LITERATURE AND PUBLICATIONS

From our March 2024 Newsletter

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1. Short oral regimens for pulmonary rifampicin-resistant tuberculosis (TB-PRACTECAL): an open-label, randomised, controlled, phase 2B-3, multi-arm, multicentre, non-inferiority trial.
 
Lancet Respir Med. 2024 Feb;12(2):117-128. doi: 10.1016/S2213-2600(23)00389-2. Epub 2023 Nov 16.
 
Nyang'wa BT(1), Berry C(2), Kazounis E(2), Motta I(2), Parpieva N(3), Tigay Z(4), Moodliar R(5), Dodd M(6), Solodovnikova V(7), Liverko I(3), Rajaram S(8), Rassool M(8), McHugh T(9), Spigelman M(10), Moore DA(6), Ritmeijer K(11), du Cros P(12), Fielding K(6); TB-PRACTECAL team.
 
Collaborators: Da Costa E, Lachenal N, James N, Sinha A, LeBeau K, Douch E, Jolivert P, Poulsom H, Conijn M, King S, Spencer H, Cunden E, Batts C, Vuong T, Dietrich S, McRae M, Wong S, Sun E, Olugbosi M, Shanks L, Hughes M, Nahid P, Kumwenda J, Lorenz T, Majumdar S, Horsburgh RC, Nuermberger E, Meintjes G, Eisenach K, Lienhardt C, Nunn A, Lange C, Park L, Gatts C, Warren D, Kleiman R, Mokua Nyangweso G, Ochieng M, Egondi T, Onyango K, Omollo T, Omollo R, Sturgess J, Saunders S, Allen E, Gajewski S, Butoescu V, Hanekova J, Etter C, Kambarov Y, Mphele S, Sukhinina V, Huzar O, Reshetnikov A, Cilliè C, Ahmed N, Hunt R, Merle C, Gulayim A, Mbenga M, Baltasheva ZS, Abdrasuliev T, Margaryan H, Urgenishbaevna UG, Skrahina A,Yatskevich N, Viatushka D, Apanasevich T, Skrahin A, Duckworth L, Narasimooloo C, Lesego NE, Motlhako S, Mashamaite ME, Mojapelo E.
 
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.
FUNDING: Médecins Sans Frontières.
 
Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All 
rights reserved.
 
DOI: 10.1016/S2213-2600(23)00389-2
PMID: 37980911 [Indexed for MEDLINE]

2. Low body mass index as a predictor of sputum culture conversion and treatment outcomes among patients receiving treatment for multidrug-resistant tuberculosis in Lesotho.

Glob Health Action. 2024 Dec 31;17(1):2305930. doi: 10.1080/16549716.2024.2305930. Epub 2024 Feb 2.
 
Oyewusi L(1), Zeng C(2), Seung KJ(3), Mpinda S(1), Kunda M(1), Mitnick CD(2), Kanu M(1), Tamirat M(1), Makaka J(1), Mofolo M(1), Maime R(1), Maama L(4), Senyo N(1), Oguntoyinbo B(1), Mayombo L(1), Franke MF(2).
 
BACKGROUND: A low body mass index (BMI) at the start of treatment for rifampicin- or multidrug-resistant tuberculosis (MDR/RR-TB) is associated with poor treatment outcomes and may contribute to delayed sputum culture conversion, thereby prolonging the period of potential transmission to others. Whether the relative importance of low BMI in predicting treatment outcomes differs by HIV status is unclear.

OBJECTIVES: We evaluated the association between low BMI and two dependent variables, sputum culture conversion and end-of-treatment outcome, among patients receiving treatment for MDR/RR-TB in Lesotho, a setting with a high prevalence of HIV infection.

METHODS: Secondary data from a prospective cohort of patients initiating a longer (18-20 months) treatment containing bedaquiline and/or delamanid under routine programmatic conditions in Lesotho were analysed. Risk ratios and differences were adjusted for potential confounders using multivariable logistic regression, and estimates were stratified by HIV status.

RESULTS: Of 264 patients, 105 and 250 were eligible for culture conversion and end-of-treatment analyses, respectively. Seventy-one per cent of patients (74/105) experienced culture conversion within six months, while 74% (184/250) experienced a favourable end-of-treatment outcome. Low BMI was associated with a lower frequency of culture conversion at six months among those who were not living with HIV (relative risk [RR]: 0.50 [95% CI: 0.21, 0.79]); this association was attenuated among those living with HIV (RR: 0.88 [95% CI: 0.68, 1.23]). A low BMI was moderately associated with a lower frequency of treatment success (RR = 0.89 [95% CI: 0.77, 1.03]), regardless of HIV status.

CONCLUSIONS: Low BMI was common and associated with the frequency of six-month culture conversion and end-of-treatment outcomes. The association with culture conversion was more pronounced among those not living with HIV. Addressing the myriad factors that drive low BMI in this setting could hasten culture conversion and improve end-of-treatment outcomes. This will require a multipronged approach focused on alleviating food insecurity and enabling prompt diagnosis and treatment of HIV and TB.
 
DOI: 10.1080/16549716.2024.2305930
PMCID: PMC10840591
PMID: 38305025 [Indexed for MEDLINE]

3. The use of BPaL containing regimen in the MDR/PreXDR TB treatments in Thailand.
 
J Clin Tuberc Other Mycobact Dis. 2023 Dec 3;34:100408. doi: 10.1016/j.jctube.2023.100408. eCollection 2024 Feb.
 
Sangsayunh P(1), Sanchat T(1), Chuchottaworn C(1), Cheewakul K(2), Rattanawai S(3).
 
The primary objective of this study was to evaluate the real-world effectiveness, side effects and challenges associated with the implementing of the groundbreaking BPaL-containing regimen in Thailand. Another aim was to investigate the characteristics and severity of the disease, the presence of abnormal extensive lesions in chest X-Rays and the influence of cavitation on sputum conversion.

MATERIAL AND METHOD: The case series study included patients at TB clinic of Central chest institute of Thailand between August 2021-April 2023. All 28 Patients fullfilled the diagnostic criterial for MDR-TB by molecular tests and/or sputum culture. Sputum molecular test, utilizing GeneXpert MRB/XDR or Genotype MTBDRsl assay, was conducted. The 8 Pre-XDR patients who exhibited quinolone resistance and the 2 MDR-TB patients who encountered side effected from quinolone drugs were treated with BPaL regimen, while the remainder received BPaLM regimens.

RESULTS: Among the 28 patients, 23 (82.1 %) successfully completed the treatment with favorable outcomes. However, one patient from the BpaL regimen died due to severe destroy lung lesion, and four patients from the BpalM regimen discontinued treatment. The investigation into the correlation between extension lesion, cavitation lesions, and culture conversion unveiled that the group with extension lesions and cavitation ≥4 cm had a diminished probability of achieving sputum culture conversion within 8 weeks in comparison to the group without attributes. The associated risk ratio was 0.56 (95 % CI, 0.14-2.27), p = 0.14. Although the study report minimal side effects, 6 patients (22.2 %) experienced peripheral neuropathy and a notable adverse reaction identified was optic neuritis, affecting 2 cases (7.1 %).

SUMMARY: The administration of the BPaL-containing regimen resulted in rapid sputum conversion within 8 weeks and had minimal side effects.
 
© 2023 The Authors.
 
DOI: 10.1016/j.jctube.2023.100408
PMCID: PMC10788258
PMID: 38225943

4.Pharmacokinetics and Optimal Dosing of Levofloxacin in Children for Drug-Resistant Tuberculosis: An Individual Patient Data Meta-Analysis.

Clin Infect Dis. 2024 Feb 10:ciae024. doi: 10.1093/cid/ciae024. Online ahead of print.
 
White YN(1), Solans BP(1)(2), Denti P(3), van der Laan LE(3)(4), Schaaf HS(4), Vonasek B(5), Malik AA(6)(7), Draper HR(4), Hussain H(6), Hesseling AC(4), Garcia-Prats AJ(4)(5), Savic RM(1)(2).
 
BACKGROUND: Each year 25 000-32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children.

METHODS: Levofloxacin concentration and demographic data were pooled from 5 studies and analyzed using nonlinear mixed effects modeling. Simulations were performed using current World Health Organization (WHO)-recommended and model-informed optimized doses. Optimal levofloxacin doses were identified to target median adult area under the time-concentration curve (AUC)24 of 101 mg·h/L given current standard adult doses.

RESULTS: Data from 242 children (2.8 years [0.2-16.8] was used). Apparent clearance was 3.16 L/h for a 13-kg child. Age affected clearance, reaching 50% maturation at birth and 90% maturation at 8 months. Nondispersible tablets had 29% lower apparent oral bioavailability compared to dispersible tablets. Median exposures at current WHO-recommended doses were below the AUC target for children weighing <24 kg and under <10 years, resulting in approximately half of the exposure in adults. Model-informed doses of 16-33 mg/kg for dispersible  tablets or 16-50 mg/kg for nondispersible tablets were required to meet the AUC target without significantly exceeding the median adult Cmax.

CONCLUSIONS: Revised weight-band dosing guidelines with doses of >20 mg/kg are required to ensure adequate exposure. Further studies are needed to determine safety and tolerability of these higher doses.
 
© The Author(s) 2024. Published by Oxford University Press on behalf of 
Infectious Diseases Society of America.
 
DOI: 10.1093/cid/ciae024
PMID: 38340060

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From our February 2024 Newsletter

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1. Pharmacokinetics and cardiac safety of clofazimine in children with rifampicin-resistant tuberculosis.

Antimicrob Agents Chemother. 2024 Jan 10;68(1):e0079423. doi: 10.1128/aac.00794-23. Epub 2023 Dec 19.
 
Ali AM(1)(2), P Solans B(1), Hesseling AC(3), Winckler J(3), Schaaf HS(3), Draper HR(3), van der Laan L(3), Hughes J(3), Fourie B(3), Nielsen J(4), Wiesner L(5), Garcia-Prats AJ(#)(3)(6), Savic RM(#)(1).
 
Clofazimine is recommended for the treatment of rifampicin-resistant tuberculosis (RR-TB), but there is currently no verified dosing guideline for its use in children. There is only limited safety and no pharmacokinetic (PK) data available for children. We aimed to characterize clofazimine PK and its relationship with QT-interval prolongation in children. An observational cohort study of South African children <18 years old routinely treated for RR-TB with a clofazimine-containing regimen was analyzed. Clofazimine 100 mg gelatin capsules were given orally once daily (≥20 kg body weight), every second day (10 to <20 kg), or thrice weekly (<10 kg). PK sampling and electrocardiograms were completed pre-dose and at 1, 4, and 10 hours post-dose, and the population PK and Fridericia-corrected QT (QTcF) interval prolongation were characterized. Fifty-four children contributed both PK and QTcF data, with a median age (2.5th-97.5th centiles) of 3.3 (0.5-15.6) years; five children were living with HIV. Weekly area under the time-concentration curve at steady state was 79.1 (15.0-271) mg.h/L compared to an adult target of 60.9 (56.0-66.6) mg.h/L. Children living with HIV had four times higher clearance compared to those without. No child had a QTcF ≥500 ms. A linear concentration-QTcF relationship was found, with a drug effect of 0.05 (0.027, 0.075) ms/µg/L. In some of the first PK data in children, we found clofazimine exposure using an off-label dosing strategy was higher in children versus adults. Clofazimine concentrations were associated with an increase in QTcF, but severe prolongation was not observed. More data are required to inform dosing strategies in children.
 
DOI: 10.1128/aac.00794-23
PMCID: PMC10777824
PMID: 38112526 [Indexed for MEDLINE]
 
2. Quantitative measurement of antibiotic resistance in Mycobacterium tuberculosis reveals genetic determinants of resistance and susceptibility in a target gene approach.

 
Nat Commun. 2024 Jan 12;15(1):488. doi: 10.1038/s41467-023-44325-5.
 
CRyPTIC Consortium.
 
Collaborators: Barilar I, Battaglia S, Borroni E, Brandao AP, Brankin A, Cabibbe AM, Carter J, Chetty D, Cirillo DM, Claxton P, Clifton DA, Cohen T, Coronel J, Crook DW, Dreyer V, Earle SG, Escuyer V, Ferrazoli L, Fowler PW, Gao GF, Gardy J, Gharbia S, Ghisi KT, Ghodousi A, Gibertoni Cruz AL, Grandjean L, Grazian C, Groenheit R, Guthrie JL, He W, Hoffmann H, Hoosdally SJ, Hunt M, Iqbal Z, Ismail NA, Jarrett L, Joseph L, Jou R, Kambli P, Khot R, Knaggs J, Koch A, Kohlerschmidt D, Kouchaki S, Lachapelle AS, Lalvani A, Lapierre SG, Laurenson IF, Letcher B, Lin WH, Liu C, Liu D, Malone KM, Mandal A, Mansjö M, Calisto Matias DVL, Meintjes G, de Freitas Mendes F, Merker M, Mihalic M, Millard J, Miotto P, Mistry N, Moore D, Musser KA, Ngcamu D, Nhung HN, Niemann S, Nilgiriwala KS, Nimmo C, O'Donnell M, Okozi N, Oliveira RS, Omar SV, Paton N, Peto TEA, Pinhata JMW, Plesnik S, Puyen ZM, Rabodoarivelo MS, Rakotosamimanana N, Rancoita PMV, Rathod P, Robinson ER, Rodger G, Rodrigues C, Rodwell TC, Roohi A, Santos-Lazaro D, Shah S, Smith G, Kohl TA, Solano W, Spitaleri A, Steyn AJC, Supply P, Surve U, Tahseen S, Thuong NTT, Thwaites G, Todt K, Trovato A, Utpatel C, Van Rie A, Vijay S, Walker AS, Walker TM, Warren R, Werngren J, Wijkander M, Wilkinson RJ, Wilson DJ, Wintringer P, Xiao YX, Yang Y, Yanlin Z, Yao SY, Zhu B.
 
Update of Res Sq. 2023 Oct 02;:
 
The World Health Organization has a goal of universal drug susceptibility testing for patients with tuberculosis. However, molecular diagnostics to date have focused largely on first-line drugs and predicting susceptibilities in a binary manner (classifying strains as either susceptible or resistant). Here, we used a multivariable linear mixed model alongside whole genome sequencing and a quantitative microtiter plate assay to relate genomic mutations to minimum inhibitory concentration (MIC) in 15,211 Mycobacterium tuberculosis clinical isolates from 23 countries across five continents. We identified 492 unique MIC-elevating variants across 13 drugs, as well as 91 mutations likely linked to hypersensitivity. Our results advance genetics-based diagnostics for tuberculosis and serve as a curated training/testing dataset for development of drug resistance prediction algorithms.
 
© 2024. The Author(s).
 
DOI: 10.1038/s41467-023-44325-5
PMCID: PMC10786857
PMID: 38216576 [Indexed for MEDLINE]

3. Association of indicators of extensive disease and rifampin-resistant tuberculosis treatment outcomes: an individual participant data meta-analysis.
 
Thorax. 2024 Jan 18;79(2):169-178. doi: 10.1136/thorax-2023-220249.
 
Campbell JR(1)(2)(3), Brode SK(4)(5), Barry P(6), Bastos ML(7), Bonnet M(8), Guglielmetti L(9), Kempker R(10), Klimuk D(11), Laborín RL(12), Milanov V(13), Singla R(14), Skrahina A(11), Trajman A(3)(15), van der Werf TS(16), Viiklepp P(17), Menzies D(7)(2)(3).
 
BACKGROUND: Indicators of extensive disease-acid fast bacilli (AFB) smear positivity and lung cavitation-have been inconsistently associated with clinical rifampin-resistant/multidrug-resistant tuberculosis (RR/MDR-TB) outcomes. We evaluated the association of these indicators with end-of-treatment outcomes.

METHODS: We did an individual participant data meta-analysis of people treated for RR/MDR-TB with longer regimens with documented AFB smear and chest radiography findings. We compared people AFB smear-negative without cavities to people: (1) smear-negative with lung cavities; (2) smear-positive without lung cavities and (3) AFB smear-positive with lung cavities. Using multivariable logistic regression accounting for demographic, treatment and clinical factors, we calculated adjusted ORs (aOR) for any unfavourable outcome (death, lost to follow-up, failure/recurrence), and mortality and treatment failure/recurrence alone.

RESULTS: We included 5596 participants; included participants significantly differed from excluded participants. Overall, 774 (13.8%) were AFB smear-negative without cavities, 647 (11.6%) only had cavities, 1424 (25.4%) were AFB smear-positive alone and 2751 (49.2%) were AFB smear-positive with cavities. The median age was 37 years (IQR: 28-47), 3580 (64%) were male and 686 (12.5%) had HIV. Compared with participants AFB smear-negative without cavities, aOR (95% CI) for any unfavourable outcome was 1.0 (0.8 to 1.4) for participants smear-negative with lung cavities, 1.2 (0.9 to 1.5) if smear-positive without cavities and 1.6 (1.3 to 2.0) if AFB smear-positive with lung cavities. Odds were only significantly increased for mortality (1.5, 95% CI 1.1 to 2.1) and failure/recurrence (2.2, 95% CI 1.5 to 3.3) among participants AFB smear-positive with lung cavities.

CONCLUSION: Only the combination of AFB smear-positivity and lung cavitation was associated with unfavourable outcomes, suggesting they may benefit from stronger regimens.
 
© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and 
permissions. Published by BMJ.
 
DOI: 10.1136/thorax-2023-220249
PMID: 38135489 [Indexed for MEDLINE]

4. Drug-induced hypothyroidism in tuberculosis.
 
Expert Rev Endocrinol Metab. 2024 Jan 19:1-8. doi: 10.1080/17446651.2024.2307525. Online ahead of print.
 
Quiroz-Aldave JE(1), Durand-Vásquez MDC(1), Gamarra-Osorio ER(2), Concepción-Urteaga LA(3), Pecho-Silva S(4)(5), Rodríguez-Hidalgo LA(3), Concepción-Zavaleta MJ(4).
 
INTRODUCTION: Adverse reactions to tuberculosis treatment can impact patient adherence and prognosis. Hypothyroidism is a frequent adverse reaction caused using ethionamide, prothionamide, and para-aminosalicylic acid and is often underdiagnosed.

AREAS COVERED: We searched Scielo, Scopus, and EMBASE databases, including 67 articles. Antitubercular drug-induced hypothyroidism has a prevalence of 17%. It occurs after 2 to 3 months of treatment and resolves within 4 to 6 weeks after discontinuation. It is postulated to result from the inhibition of thyroperoxidase function, blocking thyroid hormone synthesis. Symptoms are nonspecific, necessitating individualized thyroid-stimulating hormone measurement for detection. Specific guidelines for management are lacking, but initiation of treatment with levothyroxine, as is customary for primary hypothyroidism, is recommended. Discontinuation of antitubercular drugs is discouraged, as it may lead to unfavorable consequences.

EXPERT OPINION: Antitubercular drug-induced hypothyroidism is more common than previously thought, affecting one in six MDR-TB patients. Despite diagnostic and treatment recommendations, implementation is hindered in low-income countries due to the lack of certified laboratories. New drugs for tuberculosis treatment may affect thyroid function, requiring vigilant monitoring for complications, including hypothyroidism.
 
DOI: 10.1080/17446651.2024.2307525
PMID: 38258451

5. Impaired lung function in adolescents with pulmonary tuberculosis during treatment and following treatment completion.

 
EClinicalMedicine. 2024 Jan 3;67:102406. doi: 10.1016/j.eclinm.2023.102406. eCollection 2024 Jan.
 
van der Zalm MM(1), Jongen VW(1)(2), Swanepoel R(3), Zimri K(1), Allwood B(4), Palmer M(1), Dunbar R(1), Goussard P(5), Schaaf HS(1), Hesseling AC(1), Seddon JA(1)(6).
 
BACKGROUND: Little is known about post-tuberculosis lung disease in adolescents. We prospectively assessed lung function in adolescents with microbiologically confirmed pulmonary tuberculosis during treatment and after treatment completion.

METHODS: In a prospective study, we enrolled adolescents diagnosed with microbiologically confirmed tuberculosis and healthy tuberculosis-exposed household controls, between October 2020 and July 2021 in Cape Town, South Africa. Spirometry, plethysmography, diffusion capacity lung function tests and 6-min walking test (6MWT) were completed according to international guidelines 2 months into treatment and following treatment completion. Abnormal lung function was defined as abnormal spirometry (z-score < -1.64 for forced expiratory volume in 1 s (FEV1) and/or forced vital capacity (FVC) and/or FEV1/FVC), plethysmography (total lung capacity (TLC) < 80% of predicted, residual volume over TLC of >45%) and/or diffusion capacity (DLCO z-score < -1.64).

FINDINGS: One-hundred adolescents were enrolled; 50 (50%) with tuberculosis and 50 (50%) healthy tuberculosis-exposed controls. Of the 50 adolescents with tuberculosis, ten had multidrug-resistant tuberculosis. Mean age of the group was 14.9 years (SD 2.7), 6 (6.0%) were living with HIV and 9 (9.0%) were previously treated for tuberculosis. Lung function improved over time; during treatment abnormal lung function was found in 76% of adolescents with tuberculosis, compared to 65% after treatment completion. Spirometry indices were lower in adolescents with tuberculosis compared to controls, both at 2 months and after treatment completion. Plethysmography in adolescents with tuberculosis showed that air-trapping was more common during treatment than in controls (12% vs 0%, respectively, p = 0.017); which improved following treatment completion. Adolescents with tuberculosis both during and after treatment completion walked a shorter distance than controls.

INTERPRETATION: Adolescents with tuberculosis have impaired lung function even after treatment completion. It is crucial to include adolescents in trials on the prevention and treatment of tuberculosis-associated respiratory morbidity.

FUNDING: EDCTP, National Institute of Health, Medical Research Council, BMBF.
 
© 2023 The Author(s).
 
DOI: 10.1016/j.eclinm.2023.102406
PMCID: PMC10796966
PMID: 38261903

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From our January 2024 Newsletter

1. Economic burden of multidrug-resistant tuberculosis on patients and households: a global systematic review and meta-analysis.

Sci Rep. 2023 Dec 15;13(1):22361. doi: 10.1038/s41598-023-47094-9.
 
Akalu TY(1)(2)(3), Clements ACA(4)(5), Wolde HF(6)(4)(7), Alene KA(6)(4).
 
Multidrug-resistant tuberculosis (MDR-TB) is a major health threat worldwide, causing a significant economic burden to patients and their families. Due to the longer duration of treatment and expensive second-line medicine, the economic burden of MDR-TB is assumed to be higher than drug-susceptible TB. However, the costs associated with MDR-TB are yet to be comprehensively quantified. We conducted this systematic review and meta-analysis to determine the global burden of catastrophic costs associated with MDR-TB on patients and their 
households. We systematically searched five databases (CINHAL, MEDLINE, Embase, Scopus, and Web of Science) from inception to 2 September 2022 for studies reporting catastrophic costs on patients and affected families of MDR-TB. The primary outcome of our study was the proportion of patients and households with catastrophic costs. Costs were considered catastrophic when a patient spends 20% or more of their annual household income on their MDR-TB diagnosis and care. The pooled proportion of catastrophic cost was determined using a random-effects meta-analysis. Publication bias was assessed using visualization of the funnel 
plots and the Egger regression test. Heterogeneity was assessed using I2, and sub-group analysis was conducted using study covariates as stratification variables. Finally, we used the Preferred Reporting Items for Reporting Systematic Review and Meta-Analysis-20 (PRISMA-20). The research protocol was registered in PROSPERO (CRD42021250909). Our search identified 6635 studies, of which 11 were included after the screening. MDR-TB patients incurred total costs ranging from $USD 650 to $USD 8266 during treatment. The mean direct cost and indirect cost incurred by MDR-TB patients were $USD 1936.25 (SD ± $USD 1897.03) and $USD 1200.35 (SD ± $USD 489.76), respectively. The overall burden of catastrophic cost among MDR-TB patients and households was 81.58% (95% Confidence Interval (CI) 74.13-89.04%). The catastrophic costs incurred by MDR-TB patients were significantly higher than previously reported for DS-TB patients. MDR-TB patients incurred more expenditure for direct costs than indirect costs. Social protection and financial support for patients and affected families are needed to mitigate the catastrophic economic consequences of MDR-TB.
 
© 2023. The Author(s).
 
DOI: 10.1038/s41598-023-47094-9
PMCID: PMC10724290
PMID: 38102144 [Indexed for MEDLINE]


2. Designing molecular diagnostics for current tuberculosis drug regimens.
 
Emerg Microbes Infect. 2023 Dec;12(1):2178243. doi: 10.1080/22221751.2023.2178243.
 
Georghiou SB(1), de Vos M(1), Velen K(1), Miotto P(2), Colman RE(1)(3), Cirillo DM(2), Ismail N(4), Rodwell TC(1)(3), Suresh A(1), Ruhwald M(1).
 
Diagnostic development must occur in parallel with drug development to ensure the longevity of new treatment compounds. Despite an increasing number of novel and repurposed anti-tuberculosis compounds and regimens, there remains a large number of drugs for which no rapid and accurate molecular diagnostic option 
exists. The lack of rapid drug susceptibility testing for linezolid, bedaquiline, clofazimine, the nitroimidazoles (i.e pretomanid and delamanid) and pyrazinamide at any level of the healthcare system compromises the effectiveness of current tuberculosis and drug-resistant tuberculosis treatment regimens. In the context of current WHO tuberculosis treatment guidelines as well as promising new regimens, we identify the key diagnostic gaps for initial and follow-on tests to diagnose emerging drug resistance and aid in regimen selection. Additionally, we comment on potential gene targets for inclusion in rapid molecular drug susceptibility assays and sequencing assays for novel and repurposed drug compounds currently prioritized in current regimens, and evaluate the feasibility of mutation detection given the design of existing technologies. Based on current knowledge, we also propose design priorities for next generation molecular assays to support triage of tuberculosis patients to appropriate and effective treatment regimens. We encourage assay developers to prioritize development of these key molecular assays and support the continued evolution, uptake, and utility of sequencing to build knowledge of tuberculosis resistance mechanisms and further inform rapid treatment decisions in order to curb resistance to critical drugs in current regimens and achieve End TB targets.
Trial registration: ClinicalTrials.gov identifier: NCT05117788..
 
DOI: 10.1080/22221751.2023.2178243
PMCID: PMC9980415
PMID: 36752055 [Indexed for MEDLINE]


3. Bedaquiline resistance in patients with drug-resistant tuberculosis in Cape Town, South Africa: a retrospective longitudinal cohort study.
 
Lancet Microbe. 2023 Dec;4(12):e972-e982. doi: 10.1016/S2666-5247(23)00172-6. Epub 2023 Nov 3.
 
Derendinger B(1), Dippenaar A(2), de Vos M(3), Huo S(4), Alberts R(1), Tadokera R(1), Limberis J(5), Sirgel F(1), Dolby T(6), Spies C(1), Reuter A(7), Folkerts M(8), Allender C(8), Lemmer D(8), Van Rie A(9), Gagneux S(10), Rigouts L(11), Te Riele J(12), Dheda K(13), Engelthaler DM(8), Warren R(1), Metcalfe J(5), Cox H(14), Theron G(15).
 
BACKGROUND: Bedaquiline is a life-saving tuberculosis drug undergoing global scale-up. People at risk of weak tuberculosis drug regimens are a priority for novel drug access despite the potential source of Mycobacterium tuberculosis-resistant strains. We aimed to characterise bedaquiline resistance in individuals who had sustained culture positivity during bedaquiline-based treatment.
 
METHODS: We did a retrospective longitudinal cohort study of adults (aged ≥18 years) with culture-positive pulmonary tuberculosis who received at least 4 months of a bedaquiline-containing regimen from 12 drug-resistant tuberculosis treatment facilities in Cape Town, South Africa, between Jan 20, 2016, and Nov 20, 2017. Sputum was programmatically collected at baseline (ie, before bedaquiline initiation) and each month to monitor treatment response per the national algorithm. The last available isolate from the sputum collected at or after 4 months of bedaquiline was designated the follow-up isolate. Phenotypic drug susceptibility testing for bedaquiline was done on baseline and follow-up isolates in MGIT960 media (WHO-recommended critical concentration of 1 μg/mL).Targeted deep sequencing for Rv0678, atpE, and pepQ, as well as whole-genome sequencing were also done.
 
FINDINGS: In total, 40 (31%) of 129 patients from an estimated pool were eligible for this study. Overall, three (8%) of 38 patients assessable by phenotypic drug susceptibility testing for bedaquiline had primary resistance, 18 (47%) gained resistance (acquired or reinfection), and 17 (45%) were susceptible at both baseline and follow-up. Several Rv0678 and pepQ single-nucleotide polymorphisms and indels were associated with resistance. Although variants occurred in Rv0676c and Rv1979c, these variants were not associated with resistance. Targeted deep sequencing detected low-level variants undetected by whole-genome sequencing; however, none were in genes without variants already detected by whole-genome sequencing. Patients with baseline fluoroquinolone resistance, clofazimine exposure, and four or less effective drugs were more likely to have bedaquiline-resistant gain. Resistance gain was primarily due to acquisition; however, some reinfection by resistant strains occurred.
 
INTERPRETATION: Bedaquiline-resistance gain, for which we identified risk factors, was common in these programmatically treated patients with sustained culture positivity. Our study highlights risks associated with implementing life-saving new drugs and shows evidence of bedaquiline-resistance transmission. Routine drug susceptibility testing should urgently accompany scale-up of new drugs; however, rapid drug susceptibility testing for bedaquiline remains challenging given the diversity of variants observed.
 
FUNDING: Doris Duke Charitable Foundation, US National Institute of Allergy and Infectious Diseases, South African Medical Research Council, National Research Foundation, Research Foundation Flanders, Stellenbosch University Faculty of Medicine Health Sciences, South African National Research Foundation, Swiss National Science Foundation, and Wellcome Trust.
 
Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd. All rights reserved.
 
DOI: 10.1016/S2666-5247(23)00172-6
PMID: 37931638 [Indexed for MEDLINE]

4. Determinants of catastrophic costs among households affected by multi-drug resistant tuberculosis in Ho Chi Minh City, Viet Nam: a prospective cohort study.
 
BMC Public Health. 2023 Dec 3;23(1):2372. doi: 10.1186/s12889-023-17078-5.
 
Pham TAM(1), Forse R(2)(3), Codlin AJ(1)(4), Phan THY(5), Nguyen TT(5), Nguyen N(4), Vo LNQ(5), Dat PT(6), Minh HDT(6), Nguyen LH(6), Nguyen HB(7), Nguyen NV(7)(8), Bodfish M(9), Lönnroth K(1), Wingfield T(1)(10)(11), Annerstedt KS(1).
 
BACKGROUND: Globally, most people with multidrug-resistant tuberculosis (MDR-TB) and their households experience catastrophic costs of illness, diagnosis, and care. However, the factors associated with experiencing catastrophic costs are poorly understood. This study aimed to identify risk factors associated with catastrophic costs incurrence among MDR-TB-affected households in Ho Chi Minh City (HCMC), Viet Nam.
 
METHODS: Between October 2020 and April 2022, data were collected using a locally-adapted, longitudinal WHO TB Patient Cost Survey in ten districts of HCMC. Ninety-four people with MDR-TB being treated with a nine-month TB regimen were surveyed at three time points: after two weeks of treatment initiation, completion of the intensive phase and the end of the treatment (approximately five and 10 months post-treatment initiation respectively). The catastrophic costs threshold was defined as total TB-related costs exceeding 20% of annual pre-TB household income. Logistic regression was used to identify variables associated with experiencing catastrophic costs. A sensitivity analysis examined the prevalence of catastrophic costs using alternative thresholds and cost estimation approaches.

RESULTS: Most participants (81/93 [87%]) experienced catastrophic costs despite the majority 86/93 (93%) receiving economic support through existing social protection schemes. Among participant households experiencing and not experiencing catastrophic costs, median household income was similar before MDR-TB treatment. However, by the end of MDR-TB treatment, median household income was lower (258 [IQR: 0-516] USD vs. 656 [IQR: 462-989] USD; p = 0.003), and median income loss was higher (2838 [IQR: 1548-5418] USD vs. 301 [IQR: 0-824] USD; p < 0.001) amongst the participant households who experienced catastrophic costs. Being the household's primary income earner before MDR-TB treatment (aOR = 11.2 [95% CI: 1.6-80.5]), having a lower educational level (aOR = 22.3 [95% CI: 1.5-344.1]) and becoming unemployed at the beginning of MDR-TB treatment (aOR = 35.6 [95% CI: 2.7-470.3]) were associated with experiencing catastrophic costs.
 
CONCLUSION: Despite good social protection coverage, most people with MDR-TB in HCMC experienced catastrophic costs. Incurrence of catastrophic costs was independently associated with being the household's primary income earner or being unemployed. Revision and expansion of strategies to mitigate TB-related catastrophic costs, in particular avoiding unemployment and income loss, are urgently required.
 
© 2023. The Author(s).
 
DOI: 10.1186/s12889-023-17078-5
PMCID: PMC10693707
PMID: 38042797 [Indexed for MEDLINE]


5. Addressing the needs of people with extensively drug-resistant TB through pre-approval access to drugs and research.
 
Public Health Action. 2023 Dec;13(4):126-129. doi: 10.5588/pha.23.0033. Epub 2023 Dec 7.
 
Stillo J(1)(2), Frick M(2)(3), Galarza J(2)(4), Kondratyuk S(2), Makone A(2)(5), McKenna L(2)(3), Vandevelde W(2)(6), Winarni P(2), Agbassi P(2).
 
Multiple therapeutic options exist for people with drug-resistant TB (DR-TB), but there is an urgent need to improve access to novel compounds and regimens for people with difficult to treat forms of TB. In additional to formal research studies and clinical trials, other mechanisms of accessing promising new TB compounds need to be introduced as soon as these drugs have shown efficacy and safety in phase II trials. Pre-approval access programs for newer TB drugs such as bedaquiline, delamanid, and pretomanid all suffered from shortcomings. These can be addressed for the next generation of new TB drugs through a series of concerted actions by stakeholders at multiple levels. In this viewpoint, we advocate for transparent, accessible pre-approval access as a core element of person-centered care for DR-TB.
 
© 2023 The Union.
 
DOI: 10.5588/pha.23.0033
PMCID: PMC10703140
PMID: 38077718

​

​From our December 2023 Newsletter

1. Pediatric multi-drug-resistant tuberculosis in Germany - diagnostic and 
therapeutic challenges of an "orphan disease"

Eur J Pediatr. 2023 Nov;182(11):5167-5179. doi: 10.1007/s00431-023-05167-x. Epub 2023 Sep 14.
 
Schäfer HL(1), Barker M(2), Follmann P(3), Günther A(2), Hörning A(4), Kaiser-Labusch P(5), Kerzel S(6), Maier C(7), Roth S(6), Schmidt C(8), Schütz K(9), Stehling F(10), Struffert M(7), Timmesfeld N(11), Vöhringer P(12), Brinkmann F(7)(13).
 
Delay in diagnosing multidrug-resistant tuberculosis (MDR-pTB) in children prolongs time to effective treatment. Data on risk factors for pediatric MDR from low-incidence countries are scarce. Retrospective nationwide case-control study to analyze MDR-pTB cases in Germany between 2010 and 2020 in comparison to a drug-susceptible (DS)-pTB group. We included 52 MDR cases (24 tuberculosis (TB), 28 TB infection (TBI); mean age 7.3 years) and 56 DS cases (31 TB, 26 TBI; mean age 7.9 years). Groups were similar for sex, household size, and migration background. Compared to the DS group, more children with MDR were born in the Commonwealth of Independent States (CIS) (22% MDR-pTB vs. 13% DS-pTB, n.s.) and had more MDR index cases (94% MDR-pTB, 5% DS-pTB, p < 0.001). The interval between first healthcare contact and initiation of effective therapy was significantly longer in MDR-pTB (47 days) than in DS-pTB (11 days, p < 0.001), correlating with disease progression. Treatment for MDR-pTB was successful in 74%, but 22% experienced long-term adverse effects (e.g., hepatopathy, hearing loss).

CONCLUSIONS: Close contact to MDR cases or birth in MDR-TB-high-incidence countries are risk factors for MDR-pTB. Early identification of potential MDR index cases by contact investigation, and susceptibility testing in children from high-burden MDR-TB countries are essential for timely diagnosis and treatment, reducing the severity of disease and treatment side effects.

TRIAL REGISTRATION: Deutsches Register Klinischer Studien (https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023817), DRKS00023817, 2020-09-08.

WHAT IS KNOWN: •Management of children with MDR-TB remains challenging due to difficulties in diagnosing MDR-TB (lack of information on MDR index case, lack of microbiological confirmation in paucibacillary disease).•Choice of treatment regimen and monitoring of side effects.

WHAT IS NEW: •Children with an MDR-TB index or born in a MDR-TB-high-incidence country are at higher risk of developing MDR-TB in a low incidence country. •The time lag to initiate treatment in MDR-TB is longer than in DS-TB and MDR-TB treatment involves a higher risk of adverse effects in longer treatment regimens especially with injectables.
 
© 2023. The Author(s).
 
DOI: 10.1007/s00431-023-05167-x
PMCID: PMC10640426
PMID: 37707590 [Indexed for MEDLINE]

2. Bedaquiline resistance in patients with drug-resistant tuberculosis in Cape Town, South Africa: a retrospective longitudinal cohort study.
 
Lancet Microbe. 2023 Nov 3:S2666-5247(23)00172-6. doi: 10.1016/S2666-5247(23)00172-6. Online ahead of print.
 
Derendinger B(1), Dippenaar A(2), de Vos M(3), Huo S(4), Alberts R(1), Tadokera R(1), Limberis J(5), Sirgel F(1), Dolby T(6), Spies C(1), Reuter A(7), Folkerts M(8), Allender C(8), Lemmer D(8), Van Rie A(9), Gagneux S(10), Rigouts L(11), Te Riele J(12), Dheda K(13), Engelthaler DM(8), Warren R(1), Metcalfe J(5), Cox H(14), Theron G(15).
 
BACKGROUND: Bedaquiline is a life-saving tuberculosis drug undergoing global scale-up. People at risk of weak tuberculosis drug regimens are a priority for novel drug access despite the potential source of Mycobacterium tuberculosis-resistant strains. We aimed to characterise bedaquiline resistance in individuals who had sustained culture positivity during bedaquiline-based treatment.

METHODS: We did a retrospective longitudinal cohort study of adults (aged ≥18 years) with culture-positive pulmonary tuberculosis who received at least 4 months of a bedaquiline-containing regimen from 12 drug-resistant tuberculosis treatment facilities in Cape Town, South Africa, between Jan 20, 2016, and Nov 20, 2017. Sputum was programmatically collected at baseline (ie, before bedaquiline initiation) and each month to monitor treatment response per the national algorithm. The last available isolate from the sputum collected at or after 4 months of bedaquiline was designated the follow-up isolate. Phenotypic drug susceptibility testing for bedaquiline was done on baseline and follow-up isolates in MGIT960 media (WHO-recommended critical concentration of 1 μg/mL).Targeted deep sequencing for Rv0678, atpE, and pepQ, as well as whole-genome sequencing were also done.

FINDINGS: In total, 40 (31%) of 129 patients from an estimated pool were eligible for this study. Overall, three (8%) of 38 patients assessable by phenotypic drug susceptibility testing for bedaquiline had primary resistance, 18 (47%) gained resistance (acquired or reinfection), and 17 (45%) were susceptible at both baseline and follow-up. Several Rv0678 and pepQ single-nucleotide polymorphisms and indels were associated with resistance. Although variants occurred in Rv0676c and Rv1979c, these variants were not associated with resistance. Targeted deep sequencing detected low-level variants undetected by whole-genome sequencing; however, none were in genes without variants already detected by whole-genome sequencing. Patients with baseline fluoroquinolone resistance, clofazimine exposure, and four or less effective drugs were more likely to have bedaquiline-resistant gain. Resistance gain was primarily due to acquisition; however, some reinfection by resistant strains occurred.

INTERPRETATION: Bedaquiline-resistance gain, for which we identified risk factors, was common in these programmatically treated patients with sustained culture positivity. Our study highlights risks associated with implementing life-saving new drugs and shows evidence of bedaquiline-resistance transmission. Routine drug susceptibility testing should urgently accompany scale-up of new drugs; however, rapid drug susceptibility testing for bedaquiline remains challenging given the diversity of variants observed.

FUNDING: Doris Duke Charitable Foundation, US National Institute of Allergy and Infectious Diseases, South African Medical Research Council, National Research Foundation, Research Foundation Flanders, Stellenbosch University Faculty of Medicine Health Sciences, South African National Research Foundation, Swiss National Science Foundation, and Wellcome Trust.
 
Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open 
Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. 
All rights reserved.
 
DOI: 10.1016/S2666-5247(23)00172-6
PMID: 37931638
 
3. Tuberculosis Variant with Rifampin Resistance Undetectable by Xpert MTB/RIF, Botswana.
 
Emerg Infect Dis. 2023 Nov;29(11):2403-2406. doi: 10.3201/eid2911.230987.
 
Modongo C, Barilar I, Wang Q, Molefi T, Makhondo T, Niemann S, Shin SS.
 
GeneXpert MTB/RIF, a tool widely used for diagnosing tuberculosis, has limitations for detecting rifampin resistance in certain variants. We report transmission of a pre-extensively drug-resistant variant in Botswana that went undetected by GeneXpert. The public health impact of misdiagnosis emphasizes the need for comprehensive molecular testing to identify resistance and guide treatment.
 
DOI: 10.3201/eid2911.230987
PMCID: PMC10617350
PMID: 37877680 [Indexed for MEDLINE]

4. Community-based directly observed therapy is effective and results in better treatment outcomes for patients with multi-drug resistant tuberculosis in Uganda.
 
BMC Health Serv Res. 2023 Nov 13;23(1):1248. doi: 10.1186/s12913-023-10120-7.
 
Makabayi-Mugabe R(1)(2), Musaazi J(3), Zawedde-Muyanja S(3)(4), Kizito E(3), Fatta K(5), Namwanje-Kaweesi H(4), Turyahabwe S(6), Nkolo A(4).
 
BACKGROUND: Health facility-based directly observed therapy (HF DOT) is the main strategy for the management of patients with drug-resistant tuberculosis (DR TB) in Uganda, however, this still yields sub-optimal treatment outcomes. We set out to assess the effectiveness of community-based directly observed therapy (CB DOT) for the treatment of DR TB in Uganda.

METHODS: Using a previously developed patient-centered model for CB DOT, we assigned community health workers (CHWs) as primary caregivers to patients diagnosed with DR TB. CHWs administered daily DOT to patients in their homes. Once a month, patients received travel vouchers to attend clinic visits for treatment monitoring. We assessed the effectiveness of this model using a quasi-experimental pre and post-study. From December 2020 to March 2022, we enrolled adult DR-TB patients on the CB DOT model. We collected retrospective data from patients who had received care using the HF DOT model during the year before the study started. The adjusted effect of CB DOT versus HF DOT on DR TB treatment success was estimated usingmodified Poisson regression model with robust cluster variance estimator.

RESULTS: We analyzed data from 264 DR TB patients (152 HF DOT, 112 CB DOT). The majority were males (67.8%) with a median age of 36 years (IQR 29 to 44 years). Baseline characteristics were similar across the comparison groups, except for educational level, regimen type, and organizational unit with age being borderline. The treatment success rate in the CB DOT group was 12% higher than that in the HF DOT (adjusted prevalence ratio (aPR)= 1.12 [95%CI 1.01, 1.24], P-value=0.03). Males were less likely to achieve treatment success compared to their female counterparts (aPR=0.87 [95% CI 0.78, 0.98], P-value=0.02). A total of 126 (47.7%) of 264 patients reported at least one adverse event. The HF DOT group had a higher proportion of patients with at least one adverse event compared to the CB DOT group (90/152 [59.2%] versus 36/112 [32.1], P-value<0.01). The model was acceptable among patients (93.6%) and health workers (94.1%).

CONCLUSIONS: CB DOT for DR-TB care is effective and results in better treatment outcomes than HF DOT. The cost-effectiveness of this model of care should be further evaluated.
 
© 2023. The Author(s).
 
DOI: 10.1186/s12913-023-10120-7
PMCID: PMC10644403
PMID: 37957610 [Indexed for MEDLINE]