World Health Organization recommendations on the treatment of drug-resistant tuberculosis, 2020 update.

Antimicrobial resistance is a major public health problem globally. Likewise, forms of tuberculosis (TB) resistant to first- and second-line TB medicines present a major challenge for patients, healthcare workers and healthcare services. In November 2019, the World Health Organization (WHO) convened an independent international expert panel to review new evidence on the treatment of multidrug- (MDR) and rifampicin-resistant (RR) TB, using the Grading of Recommendations Assessment, Development and Evaluation approach.Updated WHO guidelines emerging from this review, published in June 2020, recommend a shorter treatment regimen for patients with MDR/RR-TB not resistant to fluoroquinolones (of 9-11 months), with the inclusion of bedaquiline instead of an injectable agent, making the regimen all oral. For patients with MDR-TB and additional fluoroquinolone resistance, a regimen composed of bedaquiline, pretomanid and linezolid may be used under operational research conditions (6-9 months). Depending on the drug-resistance profile, extent of TB disease or disease severity, a longer (18-20 months) all-oral, individualised treatment regimen may be used. In addition, the review of new data in 2019 allowed the WHO to conclude that there are no major safety concerns on the use of bedaquiline for >6 months' duration, the use of delamanid and bedaquiline together and the use of bedaquiline during pregnancy, although formal recommendations were not made on these topics.The 2020 revision has highlighted the ongoing need for high-quality evidence and has reiterated the need for clinical trials and other research studies to contribute to the development of evidence-based policy.

Prevalence and genetic profiles of isoniazid resistance in tuberculosis patients: A multicountry analysis of cross-sectional data.

BACKGROUND: The surveillance of drug resistance among tuberculosis (TB) patients is central to combatting the global TB epidemic and preventing the spread of antimicrobial resistance. Isoniazid and rifampicin are two of the most powerful first-line anti-TB medicines, and resistance to either of them increases the risk of treatment failure, relapse, or acquisition of resistance to other drugs. The global prevalence of rifampicin resistance is well documented, occurring in 3.4% (95% CI 2.5%-4.4%) of new TB patients and 18% (95% CI 7.6%-31%) of previously treated TB patients in 2018, whereas the prevalence of isoniazid resistance at global and regional levels is less understood. In 2018, the World Health Organization (WHO) recommended a modified 6-month treatment regimen for people with isoniazid-resistant, rifampicin-susceptible TB (Hr-TB), which includes rifampicin, pyrazinamide, ethambutol, and levofloxacin. We estimated the global prevalence of Hr-TB among TB patients and investigated associated phenotypic and genotypic drug resistance patterns. METHODS AND FINDINGS: Aggregated drug resistance data reported to WHO from either routine continuous surveillance or nationally representative periodic surveys of TB patients for the period 2003-2017 were reviewed. Isoniazid data were available from 156 countries or territories for 211,753 patients. Among these, the global prevalence of Hr-TB was 7.4% (95% CI 6.5%-8.4%) among new TB patients and 11.4% (95% CI 9.4%-13.4%) among previously treated TB patients. Additional data on pyrazinamide and levofloxacin resistance were available from 6 countries (Azerbaijan, Bangladesh, Belarus, Pakistan, the Philippines, and South Africa). There were no cases of resistance to both pyrazinamide and levofloxacin among Hr-TB patients, except for the Philippines (1.8%, 95% CI 0.2-6.4) and Belarus (5.3%, 95% CI 0.1-26.0). Sequencing data for all genomic regions involved in isoniazid resistance were available for 4,563 patients. Among the 1,174 isolates that were resistant by either phenotypic testing or sequencing, 78.6% (95% CI 76.1%-80.9%) had resistance-conferring mutations in the katG gene and 14.6% (95% CI 12.7%-16.8%) in both katG and the inhA promoter region. For 6.8% (95% CI 5.4%-8.4%) of patients, mutations occurred in the inhA promoter alone, for whom an increased dose of isoniazid may be considered. The main limitations of this study are that most analyses were performed at the national rather than individual patient level and that the quality of laboratory testing may vary between countries. CONCLUSIONS: In this study, the prevalence of Hr-TB among TB patients was higher than the prevalence of rifampicin resistance globally. Many patients with Hr-TB would be missed by current diagnostic algorithms driven by rifampicin testing, highlighting the need for new rapid molecular technologies to ensure access to appropriate treatment and care. The low prevalence of resistance to pyrazinamide and fluoroquinolones among patients with Hr-TB provides further justification for the recommended modified treatment regimen.

Priority-Setting for Novel Drug Regimens to Treat Tuberculosis: An Epidemiologic Model.

BACKGROUND: Novel drug regimens are needed for tuberculosis (TB) treatment. New regimens aim to improve on characteristics such as duration, efficacy, and safety profile, but no single regimen is likely to be ideal in all respects. By linking these regimen characteristics to a novel regimen's ability to reduce TB incidence and mortality, we sought to prioritize regimen characteristics from a population-level perspective. METHODS AND FINDINGS: We developed a dynamic transmission model of multi-strain TB epidemics in hypothetical populations reflective of the epidemiological situations in India (primary analysis), South Africa, the Philippines, and Brazil. We modeled the introduction of various novel rifampicin-susceptible (RS) or rifampicin-resistant (RR) TB regimens that differed on six characteristics, identified in consultation with a team of global experts: (1) efficacy, (2) duration, (3) ease of adherence, (4) medical contraindications, (5) barrier to resistance, and (6) baseline prevalence of resistance to the novel regimen. We compared scale-up of these regimens to a baseline reflective of continued standard of care. For our primary analysis situated in India, our model generated baseline TB incidence and mortality of 157 (95% uncertainty range [UR]: 113-187) and 16 (95% UR: 9-23) per 100,000 per year at the time of novel regimen introduction and RR TB incidence and mortality of 6 (95% UR: 4-10) and 0.6 (95% UR: 0.3-1.1) per 100,000 per year. An optimal RS TB regimen was projected to reduce 10-y TB incidence and mortality in the India-like scenario by 12% (95% UR: 6%-20%) and 11% (95% UR: 6%-20%), respectively, compared to current-care projections. An optimal RR TB regimen reduced RR TB incidence by an estimated 32% (95% UR: 18%-46%) and RR TB mortality by 30% (95% UR: 18%-44%). Efficacy was the greatest determinant of impact; compared to a novel regimen meeting all minimal targets only, increasing RS TB treatment efficacy from 94% to 99% reduced TB mortality by 6% (95% UR: 1%-13%, half the impact of a fully optimized regimen), and increasing the efficacy against RR TB from 76% to 94% lowered RR TB mortality by 13% (95% UR: 6%-23%). Reducing treatment duration or improving ease of adherence had smaller but still substantial impact: shortening RS TB treatment duration from 6 to 2 mo lowered TB mortality by 3% (95% UR: 1%-6%), and shortening RR TB treatment from 20 to 6 mo reduced RR TB mortality by 8% (95% UR: 4%-13%), while reducing nonadherence to the corresponding regimens by 50% reduced TB and RR TB mortality by 2% (95% UR: 1%-4%) and 6% (95% UR: 3%-10%), respectively. Limitations include sparse data on key model parameters and necessary simplifications to model structure and outcomes. CONCLUSIONS: In designing clinical trials of novel TB regimens, investigators should consider that even small changes in treatment efficacy may have considerable impact on TB-related incidence and mortality. Other regimen improvements may still have important benefits for resource allocation and outcomes such as patient quality of life.

Ebola virus disease in the Democratic Republic of Congo.

BACKGROUND: The seventh reported outbreak of Ebola virus disease (EVD) in the equatorial African country of the Democratic Republic of Congo (DRC) began on July 26, 2014, as another large EVD epidemic continued to spread in West Africa. Simultaneous reports of EVD in equatorial and West Africa raised the question of whether the two outbreaks were linked. METHODS: We obtained data from patients in the DRC, using the standard World Health Organization clinical-investigation form for viral hemorrhagic fevers. Patients were classified as having suspected, probable, or confirmed EVD or a non-EVD illness. Blood samples were obtained for polymerase-chain-reaction-based diagnosis, viral isolation, sequencing, and phylogenetic analysis. RESULTS: The outbreak began in Inkanamongo village in the vicinity of Boende town in Équateur province and has been confined to that province. A total of 69 suspected, probable, or confirmed cases were reported between July 26 and October 7, 2014, including 8 cases among health care workers, with 49 deaths. As of October 7, there have been approximately six generations of cases of EVD since the outbreak began. The reported weekly case incidence peaked in the weeks of August 17 and 24 and has since fallen sharply. Genome sequencing revealed Ebola virus (EBOV, Zaire species) as the cause of this outbreak. A coding-complete genome sequence of EBOV that was isolated during this outbreak showed 99.2% identity with the most closely related variant from the 1995 outbreak in Kikwit in the DRC and 96.8% identity to EBOV variants that are currently circulating in West Africa. CONCLUSIONS: The current EVD outbreak in the DRC has clinical and epidemiologic characteristics that are similar to those of previous EVD outbreaks in equatorial Africa. The causal agent is a local EBOV variant, and this outbreak has a zoonotic origin different from that in the 2014 epidemic in West Africa. (Funded by the Centre International de Recherches Médicales de Franceville and others.).

World Health Organization treatment guidelines for drug-resistant tuberculosis, 2016 update.

Antimicrobial resistance is a major global concern. Tuberculosis (TB) strains resistant to rifampicin and other TB medicines challenge patient survival and public health. The World Health Organization (WHO) has published treatment guidelines for drug-resistant TB since 1997 and last updated them in 2016 based on reviews of aggregated and individual patient data from published and unpublished studies. An international expert panel formulated recommendations following the GRADE approach. The new WHO guidelines recommend a standardised 9-12 months shorter treatment regimen as first choice in patients with multidrug- or rifampicin-resistant TB (MDR/RR-TB) strains not resistant to fluoroquinolones or second-line injectable agents; resistance to these two classes of core second-line medicines is rapidly detectable with molecular diagnostics also approved by WHO in 2016. The composition of longer regimens for patients ineligible for the shorter regimen was modified. A first-ever meta-analysis of individual paediatric patient data allowed treatment recommendations for childhood MDR/RR-TB to be made. Delamanid is now also recommended in patients aged 6-17 years. Partial lung resection is a recommended option in MDR/RR-TB care. The 2016 revision highlighted the continued shortage of high-quality evidence and implementation research, and reiterated the need for clinical trials and best-practice studies to improve MDR/RR-TB patient treatment outcomes and strengthen policy.

Updating the WHO target product profile for next-generation Mycobacterium tuberculosis drug susceptibility testing at peripheral centres.

There were approximately 10 million tuberculosis (TB) cases in 2020, of which 500,000 were drug-resistant. Only one third of drug-resistant TB cases were diagnosed and enrolled on appropriate treatment, an issue partly driven by a lack of rapid, accurate drug-susceptibility testing (DST) tools deployable in peripheral settings. In 2014, World Health Organization (WHO) published target product profiles (TPPs) which detailed minimal and optimal criteria to address high-priority TB diagnostic needs, including DST. Since then, the TB community's needs have evolved; new treatment regimens, changes in TB definitions, further emergence of drug resistance, technological advances, and changing end-users requirements have necessitated an update. The DST TPP's revision was therefore undertaken by WHO with the Stop TB Partnership New Diagnostics Working Group. We describe the process of updating the TPP for next-generation TB DST for use at peripheral centres, highlight key updates, and discuss guidance regarding technical and operational specifications.

Using GRADE evidence to decision frameworks to choose from multiple interventions.

BACKGROUND AND OBJECTIVE: Guideline development groups or other health care decision makers frequently encounter situations that require a simultaneous comparison of multiple interventions. This sometimes becomes apparent either when they identify questions of interest, before they formulate recommendations, or it may surface only when recommendations have already been formulated based on pairwise comparisons. METHODS: Using examples from the World Health Organization, the European Commission, and a professional society, we developed a flexible approach to developing recommendations when a multiple-intervention comparison (MC) is needed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence to decision (EtD) frameworks. We iteratively refined this approach through user testing and then included a module in GRADE's official software GRADEpro to test the approach in two real and one theoretical guideline recommendations. RESULTS: We found the approach feasible and that all EtD criteria should be considered in an MC approach. We judged that guideline development groups and other decision makers will benefit from the availability of a network meta-analyses (NMA) of intervention effects to support decisions; however, NMA supports only one of many criteria, that is, the balance of health benefits and harms, and is therefore helpful, but not essential to the approach we propose. When similar but not identical comparators are used to address MC, challenges may arise with intransitivity and the relative rankings of interventions. CONCLUSION: We successfully applied the MC approach and software module in generating recommendations across different scenarios and identified challenges. The MC approach allows guideline groups and other decision makers to transparently and critically assess multiple options for a given health question. Application of the approach by others may lead to refinement and allow for better understanding of its impact in developing recommendations and making choices.