3Methods

3.1. WHO guidelines development process

These WHO guidelines were produced by following the recommendations for standard guidelines, as described in the WHO Handbook for guideline development (70). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was followed (71). A WHO Steering Committee was constituted, which included individuals with relevant expertise from different WHO departments. This Committee oversaw the entire guidelines development process.

A Guidelines Development Group was constituted to ensure representation from various stakeholder groups, including members of organizations that represent patients’ groups, advocacy groups, researchers and clinicians. Group members were also selected to achieve geographical representation and gender balance.

Systematic reviews were undertaken to assess the safety and efficacy of treatment regimens in adults and children, to examine the morbidity and mortality from extrahepatic manifestations in persons with HCV infection and to review the literature on cost–effectiveness. In addition, modelling was carried out. Outcomes were ranked by the Guidelines Development Group based on their importance to the patient population. Members of the Group met in Geneva in September 2017.

3.2. Formulation of recommendations

At the Guidelines Development Group meeting, the results of the systematic reviews, meta-analyses and complementary information were presented, and the evidence profiles and decision-making tables were reviewed to ensure that there was understanding and agreement on the scoring criteria. See Web annexes 3.1, 3.2 and 8 for the reviews and Web annexes 1, 2 and 6 for the decision-making tables. The GRADE method was used to rate the certainty of the evidence and determine the strength of the recommendations. The strength of the recommendations was rated as either strong (the panel was confident that the desirable effects of the intervention outweighed the undesirable effects) or conditional (the panel considered that the desirable effects of the intervention probably outweighed the undesirable effects). The certainty of evidence supporting each recommendation was graded as high, moderate, low or very low. Recommendations were then formulated by members of the Guidelines Development Group through discussions based on the certainty of the evidence, the balance of benefits and harms, considerations of values and preferences, resource use and the feasibility of carrying out the intervention (72). The Chairs and methodologist worked to reach consensus during the meeting. After addressing all comments and questions from members of the Group, the Chair asked Group members whether they agreed with the recommendations to document consensus. All Group members agreed with all the recommendations. Implementation needs were subsequently evaluated, and areas and topics requiring further research identified.

The draft guidelines was reviewed by the Guidelines Development Group and an external review group.

3.3. Roles

The Guidelines Development Group formulated the questions on population, intervention, comparison, outcomes (PICO), reviewed the evidence profiles and decision-making tables, composed and agreed upon the wording of the recommendations, and reviewed drafts of the guidelines document.

The guidelines methodologist ensured that the GRADE framework was appropriately applied throughout the guidelines development process. This included formulation 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.

The External Review Group reviewed the draft guidelines document and provided critical feedback.

3.4. Declarations of interest and management of conflicts of interest

In accordance with WHO policy, all external contributors to the guidelines, including members of the Guidelines Development Group and the External Review Group, completed a WHO declaration of interest form (see Annexes 1 and 2, pages 80 and 83). A brief biography of each member of the Guidelines Development Group was posted on the web. The biographies of the Group members are available on http://www.who.int/hepatitis/news-events/gdg-hepatitis-c/en/. The Steering Committee reviewed and assessed the declarations submitted by each member and agreed on an approach to assess potential conflicts of interest, which they discussed with a staff member of the WHO Compliance and Risk Management and Ethics Department. At the meeting, declarations of interest were reported according to WHO standard requirements.

Individuals from organizations that had received significant funding from private (primarily pharmaceutical) companies and individual researchers or clinicians who had received honoraria above US$ 5000 from pharmaceutical companies were considered to have a conflict of interest, and their participation in the Guidelines Development Group was classified as restricted. The Group members whose participation was restricted were Charles Gore, Francesco Negro, Jurgen Rockstroh and Alexander Thompson. These individuals contributed to the development of the PICO questions and provided technical expertise in reviewing the evidence summaries but were excluded from participation in the discussion, voting and formulation of the recommendations (see Annex 1, page 80).

The declarations of interest forms from members of the External Review Group were reviewed in accordance with the WHO guidelines development policy. Any conflicts of interest identified were considered when interpreting comments from External Review Group members during the external review process. The external reviewers could not and did not make changes in the recommendations (see Annex 2, page 83).

3.5. Dissemination and updating of the guidelines

The Global Hepatitis Programme Secretariat will disseminate the guidelines through WHO regional offices to WHO country offices and Ministries of Health, as well as to key international, regional and national collaborating centres, civil society organizations and national programmes. In addition, the guidelines will be made accessible on the WHO website with links to other United Nations and related websites.

The successful implementation of the recommendations in these guidelines will depend on a well-planned and appropriate process of adaptation and integration into relevant regional and national strategies. It is a process that will be determined by available resources, existing enabling policies and practices, and levels of support from partner agencies, nongovernmental organizations (NGOs) and civil society.

Implementation of these guidelines can be measured by the number of countries that incorporate them into their national treatment programmes and actual treatment onset rates in countries, which is part of the cascade of care. With respect to policy uptake, the Global Hepatitis Programme (GHP) conducted a country profile survey in 2016/2017. With respect to the cascade of care, GHP has set up a monitoring and evaluation framework (73) and led a process to generate initial estimates for 2015 (9) and 2016 (4). In 2018, GHP will be setting up a new system of routine reporting to obtain yearly updates on these two levels of indicators. This new system will be instrumental in measuring how much these guidelines are resulting in impact at country level.

The Guidelines Development Group recognized that the field of hepatitis treatment is evolving rapidly. New data are expected for the treatment of HCV-infected adolescents and children in the coming year; therefore, it is anticipated that an update will be needed in 2020.

3.6. Evidence that informed the recommendations

Systematic reviews, meta-analyses, modelling, cost–effectiveness analyses, values and preferences and a feasibility survey were undertaken to support the process of formulating recommendations and identifying patient-important outcomes. Existing national and international guidelines were also evaluated.