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3. Methods and process for developing the guidelines

for developing the guidelines

1 Introduction

Methods and process

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3.1 Overview 46 3.2 Information sources 46 3.3 External participation 47 3.3.1 Guideline Development Groups and peer review process 47 3.3.2 Conflicts of interest 47 3.4 Process of formulating recommendations 48 3.5 Other methods 51 3.6 Dissemination 51


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Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

3. Methods and process for developing the guidelines 3.1 Overview

The 2013 consolidated guidelines compile new recommendations, existing recommendations and other guidance across the continuum of HIV care. This includes guidance on HIV diagnosis, general HIV care and the strategic use of ARV drugs for treating and preventing HIV infection, based on a public health approach. New clinical and operational recommendations were developed in accordance with procedures outlined by the WHO Guidelines Review Committee (1) and are based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system (2–11). Most recommendations cited from existing guidance were developed using the GRADE system. In a few cases where GRADE was not used, the text notes this. Chapter 10 did not use the GRADE approach, since the programmatic guidance does not contain any formal recommendations.

3.2 Information sources The following sources of information were used in developing new recommendations. Systematic reviews were commissioned on 41 topics framed using Population,

Intervention, Comparison and Outcome (PICO) format by the WHO Guideline Steering Group (3) (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). The 41 topics covered the continuum of HIV care (9 on when to start; 11 on what to start; 4 on monitoring the response to treatment; 6 on monitoring toxicity; 11 on various aspects of service delivery; and 5 on adherence interventions). The WHO Guideline Steering Group established the critical outcomes for the reviews of clinical evidence (mortality, morbidity, transmission and severe adverse reactions) and for the reviews of operational service delivery (mortality, morbidity, transmission, access, retention in care, viral suppression and adherence) in consultation with the Guidelines Development Groups. Systematic reviews were outsourced to researchers who developed search protocols and conducted reviews of the available scientific evidence. Searches of electronic databases (MEDLINE/PubMed, Embase, CENTRAL), conference databases (Aegis, AIDSearch, NLM Gateway and hand searches) and clinical trial registers (http://clinicaltrials.gov, www.controlled-trials.com and www.pactr.org) used relevant keywords and search strings. The Web Annex (www. who.int/hiv/pub/guidelines/arv2013/annexes) includes the search protocols, the full list of review questions and the GRADE tables and evidence summaries for each topic. A standardized GRADE evidence table was used to present quantitative summaries

of the evidence and assessment of its quality for each PICO question by outcome. The GRADE system was used to rate the quality of evidence (4–10) and the strength of the recommendations (11) (Box 3.1; Web Annex www.who.int/hiv/pub/guidelines/ arv2013/annexes). C ommunity consultations on values and preferences in priority areas for the

guidelines were conducted through an online e-survey and moderated e-forum discussions with civil society networks and coordinated by the International HIV/ AIDS Alliance and the Global Network of People Living with HIV (GNP+). Focus group discussions were also held in Uganda and Malawi on the experiences of pregnant women with lifelong ART, and on PMTCT and paediatric ART in South Africa (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes).


3. Methods and process for developing the guidelines

continuum of care in generalized and concentrated epidemic settings.

Consultations with health workers working with adults and with children on the values

and preferences related to priority areas in the guidelines were conducted through an e-survey (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). The sixth annual survey in 2012 of the WHO AIDS Medicines and Diagnostics

Service on the use of ARV drugs and diagnostics in 80 low- and low-middle-income countries (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). Mathematical modelling on the impact and cost–effectiveness of earlier ART in

various populations and settings, based on data from countries with both generalized and concentrated epidemics (India, Kenya, South Africa, Viet Nam and Zambia), together with modelling of various treatment monitoring strategies were undertaken by the HIV Modelling Consortium (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). A n impact assessment using the Spectrum model to estimate the increased number of

adults and children eligible for ART based on various eligibility criteria (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes).

Reports on country implementation experiences were provided on using option

B+ for PMTCT in Malawi; introducing TDF in first-line ART regimens in Zambia; phasing out d4T in Zimbabwe; and scaling up viral load monitoring in MÊdecins Sans Frontières programmes in southern Africa. A n electronic e-survey of country-level end-users was undertaken of WHO guidelines

on ARV drugs to identify areas for improvement in format, presentation and dissemination (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes).

3.3 External participation 3.3.1 Guideline Development Groups and peer review process The process was supported by four, separate, external Guideline Development Groups (Adult; Maternal and Child Health; Operational and Service Delivery; and Programmatic, comprising 108 individuals) and an external peer review group of over 100 individuals. The acknowledgements list the members of these Groups. The composition of the Groups was in accordance with WHO procedures for developing guidelines (1) and included HIV experts, researchers, programme managers, guideline methodologists, epidemiologists, human rights experts, development agencies, United Nations partners, civil society representatives and representatives from networks of people living with HIV. Appropriate representation by geography and sex was considered. Community group members were selected following an open call for nominations. A full draft of the guidelines was circulated for comment to members of the Guideline Development Groups and the external peer review group.

3.3.2 Conflicts of interest All members of the Guideline Development Groups and peer review group completed WHO declaration of interest forms (including participation in consulting and advisory panels, research support and financial investment). A total of 21 Guideline Development Group members and 12 peer reviewers declared membership of pharmaceutical industry or other advisory panels or receipt of consulting fees, and 23 Guideline Development Group members and 13 peer reviewers declared pharmaceutical industry financial support through grants for research.

3 Methods and process for developing the guidelines

Two global community and civil society consultations on service delivery across the

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Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

The focus of the 2013 guidelines was on the development of new or updated recommendations on the use of ARV drugs in adults, adolescents, children and pregnant women. The WHO secretariat and co-chairs of each Guideline Development Group considered that important areas for potential conflict of interest would be evidence for exclusive engagement with one pharmaceutical company, or a major role within completed, ongoing or planned trials on either the timing of ART, or evaluation of specific ART regimens. The WHO Guideline Steering Group reviewed all declarations, and found no case where there was exclusive membership of an advisory group panel, receipt of consulting fees or financial support through research grants from only one pharmaceutical company. There was also a further declaration at the Guideline Development Group meeting of the involvement of members as investigators in key trials and studies. Overall, the WHO Guideline Steering Group and co-chairs of each Guideline Development Group were satisfied that there had been a transparent declaration of interests, and that no case necessitated exclusion from the deliberations. The broad range of constituencies represented on the different Guideline Development Group panels was also noted, and that the majority of members had no declared interests. All individuals with declared interests therefore proceeded to participate fully in the Guideline Development Group meetings or to act as peer reviewers.

3.4 P rocess of formulating recommendations Four Guideline Development Group meetings were held in Geneva, Switzerland between November 2012 and January 2013 (Operational and Service Delivery Guideline Development Group, November 2012; Adult Guideline Development Group and Maternal and Child Health Guideline Development Group, December 2012; and Programmatic Guideline Development Group, January 2013). The systematic reviews, evidence tables prepared in accordance with GRADE and other relevant information described in section 3.2 were presented and discussed at these meetings and made available through a password-protected web site. The proposed recommendations were then considered, informed by a standardized decision-making table for each topic (Box 3.1) encompassing the following elements: existing and proposed recommendations; summary of the evidence; benefits and risks; community and health care worker values and preferences; costs and resource implications; cost-effectiveness; feasibility and barriers to implementation; equity, ethics and human rights implications; the suggested rating of the strength of recommendations (strong or conditional) and quality of the evidence; research gaps and needs; and the overall rationale for the recommendations. The Guideline Development Groups discussed both the proposed wording of the recommendations and the rating of its strength (strong or conditional). All decisions were reached by discussion and consensus on the recommendations, including their strength and, where appropriate, the conditions to be attached to the recommendations. Disagreements were resolved through e-mail discussions, teleconferences and redrafting recommendations and rationale. Early drafts of sections of the guidelines were circulated to Guideline Development Group members, and a full draft of the guidelines was circulated to Guideline Development Group members and peer reviewers for comment. The extensive comments from more than 100 reviewers were addressed where possible and incorporated into the revised guidelines.


3. Methods and process for developing the guidelines

Since 2008, WHO has followed the GRADE system. GRADE separates the rating of the quality of evidence from the rating of the strength of the recommendation. The quality of evidence is defined as the confidence that the reported estimates of effect are adequate to support a specific recommendation. The GRADE system classifies the quality of evidence as high, moderate, low and very low (Table 3.1) (4–10) . Randomized controlled trials are initially rated as high-quality evidence but may be downgraded for several reasons, including the risk of bias, inconsistency of results across studies, indirectness of evidence, imprecision and publication bias. Observational studies are initially rated as low-quality evidence but may be upgraded if the magnitude of the treatment effect is very large, if multiple studies show the same effect, if evidence indicates a dose–response relationship or if all plausible biases would underestimate the effect (10) . The higher the quality of evidence, the more likely a strong recommendation can be made. The strength of a recommendation reflects the extent to which the Guideline Development Group was confident that the desirable effects of following a recommendation outweigh the potential undesirable effects. The strength is influenced by the following factors: the quality of the evidence, the balance of benefits and harms, values and preferences, resource use and the feasibility of the intervention (Table 3.2). The GRADE system classifies the strength of a recommendation in two ways: “strong” and “conditional” (11) . A strong recommendation is one for which the Guideline Development Group was confident that the desirable effects of adhering to the recommendation outweigh the undesirable effects. A conditional recommendation is one for which the Guideline Development Group concluded that the desirable effects of adhering to the recommendation probably outweigh the undesirable effects but the Guideline Development Group is not confident about these trade-offs. Table 3.3 summarizes the implications of a strong or conditional recommendation for individuals, clinicians and policy-makers. The reasons for making a conditional recommendation include the absence of highquality evidence; imprecision in outcome estimates; variability in the values and preferences of individuals regarding the outcomes of interventions; small benefits; applicability in all settings versus specific settings; and benefits that may not be worth the costs (including the costs of implementing the recommendation).

3.4 Process of formulating recommendations

Box 3.1 Approach to rating the quality of evidence and strength of recommendations using the GRADE system

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Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 3.1 GRADE classification of the level of evidence Level of evidence

Rationale

High

Further research is very unlikely to change our confidence in the estimate of effect

Moderate

Further research is likely to have an important impact on our confidence in the effect

Low

Further research is very likely to have an estimate of effect and is likely to change the estimate

Very low

Any estimate of effect is very uncertain

Table 3.2 Key domains considered in determining the strength of recommendations Domain

Rationale

Benefits and risks

Desirable effects (benefits) need to be weighed against undesirable effects (risks). The more that the benefits outweigh the risks, the more likely that a strong recommendation will be made.

Values and preferences (acceptability)

If the recommendation is likely to be widely accepted or highly valued, a strong recommendation will probably be made. If there are strong reasons that the recommended course of action is unlikely to be accepted, a conditional recommendation is more likely to be made.

Costs and financial implications (resource use)

Lower costs (monetary, infrastructure, equipment or human resources) or greater cost–effectiveness will more likely result in a strong recommendation.

Feasibility

If an intervention is achievable in a setting where the greatest impact is expected, a strong recommendation is more probable.

Table 3.3 Implications for strong and conditional recommendations for individuals, clinicians and policy-makers Strong recommendation

Conditional recommendation

Individual

Most people in your situation would want the recommended course of action and only a small proportion would not

The majority of people in your situation would want the recommended course of action, but many would not

Clinician

Most individuals should receive the recommended course of action

Be prepared to help individuals to make a decision that is consistent with their own values

Policy-maker

The recommendation can be adapted as a policy in most situations

There is a need for substantial debate and involvement of stakeholders


3. Methods and process for developing the guidelines

Recommendations from existing guidelines. In addition to new recommendations based on the GRADE system, the guidelines summarize existing relevant recommendations from other WHO guidelines). Most of these recommendations were developed using the GRADE system or an alternative grading used prior to 2008 (A (strongly recommended) to C (optional)) and I–IV (level of evidence) (Web Annex www.who.int/hiv/pub/guidelines/ arv2013/annexes). For these existing recommendations, no new evidence reviews were undertaken. Recommendations that require updating are noted, and it is clearly stated where updated guidelines are planned. Where systematic reviews and GRADE assessment of quality of evidence to support new recommendations were not possible or appropriate, qualitative reviews of the literature were undertaken and presented. This applies to specific topics in Chapter 9, including retention across the continuum of care, but this did not lead to formal recommendations. Guidance for programme managers on programmatic decision-making. Chapter 10 and Chapter 11 did not involve formulating recommendations or rating of the quality of evidence and therefore did not follow the GRADE system. The process involved a narrative review of literature on both the process and criteria for evidence-based ethical decisionmaking, a review of relevant WHO policies and World Health Assembly resolutions, and results from mathematical modelling on the impact and cost–effectiveness of earlier ART in various populations and settings. Structured discussions were held among Guideline Development Group members regarding setting priorities for key clinical recommendations in various epidemic scenarios (settings with generalized and concentrated epidemics and with low, moderate and high ART coverage).

3.6 Dissemination The guidelines will be disseminated as a printed publication and electronically on the WHO web site in the six official United Nations languages. The web version will include all annexes. A short version will summarize key new and existing recommendations for easy reference. A library of all supporting documentation and evidence will also be made available on the web site. WHO headquarters will work closely with regional and country offices and implementing partners to ensure their wide dissemination through regional and subregional meetings. Assistance will be provided to Member States to adapt the guidelines to their national contexts. An evaluation of how users have implemented the guidelines has been developed to assess the uptake of the recommendations and the barriers to effective implementation. A review of the guidelines is planned for 2015. Interim technical and programmatic updates may be developed if important new evidence becomes available.

3.6 Dissemination

3.5 Other methods

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WHO Consolidated ARV guidelines 2013: chapter 3