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.

Improving Quality of Patient Data for Treatment of Multidrug- or Rifampin-Resistant Tuberculosis.

International policy for treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR TB) relies largely on individual patient data (IPD) from observational studies of patients treated under routine conditions. We prepared guidance on which data to collect and what measures could improve consistency and utility for future evidence-based recommendations. We highlight critical stages in data collection at which improvements to uniformity, accuracy, and completeness could add value to IPD quality. Through a repetitive development process, we suggest essential patient- and treatment-related characteristics that should be collected by prospective contributors of observational IPD in MDR/RR TB.

Standardised shorter regimens versus individualised longer regimens for rifampin- or multidrug-resistant tuberculosis.

We sought to compare the effectiveness of two World Health Organization (WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant (RR/MDR) tuberculosis (TB): a standardised regimen of 9-12 months (the "shorter regimen") and individualised regimens of ≥20 months ("longer regimens").We collected individual patient data from observational studies identified through systematic reviews and a public call for data. We included patients meeting WHO eligibility criteria for the shorter regimen: not previously treated with second-line drugs, and with fluoroquinolone- and second-line injectable agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects meta-regression to calculate adjusted odds ratios and adjusted risk differences (aRDs) for failure or relapse, death within 12 months of treatment initiation and loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine studies of shorter regimens and 2717 out of 13 104 (20.7%) individuals from 53 studies of longer regimens. Treatment success was higher with the shorter regimen than with longer regimens (pooled proportions 80.0% versus 75.3%), due to less loss to follow-up with the former (aRD -0.15, 95% CI -0.17- -0.12). The risk difference for failure or relapse was slightly higher with the shorter regimen overall (aRD 0.02, 95% CI 0-0.05) and greater in magnitude with baseline resistance to pyrazinamide (aRD 0.12, 95% CI 0.07-0.16), prothionamide/ethionamide (aRD 0.07, 95% CI -0.01-0.16) or ethambutol (aRD 0.09, 95% CI 0.04-0.13).In patients meeting WHO criteria for its use, the standardised shorter regimen was associated with substantially less loss to follow-up during treatment compared with individualised longer regimens and with more failure or relapse in the presence of resistance to component medications. Our findings support the need to improve access to reliable drug susceptibility testing.

Adherence interventions and outcomes of tuberculosis treatment: A systematic review and meta-analysis of trials and observational studies.

BACKGROUND: Incomplete adherence to tuberculosis (TB) treatment increases the risk of delayed culture conversion with continued transmission in the community, as well as treatment failure, relapse, and development or amplification of drug resistance. We conducted a systematic review and meta-analysis of adherence interventions, including directly observed therapy (DOT), to determine which approaches lead to improved TB treatment outcomes. METHODS AND FINDINGS: We systematically reviewed Medline as well as the references of published review articles for relevant studies of adherence to multidrug treatment of both drug-susceptible and drug-resistant TB through February 3, 2018. We included randomized controlled trials (RCTs) as well as prospective and retrospective cohort studies (CSs) with an internal or external control group that evaluated any adherence intervention and conducted a meta-analysis of their impact on TB treatment outcomes. Our search identified 7,729 articles, of which 129 met the inclusion criteria for quantitative analysis. Seven adherence categories were identified, including DOT offered by different providers and at various locations, reminders and tracers, incentives and enablers, patient education, digital technologies (short message services [SMSs] via mobile phones and video-observed therapy [VOT]), staff education, and combinations of these interventions. When compared with DOT alone, self-administered therapy (SAT) was associated with lower rates of treatment success (CS: risk ratio [RR] 0.81, 95% CI 0.73-0.89; RCT: RR 0.94, 95% CI 0.89-0.98), adherence (CS: RR 0.83, 95% CI 0.75-0.93), and sputum smear conversion (RCT: RR 0.92, 95% CI 0.87-0.98) as well as higher rates of development of drug resistance (CS: RR 4.19, 95% CI 2.34-7.49). When compared to DOT provided by healthcare providers, DOT provided by family members was associated with a lower rate of adherence (CS: RR 0.86, 95% CI 0.79-0.94). DOT delivery in the community versus at the clinic was associated with a higher rate of treatment success (CS: RR 1.08, 95% CI 1.01-1.15) and sputum conversion at the end of two months (CS: RR 1.05, 95% CI 1.02-1.08) as well as lower rates of treatment failure (CS: RR 0.56, 95% CI 0.33-0.95) and loss to follow-up (CS: RR 0.63, 95% CI 0.40-0.98). Medication monitors improved adherence and treatment success and VOT was comparable with DOT. SMS reminders led to a higher treatment completion rate in one RCT and were associated with higher rates of cure and sputum conversion when used in combination with medication monitors. TB treatment outcomes improved when patient education, healthcare provider education, incentives and enablers, psychological interventions, reminders and tracers, or mobile digital technologies were employed. Our findings are limited by the heterogeneity of the included studies and lack of standardized research methodology on adherence interventions. CONCLUSION: TB treatment outcomes are improved with the use of adherence interventions, such as patient education and counseling, incentives and enablers, psychological interventions, reminders and tracers, and digital health technologies. Trained healthcare providers as well as community delivery provides patient-centered DOT options that both enhance adherence and improve treatment outcomes as compared to unsupervised, SAT alone.

The impact of digital health technologies on tuberculosis treatment: a systematic review.

Digital technologies are increasingly harnessed to support treatment of persons with tuberculosis (TB). Since in-person directly observed treatment (DOT) can be resource intensive and challenging to implement, these technologies may have the potential to improve adherence and clinical outcomes. We reviewed the effect of these technologies on TB treatment adherence and patient outcomes.We searched several bibliographical databases for studies reporting the effect of digital interventions, including short message service (SMS), video-observed therapy (VOT) and medication monitors (MMs), to support treatment for active TB. Only studies with a control group and which reported effect estimates were included.Four trials showed no statistically significant effect on treatment completion when SMS was added to standard care. Two observational studies of VOT reported comparable treatment completion rates when compared with in-person DOT. MMs increased the probability of cure (RR 2.3, 95% CI 1.6-3.4) in one observational study, and one trial reported a statistically significant reduction in missed treatment doses relative to standard care (adjusted means ratio 0.58, 95% CI 0.42-0.79).Evidence of the effect of digital technologies to improve TB care remains limited. More studies of better quality are needed to determine how such technologies can enhance programme performance.

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.

Effectiveness and safety of standardised shorter regimens for multidrug-resistant tuberculosis: individual patient data and aggregate data meta-analyses.

We assessed the effectiveness and safety of standardised, shorter multidrug-resistant tuberculosis (MDR-TB) regimens by pooling data from observational studies.Published studies were identified from medical databases; unpublished studies were identified from expert consultation. We conducted aggregate data meta-analyses to estimate pooled proportions of treatment outcomes and individual patient data (IPD) meta-regression to identify risk factors for unsuccessful treatment in patients treated with 9- to 12-month MDR-TB regimens composed of a second-line injectable, gatifloxacin/moxifloxacin, prothionamide, clofazimine, isoniazid, pyrazinamide and ethambutol.We included five studies in which 796 out of 1279 (62.2%) individuals with confirmed MDR-TB (98.4%) or rifampin-resistant TB (1.6%), and not previously exposed to second-line drugs, were eligible for shorter regimens. 669 out of 796 participants were successfully treated (83.0%, 95% CI 71.9-90.3%). In IPD meta-regression (three studies, n=497), failure/relapse was associated with fluoroquinolone resistance (crude OR 46, 95% CI 8-273), pyrazinamide resistance (OR 8, 95% CI 2-38) and no culture conversion by month 2 of treatment (OR 7, 95% CI 3-202). Two participants acquired extensive drug resistance. Four studies reported grade 3 or 4 adverse events in 55 out of 304 (18.1%) participants.Shorter regimens were effective in treating MDR-TB; however, there is uncertainty surrounding the generalisability of the high rate of treatment success to less selected populations, to programmatic settings and in the absence of drug susceptibility tests to key component drugs.

Decentralized care for multidrug-resistant tuberculosis: a systematic review and meta-analysis.

OBJECTIVE: To assess the effectiveness of decentralized treatment and care for patients with multidrug-resistant (MDR) tuberculosis, in comparison with centralized approaches. METHODS: We searched ClinicalTrials.gov, the Cochrane library, Embase®, Google Scholar, LILACS, PubMed®, Web of Science and the World Health Organization's portal of clinical trials for studies reporting treatment outcomes for decentralized and centralized care of MDR tuberculosis. The primary outcome was treatment success. When possible, we also evaluated, death, loss to follow-up, treatment adherence and health-system costs. To obtain pooled relative risk (RR) estimates, we performed random-effects meta-analyses. FINDINGS: Eight studies met the eligibility criteria for review inclusion. Six cohort studies, with 4026 participants in total, reported on treatment outcomes. The pooled RR estimate for decentralized versus centralized care for treatment success was 1.13 (95% CI: 1.01-1.27). The corresponding estimate for loss to follow-up was RR: 0.66 (95% CI: 0.38-1.13), for death RR: 1.01 (95% CI: 0.67-1.52) and for treatment failure was RR: 1.07 (95% CI: 0.48-2.40). Two of three studies evaluating health-care costs reported lower costs for the decentralized models of care than for the centralized models. CONCLUSION: Treatment success was more likely among patients with MDR tuberculosis treated using a decentralized approach. Further studies are required to explore the effectiveness of decentralized MDR tuberculosis care in a range of different settings.

Modelling the effect of short-course multidrug-resistant tuberculosis treatment in Karakalpakstan, Uzbekistan.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is a major threat to global TB control. MDR-TB treatment regimens typically have a high pill burden, last 20 months or more and often lead to unsatisfactory outcomes. A 9-11 month regimen with seven antibiotics has shown high success rates among selected MDR-TB patients in different settings and is conditionally recommended by the World Health Organization. METHODS: We construct a transmission-dynamic model of TB to estimate the likely impact of a shorter MDR-TB regimen when applied in a low HIV prevalence region of Uzbekistan (Karakalpakstan) with high rates of drug resistance, good access to diagnostics and a well-established community-based MDR-TB treatment programme providing treatment to around 400 patients. The model incorporates acquisition of additional drug resistance and incorrect regimen assignment. It is calibrated to local epidemiology and used to compare the impact of shorter treatment against four alternative programmatic interventions. RESULTS: Based on empirical outcomes among MDR-TB patients and assuming no improvement in treatment success rates, the shorter regimen reduced MDR-TB incidence from 15.2 to 9.7 cases per 100,000 population per year and MDR-TB mortality from 3.0 to 1.7 deaths per 100,000 per year, achieving comparable or greater gains than the alternative interventions. No significant increase in the burden of higher levels of resistance was predicted. Effects are probably conservative given that the regimen is likely to improve success rates. CONCLUSIONS: In addition to benefits to individual patients, we find that shorter MDR-TB treatment regimens also have the potential to reduce transmission of resistant strains. These findings are in the epidemiological setting of treatment availability being an important bottleneck due to high numbers of patients being eligible for treatment, and may differ in other contexts. The high proportion of MDR-TB with additional antibiotic resistance simulated was not exacerbated by programmatic responses and greater gains may be possible in contexts where the regimen is more widely applicable.

Digital health for the End TB Strategy: developing priority products and making them work.

In 2014, the World Health Organization (WHO) developed the End TB Strategy in response to a World Health Assembly Resolution requesting Member States to end the worldwide epidemic of tuberculosis (TB) by 2035. For the strategy's objectives to be realised, the next 20 years will need novel solutions to address the challenges posed by TB to health professionals, and to affected people and communities. Information and communication technology presents opportunities for innovative approaches to support TB efforts in patient care, surveillance, programme management and electronic learning. The effective application of digital health products at a large scale and their continued development need the engagement of TB patients and their caregivers, innovators, funders, policy-makers, advocacy groups, and affected communities.In April 2015, WHO established its Global Task Force on Digital Health for TB to advocate and support the development of digital health innovations in global efforts to improve TB care and prevention. We outline the group's approach to stewarding this process in alignment with the three pillars of the End TB Strategy. The supplementary material of this article includes target product profiles, as developed by early 2016, defining nine priority digital health concepts and products that are strategically positioned to enhance TB action at the country level.

Towards cash transfer interventions for tuberculosis prevention, care and control: key operational challenges and research priorities.

BACKGROUND: Cash transfer interventions are forms of social protection based on the provision of cash to vulnerable households with the aim of reduce risk, vulnerability, chronic poverty and improve human capital. Such interventions are already an integral part of the response to HIV/AIDS in some settings and have recently been identified as a core element of World Health Organization's End TB Strategy. However, limited impact evaluations and operational evidence are currently available to inform this policy transition. DISCUSSION: This paper aims to assist national tuberculosis (TB) programs with this new policy direction by providing them with an overview of concepts and definitions used in the social protection sector and by reviewing some of the most critical operational aspects associated with the implementation of cash transfer interventions. These include: 1) the various implementation models that can be used depending on the context and the public health goal of the intervention; 2) the main challenges associated with the use of conditionalities and how they influence the impact of cash transfer interventions on health-related outcomes; 3) the implication of targeting diseases-affected households and or individuals versus the general population; and 4) the financial sustainability of including health-related objectives within existing cash transfer programmes. We aimed to appraise these issues in the light of TB epidemiology, care and prevention. For our appraisal we draw extensively from the literature on cash transfers and build upon the lessons learnt so far from other health outcomes and mainly HIV/AIDS. CONCLUSIONS: The implementation of cash transfer interventions in the context of TB is still hampered by important knowledge gaps. Initial directions can be certainly derived from the literature on cash transfers schemes and other public health challenges such as HIV/AIDS. However, the development of a solid research agenda to address persisting unknowns on the impact of cash transfers on TB epidemiology and control is vital to inform and support the adoption of the post-2015 End TB strategy.

Multidrug-resistant tuberculosis around the world: what progress has been made?

Multidrug-resistant tuberculosis (MDR-TB) (resistance to at least isoniazid and rifampicin) will influence the future of global TB control. 88% of estimated MDR-TB cases occur in middle- or high-income countries, and 60% occur in Brazil, China, India, the Russian Federation and South Africa. The World Health Organization collects country data annually to monitor the response to MDR-TB. Notification, treatment enrolment and outcome data were summarised for 30 countries, accounting for >90% of the estimated MDR-TB cases among notified TB cases worldwide. In 2012, a median of 14% (interquartile range 6-50%) of estimated MDR-TB cases were notified in the 30 countries studied. In 15 of the 30 countries, the number of patients treated for MDR-TB in 2012 (71 681) was >50% higher than in 2011. Median treatment success was 53% (interquartile range 40-70%) in the 25 countries reporting data for 30 021 MDR-TB cases who started treatment in 2010. Although progress has been noted in the expansion of MDR-TB care, urgent efforts are required in order to provide wider access to diagnosis and treatment in most countries with the highest burden of MDR-TB.

Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries.

Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100 000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9 month isoniazid; 12 week rifapentine plus isoniazid; 3-4 month isoniazid plus rifampicin; or 3-4 month rifampicin alone.

Financial burden for tuberculosis patients in low- and middle-income countries: a systematic review.

In order to inform the development of appropriate strategies to improve financial risk protection, we conducted a systematic literature review of the financial burden of tuberculosis (TB) faced by patients and affected families. The mean total costs ranged from $55 to $8198, with an unweighted average of $847. On average, 20% (range 0-62%) of the total cost was due to direct medical costs, 20% (0-84%) to direct non-medical costs, and 60% (16-94%) to income loss. Half of the total cost was incurred before TB treatment. On average, the total cost was equivalent to 58% (range 5-306%) of reported annual individual and 39% (4-148%) of reported household income. Cost as percentage of income was particularly high among poor people and those with multidrug-resistant TB. Commonly reported coping mechanisms included taking a loan and selling household items. The total cost of TB for patients can be catastrophic. Income loss often constitutes the largest financial risk for patients. Apart from ensuring that healthcare services are fairly financed and delivered in a way that minimises direct and indirect costs, there is a need to ensure that TB patients and affected families receive appropriate income replacement and other social protection interventions.

A scoping review of interventions to address TB associated respiratory disability.

There is a growing body of data describing a high burden of respiratory morbidity amongst pulmonary TB patients and survivors, with up to half thought to experience residual respiratory symptoms, abnormal spirometry, or structural pathology after TB treatment completion. Many patients experiencing marked impacts on their lives and livelihoods. However, there remain no guidelines or evidence-based frameworks for integrated TB-respiratory care during or post TB treatment completion. In this scoping review, completed in collaboration with the WHO Global Tuberculosis Programme, we have identified a lack of primary data on the clinical efficacy, cost effectiveness or feasibility of six potential interventions for the prevention and management of TB-associated respiratory impairment and disability, with a lack of studies in children and adolescents. There is a need for robust interventional trials to improve the long-term respiratory outcomes of people affected by pulmonary TB disease, and to explore how these might be implemented within resource-limited settings.