an HPV test followed by VIA or with VIA alone outweighed the harms. However, the harms may be greater when using VIA only, which is likely due to overtreatment. Although a slightly larger number of cancers may be detected on initial screen with VIA only. This recommendation is conditional due to the uncertain costs of providing the sequence of two tests (HPV test followed by VIA) over the single VIA test. In countries where an HPV test is not available, we suggest screening with VIA only. This recommendation applies to women regardless of HIV status. See Supplemental material, Sections A and B.
Summary of the evidence: As there were no studies evaluating the diagnostic accuracy of an HPV test followed by VIA, the effects were calculated by combining diagnostic data from an HPV test only with data for VIA only, resulting in lower-quality evidence. This evidence showed little to no difference in CIN2+ recurrence, cervical cancer, and related mortality between a screen-and-treat strategy using an HPV test followed by VIA and a strategy using VIA only. This was likely due to the relatively small differences in the number of missed cases of CIN2+ between the two strategies. Although the number of cancers detected at first-time screening may be slightly greater with VIA only (7/10 000 more), there may be more women treated unnecessarily (1/10 more) due to higher false-positive rates with VIA only (incurring higher resource use for overtreatment).
Overtreatment may also result in greater complications with VIA only. These results are similar to the benefits and harms found when modelled for women of HIV-positive status.
Recommendation 8. The expert panel suggests a strategy of screen with an HPV test followed by VIA and treat with cryotherapy (or LEEP when not eligible for cryotherapy) over a strategy of screen with cytology followed by colposcopy (with or without biopsy) and treat with cryotherapy (or LEEP when not eligible) (conditional recommendation, evidence)
Remarks: The benefits of the two screenand-treat strategies are similar. However, there may be higher resources required in cytology programmes due to quality control, training, and waiting time. The addition of colposcopy requires a second visit. This recommendation applies to women regardless of HIV status. See Supplemental material, Sections A and B.
Summary of the evidence: As there were few to no studies evaluating the diagnostic accuracy of cytology followed by colposcopy compared to an HPV test followed by VIA, the effects of the sequence of tests were calculated by combining diagnostic data, resulting in lower-quality evidence. For the strategy of cytology followed by colposcopy (with or without biopsy), we analysed data for two scenarios: (1) Women who screened positive on cytology underwent colposcopy only (i.e. treatment was based on colposcopic impression); and ( 2) Women who screened positive on cytology underwent colposcopy, and then women with positive colposcopy results were biopsied (i.e. treatment was based on the biopsy result). Evidence showed that there may be little to no difference in CIN2+ recurrence, cervical cancers, and related mortality between the strategies. There may also be little to no difference in overtreatment between the strategies. The number of cancers detected at first-time screening may be slightly greater with the cytology followed by colposcopy strategy (2/1000 more).
Recommendation 9. The expert panel suggests a strategy of screen with an HPV test followed by VIA and treat with cryotherapy (or LEEP when not eligible for cryotherapy) over a strategy of screen with an HPV test followed by colposcopy (with or without biopsy) and treat with cryotherapy (or LEEP when not eligible) (conditional recommendation, evidence)
Remarks: The reductions in cancer and related mortality of screen-and-treat with an HPV test followed by colposcopy (with or without biopsy) may be slightly greater compared to an HPV test followed by VIA. The panel agreed that the benefits of either strategy outweigh the harms and costs; however, the difference in costs between the strategies is uncertain. There may be more resource implications with colposcopy due to increased training of providers, quality control, waiting time, and the potential for more women to be lost to follow-up. It is also unclear whether women would perceive a difference between VIA and colposcopy; however, a biopsy during colposcopy may be less acceptable than VIA. This recommendation applies to women regardless of HIV status. See Supplemental material, Sections A and B.
Summary of the evidence: As there were few to no studies evaluating the diagnostic accuracy of both screening strategies, the effects of the strategies were calculated by combining diagnostic data from the individual tests, resulting in lower-quality evidence. For the strategy of an HPV test followed by colposcopy (with or without biopsy), we analysed data for two scenarios: (1) Women who screened positive on HPV testing underwent colposcopy only (i.e. treatment was based on colposcopic impression); and ( 2) Women who screened positive on HPV testing underwent colposcopy, and then women with positive colposcopy results were biopsied (i.e. treatment was based on the biopsy result). Evidence showed that there may be fewer CIN2+ recurrences with the HPV test followed by colposcopy without biopsy (3/1000 fewer) and with biopsy (4/1000 fewer), as well as fewer cervical cancers (1/10 000 fewer with or without biopsy) and fewer deaths (6/100 000 fewer, with or without biopsy) than with an HPV test followed by VIA. These differences result from fewer missed cases of CIN2+ with the HPV test followed by colposcopy strategy when compared to an HPV test followed by VIA strategy (i.e. fewer false negatives). Overtreatment, however, may be greater with an HPV test followed by colposcopy without biopsy than with an HPV test followed by VIA (7/100 more women). There may be little to no difference between the strategies in the number of cancers detected at first-time screening.

# Research gaps and further considerations
The best evidence to assess the effects of a screen-and-treat strategy is from randomized controlled trials in which women are randomly allocated to receive one or another screen-andtreat strategy and then all screened women are followed and patient-important health outcomes -such as CIN recurrence, cervical cancer and complications of treatment -are measured.
We identified few randomized controlled trials that evaluated screen-and-treat strategies and patient-important outcomes. In particular, there were very few studies that assessed the strategies that the GDG ranked as clinically relevant (e.g. HPV test followed by VIA). In fact, few studies were found, randomized controlled trials or otherwise, that assessed a sequence of tests, such as an HPV test followed by VIA. There were also few studies that assessed the accuracy of diagnostic tests or reported on patient outcomes in women who are HIV-positive or at high risk of being HIV-positive.
There is some concern about the use of cytology programmes in areas where health systems are not robust, resources are limited, or quality assurance is not maintained. Cytology programmes have been and remain difficult to establish in low-and middle-income settings. Quality assurance to ensure accurate and reproducible results in cytology programmes requires greater human and financial resources than other screening strategies, and, as cytology results are not available quickly, there is a greater chance of women being lost to follow-up, which reduces the benefits of cytology-based programmes. Cytology followed by colposcopy (with or without biopsy) was not shown in this review of the literature to lead to better outcomes as compared with other screening strategies for cervical cancer prevention. Using another screening test, such as an HPV test, prior to cytology was also not investigated in this evidence review, nor modelled for these recommendations.
Although the potential value of a screenand-treat algorithm focusing on HPV testing followed by cytology is of interest to some workers in this area, the expert panel did not rank an exploration of this algorithm highly enough for it to be among the PICO questions (population, intervention, comparison, outcome) addressed as part of the process of preparing these guidelines. This was largely due to the fact that, for the audience likely to benefit most from these guidelines, the expert panel felt that questions concerning cytology were not as germane to programme guidance as questions relating to HPV and VIA testing coupled with cryotherapy. Another reason was that there was consensus among the expert panel that adding a cytology component could place significant constraints on the intent to have expeditious links between testing and treatment. Therefore an evidence base on the question of an HPV test followed by cytology was not developed and no recommendations on this algorithm are offered at present. Once studies become available that provide rigorous comparisons between, for example, an HPV test/cytology and an HPV test/VIA (or vice versa), then these could be the focus of a subsequent GRADE analysis, which could then generate evidence-based recommendations.
These recommendations make a distinction between the use of VIA as a method to determine eligibility for treatment with cryotherapy or LEEP and the use of VIA to determine whether to treat or not (see explanation in Chapter 3, under the subheading Considerations for treatments). When VIA is used following a positive test for HPV, women are treated only if they are also VIA-positive. However, there are few studies that evaluated the overall diagnostic test accuracy of this sequence of screening tests or measured patient-important outcomes after providing this sequence of tests. There are also no studies that compare outcomes when using VIA to determine eligibility for cryotherapy.
The GDG also made a distinction between the use of 'colposcopic impression' versus 'colposcopic impression and biopsy when indicated'. In the former, a woman who was positive on a first screening test would be treated only if the visualization by colposcopy was positive for a lesion. However, in the latter, a positive colposcopy would be followed by a biopsy and only women with a positive biopsy would be treated (essentially not a screen-andtreat strategy). Again, this sequence of tests was not evaluated or compared in randomized controlled trials, nor was any evidence available from observational diagnostic test accuracy studies. Therefore modelling was used to determine if eliminating the biopsy step from the strategy would still result in similar net benefits, while reducing the use of resources.
Because few randomized controlled trials evaluated screen-and-treat strategies, the MG used a model and therefore needed data about the baseline risks and the natural history of the disease. Data for the natural progression and regression of CIN2+ across women of many age groups and for women of HIV-positive status were all unclear. While there are ethical issues to consider, it should be possible to conduct studies that follow women over longer periods of time. Due to the lack of such data, it was challenging to determine the age at which screening should be started and ended, and how often rescreening should occur. There were many unanswered questions about women aged 20-35 years, and women over the age of 50, and about the optimal intervals for follow-up after treatment. Yet the recommendations included in this guideline are based on modelling scenarios that illustrate what age groups, what screening frequency, and what follow-up period has the greatest impact on cervical cancer mortality.
Lastly, the GDG identified and prioritized outcomes for screen-and-treat strategies that were important to the decision-making process. For many of these outcomes, there was low-quality to very-low-quality evidence, and only indirect evidence. The GDG identified, in particular, fertility and reproductive outcomes as a concern for many women. Also of concern was HIV transmission, but there is little research measuring this outcome. Other benefits of screening were also identified by the GDG, such as the detection of sexually transmitted infections or the detection of cervical cancer, which may be dependent on the screening test used (e.g. HPV test versus VIA). However, these benefits are not currently or consistently measured in studies.

# Use of the guideline

# Guideline dissemination
These guidelines will be available online at the WHO Library database and there will be a link on WHO's Sexual and Reproductive Health web page and in the WHO Reproductive Health Library (RHL), an electronic review journal. 7 The publication will also be announced in the potential publishers of translated versions, as well as all those who contributed to the documents.
Conference invitations to discuss and present the guidelines will be accepted.
Regional conferences are already planned in the Americas and Africa to present the new recommendations to a number of stakeholders involved in national programme planning in 2013. The other regions will be covered in 2014.
If requested by regional offices, countries will be supported to adapt the guideline to their country-specific needs and to integrate the material with existing national guidelines. Adaptation will be done by organizing regional, sub-regional and country-level workshops for discussion of each recommendation, in order to adapt them to the national epidemiologic, cultural, and socioeconomic context.
Initially, the guidelines will be available in English only and translations will be developed subject to the availability of funding. Translation into non-UN languages and publication in these languages by third parties will be encouraged.

# Guideline evaluation
The number of downloads from the WHO web sites (headquarters and regional) will be used as an indicator of interest in these guidelines.
We are working with the WHO regional offices to monitor requests from countries for technical assistance to use these guidelines. For this purpose, national stakeholder meetings will be organized in-country, and feedback on the clarity, feasibility, and usefulness of the recommendations will be recorded.
We will also monitor, with the regional offices, how many countries change their recommendations based on the publication of these new recommendations for screen-andtreat strategies.

# Guideline update
The GDG will continue to work with WHO in an ad hoc manner, so that the research gaps identified during the process can be addressed. In addition, evidence published on new screening and treatment methods will be monitored so that updates to these recommendations can be considered promptly. We anticipate that around five years after the publication of these recommendations sufficient new evidence will be available to update the present recommendations and potentially add new ones.

# Annex 1. Declarations of interest
Out of the 54 experts who participated in this work, 15 declared an interest related to cervical cancer. Although not all of these interests are specifically related to cervical cancer screening and treatment, they are nonetheless all disclosed and summarized below.

# Annex 2. Decision-making flowchart for screen-andtreat strategies
This decision-making flowchart or algorithm provides a decision tree to use as a quick reference when choosing a screen-and-treat strategy at the programme level. Programme managers and decision-makers can start at the top and answer the questions accordingly to determine which screen-and-treat option is best in the context where it will be implemented. It highlights choices related to resources, which can include costs, staff and training. However, programme managers will also need to consider other factors, such as the number of women who are lost to follow-up with a strategy that involves more than one screening test. Refer to the screen-and-treat recommendations provided in Chapter 3 of the guideline for more specific guidance about which strategies are recommended, and for information on the specific factors to consider when deciding on a strategy. For details about the flow of each screen-and-treat strategy (e.g. HPV followed by VIA), consult the flowcharts in Annex 3 (for women of negative or unknown HIV status) and Annex 4 (for women of HIV-positive status or unknown HIV status in areas with high endemic HIV infection).
Note: each light-pink bubble refers to one strategy in Annex 3 (for women of negative or unknown HIV status) or Annex 4 (for women of HIV-positive status or unknown HIV status in areas with high endemic HIV infection) The following flowcharts describe the steps for each of the screen-and-treat strategies that are available. The flowcharts do not indicate which strategy is preferred. Refer to the screen-and-treat recommendations provided in Chapter 3 of the guideline for guidance about which strategies are recommended, and to the decision-making flowchart in Annex 2. For detailed information about the specific factors the guideline panel considered when making the recommendations, refer to the evidence-to-recommendation tables for each recommendation (Supplemental material, Sections A and B).
Screen with an HPV test and treat with cryotherapy, or LEEP when not eligible for cryotherapy
When an HPV test is positive, treatment is provided. With this strategy, visual inspection with acetic acid (VIA) is used to determine eligibility for cryotherapy.

# HPV test
Note: Refer to the screen-and-treat recommendations provided in Chapter 3 of the guideline for guidance about which strategies are recommended, and for information on the specific factors to consider when deciding on a strategy.
Screen with an HPV test followed by VIA and treat with cryotherapy, or LEEP when not eligible for cryotherapy
When an HPV test is positive, then VIA is provided as a second screening test to determine whether or not treatment is offered. Treatment is only provided if BOTH the HPV test and VIA are positive.
Note: Refer to the screen-and-treat recommendations provided in Chapter 3 of the guideline for guidance about which strategies are recommended, and for information on the specific factors to consider when deciding on a strategy. Screen with VIA and treat with cryotherapy, or LEEP when not eligible for cryotherapy Note: Refer to the screen-and-treat recommendations provided in Chapter 3 of the guideline for guidance about which strategies are recommended, and for information on the specific factors to consider when deciding on a strategy. Screen with cytology followed by colposcopy (with or without biopsy) 1 and treat with cryotherapy, or LEEP when not eligible for cryotherapy Note: Refer to the screen-and-treat recommendations provided in Chapter 3 of the guideline for guidance about which strategies are recommended, and for information on the specific factors to consider when deciding on a strategy.
Women with positive colposcopic impression can receive biopsy for histological confirmation or be treated immediately. The following flowcharts describe the steps for each of the screen-and-treat strategies that are avail able. The flowcharts do not indicate which strategy is preferred. Refer to the screen-and-treat recommendations provided in Chapter 3 of the guideline for guidance about which strategies are recommended, and to the decision-making flowchart in Annex 2. For detailed information about the specific factors the guideline panel considered when making the recommendations, refer to the evidence-to-recommendation tables for each recommendation (Supplemental material, Sections A and B).
Screen with an HPV test and treat with cryotherapy, or LEEP when not eligible for cryotherapy
When an HPV test is positive, treatment is provided. With this strategy, visual inspection with acetic acid (VIA) is used to determine eligibility for cryotherapy.
Note: Refer to the screen-and-treat recommendations provided in Chapter 3 of the guideline for guidance about which strategies are recommended, and for information on the factors to consider when deciding on a strategy. Screen with an HPV test followed by VIA and treat with cryotherapy, or LEEP when not eligible for cryotherapy
When an HPV test is positive, then VIA is provided as a second screening test to determine whether or not treatment is offered. Treatment is only provided if BOTH the HPV test and VIA are positive.
Note: Refer to the screen-and-treat recommendations provided in Chapter 3 of the guideline for guidance about which strategies are recommended, and for information on the factors to consider when deciding on a strategy. Screen with cytology followed by colposcopy (with or without biopsy) 1 and treat with cryotherapy or LEEP (when not eligible for cryotherapy)
Note: Refer to the screen-and-treat recommendations provided in Chapter 3 of the guideline for guidance about which strategies are recommended, and for information on the factors to consider when deciding on a strategy.
Women with positive colposcopic impression can receive biopsy for histological confirmation or be treated immediately. Searches in EMBASE, the Cochrane Library and LILACS
The OVID MEDLINE search was adapted to the subject headings appropriate for each database.
Searches in OVID MEDLINE and EMBASE (up to September 2012) 1 exp uterine cervix disease/di 2 cervical intraepithelial neoplasia/ 3 uterine cervical dysplasia/ 4 uterine cervical neoplasms/ 5 ((precancer or pre-cancer or neoplas or dysplasia or lesion or premalignan or malignan or cancer or carcinoma) adj3 cervi).tw. 6(cin or cin2 or cin3 or cin1).tw. 7
(colposcopy and (sensitivity or specificity or receiver operator characteristic or receiver operating characteristic or receiver operator characteristics or receiver operating characteristics or roc or roc curve or predictive value or likelihood ratio or accurac or diagnosis or diagnostic)). tw. 9
7 and 8