Economic implications of novel regimens for tuberculosis treatment in three high-burden countries: a modelling analysis.

BACKGROUND: With numerous trials investigating novel drug combinations to treat tuberculosis, we aimed to evaluate the extent to which future improvements in tuberculosis treatment regimens could offset potential increases in drug costs. METHODS: In this modelling analysis, we used an ingredients-based approach to estimate prices at which novel regimens for rifampin-susceptible and rifampin-resistant tuberculosis treatment would be cost-neutral or cost-effective compared with standards of care in India, the Philippines, and South Africa. We modelled regimens meeting targets set in the WHO's 2023 Target Regimen Profiles (TRPs). Our decision-analytical model tracked cohorts of adults initiating rifampin-susceptible or rifampin-resistant tuberculosis treatment, simulating their health outcomes and costs accumulated during and following treatment under standard-of-care and novel regimen scenarios. Price thresholds included short-term cost-neutrality (considering only savings accrued during treatment), medium-term cost-neutrality (additionally considering savings from averted retreatments and secondary cases), and cost-effectiveness (incorporating willingness-to-pay for improved health outcomes). FINDINGS: Total medium-term costs per person treated using standard-of-care regimens were estimated at US$450 (95% uncertainty interval 310-630) in India, $560 (350-860) in the Philippines, and $730 (530-1090) in South Africa for rifampin-susceptible tuberculosis (current drug costs $46) and $2100 (1590-2810) in India, $2610 (2090-3280) in the Philippines, and $3790 (3090-4630) in South Africa for rifampin-resistant tuberculosis (current drug costs $432). A rifampin-susceptible tuberculosis regimen meeting the optimal targets defined in the TRPs could be cost-neutral in the short term at drug costs of $140 (90-210) per full course in India, $230 (130-380) in the Philippines, and $280 (180-460) in South Africa. For rifampin-resistant tuberculosis, short-term cost-neutral thresholds were higher with $930 (720-1230) in India, $1180 (980-1430) in the Philippines, and $1480 (1230-1780) in South Africa. Medium-term cost-neutral prices were approximately $50-100 higher than short-term cost-neutral prices for rifampin-susceptible tuberculosis and $250-550 higher for rifampin-resistant tuberculosis. Health system cost-neutral prices that excluded patient-borne costs were 45-70% lower (rifampin-susceptible regimens) and 15-50% lower (rifampin-resistant regimens) than the cost-neutral prices that included patient costs. Cost-effective prices were substantially higher. Shorter duration was the most important driver of medium-term savings with novel regimens, followed by ease of adherence. INTERPRETATION: Improved tuberculosis regimens, particularly shorter regimens or those that facilitate better adherence, could reduce overall costs, potentially offsetting higher prices. FUNDING: WHO.

Treatment of Multidrug-resistant or Rifampicin-resistant Tuberculosis With an All-oral 9-month Regimen Containing Linezolid or Ethionamide in South Africa: A Retrospective Cohort Study.

BACKGROUND: In 2019, the South African tuberculosis program replaced ethionamide with linezolid as part of an all-oral 9-month regimen. We evaluated treatment outcomes for patients assigned to regimens including linezolid in 2019 and ethionamide in 2017. METHODS: This retrospective cohort study included patients treated for multidrug-resistant/rifampicin-resistant tuberculosis throughout South Africa between 1 January and 31 December 2017 and 1 January to 31 December 2019. The cohort treated with a 9-month regimen containing ethionamide for four months, was compared with a cohort treated with a 9-month regimen containing linezolid for 2 months. The regimens were otherwise identical. Inverse probability weighting of propensity scores was used to adjust for potential confounding. A log-binomial regression model was used to estimate adjusted relative risk (aRR) comparing 24-month outcomes between cohorts including treatment success, death, loss to follow up, and treatment failure. Adverse event data were available for the linezolid cohort. FINDINGS: In total, 817 patients were included in the cohort receiving ethionamide and 4244 in the cohort receiving linezolid. No evidence for a difference was observed between linezolid and ethionamide regimens for treatment success (aRR = 0.96, 95% confidence interval [CI] .91-1.01), death (aRR = 1.01, 95% CI .87-1.17) or treatment failure (aRR = 0.87, 95% CI .44-1.75). Loss to follow-up was more common in the linezolid group, although estimates were imprecise (aRR = 1.22, 95% CI .99-1.50). CONCLUSIONS: No significant differences in treatment success and survival were observed with substitution of linezolid for ethionamide as a part of an all-oral 9-month regimen. Linezolid is an acceptable alternative to ethionamide in this shorter regimen for treatment of multidrug-resistant/rifampicin-resistant tuberculosis.

Multidrug-resistant tuberculosis.

Tuberculosis (TB) remains the foremost cause of death by an infectious disease globally. Multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB; resistance to rifampicin and isoniazid, or rifampicin alone) is a burgeoning public health challenge in several parts of the world, and especially Eastern Europe, Russia, Asia and sub-Saharan Africa. Pre-extensively drug-resistant TB (pre-XDR-TB) refers to MDR/RR-TB that is also resistant to a fluoroquinolone, and extensively drug-resistant TB (XDR-TB) isolates are additionally resistant to other key drugs such as bedaquiline and/or linezolid. Collectively, these subgroups are referred to as drug-resistant TB (DR-TB). All forms of DR-TB can be as transmissible as rifampicin-susceptible TB; however, it is more difficult to diagnose, is associated with higher mortality and morbidity, and higher rates of post-TB lung damage. The various forms of DR-TB often consume >50% of national TB budgets despite comprising <5-10% of the total TB case-load. The past decade has seen a dramatic change in the DR-TB treatment landscape with the introduction of new diagnostics and therapeutic agents. However, there is limited guidance on understanding and managing various aspects of this complex entity, including the pathogenesis, transmission, diagnosis, management and prevention of MDR-TB and XDR-TB, especially at the primary care physician level.

The Safety and Tolerability of Linezolid in Novel Short-Course Regimens Containing Bedaquiline, Pretomanid, and Linezolid to Treat Rifampicin-Resistant Tuberculosis: An Individual Patient Data Meta-analysis.

BACKGROUND: Effectiveness, safety, tolerability, and adherence are critical considerations in shifting to shorter tuberculosis (TB) regimens. Novel 6-month oral regimens that include bedaquiline (B), pretomanid (Pa), and linezolid (L), with or without a fourth drug, have been shown to be as or more effective than the established longer regimens for the treatment of multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB). We aimed to evaluate the safety and tolerability of linezolid in BPaL-containing regimens for the treatment of MDR/RR-TB among recently completed clinical trials. METHODS: A review and meta-analysis was undertaken including published and unpublished data from clinical trials, conducted between 2010 and 2021, that evaluated regimens containing BPaL for the treatment of MDR/RR-TB. Individual patient data were obtained. For each BPaL-containing regimen, we evaluated the frequency and severity of treatment-related adverse events. The risk difference of adverse events for each regimen was calculated, in comparison to patients assigned to receiving the lowest cumulative exposure of linezolid. RESULTS: Data from 3 clinical trials investigating 8 unique BPaL-containing regimens were included, comprising a total of 591 participants. Adverse events were more frequent in groups randomized to a higher cumulative linezolid dose. Among patients who were randomized to a daily dose of 1200 mg linezolid, 68 of 195 (35%) experienced a grade 3-4 adverse event versus 89 of 396 (22%) patients receiving BPaL-containing regimens containing 600 mg linezolid. CONCLUSIONS: Regimens containing BPaL were relatively well tolerated when they included a daily linezolid dose of 600 mg. These novel regimens promise to improve the tolerability of treatment for MDR/RR-TB.

Global burden of disease due to rifampicin-resistant tuberculosis: a mathematical modeling analysis.

In 2020, almost half a million individuals developed rifampicin-resistant tuberculosis (RR-TB). We estimated the global burden of RR-TB over the lifetime of affected individuals. We synthesized data on incidence, case detection, and treatment outcomes in 192 countries (99.99% of global tuberculosis). Using a mathematical model, we projected disability-adjusted life years (DALYs) over the lifetime for individuals developing tuberculosis in 2020 stratified by country, age, sex, HIV, and rifampicin resistance. Here we show that incident RR-TB in 2020 was responsible for an estimated 6.9 (95% uncertainty interval: 5.5, 8.5) million DALYs, 44% (31, 54) of which accrued among TB survivors. We estimated an average of 17 (14, 21) DALYs per person developing RR-TB, 34% (12, 56) greater than for rifampicin-susceptible tuberculosis. RR-TB burden per 100,000 was highest in former Soviet Union countries and southern African countries. While RR-TB causes substantial short-term morbidity and mortality, nearly half of the overall disease burden of RR-TB accrues among tuberculosis survivors. The substantial long-term health impacts among those surviving RR-TB disease suggest the need for improved post-treatment care and further justify increased health expenditures to prevent RR-TB transmission.

Global prevalence of hepatitis B or hepatitis C infection among patients with tuberculosis disease: systematic review and meta-analysis.

Background: There is a substantial overlap in the epidemiology of chronic hepatitis B (HBV), hepatitis C (HCV) and tuberculosis (TB) due to overlapping risk factors. Testing for viral hepatitis is not widely recommended for patients with TB. The aim of this systematic review was to evaluate the global prevalence of chronic viral hepatitis infection among patients with TB. Methods: MEDLINE, EMBASE, Web of Science, Cochrane Library, African Journals Online, LILACS, and country TB reports were searched for studies published between January 1st, 2011 and June 17th 2021. Random-effects meta-analyses for proportions were conducted to obtain pooled prevalences. The prevalence of chronic HBV/HCV infection among patients with TB was also compared to that in the general population. The protocol was registered on PROSPERO (CRD42021276468). Findings: This analysis included 127 studies (83 for both HBV and HCV, 28 for HBV only, and 25 for HCV only) and data from 94,936 patients. The global pooled seroprevalence was 5.8% (95% CI 5.0-6.8) for HBs-antigen and 10.3% (95% CI 8.4-12.3) for HCV-antibodies. Pooled prevalence was highest in the WHO African Region for HBV at 7.8% (95% CI 5.2-10.9) and in the WHO European Region at 17.5% (95% CI 12.2-23.5) for HCV. In studies among TB patients who inject drugs, HCV prevalence was 92.5% (95% CI 80.8-99.0). Pooled HCV-antibody seroprevalence among patients with TB was higher than in the general population in all six WHO regions while HBs-antigen seroprevalence was higher in 3/6 regions. Interpretation: This review highlights the syndemicity of chronic viral hepatitis and TB and suggests that routine testing for hepatitis upon TB diagnosis may be justified. The prevalence of chronic HBV and HCV infections was higher among patients with TB than in the general population. Funding: This study was study was funded by the Global Tuberculosis Programme, World Health Organization.

Effectiveness and Pharmacokinetic Exposures of First-Line Drugs Used to Treat Drug-Susceptible Tuberculosis in Children: A Systematic Review and Meta-Analysis.

BACKGROUND: Optimal doses of first-line drugs for treatment of drug-susceptible tuberculosis in children and young adolescents remain uncertain. We aimed to determine whether children treated using World Health Organization-recommended or higher doses of first-line drugs achieve successful outcomes and sufficient pharmacokinetic (PK) exposures. METHODS: Titles, abstracts, and full-text articles were screened. We searched PubMed, EMBASE, CENTRAL, and trial registries from 2010 to 2021. We included studies in children aged <18 years being treated for drug-susceptible tuberculosis with rifampicin (RIF), pyrazinamide, isoniazid, and ethambutol. Outcomes were treatment success rates and drug exposures. The protocol for the systematic review was preregistered in PROSPERO (no. CRD42021274222). RESULTS: Of 304 studies identified, 46 were eligible for full-text review, and 12 and 18 articles were included for the efficacy and PK analyses, respectively. Of 1830 children included in the efficacy analysis, 82% had favorable outcomes (range, 25%-95%). At World Health Organization-recommended doses, exposures to RIF, pyrazinamide, and ethambutol were lower in children than in adults. Children ≤6 years old have 35% lower areas under the concentration-time curve (AUCs) than older children (mean of 14.4 [95% CI 9.9-18.8] vs 22.0 [13.8-30.1] µg·h/mL) and children with human immunodeficiency virus (HIV) had 35% lower RIF AUCs than HIV-negative children (17.3 [11.4-23.2] vs 26.5 [21.3-31.7] µg·h/mL). Heterogeneity and small sample sizes were major limitations. CONCLUSIONS: There is large variability in outcomes, with an average of 82% favorable outcomes. Drug exposures are lower in children than in adults. Younger children and/or those with HIV are underexposed to RIF. Standardization of PK pediatric studies and individual patient data analysis with safety assessment are needed to inform optimal dosing.

Profiling Pretomanid as a Therapeutic Option for TB Infection: Evidence to Date.

Tuberculosis (TB) is the most deadly infectious disease globally. Although most individuals achieve a cure, a substantial portion develop multi-drug resistant TB which is exceedingly difficult to treat, and the number of effective agents is dwindling. Development of new anti-tubercular medications is imperative to combat existing drug resistance and accelerate global eradication of TB. Pretomanid (PA-824) represents one of the newest drug classes (ie, nitroimidazooxazines) approved in 2019 by the United States Food and Drug Administration as part of a multi-drug regimen (with bedaquiline and linezolid, BPaL) and recommended by the World Health Organization (WHO) to treat extensively-resistant (XR-TB) and multi-drug resistant tuberculosis (MDR-TB). Approval was granted through the FDA's Limited Population Pathway for Antibacterial and Antifungal Drugs, which accelerates approval for antimicrobial drugs used to treat life-threatening or serious infections in a limited population with unmet need. This review details the pharmacology, efficacy, and safety of this new agent and describes evidence to date for its role in the treatment of drug resistant TB including published, ongoing, and planned studies.

Situational analysis of 10 countries with a high burden of drug-resistant tuberculosis 2 years post-UNHLM declaration: progress and setbacks in a changing landscape.

OBJECTIVES: Globally, drug-resistant tuberculosis (DR-TB) is the leading cause of death globally related to antimicrobial resistance, affecting 500,000 emergent cases annually. In 2018, the first United Nations High-Level Meeting (UNHLM) on tuberculosis declared DR-TB a global public health priority. Bold country targets were established for 2018-2022. This study reviews the DR-TB situation in 2018, and the UNHLM target accomplishments in 10 high-burden countries (HBCs). METHODS: An ecological descriptive analysis of the top 10 DR-TB HBCs (Bangladesh, China, India, Indonesia, Myanmar, Nigeria, Pakistan, Philippines, Russian Federation, and South Africa), which share 70% of the global DR-TB burden, was undertaken, complemented by a cascade-of-care analysis and a survey gathering additional information on key advances and setbacks 2 years after the UNHLM declaration. RESULTS: Most countries are showing historic advances and are on track for the 2018 and 2019 targets. However, according to the cascade-of-care, none of the countries are capable of providing effective care for 50% of the estimated patients. Increasing levels of fluoroquinolone resistance and access to timely susceptibility testing can jeopardize ongoing adoption of shorter, all-oral treatment regimens. The programmatic management of DR-TB in children remains minimal. Achievements for 2020 and beyond may be affected significantly by the coronavirus disease 2019 (COVID-19) pandemic. CONCLUSION: Triggered by the COVID-19 pandemic, there is a global risk of recoil in DR-TB care with long-term consequences in terms of deaths, suffering and wider transmission. Investment to support DR-TB services is more important now than ever to meet the aspirations of the UNHLM declaration.

Recommendation mapping of the World Health Organization's guidelines on tuberculosis: A new approach to digitizing and presenting recommendations.

OBJECTIVE: Having up-to-date health policy recommendations accessible in one location is in high demand by guideline users. We developed an easy to navigate interactive approach to organize recommendations and applied it to tuberculosis (TB) guidelines of the World Health Organization (WHO). STUDY DESIGN: We used a mixed-methods study design to develop a framework for recommendation mapping with seven key methodological considerations. We define a recommendation map as an online repository of recommendations from several guidelines on a condition, providing links to the underlying evidence and expert judgments that inform them, allowing users to filter and cross-tabulate the search results. We engaged guideline developers, users, and health software engineers in an iterative process to elaborate the WHO eTB recommendation map. RESULTS: Applying the seven-step framework, we included 228 recommendations, linked to 103 guideline questions and organized the recommendation map according to key components of the health question, including the original recommendations and rationale (https://who.tuberculosis.recmap.org/). CONCLUSION: The recommendation mapping framework provides the entire continuum of evidence mapping by framing recommendations within a guideline questions' population, interventions, and comparators domains. Recommendation maps should allow guideline developers to organize their work meaningfully, standardize the automated publication of guidelines through links to the GRADEpro guideline development tool, and increase their accessibility and usability.

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.

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.

Tuberculosis Supranational Reference Laboratories: A Global Approach.

The World Health Organization Supranational TB Reference Laboratory Network (SRLN) has served as the backbone for TB drug-resistance surveillance and diagnosis since 1994 and remains a key WHO programme for antimicrobial resistance (AMR) surveillance at the global level. SRLN is a great technical resource for proficiency testing to ensure accuracy of drug-susceptibility testing, scale-up, capacity development in countries and provides unique support to the reliable detection of drug resistance. Technical assistance from individual SRLs has been supported by a variety of mechanisms but funding for the SRLN has become increasingly challenging.