Annex 1: Declarations of interest Annex 2: Search strategies for evidence reviews Annex 3: PRISMA flow diagram for inclusion and exclusion of studies for evidence reviews Annex 4: List of references for studies included in evidence reviews Supplemental material: GRADE evidence-to-recommendation tables and evidence profiles for each recommendation# Roles of the technical and working groups
to make treatment recommendations. In 2011, WHO recommendations for the use of cryotherapy to treat CIN were developed and published (8,9). Those recommendations covered the use of different techniques of cryotherapy, such as single-and double-freeze methods, and its use in specific populations, including pregnant women, and women of HIV-positive status. This guideline covers treatments for histologically confirmed CIN2+, including cryotherapy, LEEP, and CKC. Another guideline has been developed concurrently on strategies to screen and treat precancerous cervical lesions when there is no histological confirmation of CIN2+ (10).

# Target audience
This document is intended primarily for policymakers, managers, programme officers, and other professionals in the health sector who have responsibility of choosing strategies for cervical cancer prevention, at country, regional, and district levels. Individuals working in reproductive health care programmes, particularly programmes for prevention of sexually transmitted infections (STIs) including HIV/AIDS and for family planning, at the district and primary health care levels, should also consult this document 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 builds upon the WHO guidelines: use of cryotherapy for cervical intraepithelial neoplasia published in 2011 (9), and provides recommendations for the use of cryotherapy versus LEEP versus CKC for the treatment of histologically confirmed CIN2+, and additional recommendations for the treatment of histologically confirmed AIS. This document also describes the WHO methodology that was used for the development of these guidelines based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach, and provides GRADE evidence profiles 3 and evidence-to-recommendation tables 4 for each 3
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.
recommendation (see: Supplemental material: GRADE evidence-to-recommendation tables and evidence profiles for each recommendation).
The methods to develop these guidelines followed the WHO handbook for guideline development (11,12).

# Guideline groups
WHO formed a Guideline Development Group (GDG), chaired by Joanna Cain.

# Formulating questions and determining outcomes
In February 2011, the GDG met to discuss the questions and outcomes to address in the chapter on the treatment of CIN and AIS to appear in the updated C4-GEP, in order to incorporate new evidence. The GDG identified nine potential questions to guide the evidence review on the treatment of CIN and AIS. The treatment questions followed the format of PICO (population, intervention, comparison, and outcomes). The population (i.e. women who have histologically confirmed CIN2+ or AIS), intervention (i.e. cryotherapy, LEEP, or CKC), and comparison group (i.e. other or no treatment) are indicated in the questions below (Box 1), while the priority outcomes are described separately (see Box 2).
During this same meeting, the GDG developed a list of outcomes that should be considered when making decisions and recommendations for the treatment strategies. These outcomes - Should cryotherapy or no treatment be recommended for women who have histologically confirmed CIN2+ disease?
- Should LEEP or no treatment be recommended for women who have histologically confirmed CIN2+ disease?
- Should CKC or no treatment be recommended for women who have histologically confirmed CIN2+ disease?
- Should cryotherapy or CKC be recommended for women who have histologically confirmed CIN2+ disease?
- Should CKC or LEEP be recommended for women who have histologically confirmed CIN2+ disease?
- Should CKC or no treatment be recommended for women who have histologically confirmed AIS disease?
- Should cryotherapy or no treatment be recommended for women who have histologically confirmed AIS disease?
- Should LEEP or no treatment be recommended for women who have histologically confirmed AIS disease?
- Should cryotherapy, LEEP or CKC be recommended for women who have histologically confirmed AIS disease?
were informed by the work previously conducted for the preparation of the 2011 WHO guidelines: use of cryotherapy for cervical intraepithelial neoplasia. Following the meeting, the MG surveyed all GDG and ERG members online using Survey Monkey 5 and asked them 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 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 for the evidence review and considered when making the recommendations (see Box 2).

# Synthesis of the evidence and preparation of evidence profiles
The Two members of the MG independently abstracted data about patient characteristics, diagnosis, the surgical interventions, setting, follow-up and outcomes, using a pre-tested data abstraction form. Data to assess the quality of the studies was also collected using the Cochrane risk of bias tool for randomized controlled trials and the Newcastle-Ottawa Scale for non-randomized studies (13,14). The MG analysed the data using RevMan 5.1 (review manager software). Relative risks (e.g. Risk Ratios and Odds Ratios) were calculated when possible and the effects were normalized over a period of one year. When data were available, subgroup analyses were performed to determine the effects of treatments by HIV status and age. The results of the systematic reviews and of the meta analysis are being prepared for publication and will be available through the WHO website. 6 Two members of the MG evaluated the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluations (GRADE) approach (15,16) and presented the evidence with its quality in GRADE evidence profiles (see Supplemental material). The evidence was presented in absolute effects by applying the Risk Ratios to an agreed-upon baseline risk (typically derived from non-randomized studies). Absolute effects over one year and 95% confidence intervals (CI) around that effect were presented as "X/1000 fewer outcomes (95% CI from X to X)". 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 decisionmaking for recommendations (evidence-torecommendations tables) were produced for each recommendation. These tables included 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. A summary of the judgements of the GDG for each recommendation is also provided (see Supplemental material).
Available at: www.who.int/reproductivehealth/ publications/cancers/treatment_CIN_2-3/en/index.html

# 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. Members of the MG presented evidence profiles and evidence-torecommendation tables, which included the evidence about the benefits and harms, values and preferences, resources and feasibility.
After the April 2012 meeting, more worked was done to finalize the remarks and to confirm the data on harms. An update of the search was performed and the recommendations did not change after considering the additional evidence.
WHO has recently developed the WHO cervical cancer prevention and control costing tool (17). 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, including detailed costing of surgery, for a range of countries and the calculation tables 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 the treatments.
Recommendations were made by the GDG and ERG by balancing the overall desirable and undesirable consequences of each treatment, 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 discussed the consequences and reached consensus for the final recommendations. In rare cases of disagreement, members voted and discussed until there was 100% agreement. The results of those discussions are documented in the evidence-to-recommendation tables for each recommendation, available online in the Supplemental material. The GDG and ERG also identified key research gaps.
The recommendations were assessed as 'strong' or 'conditional' in accordance with the WHO handbook for guidelines 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
This guideline 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 GRADE evidence profiles, and the recommendations.
The final draft guideline with the recommendations was circulated among the members of the GDG for review before WHO clearance. No disagreements were noted. 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.
These guidelines provide recommendations for the treatment of histologically confirmed CIN2+ or adenocarcinoma in situ (AIS) with cryotherapy, loop electrosurgical excision procedure (LEEP)/large loop excision of the transformation zone (LLETZ), or cold knife conization (CKC). The appropriate use of these treatments should first be determined by eligibility criteria. Eligibility for cryotherapy follows the guidance provided in the update of the C4-GEP ( 7), which will be published in 2014: a woman is 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 woman is not eligible for cryotherapy.
These recommendations apply to all women regardless of HIV status. Although few studies measured the outcomes of interest according to HIV status the evidence suggests that there is no modification of the effects of treatments by HIV status.

# Recommendation 1. The expert panel recommends cryotherapy over no treatment for women who have histologically confirmed CIN2+ disease (strong recommendation,  evidence)
Remarks: This recommendation is strong, although the available evidence was very low quality. The expected benefit of cervical cancer prevention is very high and outweighs harms and any use of resources, but there is uncertainty related to preterm delivery in future pregnancies. However, the panel felt that women would prefer to be treated despite the uncertainty of these risks. This recommendation applies to women regardless of HIV status.
Summary of the evidence: Very-low-quality evidence for most outcomes was from non-randomized studies with one group of women, leading to a high risk of bias. This evidence suggests that recurrence of CIN2+ Remarks: This recommendation considers that no other treatments may be available. In such situations, CKC is recommended over no treatment as the benefits outweigh the harms, and patient preference for treatment was likely to be greater than the preference for no treatment. More data are needed to determine the risk of preterm births, the safety of CKC in settings with differing availability of resources, and whether CKC should be recommended for both CIN2 and CIN3. This recommendation applies to women regardless of HIV status.

# Summary of the evidence:
The quality of the available evidence ranged from low to very low; the available data were from non-randomized studies with one group of women, leading to a high risk of bias. There was also some inconsistency across studies. Data from 11 non-randomized studies were pooled and showed that there are probably 677/1000 fewer recurrences of CIN2+ when treated with CKC (from 690 to 670 fewer) compared to no treatment. However, there may be more harm: major bleeding (9/1000 more, 25 studies), major infections (9/1000 more, 9 studies), minor bleeding (24/1000 more, 8 studies), and damage to organs (3/1000 more, 27 studies). According to three non-randomized studies, CKC may carry a higher risk of premature delivery (Risk Ratio 3.41; 95% CI: 2.38-34.88) and a higher risk of spontaneous abortion compared to no treatment. No study reported on maternal mortality or infertility outcomes. See Supplemental material for details. Remarks: There is low-quality to very-lowquality evidence for the benefits and harms of cryotherapy and CKC. Although there may be fewer recurrences of CIN2+ with CKC than with cryotherapy, the harms may be greater.
The resources required are also greater for CKC, including the need for operating rooms, anaesthesia, and highly trained providers or specialists. The limited data on values and preferences of women for either treatment were considered similar. This recommendation applies to women regardless of HIV status.
Summary of the evidence: Evidence came from non-randomized studies with one group of women, leading to a high risk of bias most likely due to selective reporting of outcomes, and inconsistency among studies. Six non-randomized studies found that recurrence rates of CIN2+ are probably greater with cryotherapy (Risk Ratio 3.29; 95% CI: 2.67-4.02) than with CKC. However, indirect evidence from a systematic review of premature delivery showed that there may be less risk of premature delivery (<37 weeks) with cryotherapy: 45/1000 fewer preterm deliveries over 12 months. Up to 44 studies contributed data on harms and showed that there may be fewer women who have major bleeding requiring hospital admission or blood transfusion with cryotherapy (8/1000 fewer) as well as fewer major infections (7/1000 fewer), fewer women with damage to other organs requiring surgery (3/1000 fewer), and fewer women who have minor bleeding (23/1000 fewer). Due to very low quality evidence, often due to very few or no studies, it is unclear whether there is a difference in maternal mortality, HPV clearance, infertility outcomes, or spontaneous abortions. See Supplemental material for details.

#  evidence)
Remarks: The quality of evidence was low for some outcomes and very low for critical outcomes, often with inconsistent results. Therefore, the overall benefits and harms of LEEP over CKC were unclear. Typically, CKC is provided over LEEP for clinical reasons and in specific situations. However, in situations in which there is a choice, the panel agreed that most women would prefer LEEP, as CKC is considered major surgery compared to LEEP.
The resources required are also greater with CKC, including anaesthesia, operating rooms, and skilled providers. This recommendation applies to women regardless of HIV status.

# Summary of the evidence:
The available evidence was generally very low quality and came from non-randomized studies with one group of women and some randomized controlled trials, with the results often inconsistent between the studies. Recurrence rates of CIN2+ may be lower at 12 months with CKC compared to LEEP, with a Risk Ratio of 0.52 (95% CI: 0.13-1.41) based on two randomized controlled trials and Risk Ratio of 0.64 (95% CI: 0.34-1.2) based on data from seven non-randomized studies. There was inconsistent evidence for major bleeding, although there may be greater risk of major infection with CKC, as well as more preterm deliveries. There is uncertainty about the differences in spontaneous abortion, infertility, and HPV clearance. See Supplemental material for details. Remarks: This recommendation is based on very low quality evidence, which resulted in imprecise data for the differences in benefits and harms between CKC and LEEP. CKC may result in fewer recurrences and the panel felt these benefits outweighed the additional resources required for CKC. The preferences of women were also felt to be variable as women in higher income countries may not have as much aversion to CKC (e.g. anaesthesia), while women in lower income countries may prefer LEEP due to the additional risks associated with invasive surgery. This recommendation applies to women regardless of HIV status.
Summary of the evidence: Very-low-quality evidence came mostly from non-randomized studies with one group of women, but no evidence was available from randomized controlled trials. Results were imprecise due to very few events and participants in the studies.
Critical outcomes, such as recurrence of AIS, damage to other organs, major bleeding, maternal mortality, HPV status, major infections, PID, infertility, and minor bleeding were not measured. Based on seven non-randomized studies, there may be greater recurrence of AIS with LEEP compared to CKC: 31/1000 more recurrences (from 20 fewer to 137 more). There may also be 49/1000 more invasive adenocarcinomas (from 17 fewer to 282 more) with LEEP compared to CKC based on three non-randomized studies. However, not all studies reported whether invasive cancer had occurred or not. Although very-low-quality evidence indicates fewer preterm deliveries with LEEP, there may be more spontaneous abortions with LEEP compared to CKC. See Supplemental material for details.

# Research gaps and further considerations
The GDG identified and prioritized treatment outcomes that were important to the decisionmaking process. For many of these outcomes, in particular fertility and reproductive outcomes, there was low-quality to very-low-quality data, or no data. There was also little research about the effects of the treatments in women of HIV-positive status, and few studies had measured the potential for HIV transmission following treatment.
Much of the data came from non-randomized studies based on single groups of women receiving treatment without an independent comparison group. This meant that many comparisons between surgical treatments -cryotherapy versus LEEP, for example -were made by comparing the results from single-arm non-randomized studies of cryotherapy to single-arm non-randomized studies of LEEP.
When comparing these studies, it is often unclear whether the populations, settings, interventions, and outcomes are adequately similar. The results were therefore assessed as inconsistent and/or indirect, leading to low-to very-low-quality evidence. Although randomized controlled trials may not be ethically possible or feasible in some situations, there is still the potential to conduct rigorous non-randomized studies comparing two treatments, which could provide higher quality evidence.

# Use of the guidelines

# 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 international organizations, and donors, potential donors, 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 have already been held in the Americas and Africa in 2013, to present the new recommendations to a number of stakeholders involved in national programme planning. 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 to 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 treatment recommendations.

# 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. Since the search for evidence was conducted early in 2012, we will monitor the literature for additional evidence and for evidence on new treatment methods, so that updates to these recommendations can be promptly considered. We anticipate that approximately three years after the publication of these recommendations sufficient new evidence will be available to update the present recommendations and potentially add new ones. Silvia de Sanjose has received occasional travel support from Sanofi, Merck and Qiagen to attend and present results of studies coordinated by her institution at national and international conferences. The amounts ranged from approximately US$ 1000 to US$ 3000 per trip, depending on Achim Schneider serves as an advisor to the company Karl Storz in the development of laparoscopic techniques and instruments for the treatment of cervical cancer and other benign or malignant diseases, for which he receives an annual honorarium of 40 000. Schneider has also participated in advisory board meetings and lectures relating to HPV vaccination, organized by GSK and Sanofi, respectively. For these latter activities he has received a total combined income of US$ 20 000 over the last four years.
Vivien Tsu is an employee of PATH, an international non-profit organization involved in the development and delivery of high-impact, low-cost tools for global health. As such, Tsu was involved in: ( 1