Background: On the basis of recent clinical trial data for the treatment of drug-susceptible and drug-resistant tuberculosis (TB), the American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America have updated clinical practice guidelines for TB treatment in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis.
Methods: A Joint Panel representing multiple interdisciplinary perspectives convened with American Thoracic Society methodologists to review evidence and make recommendations using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) and GRADE-ADOLOPMENT (adoption, adaptation, and, as needed, de novo development of recommendations) methodology.
Results: New drug-susceptible TB recommendations include the use of a novel 4-month regimen for people with pulmonary TB and a shortened 4-month regimen for children with nonsevere TB. Drug-resistant TB recommendation updates include the use of novel regimens containing bedaquiline, pretomanid, and linezolid with or without moxifloxacin.
Conclusions: All-oral, shorter treatment regimens for TB are now recommended for use in eligible individuals.
Treatment of isoniazid-susceptible, rifampin-susceptible TB in adults with a 4-month rifapentine-moxifloxacin versus 6-month regimen
Question: In adolescents and adults with drug-susceptible pulmonary tuberculosis (TB), is a 4-month regimen composed of 2 months of isoniazid, rifapentine, pyrazinamide, and moxifloxacin followed by 2 months of isoniazid, rifapentine, and moxifloxacin (2HPZM/2HPM) as efficacious and safe as the standard 6-month drug-susceptible TB regimen of 2 months of isoniazid, rifampin, pyrazinamide, and ethambutol (2HRZE) followed by 4 months of isoniazid, and rifampin (4HR) endorsed by the American Thoracic Society (ATS)/U.S. Centers for Disease Control and Prevention (CDC)/European Respiratory Society (ERS)/Infectious Diseases Society (IDSA) guidelines?
Recommendation: In people aged 12 years or older with drug-susceptible pulmonary tuberculosis, we conditionally recommend the use of a 4-month regimen of isoniazid, rifapentine, moxifloxacin, and pyrazinamide (conditional recommendation, moderate certainty of evidence). See Table 1 for dosing details.
Treatment of nonsevere, presumed isoniazid- and rifampin-susceptible TB in children with 4 months versus 6 months of standard therapy
Question: In children and adolescents with nonsevere, drug-susceptible pulmonary TB, is a 4-month regimen composed of standard-dose 2 months of isoniazid, rifampin, pyrazinamide, and ethambutol followed by 2 months of isoniazid and rifampin (2HRZE/2HR) as efficacious and safe as the standard 6-month drug-susceptible TB regimen of 2 months of isoniazid, rifampin, pyrazinamide, and ethambutol followed by 4 months of isoniazid and rifampin (2HRZE/4HR) endorsed by the ATS/CDC/ERS/IDSA guidelines?
Recommendation: In children and adolescents between 3 months and 16 years of age with nonsevere TB (without suspicion or evidence of multidrug-resistant [MDR]/rifampin-resistant [RR]-TB), we recommend the use of a 4-month treatment regimen of 2HRZ(E)/2HR rather than the 6-month drug-susceptible TB regimen of 2HRZ(E)/4HR (strong recommendation, moderate certainty of evidence).
Remarks: Nonsevere TB is defined as peripheral lymph node TB; intrathoracic lymph node TB without airway obstruction; uncomplicated TB pleural effusion; or paucibacillary and noncavitary disease confined to one lobe of the lungs or without a miliary pattern. Children and adolescents who do not meet the criteria for nonsevere TB should receive the standard 6-month treatment regimen (2HRZE/4HR) or recommended treatment regimens for severe forms of extrapulmonary TB. Some children may be eligible for the 4-month rifapentine-moxifloxacin regimen. Dosing is found in Table 1.
Treatment of rifampin-resistant, fluoroquinolone-resistant TB with a 6-month bedaquiline, pretomanid, and linezolid (BPaL) regimen versus 15-month or longer regimens in adolescents aged 14 and older and adults with rifampin-resistant pulmonary TB
Question: In adolescents aged 14 and older and adults with rifampin-resistant pulmonary TB, is a 6-month BPaL regimen as efficacious and safe as the current 15-month or longer drug-resistant TB regimens composed according to current ATS/CDC/ERS/IDSA drug-resistant (DR)-TB treatment guidelines?
Recommendation: In adolescents aged 14 and older and adults with rifampin-resistant pulmonary TB with resistance or patient intolerance to fluoroquinolones, who either have had no previous exposure to bedaquiline and linezolid or have been exposed for less than 1 month, we recommend the use of the 6-month treatment BPaL regimen, rather than more than 15-month regimens (strong recommendation, very low certainty of evidence). See Table 1 for dosing details.
Treatment of rifampin-resistant, fluoroquinolone-susceptible TB with a 6-month bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) regimen versus 15-month or longer regimens in adolescents aged 14 and older and adults with rifampin-resistant pulmonary TB
Question: In adolescents aged 14 and older and adults with rifampin-resistant, fluoroquinolone-susceptible pulmonary TB, is a 6-month BPaLM regimen as effective and safe as the 15-month or longer drug-resistant TB regimens composed according to current ATS/CDC/ERS/IDSA DR-TB treatment guidelines?
Recommendation: In adolescents aged 14 and older and adults with rifampin-resistant, fluoroquinolone-susceptible pulmonary TB, we recommend the use of a 6-month BPaLM treatment regimen, rather than the 15-month or longer regimens in patients with MDR/RR-TB (strong recommendation, very low certainty of evidence). See Table 1 for dosing details.
Q1: Treatment of Isoniazid-Susceptible, Rifampin-Susceptible TB in Adults | ||
---|---|---|
Recommended 4-mo Rifapentine-Moxifloxacin–Containing Regimen* | ||
Isoniazid† | 300 mg daily for 17 wk | |
Rifapentine | 1,200 mg daily for 17 wk | |
Pyrazinamide | Weight-based dosing daily for 8 wk: 40 to <55 kg: 1,000 mg; ⩾55–75 kg: 1,500 mg >75 kg: 2,000 mg | |
Moxifloxacin | 400 mg daily for 17 wk | |
Q2: Treatment of Nonsevere, Presumed Isoniazid-Susceptible, Rifampin-Susceptible TB in Children | ||
Recommended Regimen | Intensive Phase (8 wk)‡ | Continuation Phase (8 wk) |
Isoniazid† | 10–15 mg/kg | 10–15 mg/kg |
Rifampin | 10–20 mg/kg | 10–20 mg/kg |
Pyrazinamide | 35 (30–40) mg/kg | None |
Ethambutol§ | 20 (15–25) mg/kg (included/excluded based on local guidelines) | None |
Q3: Treatment of Rifampin-Resistant, Fluoroquinolone Resistant TB | ||
Recommended BPaL Regimen‖ | ||
Bedaquiline | 400 mg daily for 2 wk, then 200 mg three times/wk for subsequent 24 wk | |
Pretomanid | 200 mg daily for 26 wk | |
Linezolid | 600 mg daily for 26 wk | |
Q4: Treatment of Rifampin-Resistant, Fluoroquinolone-Susceptible TB | ||
Recommended BPaLM Regimen¶ | ||
Bedaquiline | 400 mg daily for 2 wk, then 200 mg three times/wk for subsequent 24 wk | |
Pretomanid | 200 mg daily for 26 wk | |
Linezolid | 600 mg daily for 26 wk | |
Moxifloxacin | 400 mg daily for 26 wk |
Successful treatment and cure of tuberculosis (TB) improves individual health and reduces Mycobacterium tuberculosis transmission. Historically, treatment of TB, particularly of drug-resistant TB (DR-TB), has involved prolonged courses of multiple medications and frequent adverse reactions. Patients and clinicians prefer shorter, safer, and more effective regimens with fewer pills and injections for drug-susceptible (DS)-TB and DR-TB (Table 2). Recent clinical treatment trials of both DS- and DR-TB provided new evidence toward these objectives. On the basis of favorable study outcomes, the U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) updated DS- and DR-TB treatment recommendations in 2022 (1–4).
“For individuals living with tuberculosis, the path from diagnosis to recovery is full of many challenges. Delay in diagnosis and prolonged symptoms can be common. Long periods of isolation carry both economic and emotional costs. The difficulty of high pill burden, medication side effects and long treatment regimens is frequently discussed by TB survivors in We Are TB support meetings. During my own treatment I felt the weight of 16 pills in my hand every morning, and of stigma, financial cost and isolation. I felt the added burden on my family, the medication side effects, and the physical manifestations of the disease. Progress to shorten this journey and to ease these burdens is valued by patients.” Kelly Holland, We Are TB patient advocate |
This guideline update, written by a panel of American Thoracic Society (ATS), CDC, European Respiratory Society (ERS), and Infectious Diseases Society of America (IDSA) specialists, relied on recent reviews of clinical data conducted by the WHO Guideline Development Group (GDG). This Joint Panel guideline focuses on TB in low-incidence settings without significant resource limitations.
The Joint Panel was composed of 25 international specialists in pulmonary medicine, infectious diseases, pediatrics, epidemiology, and public health. A member of We Are TB, a patient advocacy organization, was included for patient perspective. All members helped to review and rate evidence with guidance from the methodology team. The co-sponsoring organizations each provided a co-chair and representatives responsible for the content of the manuscript.
Guideline panel members disclosed all potential conflicts of interest (CoIs) according to the ATS policies (see author disclosures). The chairs and ATS reviewed and managed potential CoIs. Panel members with potential CoIs abstained from decisions about specific questions and recommendations related to their potential CoIs. Most panelists had no substantial CoIs and were approved to participate without limitation. One protocol chair panelist (P.N.) participated in the discussions but was recused from formulating, grading, writing, or editing the recommendation related to the treatment of DS-TB in adults. Another panelist (A.J.G.-P.) had a manageable conflict requiring recusal from the formulation of antibiotic-related recommendations pertaining to DR-TB.
This guideline is a targeted update to the treatment of TB and specifically as an adaptation (5) of the WHO 2022 guidelines (1, 2) relevant to the prior Joint Panel’s guideline recommendations (6, 7). Four methodologists followed the GRADE-ADOLOPMENT (Grading of Recommendations Assessment, Development and Evaluation – adoption, adaptation, and, as needed, de novo development of recommendations) (5) process and used the evidence-to-decision (EtD) frameworks in the adaptation of published WHO guidelines (1, 2). ADOLOPMENT is a GRADE framework that involves either adoption of recommendations from existing guidelines, adaptation of recommendations from existing guidelines, or, if needed, de novo development of recommendations (5).
The methodologists administered online surveys to confirm the panelists’ selection of PICO (population, intervention, comparison, outcome) questions for ADOLOPMENT and prioritization of critical outcomes on the basis of recently published treatment trials and recent CDC and WHO guidelines (1–4) through a modified Delphi process. The Joint Panel arrived at consensus to use the WHO prioritization of critical outcomes. Specifically, the Joint Panel consensus was to adapt specific questions on DS- and DR-TB as worded in the WHO guidelines pertaining to TB treatment (1, 2) provided in an update to the 2016 and 2019 Joint Panel’s guidelines on TB treatment (6, 7). Subsequently, the Joint Panel used the same wording of questions as noted in WHO guidelines, except to refer to the standard of care (SoC) noted in the prior Joint Panel’s guidelines as active comparators as opposed to active comparators from the SoC from prior WHO guidelines (1, 2).
The Joint Panel chose through consensus to adapt the 2022 WHO guidelines on TB treatment (1, 2) on the basis of the relevance, rigor, quality of evidence, and GRADE methodology used in their development. In addition, the methodology team conducted a targeted literature search in three databases (Medline, Embase, Cochrane Central Register of Clinical Trials), using “tuberculosis” and “randomized clinical trial” as filters to confirm the absence of new clinical trial data pertinent to selected PICO questions since the publication of the WHO Guidelines in 2022 (1, 2).
The following steps were conducted after the literature search: 1) title and abstract screening (a preliminary screen review of all titles and abstracts to determine which studies are potentially eligible) and 2) full-text screening (a more in-depth review of the full text for all included studies from the title/abstract phase to establish final eligibility for the review). For steps 1 and 2, the methodology team screened the titles and abstracts (TAs) of the uncovered citations and excluded studies on the basis of the predefined study selection criteria that were specific to each of the four study PICOs. Only studies that were deemed eligible (or were judged “unsure” by screeners) went on to the full-text (FT) phase. At the TA and FT phases of screening, screening was performed in duplicate and independently by pairs of screeners with consensus debate to settle disagreements and third-party adjudication when and if needed. At the FT phase, the full studies were retrieved so that the screeners could read the study in its entirety to make a definitive decision on whether a study would be retained to inform the respective PICO. Panel members were asked to be alert to any recently published trials or any studies that they thought were relevant to a particular PICO and that may have been missed in the electronic database search or TA and FT screening steps.
The methodology team provided transcribed versions of the EtDs of the selected WHO guidelines (1, 2) in GDT (http://www.gradepro.org/) (8). The terms, definitions of data, and evidence tables included in each EtD framework are derived from the published WHO consolidated guidelines on TB (1, 2) with the addition of data for the percentages of participants for each outcome and the treatment effect estimates derived from the evidence tables and EtD tables, respectively. The analyses documented in the published WHO guidelines’ EtD tables were used for the GRADE-ADOLOPMENT process with inclusion of intervention and control population numbers from corresponding evidence tables. Joint Panel members without a CoI reviewed the EtD tables derived from WHO (1, 2) EtD tables from corresponding PICO questions and recommendations and voted on the recommendations. As part of the ADOLOPMENT process, the Joint Panel critically appraised and evaluated the WHO guidelines on TB treatment, particularly focusing on the relevance of the EtD judgments in the context of low TB burden, high-resource settings, in contrast to the WHO’s focus on higher TB burden, low-resource settings (reassessed EtDs are provided in Tables E1–E4 in the data supplement). The Joint Panel and methodology team revised the EtD tables transcribed from the WHO EtDs (1, 2) to reflect the Joint Panel reassessments of the judgments for each PICO. Recommendations were formulated and rated as either “strong” or “conditional” as explicit statements of recommendation strength as per GRADE guidance (Table 3) (9, 10). The term “we recommend” is used for a “strong” recommendation; “we conditionally recommend” is used for a “conditional” recommendation, analogous to “we suggest” used in the Joint Panel’s 2016 and 2019 guidelines (6, 7). The Joint Panel’s recommendations are based on the quality of evidence, the balance between benefits and harms, the certainty of the evidence, and other factors. Sequential observational evidence was considered when published randomized controlled trial evidence was not available. All panel members without a declared CoI reviewed the EtD tables and recommendations and voted on the Joint Panel’s recommendations. The Joint Panel and methodology team drafted the adapted guidelines EtDs and the document manuscript.
Strong Recommendation (“We recommend…”)* | Conditional Recommendation (“We conditionally recommend…”)† | |
---|---|---|
For patients | The overwhelming majority of individuals in this situation would want the recommended course of action, and only a small minority would not | The majority of individuals in this situation would want the suggested course of action, but a sizable minority would not |
For clinicians | The overwhelming majority of individuals should receive the recommended course of action. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences | Different choices will be appropriate for different patients, and you must help each patient arrive at a management decision consistent with her or his values and preferences Decision aids may be useful to help individuals make decisions consistent with their values and preferences Clinicians should expect to spend more time with patients when working toward a decision |
For policy makers | The recommendation can be adapted as policy in most situations, including for use as performance indicators | Policy making will require substantial debates and involvement of many stakeholders. Policies are also more likely to vary between regions Performance indicators would have to focus on the fact that adequate deliberation about the management options has taken place |
The resulting final guideline was reviewed by the ATS documents editor, by anonymous peer reviewers, ERS, IDSA, and CDC and approved for publication by the ATS Executive Committee.
The ATS provided logistical and methodological support and was responsible for CoI disclosures, vetting, and management. The guideline will be reevaluated for updating by the sponsoring ATS Assembly 3 years after publication or sooner.
PICO Question 1: In adolescents and adults with DS pulmonary TB, is a 4-month regimen composed of 2 months of isoniazid, rifapentine, pyrazinamide, and moxifloxacin followed by 2 months of isoniazid, rifapentine, and moxifloxacin (2HPZM/2HPM) as efficacious and safe as the standard 6-month DS-TB regimen of 2 months of isoniazid, rifampin, pyrazinamide, and ethambutol (2HRZE) followed by 4 months of isoniazid and rifampin (4HR) endorsed by the ATS/CDC/ERS/IDSA guidelines?
1. | Topic/overview/background Standard treatment for culture-positive DS-TB has required ⩾6 months of antibiotics (6). Shorter, effective regimens enable patients to be cured faster and can potentially reduce treatment costs, improve patient quality of life, and increase completion of therapy. The Joint Panel reviewed evidence from Study 31/A5349, a randomized, open-label, phase III trial comparing two 4-month rifapentine-containing regimens with the standard 6-month control regimen (11). Participants aged 12 years and older with newly diagnosed pulmonary TB were enrolled at 34 trial sites worldwide (Table 4). | ||||
2. | Summary of evidence for benefits and harms For the 4-month rifapentine and moxifloxacin (RPT-MOX)-based regimen compared with the standard 6-month regimen (consisting of 2 mo of isoniazid, rifampin, pyrazinamide, and ethambutol followed by 4 mo of isoniazid and rifampin [2HRZE/4HR]), the Joint Panel assessed equivalent outcomes of TB disease-free survival at 12 months postrandomization (cure/favorable outcome), treatment retention, acquired drug resistance, adverse events (grade 3 or higher), and all-cause mortality within 14 days after the last dose of study medication (Tables 4 and E1). The microbiologically eligible population for analysis had 791 participants in the 4-month RPT-MOX arm and 768 participants in the 6-month control arm, all with culture-confirmed susceptibility to isoniazid, rifampin, and fluoroquinolones. RPT-MOX was noninferior to control (84.6% vs. 85.4% cure, respectively). No significant differences in outcomes were identified for RPT-MOX and 6-month standard regimens on the basis of smear grade, cavitation, radiologic extent, age, diabetes, body weight, or HIV status. However, the number of participants living with HIV infection, diabetes, or extreme weight or age was small (e.g., ∼9% of trial participants were people living with HIV infection with CD4 count ⩾100 cells/μl, and most participants were aged under 35 years) (11, 12) (Table E1). As part of the ADOLOPMENT process, we adapted the WHO guideline question, evidence table, EtD framework, and recommendation to the scope and audience of this guideline. We performed a literature search to update the evidence base. The literature search revealed no other clinical trials to include in this question, and only one study and corresponding analysis from the WHO guideline was used. Although other clinical trials included shorter regimens for the treatment of DS-TB, they did not address the specific PICO question regarding a rifapentine-moxifloxacin regimen. | ||||
3. | Monitoring and additional considerations Individuals with TB affecting the central nervous system, bones, or joints, miliary TB, and/or pericardial TB were not included in the above study and would not usually be treated with a 6- or 4-month regimen. In low-incidence settings, more people with TB may be older than in the clinical trial and may receive concurrent medications or have underlying comorbidities with a higher risk for adverse events. Specifically, this may include fluoroquinolone-related adverse events, including neuropathology, tendinitis, QT prolongation, and dysglycemia (13). There was no evidence in the trial to suggest that routine baseline or subsequent electrocardiographic (ECG) monitoring is required. The panel did not recommend baseline ECG monitoring for those receiving the shorter regimen (unless clinically indicated, such as by older age, presence of cardiac conditions, history of prolonged QT interval, or use of additional QT prolonging medication). The Joint Panel noted that the RPT-MOX regimen avoids the potential ocular toxicity of ethambutol and decreases the time to culture conversion. Implementation of the RPT-MOX regimen may face challenges related to feasibility and cost. Although the shorter treatment duration may benefit patients and healthcare systems, the RPT-MOX regimen increases daily pill burden, especially compared with fixed-dose combinations (FDCs) that might be used in some European locations for the 6-month regimen. The trial used directly observed therapy (DOT) for at least 5 of 7 treatment days per week as recommended (6), which may have improved adherence. DOT may not be feasible in settings that rely on unsupervised self-administered therapy. Although the likelihood of fluoroquinolone resistance was considered small (<5%) in otherwise DS-TB, there is widespread community use of fluoroquinolones. Therefore, obtaining samples to send for molecular and possibly phenotypic fluoroquinolone DST is advisable before starting the RPT-MOX regimen. The availability and affordability of rifapentine and other medications pose significant challenges in some settings. Nitrosamine impurities in rifampin and rifapentine may also impact availability, although joint panel opinion agreed with the U.S. Food and Drug Administration (FDA) assessment that the benefit of treating TB with rifamycins likely exceeds the risk (https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-nitrosamines-rifampin-and-rifapentine). ECG monitoring might be used in some patients at risk for cardiac events and could increase costs. In terms of health equity, no information was available regarding the use of RPT-MOX for extrapulmonary TB (EPTB) or during pregnancy or in young children. Rifapentine with isoniazid was not associated with unfavorable pregnancy outcomes in trials including weekly therapy for latent TB infection treatment (14). Pediatric studies are enrolling for pharmacokinetics underlying the 4-month RPT-MOX regimen (ClinicalTrials.gov identifier NCT03730181), and weekly rifapentine with isoniazid is recommended therapy for latent TB infection for persons aged 2 years and older (15). | ||||
4. | Certainty of evidence The Joint Panel concurred with the WHO GDG that the overall certainty of evidence for benefits of cure and retention in treatment is high, moderate for adverse events, and low for acquisition of drug resistance and for all-cause mortality, based on the low frequency of harmful events. Although typically overall certainty is based on the lowest certainty for the agreed critical outcomes, the panel agreed with WHO in using GRADE guidance (10) that drug resistance and all-cause mortality would no longer rate as critical outcomes, because the range of effect would not impact the strength or direction of recommendations. Thus, the panel concurred with WHO that the overall certainty of evidence is moderate. | ||||
5. | Panel recommendation In people aged 12 years or older with DS pulmonary tuberculosis, we conditionally recommend the use of a 4-month regimen of isoniazid, rifapentine, moxifloxacin, and pyrazinamide (conditional recommendation, moderate certainty of evidence; Table E1). See Table 1 for dosing details. |
Study 31/A5349* | ||||
---|---|---|---|---|
Design | Randomized, open-label, phase III, noninferiority trial Compared a 4-mo regimen (including moxifloxacin and rifapentine) with standard 6-mo regimen | |||
Setting | International, multicenter (34 sites): Brazil, China, Haiti, India, Kenya, Malawi, Peru, South Africa, Thailand, Uganda, United States of America, Vietnam, Zimbabwe) | |||
Inclusion criteria | Participants ⩾12 yr old with TB (sputum acid-fast bacilli smear or rapid nucleic acid amplification test positive) susceptible to isoniazid, rifampin, and fluoroquinolones If HIV positive, CD4 T cell count ⩾100 cells/mm3, on (or planned) efavirenz-based antiretroviral therapy | |||
Exclusion criteria | Pregnant and breastfeeding women Receiving >5 d of treatment directed against TB or latent TB infection within prior 6 mo or >5 d latent TB infection treatment with isoniazid, rifamycins, pyrazinamide, or any fluoroquinolone within prior 30 d Known history of prolonged QT syndrome Extrapulmonary TB (central nervous system, bones or joints, miliary) Weight <40 kg Known drug resistance | |||
Regimen and duration | Intervention: 4-mo regimen 2HPZM/2HPM† | Comparator: 6-mo regimen 2HRZE/4HR‡ | ||
WHO Outcomes | Intervention Percentage | Comparator Percentage | Relative Effect (95% CI) Anticipated Absolute Difference (95% CI) | Certainty of the Evidence (GRADE) |
Cure (n = 1,559) | 84.6% | 85.4% | RR 0.99 (0.95 to 1.03) 9 fewer per 1,000 (from 43 fewer to 26 more) | ⨁⨁⨁⨁ High |
Retention in treatment (n = 1,559) | 99.9% | 99.0% | RR 1.01 (1.00 to 1.02) 10 more per 1,000 (from 0 fewer to 20 more) | ⨁⨁⨁⨁ High |
Amplified drug resistance (n = 1,559) | 0.0% | 0.0% | RR 3.13 (0.13 to 76.69) 0 fewer per 1,000 (from 0 fewer to 0 more) | ⨁⨁◯◯ Low |
Adverse events during treatment (grade 3 or higher; n = 1,671) | 18.7% | 19.3% | RR 0.97 (0.76 to 1.24) 6 fewer per 1,000 (from 46 fewer to 46 more) | ⨁⨁⨁◯ Moderate |
All-cause mortality (within 14 d after end of treatment; n = 1,671) | 0.4% | 0.8% | RR 0.42 (0.11 to 1.61) 5 fewer per 1,000 (from 8 fewer to 5 more) | ⨁⨁◯◯ Low |
PICO Question 2: In children and adolescents with nonsevere DS pulmonary TB, is a 4-month regimen composed of standard-dose 2 months of isoniazid, rifampin, pyrazinamide, and ethambutol followed by 2 months of isoniazid and rifampin (2HRZE/2HR) as efficacious and safe as the standard 6-month DS-TB regimen of 2 months of isoniazid, rifampin, pyrazinamide, and ethambutol followed by 4 months of isoniazid and rifampin (2HRZE/4HR) endorsed by the ATS/CDC/ERS/IDSA guidelines?
1. | Topic/overview/background Currently recommended treatment regimens are ⩾6 months in duration, regardless of disease severity (6). The SHINE (Shorter Treatment for Minimal TB in Children) trial (16) was a multicenter, randomized, controlled, two-arm noninferiority trial comparing 4 months with 6 months of standard treatment for nonsevere TB. This was defined as intrathoracic lymph node TB without airway obstruction, uncomplicated TB pleural effusion, or paucibacillary and noncavitary disease confined to one lobe of the lungs, or without a miliary pattern. Data from this clinical trial informed these recommendations (16). As part of the ADOLOPMENT process, we adapted the WHO guideline question, evidence table, EtD framework, and recommendation to the scope and audience of this guideline. We performed a literature search to update the evidence base. The literature search revealed no other clinical trials to include in this question, and only the one study and corresponding analysis from the WHO guideline were used. | ||||
2. | Summary of evidence, benefits, and harms SHINE enrolled 1,204 children and adolescents <16 years old weighing ⩾3 kg with nonsevere TB disease (Table 5). Exclusion criteria included known drug resistance, contact to persons with DR-TB, pregnancy, and more severe TB disease (e.g., miliary TB, TB meningitis). The SHINE trial demonstrated a success rate of 97.1% for participants receiving the 4-month regimen (2 mo of isoniazid, rifampin, and pyrazinamide, with or without ethambutol, followed by 2 mo of isoniazid and rifampin [2HRZ(E)/2HR]) compared with 96.9% among those receiving the 6-month regimen (2HRZ(E)/4HR; Table 5). Noninferiority of the 4-month regimen compared with the 6-month regimen was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including the analyses restricted to patients independently adjudicated to have TB disease. Adverse event incidence was similar between the 4-month (7.8%) and 6-month regimens (8.0%) (Table 5). The SHINE trial documented similar treatment success rates and adverse events between the 4-month and 6-month regimens, supporting a recommendation for the 4-month regimen. The shortened treatment duration is a significant benefit and could reduce the use of healthcare services and potentially improve adherence. Relying on the noninferior outcome between the 4-month regimen and the current standard, the Panel judged both desirable and undesirable effects to be trivial in difference (2). The Joint Panel agreed that implementing the regimen would be cost saving for programs, although the size of this effect is uncertain. | ||||
3. | Monitoring and additional considerations Although the SHINE trial enrolled children and adolescents with symptomatic TB disease, many children are diagnosed during contact investigations with TB disease while asymptomatic. The Joint Panel agreed that, provided patients meet the demographic, radiographic, epidemiologic, and clinical criteria for nonsevere TB, without suspicion of RR/MDR-TB, these patients should also be eligible for the 4-month regimen. Recommendations for other specific subgroups are provided in Table 6. Because there is an age overlap between the RPT/MOX regimen and this 4-month regimen, some children may be eligible for either regimen. Figure 1 provides information on how to identify children eligible for the 4-month regimens, based on the data on children in the SHINE trial (16) and Study 31/A5349 (11). Children and adolescents who do not meet the criteria for nonsevere TB should receive the standard 6-month treatment regimen (2HRZ(E)/4HR) or other recommended regimens for which they are eligible or for severe forms of EPTB (6). The clinical monitoring requirements for the shorter regimen remain the same as for the 6-month regimen (6). Monitoring for potential recurrence is a priority for shorter regimens, and programs should have plans to monitor children after treatment. TB programs should also assess for barriers to offering this regimen. | ||||
4. | Certainty of evidence The Joint Panel concurred with the WHO GDG that certainty in the estimated effect was judged to be high for treatment success. Specifically, the Joint Panel judged the certainty of the evidence to be high for treatment success and moderate for both all-cause death and adverse events. This was due to imprecision for estimates of treatment failure, relapse, adherence, and loss to follow-up. The Joint Panel agreed with the WHO that overall certainty of the evidence is moderate (2). This was not downgraded for indirectness, because the trial population may be representative of patients with TB treated in the countries represented by the Joint Panel. The Joint Panel concurred with the WHO GDG that the certainty in the estimated effects was judged to be moderate for all-cause death and adverse events. The Joint Panel agreed with the WHO that the overall certainty of evidence is moderate (2). | ||||
5. | Panel Recommendation In children and adolescents between 3 months and 16 years of age with nonsevere TB (without suspicion or evidence of MDR/RR-TB), we recommend the use of a 4-month treatment regimen of 2HRZ(E)/2HR rather than the 6-month DS-TB regimen of 2HRZ(E)/4HR (strong recommendation, moderate certainty of evidence; Table E2). See Table 1 for dosing details. |
Study | SHINE Trial* | ||||
---|---|---|---|---|---|
Design | Open-label, parallel-group, noninferiority, randomized, controlled, two-arm trial Compared 4-mo (16 wk) versus standard 6-mo (24 wk) treatment using WHO-recommended anti-TB drug dosing in children <16 yr with symptomatic nonsevere TB Sample size: 1,121 (per-protocol; PP), 1,145 (modified intention-to-treat; mITT), 1,204 (intention-to-treat; ITT) | ||||
Setting | Uganda, Zambia, South Africa, India | ||||
Inclusion criteria | Age 0–16 yr Weight ⩾3 kg Symptomatic, nonsevere TB Clinician decision to treat with standard first-line regimen | ||||
Exclusion criteria | Smear-positive respiratory sample Cavitation on chest radiograph Premature (<37 wk) and aged under 3 mo Miliary TB, spinal TB, TB meningitis, osteoarticular TB, abdominal TB, congenital TB Preexisting nontuberculous disease likely to prejudice the response to, or assessment of, treatment, e.g., liver or kidney disease, peripheral neuropathy Any known contraindication to taking anti-TB drugs Known contact with drug-resistant TB adult source case (including monoresistant TB) or known TB drug resistance in the child Severely ill Pregnancy | ||||
Symptomatic, nonsevere TB defined | Disease confined to one lobe on chest radiograph No cavities or complex pleural effusion, or significant airway obstruction Extrathoracic lymph node (LN) TB Intrathoracic uncomplicated (hilar) LN TB Smear-negative on gastric aspirate/other respiratory sample | ||||
Participant characteristics | Median age 3.5 yr (range, 2 mo–15 yr), 52% male | HIV seropositive | 11% | Adherence to assigned treatment: 94% | |
Respiratory TB | 67% | ||||
Peripheral LN TB | 3% | ||||
Mixed respiratory and peripheral LN TB | 29% | ||||
Bacteriologically confirmed TB | 14% | ||||
Culture-positive | 7% | ||||
Xpert MTB/RIF-positive | 2% | ||||
Culture-Xpert MTB/RIF-positive | 5% | ||||
Drug regimen and duration | Intervention: 4 mo of isoniazid, rifampin, pyrazinamide with or without ethambutol† | Comparator: 6 mo of isoniazid, rifampin, pyrazinamide with or without ethambutol‡ | |||
WHO Outcomes | Intervention Percentage | Comparator Percentage | Relative Effect (95% CI) | Anticipated Absolute Effects (95% CI) Difference | Certainty of the Evidence (GRADE) |
Death (all-cause; n = 1,145) | 1.2% | 2.3% | RR 0.54 (0.22 to 1.34) | 10 fewer per 1,000 (from 18 fewer to 8 more) | ⨁⨁⨁◯ Moderate |
Treatment success (n = 1,145) | 96.9% | 96.9% | RR 1.00 (0.98 to 1.02) | 0 fewer per 1,000 (from 19 fewer to 19 more) | ⨁⨁⨁⨁ High |
Treatment failure (n = 1,145) | 0.50% | 0.20% | RR 3.01 (0.31 to 28.81) | 4 more per 1,000 (from 1 fewer to 49 more) | ⨁⨁⨁⨁ High |
Relapse (n = 1,145) | 1.0% | 0.7% | RR 1.50 (0.43 to 5.30) | 3 more per 1,000 (from 4 fewer to 30 more) | ⨁⨁⨁◯ Moderate |
Treatment adherence (n = 1,204) | 95.1% | 93.2% | RR 1.02 (0.99 to 1.05) | 19 more per 1,000 (from 9 fewer to 47 more) | ⨁⨁⨁◯ Moderate |
Adverse events during treatment (grade 3 or higher; n = 1,204) | 7.8% | 8.0% | RR 0.98 (0.67 to 1.44) | 2 fewer per 1,000 (from 26 fewer to 35 more) | ⨁⨁⨁◯ Moderate |
Loss to follow up (n = 1,204) | 1.8% | 1.8% | RR 1.00 (0.44 to 2.29) | 0 fewer per 1,000 (from 10 fewer to 24 more) | ⨁⨁⨁◯ Moderate |
Subgroup | SHINE Study Eligibility and Outcomes | Management Considerations/Recommendations |
---|---|---|
Children with asymptomatic disease | Not study eligible | Asymptomatic children with nonsevere TB disease should receive the 4-mo recommended regimen even without microbiologic results |
Children with peripheral lymph node TB | Included in study Despite small numbers, the 4-mo regimen was noninferior for peripheral lymph node disease across all subgroups, including those with concomitant pulmonary disease | Peripheral and intrathoracic lymph nodes may remain enlarged and regress over several months We recommend the 4-mo regimen |
Children living with HIV | Included in study The 4-mo regimen was noninferior regardless of antiretroviral treatment and CD4 count, including those with severe HIV infection (per WHO immunological classification) | Monitor children with HIV on this regimen closely, especially with severe HIV disease or opportunistic infections, and extend to 6 mo if insufficient clinical progress at 4 mo We recommend the 4-mo regimen |
Children with severe acute malnutrition (SAM) | Included in study, but no separate subgroup analysis In SHINE trial, SAM was defined as weight-for-height z-score ≤3 or mid-upper arm circumference of <115 mm | Because no separate subgroup analysis was conducted, children with SAM and nonsevere disease should preferably receive 6-mo regimen |
Premature infants <37 wk gestation and aged <3 mo or infants weighing <3 kg but ⩾37 wk gestation | Not study eligible | These children should be treated with a 6-mo regimen |
Children treated for TB in the past 2 yr | Not study eligible | Generally not eligible for this regimen, but consider individual circumstances and assess if appropriate for the 4-mo regimen |
Children exposed to drug-resistant TB (DR-TB) | Not study eligible | These children should be treated with a regimen appropriate for the DR-TB exposure |

Figure 1. Identifying children eligible for 4-month regimens. Figure developed by the Joint Panel on the basis of data in the SHINE trial and Study 31/A5349 to address eligibility of some children for either the RPT/MOX regimen or the 4-month standard drug regimen. CXR = chest x-ray; HRZE = isoniazid, rifampin, pyrazinamide, ethambutol; RPT-MOX = rifapentine-moxifloxacin.
[More] [Minimize]PICO Question 3: In adolescents aged 14 and older and adults with rifampin-resistant pulmonary TB, is a 6-month regimen composed of bedaquiline, pretomanid, and linezolid as efficacious and safe as the current 15-month or longer drug-resistant TB regimens composed according to current ATS/CDC/ERS/IDSA DR-TB treatment guidelines?
1. | Topic/overview/background MDR-TB (resistant to at least isoniazid and rifampin), RR-TB, and TB in people intolerant of rifampin (due to severity of adverse effects) are associated with significant morbidity and mortality. These conditions have required substantially different medications and extended treatment durations compared with DS-TB. Before 2019, global treatment success rates for MDR-TB ranged from 50% to 88% (1, 17), often accompanied by significant adverse events. However, the Nix-TB study demonstrated a 90% treatment success rate for treatment of extensively drug-resistant (XDR) or MDR-TB using a regimen of bedaquiline, pretomanid, and linezolid (BPaL) over a 6-month period. Adverse events associated with this regimen were primarily attributed to a daily dose of 1,200 mg of linezolid. In the ZeNix trial (18), lower linezolid dosing and shorter treatment durations were evaluated. The WHO compared ZeNix trial data with programmatic individual patient data (IPD) of SoC regimens (Table E3). The WHO also analyzed data from TB-PRACTECAL (Pragmatic Clinical Trial for More Effective Concise and Less Toxic MDR-TB Treatment Regimens) (19), a randomized controlled trial comparing programmatic SoC regimens with 6-month BPaL-based regimens (Table 7) for MDR-/RR- or pre-XDR-TB. Data from these analyses were considered in this guideline. As part of the ADOLOPMENT process, we adapted the WHO guideline question, evidence table, evidence-to-decision framework, and recommendation to the scope and audience of this guideline. We performed a literature search to update the evidence base. The literature search revealed no other clinical trials to include in this question in addition to the clinical trials and corresponding evidence analysis noted in the WHO guideline. | ||||||||||||||||||||||||||||||||||||||||||||||
2. | Summary of evidence, benefits, and harms In the ZeNix trial, 181 participants with MDR/RR- or pre-XDR-TB received 26 weeks of BPaL (Table 7). They were randomized to receive 1,200 or 600 mg of linezolid daily for 9 or 26 weeks. Treatment with 600 mg of linezolid in the regimen for 26 weeks demonstrated similar favorable outcomes with a reduced incidence of peripheral neuropathy compared with the regimen with 1,200 mg dosing. Comparing ZeNix data (linezolid 600 mg for 26 wk; n = 43) with longer observational SoC IPD (n = 850), BPaL had higher treatment success (100% vs. 74%), with lower mortality (0% vs. 11%) and loss to follow-up (0% vs. 12%) (Table 7). Grade 3 or higher adverse events were observed more frequently with BPaL (14% vs. 5%). Potential reporting bias in observational data might have led to underestimating adverse events in IPD. In TB-PRACTECAL (19), people receiving BPaL (n = 60) for 24 weeks, including linezolid initiated at 600 mg for MDR-/RR- or pre-XDR-TB, had a higher success rate than persons receiving SoC (n = 66) regimens (77% vs. 52%) and fewer grades 3 to 5 adverse events (20% vs. 51%) (Tables 7 and E3). | ||||||||||||||||||||||||||||||||||||||||||||||
3. | Certainty of evidence Certainty in estimated effects was very low because of multiple factors: bias risk from imbalance of comorbidities, high risk of unmeasured confounding, small event numbers, lack of blinding, early trial termination, population differences, varied comparator regimens (inclusion of 9- to 20-mo regimens), inconsistent treatment outcomes, and imprecision from small participant and outcome numbers (Table E4). The ZeNix versus IPD-2021 analysis lacked adjustment because of few events, potential misclassification bias in the comparator group under programmatic conditions, and indirectness from assessment and procedural differences between intervention and programmatic comparators (1). | ||||||||||||||||||||||||||||||||||||||||||||||
4. | Monitoring and additional considerations
| ||||||||||||||||||||||||||||||||||||||||||||||
5. | Panel recommendation In adolescents aged 14 years and older and adults with rifampin-resistant pulmonary TB who have resistance or patient intolerance to fluoroquinolones and either have had no previous exposure to bedaquiline and linezolid or have been exposed for less than 1 month, we recommend the use of the 6-month treatment regimen, composed of bedaquiline, pretomanid, and linezolid (BPaL), rather than more than 15-month regimens (strong recommendation, very low certainty of evidence; Table E3). See Table 1 for dosing details. |
Study | TB-PRACTECAL*,†,§,‖ | ZeNix*,‡,§,‖,¶ | WHO Long SoC Regimens Registries: Individual Patient Dataset (IPD) 2021* | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Design | Phase 2/3 open-label RCT, two stages with randomization to:
| Open-label RCT: BPaL 600 for 9 or 26 wk, or BPaL 1,200 for 9 or 26 wk | Program registry observational data | ||||||||||||
Setting | Belarus, South Africa, Uzbekistan | South Africa, Georgia, Moldova, Russia | Belarus, Georgia, Moldova, Somalia, India, Mozambique, Belgium, Armenia, South Africa, and multiple sites from Einstein, End TB, CDC, Harvard, and France datasets | ||||||||||||
Inclusion criteria | MDR/RR-TB or Pre-XDR-TB Above regardless of quinolone resistance or HIV status Aged 15 yr or more | XDR TB, Pre-XDR, RR TB Aged 14 yr or more | For long comparator regimen (target 18–24 mo), patients had each of the following: Regimen classified as long regimen in dataset Treatment duration ≤24 mo Received ≥4 drugs (regardless of DST or effectiveness) Bedaquiline allowed in regimen If cure or completion, treatment duration of 17.5 mo or more | ||||||||||||
Exclusion criteria | Pregnancy, Hepatic or heart disease Suspected resistance to bedaquiline, pretomanid, or linezolid Prior use of bedaquiline and/or pretomanid and/or linezolid for 1 or more months | HIV+ and CD4 <100, ALT and AST >3× ULN, grade >3 peripheral neuropathy, prior treatment with any of 3 trial drugs or delamanid for 2+ wk | Patients receiving injectable antibiotics excluded | ||||||||||||
Regimen (see footnotes) | TB-PRACTECAL BPaL*,†,§ (n = 126) | TB-PRACTECAL BPaLM*,†,‖ (n = 128) | WHO Long SoC, with Injectables* | ZeNix BPaL (600 mg)*,‡,¶ | WHO Long SoC, Individual Patient Data Registry | ||||||||||
Duration | 24 wk | 24 wk | 9–20 mo | 26 wk | Variable | ||||||||||
WHO Outcomes* | % | RR** (95% CI) | % | RR** (95% CI) | % | % | RR** (95% CI) | % | |||||||
Success rate | 76.7 | 1.47 (1.09 to 1.99) | 88.7 | 1.73 (1.31 to 2.27) | 51.5 | 97.7 | 1.32 (1.19 to 1.39) | 73.9 | |||||||
Failure and recurrence | 13.3 | 0.52 (0.22 to 1.18) | 8.1 | 0.26 (0.10 to 0.71) | 25.8 | 2.3 | 0.71 (0.12 to 3.80) | 3.3 | |||||||
Loss to follow-up | 10.0 | 0.60 (0.24 to 1.56) | 3.2 | 0.16 (0.04 to 0.61) | 19.7 | 0.0 | RD†† −0.11 (−0.13 to −0.03) | 11.8 | |||||||
Adverse events | 19.6 | 0.38 (0.24 to 0.60) | 21.0 | 0.41 (0.26 to 0.63) | 50.9 | 14.0 | RD†† −0.12 (−0.14 to −0.04) | 4.7 | |||||||
Death | 0.0 | RD†† 0.03 (−0.1 to 0.03 | 0.0 | RD†† −0.03 (−0.1 to 0.03) | 3.0 | 0.0 | 3.99 (1.67 to 9.57) | 11.0 | |||||||
Amplified resistance | 2.9 | 1.59 (0.32 to 7.84) | 0.0 | RD†† −0.02 (−0.07 to 0.02) | 1.9 | 0.0 | RD†† −0.02 (−0.04 to 0.06) | 2.4 |
Activity | Month of Treatment | Post-Treatment† | |||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
0 (Baseline) | 1‡ | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 3 | 6 | 12 | 18 | 24 | |||||
Sputum smear and culture§ | ● | ● | ● | ● | ● | ● | ● | ● | ● | ○ | ○ | ○ | ● | ● | ● | ● | ● | ||
Imaging (CXR, CT, other)‖ | ● | ● | ● | ○ | ○ | ○ | ○ | ○ | ○ | ||||||||||
Weight¶ | ● | ● | ● | ● | ● | ● | ● | ○ | ○ | ○ | ● | ● | ● | ● | ● | ||||
Symptom review** | ● | ● | ● | ● | ● | ● | ● | ○ | ○ | ○ | ● | ● | ● | ● | ● | ||||
DST†† | ● | ○ | |||||||||||||||||
CBC‡‡ | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ○ | ○ | ○ | |||||
Creatinine§§ | ● | ● | ● | ● | ● | ● | ● | ○ | ○ | ○ | |||||||||
ALT/AST, alkaline phosphatase, bilirubin‖‖ | ● | ● | ● | ● | ● | ● | ● | ○ | ○ | ○ | |||||||||
K+, Ca2+, Mg2+, bicarbonate¶¶ | ● | ● | ● | ● | ● | ● | ● | ○ | ○ | ○ | |||||||||
Serum drug concentration*** | ○ | ||||||||||||||||||
HIV††† | ● | ||||||||||||||||||
Pregnancy‡‡‡ | ○ | ○ | ○ | ○ | ○ | ○ | ○ | ○ | ○ | ○ | |||||||||
EKG§§§ | ● | ● | ○ | ○ | ● | ○ | ○ | ● | ○ | ○ | ○ | ||||||||
Vision exam‖‖‖ | ● | ● | ● | ● | ● | ● | ● | ○ | ○ | ○ | |||||||||
Peripheral neuropathy¶¶¶ | ● | ● | ● | ● | ● | ● | ● | ○ | ○ | ○ | |||||||||
Arthralgias**** | ● | ○ | ○ | ○ | ○ | ○ | ○ | ○ | ○ | ○ | |||||||||
Amylase, lipase, TSH†††† | ○ |
PICO Question 4: In adolescents aged 14 and older and adults with rifampin-resistant, fluoroquinolone-susceptible pulmonary TB, is a 6-month regimen composed of bedaquiline, pretomanid, linezolid, and moxifloxacin as effective and safe as the 15-month or longer DR-TB regimens composed according to current ATS/CDC/ERS/IDSA DR-TB treatment guidelines?
1. | Topic/overview/background As discussed above, MDR-TB, RR-TB, and TB in individuals intolerant of rifampin have been associated with extended treatment duration and major morbidity and mortality. In the TB-PRACTECAL trial (19), which included study participants with MDR/RR- or pre-XDR-TB with or without fluoroquinolone resistance, WHO SoC regimens were compared with three all-oral 24-week investigative regimens, including a BPaL plus moxifloxacin (BPaLM) arm. The SoC regimens included 9–12-month injectable-containing regimens; 18–24-month-long pre-2019 WHO regimens; a 9–12-month all-oral regimen; and an 18–20-month all-oral regimen. The study was an all open-label, multicenter, randomized noninferiority trial with a primary outcome of unfavorable status, which was a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis, at 72 weeks after randomization (19). TB-PRACTECAL provided evidence for an assessment by WHO in 2022 (1). For individuals treated with BPaLM who have received more than 9 weeks of linezolid but are unable to tolerate it, expert opinion suggests that some individuals, after careful review, may continue the remaining medications without linezolid (20). Prior recommendations discuss the role of surgery for DR-TB (6). | ||||||||||||||||||||||||||||||||||||||||||||||
2. | Summary of evidence, benefits, and harms Participants receiving the BPaLM regimen (n = 62) compared with those treated with SoC regimens (n = 66) experienced higher levels of treatment success (89% vs. 52%), lower levels of failure and recurrence (8% vs. 26%), lower levels of loss to follow-up (3% vs. 20%), and lower levels of grades 3 to 5 adverse events (21% vs. 51%). See Table 7. | ||||||||||||||||||||||||||||||||||||||||||||||
3. | Certainty of evidence Certainty in estimated effects was very low because of multiple factors: bias risk from imbalance of comorbidities, high risk of unmeasured confounding, small event numbers, lack of blinding, early trial termination, population differences, varied comparator regimens (inclusion of 9- to 20-mo regimens), inconsistent treatment outcomes, and imprecision from small participant and outcome numbers (Table E4). | ||||||||||||||||||||||||||||||||||||||||||||||
4. | Monitoring and other considerations
| ||||||||||||||||||||||||||||||||||||||||||||||
5. | Panel recommendation In adolescents aged 14 years and older and adults with rifampin-resistant, fluoroquinolone-susceptible pulmonary TB, we recommend the use of a 6-month treatment regimen, composed of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM), rather than the 15-month or longer regimens in patients with MDR/RR-TB (strong recommendation, very low certainty of evidence; Table E4). |
Shorter treatment duration, oral regimens, reduced number of medications, reduced pill burden, and less adverse drug effects are valued by patients and providers (34–36). Individuals with DS-TB may be eligible for effective regimens that reduce treatment duration by one-third. Previously, only patients with smear- and culture-negative “nonsevere” pulmonary TB were recommended to receive 4 months of treatment (6). Adults and adolescents with DS-TB may now be offered 4 months of an RPT-MOX-based regimen. Most children with nonsevere TB can now be treated with 4 months of standard medications. For DR-TB, new all-oral 6-month regimens are more effective and safer than SoC regimens used for decades and may reduce morbidity and mortality. The BPaL-based regimens can be considered applicable also to those with intolerance of rifampin.
The regimens and staff training can be implemented within existing programmatic efforts. Access to regimens, monitoring tests, and DST may vary and should be assured. These regimens may allow redirection of resources for other programmatic needs. Patient-centered support, case management, education, and, in some cases, incentives may improve adherence and treatment success (6, 7).
The new shorter regimens are probably acceptable to clinicians and people with TB. The SHINE acceptability substudy (16) indicated that treatment administration was more difficult for younger than older children but may be offset by an 8-week shorter regimen. In the United States, BPaL regimen uptake within 2 years of FDA approval has been reported with good clinical outcomes (24).
Access to medications is variable, notably FDCs, rifapentine, bedaquiline, and pretomanid, which may improve. Child-friendly FDCs, which reduce pill burden, are available from the Stop TB Partnership’s Global Drug Facility, but not in the United States or many places in Europe. Increased availability would promote uptake of these recommended regimens. Net costs of implementing new regimens may improve with fewer patient visits, potentially offsetting higher costs of medications and DST. Studies assessing the cost-effectiveness, impact on health equity, acceptability, and feasibility of these newest regimens are needed.
Evidence supports higher treatment success rates for MDR/RR-TB with BPaL/BALM treatment, with fewer adverse events and shorter duration than with longer SoC regimens. The 600-mg linezolid dose is preferred. A study in a country with high TB burden (37) found that BPaL-based regimens are cost-saving and more effective than WHO SoC regimens. In low TB incidence countries, bedaquiline is currently expensive and can be difficult to access. The all-oral, shorter-duration regimen with a reduced pill burden offered by BPaL/BPaLM is likely to confer substantial benefits, although these advantages were not directly quantified in clinical trials.
On the basis of the evidence available, the critical outcomes supported the benefits of BPaL/BPaLM. Although the certainty of evidence for adverse events was low, the likelihood of severe adverse events or amplification of resistance occurring was low.
A strong recommendation based on very low-quality evidence is justified because the evidence that the recommended regimen causes less overall harm is of high quality (38) despite the low certainty of evidence for desirable outcomes. Specifically, the Joint Panel had decided that the lone critical outcome for harms would be on-treatment adverse effects. This outcome was not measured in the published evidence, which had included follow-up beyond treatment completion. Therefore. the Joint Panel considered unpublished observational evidence as sequential evidence (39). The Joint Panel considered unpublished observational data from Panel members’ clinical experience in the use of both BPaL and BPaLM. The unpublished observational evidence indicated that standard therapy was associated with a very large increase in on-treatment adverse effects, which constitutes high-quality evidence. Although observationally based outcomes would, at first consideration, be rated as low certainty of evidence, with large treatment effect, the rating of the on-treatment adverse events as a critical outcome elevates by two levels the evidence to high quality of evidence.
The Joint Panel’s judged the 6-month BPaL/BPaLM regimens to be safer and easier for patient tolerance and adherence relative to prior longer SoC regimens. As the Joint Panel discussed while preparing this guideline, the de facto situation is that the 6-month all-oral BPaL regimens are the accepted treatment of choice in TB treatment centers in higher-resourced countries that have access to BPaL. Other outcomes considered important to decision making include the potential for medication adverse effects to be drawn out over long periods of time with the SoC regimens, which is not captured by the adverse event incidence data; the high value placed on the all-oral, shorter BPaL and BPaLM regimens exemplified by their widespread adoption; and the potential for more rapid reintegration of treated patients into society, which may be related to more rapid destigmatization and improved health. The Joint Panel believes that there are significant harms associated with longer SoC regimens that are improved upon by the 6-month BPaL-based regimens. Thus, the strong recommendation in favor of the 6-month regimens is warranted.
We recommend BPaLM as the first line for MDR/RR-TB without fluoroquinolone resistance or intolerance. Although BPaL is an alternative, the Joint Panel believed that BPaLM, with DOT and close monitoring, might safely add protection against the emergence of drug resistance and increase culture conversion at 2 months. The BPaL-based regimens can be considered to apply to those with intolerance of rifampin. Monitoring DST for the emergence of resistance during treatment is very important.
The main limitations of this guideline update are methodological, using ADOLOPMENT, and the level of certainty of evidence. We did not review raw data available to WHO. For all of our PICO questions, we specifically focused on WHO recommendations that updated prior joint panel guidance, and several newer regimens were out of scope of the selected PICO questions. Our PICO questions 3 and 4 were focused on 15-month or greater comparator regimens, although the WHO data available included 9-month treatment regimens. The certainty of the evidence for some outcomes was very low. Nevertheless, the beneficial treatment effects, all-oral regimen, and relatively few adverse events favored the shorter intervention regimens.
These recommendations are based on single or small studies, which may not reflect TB populations in the United States and Europe. TB clinical trial participants are younger than TB patients in the United States and Europe (40, 41). Adverse events may be more common in older individuals and may differ between trial and TB programmatic settings. These studies also excluded children with severe TB or DR-TB, pregnant individuals, and patients with severe forms of EPTB. Studies of treatment of individuals excluded from these trials, new regimens, emergence of drug resistance, and other issues will inform future guidelines (Table 9).
Diagnostic and translational studies |
Expansion of methods and use of culture-free rapid DST for moxifloxacin |
Description of the mechanism and molecular markers of pretomanid resistance, allowing development of DST methods |
Analyses of cross-resistance between drugs in current regimens with delamanid and surveillance for the development of resistance |
Analyses of cross-resistance between bedaquiline and clofazimine and surveillance for the development of resistance |
Assessment of the feasibility and accuracy of applying definitions for non-severe TB in routine clinical practice with particular emphasis on the radiographic components of the definition for children and adolescents <16 yr old |
Treatment and outcomes |
Evaluation of longer-term outcomes for newly recommended regimens |
Reports of efficacy, safety, and tolerability of newly recommended regimens for subpopulations for whom current data are limited or missing (pregnant and lactating people, young children, older adults, people with significant renal or hepatic disease) |
Evaluation of these regimens for treatment of extrapulmonary and disseminated forms of tuberculosis |
Evaluation of treatment data from other regions and countries using these regimens |
Assessment of barriers to implementation of shorter regimens |
Evaluation of the uptake of shortened treatment regimens |
Evaluation of the acceptability of shorter treatment regimens from patient, medical provider, and other perspectives |
Evaluation of efficacy and added value in multidrug regimens of pretomanid and delamanid |
Determination of efficacy of other and even shorter regimens |
Evaluation of outcomes for which current evidence is scarce (e.g., acquisition of drug resistance and quality of life) |
Examination of the geographical differences in the frequency and severity of linezolid-related adverse events and the underlying cause |
Testing replacement of moxifloxacin with levofloxacin in newly recommended regimens |
Defining the role of and methods for ECG monitoring with newly recommended regimens, particularly for older adults |
Implementation of antibiotic stewardship measures for TB and community use of fluoroquinolones |
Use of pharmacokinetic data to refine dosing or for use in treatment monitoring |
Identification of strategies to ensure treatment adherence and completion to cure |
Data collection for cost-effectiveness and feasibility of newly recommended regimens |
Impact on health equity and acceptability of newly recommended regimens |
Ascertainment of efficacy of regimens by TB lineage |
Evaluating efficacy of adding clofazimine to BPaL in fluoroquinolone-resistant TB |
Analyses of pharmacokinetic data for crushed tablets used in treating children with TB |
Developing child friendly formulations for TB medications in high income countries |
Economic analyses of shorter regimen costs, DST, and monitoring |
This Joint Panel guideline updates the 2016 and 2019 TB treatment guidelines (6, 7) in specific types of DS- and DR-TB. For patients who do not fit these categories, the Joint Panel’s prior guidelines should be consulted (6, 7). This document’s focus is TB low-incidence high-resource contexts, in contrast to WHO’s TB high-burden, lower-resource settings. DOT and integrated case management remain standard of care, as noted in the Joint Panel’s prior guidance (6, 7). The Joint Panel offered a strong recommendation for BPaL/BPaLM for MDR-/RR-TB, whereas the WHO GDG provided a conditional recommendation. We continue to recommend DST to guide therapy and DOT as standard of care for TB treatment.
The Joint Panel is very grateful to and thanks Drs. Dennis Falzon, Fuad Mirzayev, and Matteo Zignol and the WHO Global Tuberculosis Programme for sharing relevant materials for this guideline update. The authors thank John Harmon and Rachel Kaye of the American Thoracic Society for their tremendous support during the preparation and submission of this guideline. The authors also thank Dr. Beverly Sweeney and Dr. Ekaterina Kurbatova for their presentations to the Joint Panel.
This clinical practice guideline was prepared by an ad hoc joint panel of the ATS, CDC, ERS, and IDSA.
Members of the joint panel are as follows:
Raquel Duarte, M.D., Ms.P.H., Ph.D. (Co-Chair)1,2,3*
Sonal S. Munsiff, M.D., F.I.D.S.A. (Co-Chair)4‡
Payam Nahid, M.D., M.P.H. (Co-Chair)6§
Jussi J. Saukkonen, M.D., A.T.S.F. (Co-Chair)8,10§
Carla A. Winston, PH.D., M.A. (Co-Chair)11‖
Ibrahim Abubakar, Ph.D.12*
Carlos AcuÑa-VillaorduÑa, M.D.9,14‡
Pennan M. Barry, M.D., M.P.H.15§
Mayara L. Bastos, M.D., PH.D.16,17‡
Wendy Carr, PH.D.11‖
Hassan Chami, M.D., M.Sc.18¶
Lisa L. Chen, M.D.7§
Terence Chorba, M.D., D.Sc.11‖
Charles L. Daley, M.D.19§
Anthony J. Garcia-Prats, M.D., M.Sc., Ph.D.20,21§,**
Kelly Holland, M.D.22‡‡
Ioannis Konstantinidis, M.D., M.S.23¶
Marc Lipman, M.D., F.R.C.P.13,24*
Manoj J. Mammen, M.D., M.S.5§§
Giovanni Battista Migliori, M.D.25*
Farah M. Parvez, M.D., M.P.H.11‖
Adrienne E. Shapiro, M.D., Ph.D.26‡
Giovanni Sotgiu, Ph.D., M.D.27*
Jeffrey R. Starke, M.D.28‡,**
Angela M. Starks, Ph.D.11‖
Sanket Thakore, M.D.29¶
Shu-Hua Wang, M.D., Pharm.D., M.P.H.30‡
Jonathan M. Wortham, M.D.11‖
*ERS representative.
‡IDSA-selected representative.
§ATS representative.
‖CDC representative.
¶Methodology scholar.
**Pediatric specialist.
‡‡Patient representative.
§§Lead methodologist.
1EPIUnit – Instituto de Saúde Pública, Universidade do Porto, Laboratório para a Investigação Integrativa e Translacional em Saúde Populacional, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal; 2Unidade de Investigação Clínica da ARS Norte, Porto, Portugal; 3Serviço de Pneumologia, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal; 4Division of Infectious Diseases and 5Division of Pulmonary & Critical Care, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York; 6UCSF Office of Research and 7Curry International Tuberculosis Center, UCSF Center for Tuberculosis, UCSF Institute for Global Health Sciences, Division of Pulmonary & Critical Care Medicine, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, California; 8Division of Pulmonary and Critical Care Medicine and 9Section of Infectious Diseases, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts; 10Boston Veterans Administration Health Care System, West Roxbury, Massachusetts; 11Division of Tuberculosis Elimination, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, U.S. Centers for Disease Control and Prevention, Atlanta, Georgia; 12Faculty of Population Health Sciences and 13UCL Respiratory Medicine, Faculty of Medicine, University College London, London, United Kingdom; 14Lemuel Shattuck Hospital, Massachusetts Department of Public Health, Boston, Massachusetts; 15Tuberculosis Control Branch, Division of Communicable Disease Control, Center for Infectious Diseases, California Department of Public Health, Richmond, California; 16McGill International TB Center, Faculty of Medicine, McGill University, Montreal, Quebec, Canada; 17Department of Family Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; 18Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; 19Division of Mycobacterial and Respiratory Infections, Department of Medicine, National Jewish Health and University of Colorado School of Medicine, Denver, Colorado; 20Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, Wisconsin; 21Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; 22We Are TB; 23Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Veterans Affairs Pittsburgh Health Care System and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; 24Respiratory Medicine, Royal Free Hospital, London, United Kingdom; 25Servizio di Epidemiologia Clinica delle Malattie Respiratorie, Istituti Clinici Scientifici Maugeri, Istituto di Ricovero e Cura a Carattere Scientifico, Tradate, Italy; 26Department of Global Health and Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington; 27Clinical Epidemiology and Medical Statistics Unit, Department of Medicine, Surgery and Pharmacy, University of Sassari, Sassari, Italy; 28Department of Pediatrics, Baylor College of Medicine, Houston, Texas; 29Section of Pulmonary Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut; and 30Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio
1. | World Health Organization (WHO). WHO consolidated guidelines on tuberculosis. Module 4: treatment—drug-resistant tuberculosis treatment, 2022 update. Geneva, Switzerland: WHO; 2022. |
2. | World Health Organization (WHO). WHO consolidated guidelines on tuberculosis. Module 4: treatment: drug-susceptible tuberculosis treatment. Geneva, Switzerland: WHO; 2022. |
3. | Centers for Disease Control and Prevention (CDC). Provisional CDC guidance for the use of Pretomanid as component by a regimen [Bedaquiline, Pretomanid, the Linezolid (BPaL)] to treatments drug-resistant tuberculosis condition. Atlanta, GA: CDC; 2023. |
4. | Carr W, Kurbatova E, Starks A, Goswami N, Allen L, Winston C. Interim guidance: 4-month rifapentine-moxifloxacin regimen for the treatment of drug-susceptible pulmonary tuberculosis—United States, 2022. MMWR Morb Mortal Wkly Rep 2022;71:285–289. |
5. | Schünemann HJ, Wiercioch W, Brozek J, Etxeandia-Ikobaltzeta I, Mustafa RA, Manja V, et al. GRADE Evidence to Decision (EtD) frameworks for adoption, adaptation, and de novo development of trustworthy recommendations: GRADE-ADOLOPMENT. J Clin Epidemiol 2017;81:101–110. |
6. | Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America clinical practice guidelines: treatment of drug-susceptible tuberculosis. Clin Infect Dis 2016;63:e147–e195. |
7. | Nahid P, Mase SR, Migliori GB, Sotgiu G, Bothamley GH, Brozek JL, et al. Treatment of drug-resistant tuberculosis. An official ATS/CDC/ERS/IDSA clinical practice guideline. Am J Respir Crit Care Med 2019;200:e93–e142. |
8. | Evidence Prime. GRADEpro Guideline Development Tool. Hamilton, ON, Canada: McMaster University and Evidence Prime; 2024. |
9. | Akl EA, Guyatt GH, Irani J, Feldstein D, Wasi P, Shaw E, et al. “Might” or “suggest”? No wording approach was clearly superior in conveying the strength of recommendation. J Clin Epidemiol 2012;65:268–275. |
10. | Guyatt G, Oxman AD, Sultan S, Brozek J, Glasziou P, Alonso-Coello P, et al. GRADE guidelines: 11. Making an overall rating of confidence in effect estimates for a single outcome and for all outcomes. J Clin Epidemiol 2013;66:151–157. |
11. | Dorman SE, Nahid P, Kurbatova EV, Phillips PP, Bryant K, Dooley KE, et al.; Tuberculosis Trials Consortium. Four-month rifapentine regimens with or without moxifloxacin for tuberculosis. N Engl J Med 2021;384:1705–1718. |
12. | Pettit AC, Phillips PP, Kurbatova E, Vernon A, Nahid P, Dawson R, et al.; Tuberculosis Trials Consortium (TBTC) Study 31/AIDS Clinical Trials Group (ACTG) A5349 study team. Rifapentine with and without moxifloxacin for pulmonary tuberculosis in people with human immunodeficiency virus (S31/A5349). Clin Infect Dis 2023;76:e580–e589. |
13. | Stahlmann R, Lode H. Safety considerations of fluoroquinolones in the elderly: an update. Drugs Aging 2010;27:193–209. |
14. | Moro RN, Scott NA, Vernon A, Tepper NK, Goldberg SV, Schwartzman K, et al. Exposure to latent tuberculosis treatment during pregnancy. The PREVENT TB and the iAdhere trials. Ann Am Thorac Soc 2018;15:570–580. |
15. | Sterling TR, Njie G, Zenner D, Cohn DL, Reves R, Ahmed A, et al. Guidelines for the treatment of latent tuberculosis infection: recommendations from the National Tuberculosis Controllers Association and CDC, 2020. Philadelphia, PA: Elsevier; 2020. p. 1196–1206. |
16. | Turkova A, Wills GH, Wobudeya E, Chabala C, Palmer M, Kinikar A, et al.; SHINE Trial Team. Shorter treatment for nonsevere tuberculosis in African and Indian children. N Engl J Med 2022;386:911–922. |
17. | Shah N, Westenhouse J, Lowenthal P, Schecter G, True L, Mase S, et al. The California multidrug-resistant tuberculosis consult service: a partnership of state and local programs. Public Health Action 2018;8:7–13. |
18. | Conradie F, Bagdasaryan TR, Borisov S, Howell P, Mikiashvili L, Ngubane N, et al.; ZeNix Trial Team. Bedaquiline–pretomanid–linezolid regimens for drug-resistant tuberculosis. N Engl J Med 2022;387:810–823. |
19. | Nyang’wa B-T, Berry C, Kazounis E, Motta I, Parpieva N, Tigay Z, et al. A 24-week, all-oral regimen for rifampin-resistant tuberculosis. N Engl J Med 2022;387:2331–2343. |
20. | World Health Organization (WHO). WHO operational handbook on tuberculosis. Module 4: treatment—drug-resistant tuberculosis treatment, 2022 update. Geneva, Switzerland: WHO; 2022. |
21. | Moodliar R, Aksenova V, Frias M, Van de Logt J, Rossenu S, Birmingham E, et al. Bedaquiline for multidrug-resistant TB in paediatric patients. Int J Tuberc Lung Dis 2021;25:716–724. |
22. | Garcia-Prats AJ, Schaaf HS, Draper HR, Garcia-Cremades M, Winckler J, Wiesner L, et al. Pharmacokinetics, optimal dosing, and safety of linezolid in children with multidrug-resistant tuberculosis: combined data from two prospective observational studies. PLoS Med 2019;16:e1002789. |
23. | Solans BP, Imperial MZ, Olugbosi M, Savic RM. Analysis of dynamic efficacy endpoints of the Nix-TB Trial. Clin Infect Dis 2023;76:1903–1910. |
24. | Haley CA, Schechter MC, Ashkin D, Peloquin CA, Cegielski JP, Andrino BB, et al.; BPaL Implementation Group. Implementation of bedaquiline, pretomanid, and linezolid in the United States: experience using a novel all-oral treatment regimen for treatment of rifampin-resistant or rifampin-intolerant tuberculosis disease. Clin Infect Dis 2023;77:1053–1062. |
25. | U.S. Food and Drug Administration (FDA). Sirturo [prescribing information]. Silver Spring, MD: FDA; 2023 [accessed 2024 Nov 19]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/204384s017lbl.pdf. |
26. | Janssen Science. Sirturo (bedaquiline). Beerse, Belgium: Janssen Pharmaceuticals; 2024 [accessed 2024 Nov 19]. Available from: https://www.janssenscience.com/products/sirturo. |
27. | Rigouts L, Miotto P, Schats M, Lempens P, Cabibbe A, Galbiati S, et al. Fluoroquinolone heteroresistance in Mycobacterium tuberculosis: detection by genotypic and phenotypic assays in experimentally mixed populations. Sci Rep 2019;9:11760. |
28. | Ye M, Yuan W, Molaeipour L, Azizian K, Ahmadi A, Kouhsari E. Antibiotic heteroresistance in Mycobacterium tuberculosis isolates: a systematic review and meta-analysis. Ann Clin Microbiol Antimicrob 2021;20: 73–79. |
29. | UCSF. Drug Resistant TB: a Survival Guide for Clinicians, 3rd edition, 2022 [accessed 2024 Nov 11]. Available from: https://www.currytbcenter.ucsf.edu/sites/default/files/2023-06/SG3_2022_Chapter8_MonitoringCaseManagement.pdf#monitorchklist. |
30. | World Health Organization (WHO). Catalogue of mutations in Mycobacterium tuberculosis complex and their association with drug resistance. Geneva, Switzerland: WHO; 2021. |
31. | World Health Organization (WHO). Technical guide on next-generation sequencing technologies for the detection of mutations associated with drug resistance in Mycobacterium tuberculosis complex. Geneva, Switzerland: WHO; 2018. |
32. | Kadura S, King N, Nakhoul M, Zhu H, Theron G, Köser CU, et al. Systematic review of mutations associated with resistance to the new and repurposed Mycobacterium tuberculosis drugs bedaquiline, clofazimine, linezolid, delamanid and pretomanid. J Antimicrob Chemother 2020;75:2031–2043. |
33. | Song T, Lee M, Jeon H-S, Park Y, Dodd LE, Dartois V, et al. Linezolid trough concentrations correlate with mitochondrial toxicity-related adverse events in the treatment of chronic extensively drug-resistant tuberculosis. EBioMedicine 2015;2:1627–1633. |
34. | Nagarajan K, Kumarsamy K, Begum R, Panibatla V, Reddy R, Adepu R, et al. A dual perspective of psycho-social barriers and challenges experienced by drug-resistant TB patients and their caregivers through the course of diagnosis and treatment: findings from a qualitative study in Bengaluru and Hyderabad Districts of South India. Antibiotics 2022;11:1586. |
35. | Baral SC, Aryal Y, Bhattrai R, King R, Newell JN. The importance of providing counselling and financial support to patients receiving treatment for multi-drug resistant TB: mixed method qualitative and pilot intervention studies. BMC Public Health 2014;14:46–47. |
36. | Thomas BE, Shanmugam P, Malaisamy M, Ovung S, Suresh C, Subbaraman R, et al. Psycho-socio-economic issues challenging multidrug resistant tuberculosis patients: a systematic review. PLoS One 2016;11:e0147397. |
37. | Sweeney S, Berry C, Kazounis E, Motta I, Vassall A, Dodd M, et al. Cost-effectiveness of short, oral treatment regimens for rifampicin resistant tuberculosis. PLoS Glob Public Health 2022;2:e0001337. |
38. | Andrews JC, Schünemann HJ, Oxman AD, Pottie K, Meerpohl JJ, Coello PA, et al. GRADE guidelines: 15. Going from evidence to recommendation-determinants of a recommendation’s direction and strength. J Clin Epidemiol 2013;66:726–735. |
39. | Gershon AS, Lindenauer PK, Wilson KC, Rose L, Walkey AJ, Sadatsafavi M, et al. Informing healthcare decisions with observational research assessing causal effect. An official American Thoracic Society research statement. Am J Respir Crit Care Med 2021;203:14–23. |
40. | Centers for Disease Control and Prevention (CDC). Reported tuberculosis in the United States, 2023 [accessed 2024 Nov 19]. Available from: https://www.cdc.gov/mmwr/volumes/73/wr/mm7312a4.htm. |
41. | European Centre for Disease Prevention and Control and World Health Organization. Tuberculosis surveillance and monitoring in Europe 2022—2020 data. European Centre for Disease Prevention and Control; 2022 [accessed 2024 Nov 19]. Available from: https://www.ecdc.europa.eu/en/publications-data/tuberculosis-surveillance-and-monitoring-europe-2022-2020-data. |
* Joint first authors.
This official clinical practice guideline was approved by the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) September 2024, was cleared by the U.S. Centers for Disease Control and Prevention (CDC) September 2024, and was approved by the European Respiratory Society (ERS) October 2024
The American Thoracic Society provided methodological and administrative support.
A data supplement for this article is available via the Supplements tab at the top of the online article.
Joint Panel Disclosures: R.D. received research support from Unite4TB. M.M. served as a consultant for the American College of Chest Physicians; served as president-elect for the New York State Thoracic Society; and received research support from the University of Rochester. L.C. received honoraria from the Federal Advisory Council for the Elimination of Tuberculosis/DHHS; served in a leadership role for the International Union Against TB and Lung Disease North American Region and Stop-TB USA; and received research support from the CDC and USAID. C.L.D. served as a consultant for AN2, AstraZeneca, Galapagos, Genentech, Hyfe, Insmed, Juvabis, MannKind Corporation, Matinas Biopharma, Paratek Pharmaceuticals, Pfizer, Spero, and Zambon; served on a data and safety monitoring board for AN2, AstraZeneca, the Bill and Melinda Gates Foundation, Cepheid, Eli Lilly, Galapagos, Hyfe, Insmed, MannKind, Matinas, Nob Hill, Otsuka American Pharmaceuticals, Paratek, Spero, and Zambon; served as a scientific advisor and investigator for the Cystic Fibrosis Foundation; received research support from AN2, Bugworks, COPD Foundation, Cystic Fibrosis Foundation, FDA, Insmed, Juvabis, NIH, Paratek, PCORI, and Renovion; served as a speaker for Med Learning Group, NACE, RMEI, and Rockpointe; and holds stock with Nob Hill. A.J.G.P. received research support from NIH and Unitaid. K.H. received travel support from the National Tuberculosis Coalition of America. M.L. served in a leadership role for NTM Network UK and NTM Patient Care UK. A.E.S. served on a data and safety monitoring board for the Datura clinical trial; and received research support from the NIH/NIAID and Vir Biotechnology. S.H.W. served on an advisory board for the Texas Biomedical Research Institute; served in a leadership role for the National Tuberculosis Coalition of America; received research support from Oxford Immunotec and Revvity; and served as a reviewer and received royalties from UpToDate. P.N. served as an expert witness for Bowman Brooke. J.S., S.S.M., C.A.W., I.A., C.A.V., P.B., M.L.B., W.C., H.C., T.C., I.K., G.B.M., F.P., G.S., J.S., A.S., S.T., and J.M.W. reported no commercial or relevant non-commercial interests from ineligible companies.