2.1. WHO guideline development process

These WHO guidelines were developed following the recommendations for standard guidelines as described in the WHO Handbook for Guideline Development, 2012 (1). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework was followed for this process (2–11) (Tables 2.1 and 2.2). A Guidelines Development Group was formed, ensuring representation from various stakeholder groups, including members of organizations that represent persons living with chronic hepatitis, advocacy groups, researchers, clinicians and programme managers. Geographical representation and gender balance were also considerations in selecting Group members. There was an initial scoping and planning process to formulate questions across the continuum of hepatitis B care and treatment most relevant to LMICs and determine patient-important outcomes. These questions were structured in PICO format (population, intervention, comparison, outcomes) and patient-important outcomes were identified for each research question (see Web appendix 1 for PICO questions). These outcomes were refined and ranked based on their importance for the patient population (3).

TABLE 2.1

GRADE categories of the quality of evidence (4–).

TABLE 2.2

Key domains considered in determining the strength of recommendations.

Systematic reviews and meta-analyses of the primary literature were commissioned externally to address the research questions and patient-important outcomes. Criteria for inclusion and exclusion of literature (e.g. study design, sample size, duration of follow up) for the reviews were based on the evidence needed and available to answer the research questions. Search strategies and summaries of evidence are reported in Web appendix 2.

The quality of the evidence was assessed and either rated down or rated up based on the following criteria: rated down based on (i) risk of bias (using the Cochrane Risk of Bias assessment tool), including publication bias; (ii) inconsistency or heterogeneity; (iii) indirectness (addressing a different population than the one under consideration); or (iv) imprecision. Conversely, the quality of the evidence was rated up if there was no reason to rate it down, and if it met any of the following three criteria: (i) large effect size; (ii) dose–response; or (iii) plausible residual confounders (i.e. when biases from a study might be reducing the estimated apparent intervention effect). Based on the rating of the available evidence, the quality of evidence was categorized as high, moderate, low or very low (Table 2.1). Summaries of the quality of evidence to address each outcome were entered in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) profiler software (GRADEpro 3.6) (see Web appendix 2).

At the June 2014 meeting of the Guidelines Development Group, for each of the PICO questions (see Web appendix 1), the results of the systematic reviews and the evidence profiles (see Web appendix 2) were presented, and reviewed to ensure that there was understanding and agreement on the scoring criteria. Drug availability and costs of diagnostics and drugs were also considered based on the available evidence and presentations from invited external expert speakers. Recommendations were then formulated based on the overall quality of the evidence, in addition to other considerations, including the balance between benefits and harms, values and preferences, and resource implications (Table 2.2). However, no formal survey of acceptability of the proposed interventions among patients or health-care workers was undertaken for these guidelines. These were assessed through discussions among members of the Guidelines Development Group. The strength of the recommendations was rated as either strong (the panel was confident that the benefits of the intervention outweighed the risks) or conditional (the panel considered that the benefits of the intervention probably outweighed the risks). Recommendations were then formulated and the wording finalized by the entire Group. Implementation needs were subsequently evaluated, and areas and topics requiring further research identified.

The final recommendations were agreed on by consensus during a teleconference in July 2014. After all of the comments and questions from members of the Guidelines Development Group were addressed, a draft document was prepared and circulated to the members of the Guidelines Development Group. Suggested changes were incorporated into a second draft, which was circulated again to the Guidelines Development Group, as well as to the WHO Steering Group, and external peer reviewers. This document was further revised to address their comments, but modifications to the recommendations or to the scope were not considered.

2.2. Roles

The Guidelines Development Group helped formulate the PICO questions (see Web appendix 1), reviewed the evidence profiles (see Web appendix 2), formulated and agreed upon the wording of the recommendations, and reviewed all drafts of the guidelines document. The peer reviewers reviewed the draft guidelines document and provided comments and suggested editorial changes.

The guideline methodologist ensured that the GRADE framework was appropriately applied throughout the guidelines development process. This included a review of the PICO questions, ensuring the comprehensiveness and quality of the systematic reviews, and preparation of evidence profiles and decision-making tables. The methodologist also provided guidance to the Guidelines Development Group in formulating the wording and strength of the recommendations.

2.3. Management of conflicts of interest

In accordance with WHO policy, all members of the Guidelines Development Group and peer reviewers were required to complete and submit a WHO Declaration of Interest form (including participation in consulting and advisory panels, research support and financial investment) and, where appropriate, also provide a summary of research interests and activities. The WHO Secretariat then reviewed and assessed the declarations submitted by each member and, at the June 2014 meeting of the Guidelines Development Group, presented a summary to the Guidelines Development Group (see Web appendix 3). The WHO Secretariat considered significant and predominant funding from a single company whose drug was being considered for use in the treatment of HBV (e.g. tenofovir by Gilead Sciences). The Secretariat found no case where there was exclusive membership of an advisory panel, receipt of consulting fees or financial support through research grants from one pharmaceutical company. One member had received a research grant from Gilead, but this was for a community-based screening project, and unrelated to treatment. The Secretariat therefore concluded that no member should be excluded from actively taking part in formulating the recommendations during the meeting. For the peer review group, the WHO Secretariat was satisfied that there had been a transparent declaration of financial interests, and no case necessitated exclusion from the review process.

2.4. Disseminating and monitoring implementation of the guidelines

The guidelines will be launched in March 2015 at the annual meeting of the Asian Pacific Association for the Study of the Liver, which brings together approximately 5000 persons involved in hepatitis care. The guidelines will also be accessible on the WHO website with links to other related websites, and translated into the official UN languages. The Secretariat staff will work with the hepatitis points of contact in the WHO regional offices to ensure dissemination to WHO country offices and ministries of health, as well as key international, regional and national collaborating centres (e.g. civil society, foundations, donors), and national programmes. Additional tools will be developed to support country implementation.

Implementation of these guidelines will be assessed by the number of countries that incorporate them into their national treatment guidelines. This will be monitored through the biannual survey that forms the basis for the WHO Global policy report on the prevention and control of viral hepatitis. In the future, the impact of the guidelines would be measured by monitoring the number of persons treated for CHB. However, at present, there is no monitoring system that can collect this information at a national level.