Implementation of next-generation sequencing to guide care and public health action in settings with high burden of rifampicin-resistant tuberculosis: 32 stakeholder consensus statements generated using Delphi principles

Background: Comprehensive knowledge of resistance to the novel all-oral regimens for treatment of rifampicin-resistant tuberculosis (RR-TB) is important, but challenging variant detection by next-generation sequencing (NGS) in combination with variant interpretation software can diagnose resistance early. We aimed to generate a consensus on strategic issues for the implementation of NGS for routine RR-TB care.

Methods: We employed a stakeholder consensus process informed by Delphi principles. First, stakeholders participated in an online survey to provide feedback on statements using a 3-point Likert scale and free text. Responses were then summarised and follow-up discussion fora with stakeholders were held to revise statements until a consensus was reached.

Findings: Of the 116 invited stakeholders, 58 participated, representing RR-TB research (n=28), clinical care (n=11), diagnosis (n=5), RR-TB survivors and advocacy communities (n=5) from 14 countries in five of the six WHO regions. A consensus was rapidly reached for most statements with limited editorial changes needed. The debate mostly focused on statements covering performing sequencing at centralised facilities, acting on variants without statistical association with resistance in the WHO catalogue of mutations, strengthening WHO-endorsed regimens and the need for informed consent for the use of NGS for care and surveillance.

Interpretation: The consensus-building process grounded in real-world experience from a diverse group of stakeholders generated 32 consensus statements covering five strategic domains. The blueprint generated is not a definite prescriptive framework but a document that can support policymakers when developing country-specific policies for NGS-guided precision medicine and RR-TB care.

Sources of funding: This work was supported by the Global Health EDCTP3 Joint Undertaking and the Bill & Melinda Gates Foundation under the GenPath Africa project (101103171), the Research Foundation Flanders (FWO) Odysseus (G0F8316N) and TBM grants (T001018N).