New tools and approaches to drug-resistant TB

The World Health Organization estimates that 410,000 people developed a drug-resistant tuberculosis infection (DR-TB) in 2022, only 40% of whom were diagnosed and started on treatment—and only 63% then cured. Given all these points of failure, innovation in preventing, diagnosing and treating DR-TB cannot come fast enough.

To mark World TB Day (24 March 2024) the content collection linked below highlights recent work by MSF and collaborators to help change this grim picture. The TB-PRACTECAL and endTB studies delivered robust evidence for shorter, safer, more effective drug regimens that are already saving lives worldwide. Other studies explore new approaches to preventive treatment and simpler, quicker, accurate detection of TB and drug resistance—especially among difficult-to-diagnose populations such as children and people living with HIV.

But to impact DR-TB globally these innovations must become widely accessible. This requires changes on many fronts, as described in an accompanying Collection (Expanding Access to Lifesaving New TB Tools).

10 result(s)

Journal Article > ResearchFull Text

Lancet Respir Med. 2024 February 1; Volume 12 (Issue 2); 117-128.

Nyang'wa BT, Berry C, Kazounis E, Motta I, Parpieva N, et al.

Lancet Respir Med. 2024 February 1; Volume 12 (Issue 2); 117-128.

BACKGROUND
Around 500,000 people worldwide develop rifampicin-resistant tuberculosis each year. The proportion of successful treatment outcomes remains low and new treatments are needed. Following an interim analysis, we report the final safety and efficacy outcomes of the TB-PRACTECAL trial, evaluating the safety and efficacy of oral regimens for the treatment of rifampicin-resistant tuberculosis.

METHODS
This open-label, randomised, controlled, multi-arm, multicentre, non-inferiority trial was conducted at seven hospital and community sites in Uzbekistan, Belarus, and South Africa, and enrolled participants aged 15 years and older with pulmonary rifampicin-resistant tuberculosis. Participants were randomly assigned, in a 1:1:1:1 ratio using variable block randomisation and stratified by trial site, to receive 36-80 week standard care; 24-week oral bedaquiline, pretomanid, and linezolid (BPaL); BPaL plus clofazimine (BPaLC); or BPaL plus moxifloxacin (BPaLM) in stage one of the trial, and in a 1:1 ratio to receive standard care or BPaLM in stage two of the trial, the results of which are described here. Laboratory staff and trial sponsors were masked to group assignment and outcomes were assessed by unmasked investigators. The primary outcome was the percentage of participants with a composite unfavourable outcome (treatment failure, death, treatment discontinuation, disease recurrence, or loss to follow-up) at 72 weeks after randomisation in the modified intention-to-treat population (all participants with rifampicin-resistant disease who received at least one dose of study medication) and the per-protocol population (a subset of the modified intention-to-treat population excluding participants who did not complete a protocol-adherent course of treatment (other than because of treatment failure or death) and those who discontinued treatment early because they violated at least one of the inclusion or exclusion criteria). Safety was measured in the safety population. The non-inferiority margin was 12%. This trial is registered with ClinicalTrials.gov, NCT02589782, and is complete.

FINDINGS
Between Jan 16, 2017, and March 18, 2021, 680 patients were screened for eligibility, of whom 552 were enrolled and randomly assigned (152 to the standard care group, 151 to the BPaLM group, 126 to the BPaLC group, and 123 to the BPaL group). The standard care and BPaLM groups proceeded to stage two and are reported here, post-hoc analyses of the BPaLC and BPaL groups are also reported. 151 participants in the BPaLM group and 151 in the standard care group were included in the safety population, with 138 in the BPaLM group and 137 in the standard care group in the modified intention-to-treat population. In the modified intention-to-treat population, unfavourable outcomes were reported in 16 (12%) of 137 participants for whom outcome was assessable in the BPaLM group and 56 (41%) of 137 participants in the standard care group (risk difference -29·2 percentage points [96·6% CI -39·8 to -18·6]; non-inferiority and superiority p<0·0001). 34 (23%) of 151 participants receiving BPaLM had adverse events of grade 3 or higher or serious adverse events, compared with 72 (48%) of 151 participants receiving standard care (risk difference -25·2 percentage points [96·6% CI -36·4 to -13·9]). Five deaths were reported in the standard care group by week 72, of which one (COVID-19 pneumonia) was unrelated to treatment and four (acute pancreatitis, suicide, sudden death, and sudden cardiac death) were judged to be treatment-related.

INTERPRETATION
The 24-week, all-oral BPaLM regimen is safe and efficacious for the treatment of pulmonary rifampicin-resistant tuberculosis, and was added to the WHO guidance for treatment of this condition in 2022. These findings will be key to BPaLM becoming the preferred regimen for adolescents and adults with pulmonary rifampicin-resistant tuberculosis.

Other > Pre-Print

medRxiv. 2024 January 29

Guglielmetti L, Khan U, Velasquez GE, Gouillou M, Abubakirov A, et al.

medRxiv. 2024 January 29

BACKGROUND
After a history of poor treatments for rifampin-resistant tuberculosis (RR-TB), recent advances have resulted in shorter, more effective treatments. However, they are not available to everyone and have shortcomings, requiring additional treatment options.

METHODS
endTB is an international, open-label, Phase 3 non-inferiority, randomized, controlled clinical trial to compare five 9-month all-oral regimens including bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C) and pyrazinamide (Z), to the standard (control) for treatment of fluoroquinolone-susceptible RR-TB. Participants were randomized to 9BLMZ, 9BCLLfxZ, 9BDLLfxZ, 9DCLLfxZ, 9DCMZ and control using Bayesian response-adaptive randomization. The primary outcome was favorable outcome at week 73 defined by two negative sputum culture results or by favorable bacteriologic, clinical and radiologic evolution. The non-inferiority margin was 12 percentage points.

RESULTS
Of 754 randomized patients, 696 and 559 were included in the modified intention to treat (mITT) and per-protocol (PP) analyses, respectively. In mITT, the control had 80.7% favorable outcomes. Regimens 9BCLLfxZ [adjusted risk difference (aRD): 9.5% (95% confidence interval (CI), 0.4 to 18.6)], 9BLMZ [aRD: 8.8% (95%CI, -0.6 to 18.2)], and 9BDLLfxZ [3.9% (95%CI, -5.8 to 13.6)] were non-inferior in mITT and in PP. The proportion of participants experiencing grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxicity occurred in 11.7% of the experimental regimens overall and in 7.1% of the control.

CONCLUSIONS
The endTB trial increases treatment options for RR-TB with three shortened, all-oral regimens that were non-inferior to a current well-performing standard of care.

ClinicalTrials.gov: NCT02754765

Journal Article > ResearchFull Text

Microbiol Spectr. 2023 January 9; Volume 11 (Issue 1)

Rekart ML, Mun L, Aung A, Gomez D, Mulanda WK, et al.

Microbiol Spectr. 2023 January 9; Volume 11 (Issue 1)

We report the findings of a prospective laboratory diagnostic accuracy study to evaluate the sensitivity, specificity, and predictive values of the Xpert MTB/RIF Ultra assay for Mycobacterium tuberculosis detection in fresh stool specimens from children under 15?years of age with confirmed tuberculosis (TB) disease from Dushanbe, Tajikistan. Six hundred eighty-eight (688) participants were enrolled from April 2019 to October 2021. We identified 16 participants (2.3%) with confirmed TB disease, defined as =1 TB sign/symptom plus microbiologic confirmation. With the Xpert MTB/RIF Ultra assay for stool, we found a sensitivity of 68.8% (95% CI, 46.0 to 91.5) and a specificity of 98.7% (95% CI, 97.8 to 99.5) in confirmed TB disease. Our results are comparable to other published studies; however, our cohort was larger and our confirmed TB disease rate lower than most. We also demonstrated that this assay was feasible to implement in a centralized hospital laboratory in a low-middle-income Central Asian country. However, we encountered obstacles such as lack of staffing, material ruptures, outdated government protocols, and decreased case presentation due to COVID-19. We found eight patients whose only positive test was an Xpert Ultra stool assay. None needed treatment during the study; however, three were treated later, suggesting such cases require close observation. Our report is the first from Central Asia and one of a few from a low-middle-income country. We believe our study demonstrates the generalizability of the Xpert MTB/RIF Ultra assay on fresh stool specimens from children and provides further evidence supporting WHO’s approval of this diagnostic strategy.

IMPORTANCE
The importance of this report is that it provides further support for WHO’s recent recommendation that fresh stool is an acceptable sample for GeneXpert TB testing in children, especially small children who often cannot produce an adequate sputum sample. Diagnosing TB in this age group is difficult, and many cases are missed, leading to unacceptable rates of TB illness and death. In our large cohort of children from Dushanbe, Tajikistan, the GeneXpert stool test was positive in 69% of proven cases of TB, and there were very few false-positive tests. We also showed that this diagnostic strategy was feasible to implement in a low-middle-income country with an inefficient health care delivery system. We hope that many more programs will adopt this form of diagnosing TB in children.

Conference Material > Abstract

Moreto-Planas L, Sagrado MJ, Mahajan R, Gallo J, Biague E, et al.

MSF Scientific Days International 2022. 2022 May 11

INTRODUCTION
Tuberculosis (TB) is an important cause of morbidity and mortality in children and over 50% of childhood TB remains undiagnosed every year. As microbiological confirmation is low (<30%), the majority of cases in low and middle-income countries are diagnosed on clinical grounds. Point-of-care ultrasound (POCUS) is a non-invasive bedside tool, and TB-focused POCUS has been validated for diagnosis of TB in adults with HIV. We aimed to describe the performance and findings of TB-focused POCUS for children with presumptive TB at a tertiary care hospital in Guinea- Bissau, a setting with a high burden of HIV, malnutrition and TB.

METHODS
This observational study took place at Simão Mendes hospital in Bissau, from July 2019 to April 2020. Patients aged between 6 months and 15 years with presumptive TB underwent clinical and laboratory assessment, with at least one sample analysed with GeneXpert Ultra, and unblinded clinician-performed POCUS evaluation. POCUS was used to assess for subpleural nodules (SUN’s), lung consolidation, pleural effusion, pericardial effusion, ascites, liver and splenic focal lesions, and abdominal lymph nodes. Presence of any of these signs prompted a POCUS- positive result. Images and clips were evaluated by an expert reviewer and, if discordant, by a second expert reviewer.

ETHICS
This study was approved by the MSF Ethics Review Board (ERB) and by the Guinea-Bissau Ministry of Health ERB.

RESULTS
A total of 139 children were enrolled, with 62 (45%) female and 55 (40%) aged under 5 years. HIV infection and severe acute malnutrition (SAM) were found in 59 (42%) and 83 (60%) of patients, respectively. Confirmation of TB was achieved in 27 (19%); 62 (45%) had unconfirmed TB, and 50 (36%) had unlikely TB. Children with TB were more likely to have a POCUS positive result (83/89; 93%) as compared to children with unlikely TB (17/50; 34%). The most common POCUS signs in TB patients were: lung consolidation (51; 57%), SUN’s (49; 55%), pleural effusion (27; 30%), and focal splenic lesions (25; 28%). In children with confirmed TB (n=27), POCUS sensitivity was 85.2% (95% confidence interval (CI) 67.5-94.1). In those with unlikely TB (n=50), specificity was 66% (95%CI 2.2-77.6). Unlike HIV infection, SAM was associated with higher risk of positive POCUS. Cohen’s kappa coefficient for concordance between field and expert reviewers ranged from 0.6 to 0.9 depending on the POCUS sign, while overall POCUS concordance was 0.8.

CONCLUSION
We found high prevalence of any POCUS sign in children with TB, as compared to children with unlikely TB. POCUS positivity was independent of HIV status, but not of nutritional status. POCUS concordance between field and expert reviewers was moderate to high. TB-focused POCUS could potentially play a supportive role in the diagnosis of TB in children.

CONFLICTS OF INTEREST
None declared.

Journal Article > ResearchFull Text

Journal of Clinical Tuberculosis and Other Mycobacterial Diseases. 2022 May 1; Volume 27; 100316.

Rucker SCM, Lissouba P, Akinyi M, Lubega AV, Stewart RC, et al.

Journal of Clinical Tuberculosis and Other Mycobacterial Diseases. 2022 May 1; Volume 27; 100316.

BACKGROUND
The novel urine-based FujiLAM test identifies tuberculosis in HIV-positive patients but may be challenging to use at point-of-care (POC).

OBJECTIVES
We assessed the feasibility and acceptability of using the FujiLAM test at the point of care in outpatient settings.

METHODS
We conducted a mixed-methods study in four outpatient settings in Kenya, Mozambique, South Africa, and Uganda between November 2020 and September 2021. The test was performed at POC in existing clinic laboratories and consultation spaces. We performed direct observations in the four health facilities, individual questionnaires, proficiency testing evaluations, and individual interviews among healthcare workers performing the FujiLAM test (healthcare workers), and group discussions with programme managers.

RESULTS
Overall, 18/19 (95%) healthcare workers and 14/14 (100%) managers agreed to participate in the study. Most assessed healthcare workers, including lay health workers (10/11; 91%), met the minimum required theoretical knowledge and practical skill in performing the FujiLAM test. Most healthcare workers (17/18; 94%) found the FujiLAM test overall “Easy/Very easy” to perform. Some challenges were mentioned: many timed steps (5/18; 28%); ensuring correct incubation period (5/18; 28%); test result readability (4/18; 22%); and difficulties with cartridge buttons (3/18; 17%). Half of the healthcare workers regularly performing the test (4/7; 57%) found it “Easy” to integrate into routine activities. Most healthcare workers and managers believed that any healthcare worker could perform the test after adequate training.

CONCLUSIONS
Implementing the FujiLAM test in outpatient POC settings is feasible and acceptable to healthcare workers and managers. This test can be performed in various clinic locations by any healthcare worker. The timed, multi-step test procedure is challenging and may affect the workload in resource-constrained health facilities.

Journal Article > ResearchFull Text

J Clin Microbiol. 2022 February 16; Online ahead of print; jcm0236221.

Cox HS, Goig GA, Salaam-Dreyer Z, Dippenaar A, Reuter A, et al.

J Clin Microbiol. 2022 February 16; Online ahead of print; jcm0236221.

BACKGROUND
Treatment of multidrug-resistant or rifampicin-resistant tuberculosis (MDR/RR-TB), although improved in recent years with shorter, more tolerable regimens, remains largely standardised and based on limited drug susceptibility testing (DST). More individualised treatment with expanded DST access is likely to improve patient outcomes.

METHODS
To assess the potential of TB drug resistance prediction based on whole genome sequencing (WGS) to provide more effective treatment regimens, we applied current South African treatment recommendations to a retrospective cohort of MDR/RR-TB patients from Khayelitsha, Cape Town. Routine DST and clinical data were used to retrospectively categorise patients into a recommended regimen, either a standardised short regimen or a longer individualised regimen. Potential regimen changes were then described with the addition of WGS-derived DST.

FINDINGS
WGS data were available for 1274 MDR/RR-TB patient treatment episodes across 2008-2017. Among 834 patients initially eligible for the shorter regimen, 385 (46%) may have benefited from reduced drug dosage or removing ineffective drugs when WGS data were considered. A further 187 (22%) may have benefited from more effective adjusted regimens. Among 440 patients initially eligible for a longer individualised regimen, 153 (35%) could have been switched to the short regimen. Overall, 305 (24%) patients had MDR/RR-TB with second-line TB drug resistance, where the availability of WGS-derived DST would have allowed more effective treatment individualisation.

INTERPRETATION
These data suggest considerable benefits could accrue from routine access to WGS-derived resistance prediction. Advances in culture-free sequencing and expansion of the reference resistance mutation catalogue will increase the utility of WGS resistance prediction.

Journal Article > CommentaryFull Text

Int J Tuberc Lung Dis. 2020 October 1; Volume 24 (Issue 10); 1081-1086.

Seung KJ, Khan UT, Varaine FFV, Ahmed SM, Bastard M, et al.

Int J Tuberc Lung Dis. 2020 October 1; Volume 24 (Issue 10); 1081-1086.

In 2015, the initiative Expand New Drug Markets for TB (endTB) began, with the objective of reducing barriers to access to the new and repurposed TB drugs. Here we describe the major implementation challenges encountered in 17 endTB countries. We provide insights on how national TB programmes and other stakeholders can scale-up the programmatic use of new and repurposed TB drugs, while building scientific evidence about their safety and efficacy. For any new drug or diagnostic, multiple market barriers can slow the pace of scale-up. During 2015–2019, endTB was successful in increasing the number of patients receiving new and repurposed TB drugs in 17 countries. The endTB experience has many lessons, which are relevant to country level introduction of new TB drugs, as well as non-TB drugs and diagnostics. For example: the importation of TB drugs is possible even in the absence of registration; emphasis on good clinical monitoring is more important than pharmacovigilance reporting; national guidelines and expert committees can both facilitate and hinder innovative practice; clinicians use new and repurposed TB drugs when they are available; data collection to generate scientific evidence requires financial and human resources; pilot projects can drive national scale-up.

MSF Science Portal

New tools and approaches to drug-resistant TB

Linked Items

Short oral regimens for pulmonary rifampicin-resistant tuberculosis (TB-PRACTECAL): an open-label, randomised, controlled, phase 2B-3, multi-arm, multicentre, non-inferiority trial

Nine-month, all-oral regimens for rifampin-resistant tuberculosis

Detection of Mycobacterium tuberculosis complex using the Xpert MTB/RIF Ultra assay on the stool of pediatric patients in Dushanbe, Tajikistan

Pregnancy outcomes in patients undergoing drug-resistant tuberculosis treatment in two closely monitored cohorts

Can point-of-care ultrasound support tuberculosis diagnosis in children? The experience of MSF in Guinea-Bissau

Being heard on all-oral therapy for resistant tuberculosis

Feasibility and acceptability of using the novel urine-based FujiLAM test to detect tuberculosis: A multi-country mixed-methods study

Whole genome sequencing has the potential to improve treatment for rifampicin-resistant tuberculosis in high burden settings: a retrospective cohort study

Tuberculosis preventive therapy for children and adolescents: an emergency response to the COVID-19 pandemic

Introducing new and repurposed TB drugs: the endTB experience