Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 2023 December 1; Volume 27 (Issue 12); 885-898.; DOI:10.5588/ijtld.23.0341
du Cros PAK, Greig J, Cross GB, Cousins C, Berry C, et al.
Int J Tuberc Lung Dis. 2023 December 1; Volume 27 (Issue 12); 885-898.; DOI:10.5588/ijtld.23.0341
English
Français
BACKGROUND
The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.
METHODS
A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.
RESULTS
Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.
CONCLUSION
These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.
The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.
METHODS
A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.
RESULTS
Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.
CONCLUSION
These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 2023 October 1; Volume 27 (Issue 10); 748-753.; DOI:10.5588/ijtld.23.0066
Rekart ML, Aung A, Cullip T, Mulanda WK, Mun L, et al.
Int J Tuberc Lung Dis. 2023 October 1; Volume 27 (Issue 10); 748-753.; DOI:10.5588/ijtld.23.0066
BACKGROUND
Tajikistan has a high burden of rifampicin-resistant TB (RR-TB), with 2,700 new cases estimated for 2021 (28/100,000 population). TB is spread among household members through close interaction and children exposed through household contact progress to disease rapidly and frequently.
METHODS
We retrospectively analysed programmatic data from household contact tracing in Dushanbe over 50 months. We calculated person-years of follow-up, contact tracing yield, number needed to screen (NNS) and number needed to test (NNT) to find one new case, and time to diagnosis.
RESULTS
We screened 6,654 household contacts of 830 RR-TB index cases; 47 new RR-TB cases were detected, 43 in Year 1 and 4 in Years 2 or 3. Ten were aged <5 years; 46/47 had TB symptoms, 34/45 had chest radiographs consistent with TB, 11/35 were Xpert Ultra-positive, 29/32 were tuberculin skin test-positive and 28/47 had positive TB culture and phenotypic drug susceptibility results. The NNS to find one RR-TB case was 141.57 and the NNT was 34.49. The yields for different types of contacts were as follows: 0.7% for screened contacts, 2.9% for tested contacts, 17.0% for symptomatic contacts and 12.1% for symptomatic contacts aged below 5 years.
CONCLUSION
RR-TB household contact tracing was feasible and productive in Tajikistan, a low middle-income country with an inefficient healthcare delivery system.
Tajikistan has a high burden of rifampicin-resistant TB (RR-TB), with 2,700 new cases estimated for 2021 (28/100,000 population). TB is spread among household members through close interaction and children exposed through household contact progress to disease rapidly and frequently.
METHODS
We retrospectively analysed programmatic data from household contact tracing in Dushanbe over 50 months. We calculated person-years of follow-up, contact tracing yield, number needed to screen (NNS) and number needed to test (NNT) to find one new case, and time to diagnosis.
RESULTS
We screened 6,654 household contacts of 830 RR-TB index cases; 47 new RR-TB cases were detected, 43 in Year 1 and 4 in Years 2 or 3. Ten were aged <5 years; 46/47 had TB symptoms, 34/45 had chest radiographs consistent with TB, 11/35 were Xpert Ultra-positive, 29/32 were tuberculin skin test-positive and 28/47 had positive TB culture and phenotypic drug susceptibility results. The NNS to find one RR-TB case was 141.57 and the NNT was 34.49. The yields for different types of contacts were as follows: 0.7% for screened contacts, 2.9% for tested contacts, 17.0% for symptomatic contacts and 12.1% for symptomatic contacts aged below 5 years.
CONCLUSION
RR-TB household contact tracing was feasible and productive in Tajikistan, a low middle-income country with an inefficient healthcare delivery system.
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 2023 August 1; Volume 27 (Issue 8); 584-598.; DOI:10.5588/ijtld.23.0085
Chiang SS, Graham SM, Schaaf HS, Marais BJ, Sant’Anna CC, et al.
Int J Tuberc Lung Dis. 2023 August 1; Volume 27 (Issue 8); 584-598.; DOI:10.5588/ijtld.23.0085
BACKGROUND
These clinical standards aim to provide guidance for diagnosis, treatment, and management of drug-susceptible TB in children and adolescents.
METHODS
Fifty-two global experts in paediatric TB participated in a Delphi consensus process. After eight rounds of revisions, 51/52 (98%) participants endorsed the final document.
RESULTS
Eight standards were identified: Standard 1, Age and developmental stage are critical considerations in the assessment and management of TB; Standard 2, Children and adolescents with symptoms and signs of TB disease should undergo prompt evaluation, and diagnosis and treatment initiation should not depend on microbiological confirmation; Standard 3, Treatment initiation is particularly urgent in children and adolescents with presumptive TB meningitis and disseminated (miliary) TB; Standard 4, Children and adolescents should be treated with an appropriate weight-based regimen; Standard 5, Treating TB infection (TBI) is important to prevent disease; Standard 6, Children and adolescents should receive home-based/community-based treatment support whenever possible; Standard 7, Children, adolescents, and their families should be provided age-appropriate support to optimise engagement in care and clinical outcomes; and Standard 8, Case reporting and contact tracing should be conducted for each child and adolescent.
CONCLUSION
These consensus-based clinical standards, which should be adapted to local contexts, will improve the care of children and adolescents affected by TB.
These clinical standards aim to provide guidance for diagnosis, treatment, and management of drug-susceptible TB in children and adolescents.
METHODS
Fifty-two global experts in paediatric TB participated in a Delphi consensus process. After eight rounds of revisions, 51/52 (98%) participants endorsed the final document.
RESULTS
Eight standards were identified: Standard 1, Age and developmental stage are critical considerations in the assessment and management of TB; Standard 2, Children and adolescents with symptoms and signs of TB disease should undergo prompt evaluation, and diagnosis and treatment initiation should not depend on microbiological confirmation; Standard 3, Treatment initiation is particularly urgent in children and adolescents with presumptive TB meningitis and disseminated (miliary) TB; Standard 4, Children and adolescents should be treated with an appropriate weight-based regimen; Standard 5, Treating TB infection (TBI) is important to prevent disease; Standard 6, Children and adolescents should receive home-based/community-based treatment support whenever possible; Standard 7, Children, adolescents, and their families should be provided age-appropriate support to optimise engagement in care and clinical outcomes; and Standard 8, Case reporting and contact tracing should be conducted for each child and adolescent.
CONCLUSION
These consensus-based clinical standards, which should be adapted to local contexts, will improve the care of children and adolescents affected by TB.
Journal Article > LetterFull Text
Int J Tuberc Lung Dis. 2023 July 1; Volume 27 (Issue 7); 567-569.; DOI:10.5588/ijtld.22.0632
Vengurlekar D, Walker C, Mahajan R, Dalal A, Chavan VV, et al.
Int J Tuberc Lung Dis. 2023 July 1; Volume 27 (Issue 7); 567-569.; DOI:10.5588/ijtld.22.0632
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 2023 June 1; Volume 27 (Issue 6); 451-457.; DOI:10.5588/ijtld.22.0613
Rich ML, Khan UT, Zeng C, LaHood AN, Franke MF, et al.
Int J Tuberc Lung Dis. 2023 June 1; Volume 27 (Issue 6); 451-457.; DOI:10.5588/ijtld.22.0613
English
Français
BACKGROUND
Evidence of the effectiveness of the WHO-recommended design of longer individualized regimens for multidrug- or rifampicin-resistant TB (MDR/RR-TB) is limited.
OBJECTIVES
To report end-of-treatment outcomes for MDR/RR-TB patients from a 2015–2018 multi-country cohort that received a regimen consistent with current 2022 WHO updated recommendations and describe the complexities of comparing regimens.
METHODS
We analyzed a subset of participants from the endTB Observational Study who initiated a longer MDR/RR-TB regimen that was consistent with subsequent 2022 WHO guidance on regimen design for longer treatments. We excluded individuals who received an injectable agent or who received fewer than four likely effective drugs.
RESULTS
Of the 759 participants analyzed, 607 (80.0%, 95% CI 77.0–82.7) experienced successful end-of-treatment outcomes. The frequency of success was high across groups, whether stratified on number of Group A drugs or fluoroquinolone resistance, and ranged from 72.1% to 90.0%. Regimens were highly variable regarding composition and the duration of individual drugs.
CONCLUSIONS
Longer, all-oral, individualized regimens that were consistent with 2022 WHO guidance on regimen design had high frequencies of treatment success. Heterogeneous regimen compositions and drug durations precluded meaningful comparisons. Future research should examine which combinations of drugs maximize safety/tolerability and effectiveness.
Evidence of the effectiveness of the WHO-recommended design of longer individualized regimens for multidrug- or rifampicin-resistant TB (MDR/RR-TB) is limited.
OBJECTIVES
To report end-of-treatment outcomes for MDR/RR-TB patients from a 2015–2018 multi-country cohort that received a regimen consistent with current 2022 WHO updated recommendations and describe the complexities of comparing regimens.
METHODS
We analyzed a subset of participants from the endTB Observational Study who initiated a longer MDR/RR-TB regimen that was consistent with subsequent 2022 WHO guidance on regimen design for longer treatments. We excluded individuals who received an injectable agent or who received fewer than four likely effective drugs.
RESULTS
Of the 759 participants analyzed, 607 (80.0%, 95% CI 77.0–82.7) experienced successful end-of-treatment outcomes. The frequency of success was high across groups, whether stratified on number of Group A drugs or fluoroquinolone resistance, and ranged from 72.1% to 90.0%. Regimens were highly variable regarding composition and the duration of individual drugs.
CONCLUSIONS
Longer, all-oral, individualized regimens that were consistent with 2022 WHO guidance on regimen design had high frequencies of treatment success. Heterogeneous regimen compositions and drug durations precluded meaningful comparisons. Future research should examine which combinations of drugs maximize safety/tolerability and effectiveness.
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 2023 May 1; Volume 27 (Issue 5); 381-386.; DOI:10.5588/ijtld.22.0536
Moe S, Rekart ML, Hernandez D, Sholpan A, Ismailov A, et al.
Int J Tuberc Lung Dis. 2023 May 1; Volume 27 (Issue 5); 381-386.; DOI:10.5588/ijtld.22.0536
BACKGROUND:
Bedaquiline (BDQ) is widely used in the treatment of rifampicin-resistant TB (RR-TB). However, resistance to BDQ is now emerging. There are no standardised regimens for BDQ-resistant TB. This study aims to share experience in managing primary BDQ-resistant TB.
METHODS:
We performed a retrospective study of patients treated for RR-TB in Karakalpakstan, Uzbekistan, from January 2017 to March 2022. We identified patients with resistance to BDQ with no history of BDQ exposure. We describe baseline characteristics, treatment and follow-up of these patients.
RESULTS:
Twelve of the 1,930 patients (0.6%) had baseline samples resistant to BDQ with no history of BDQ exposure, 75% (9/12) of whom had been previously treated for TB. Ten (83.3%) were resistant to fluoroquinolones; respectively 66% and 50% had culture conversion by Month 3 and Month 6. The interim
treatment outcomes were as follows: unfavourable treatment outcomes (3/12, 25%), favourable outcomes (2/12, 17%); the remaining seven (58%) were continuing treatment.
CONCLUSIONS:
A large proportion of the cases had previously been treated for TB and had TB resistant to quinolone.
Both patients who had not experienced culture conversion by Month 3 had an unfavourable treatment outcome. Therefore, we recommend monthly monitoring of culture status for patients on treatment regimens for BDQ resistance.
Bedaquiline (BDQ) is widely used in the treatment of rifampicin-resistant TB (RR-TB). However, resistance to BDQ is now emerging. There are no standardised regimens for BDQ-resistant TB. This study aims to share experience in managing primary BDQ-resistant TB.
METHODS:
We performed a retrospective study of patients treated for RR-TB in Karakalpakstan, Uzbekistan, from January 2017 to March 2022. We identified patients with resistance to BDQ with no history of BDQ exposure. We describe baseline characteristics, treatment and follow-up of these patients.
RESULTS:
Twelve of the 1,930 patients (0.6%) had baseline samples resistant to BDQ with no history of BDQ exposure, 75% (9/12) of whom had been previously treated for TB. Ten (83.3%) were resistant to fluoroquinolones; respectively 66% and 50% had culture conversion by Month 3 and Month 6. The interim
treatment outcomes were as follows: unfavourable treatment outcomes (3/12, 25%), favourable outcomes (2/12, 17%); the remaining seven (58%) were continuing treatment.
CONCLUSIONS:
A large proportion of the cases had previously been treated for TB and had TB resistant to quinolone.
Both patients who had not experienced culture conversion by Month 3 had an unfavourable treatment outcome. Therefore, we recommend monthly monitoring of culture status for patients on treatment regimens for BDQ resistance.
Journal Article > LetterSubscription Only
Int J Tuberc Lung Dis. 2023 April 1; Volume 27 (Issue 4); 338-340.; DOI:10.5588/ijtld.22.0678
Campbell JR, Chan ED, Anderson LF, Bonnet M, Brode SK, et al.
Int J Tuberc Lung Dis. 2023 April 1; Volume 27 (Issue 4); 338-340.; DOI:10.5588/ijtld.22.0678
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 2023 January 1; Volume 27 (Issue 1); 34-40.; DOI:10.5588/ijtld.22.0324
Zeng C, Mitnick CD, Hewison CCH, Bastard M, Khan PY, et al.
Int J Tuberc Lung Dis. 2023 January 1; Volume 27 (Issue 1); 34-40.; DOI:10.5588/ijtld.22.0324
BACKGROUND
The WHO provides standardized outcome definitions for rifampicin-resistant (RR) and multidrug-resistant (MDR) TB. However, operationalizing these definitions can be challenging in some clinical settings, and incorrect classification may generate bias in reporting and research. Outcomes calculated by algorithms can increase standardization and be adapted to suit the research question. We evaluated concordance between clinician-assigned treatment outcomes and outcomes calculated based on one of two standardized algorithms, one which identified failure at its earliest possible recurrence (i.e., failure-dominant algorithm), and one which calculated the outcome based on culture results at the end of treatment, regardless of early occurrence of failure (i.e., success-dominant algorithm).
METHODS
Among 2,525 patients enrolled in the multi-country endTB observational study, we calculated the frequencies of concordance using cross-tabulations of clinician-assigned and algorithm-assigned outcomes. We summarized the common discrepancies.
RESULTS
Treatment success calculated by algorithms had high concordance with treatment success assigned by clinicians (95.8 and 97.7% for failure-dominant and success-dominant algorithms, respectively). The frequency and pattern of the most common discrepancies varied by country.
CONCLUSION
High concordance was found between clinician-assigned and algorithm-assigned outcomes. Heterogeneity in discrepancies across settings suggests that using algorithms to calculate outcomes may minimize bias.
The WHO provides standardized outcome definitions for rifampicin-resistant (RR) and multidrug-resistant (MDR) TB. However, operationalizing these definitions can be challenging in some clinical settings, and incorrect classification may generate bias in reporting and research. Outcomes calculated by algorithms can increase standardization and be adapted to suit the research question. We evaluated concordance between clinician-assigned treatment outcomes and outcomes calculated based on one of two standardized algorithms, one which identified failure at its earliest possible recurrence (i.e., failure-dominant algorithm), and one which calculated the outcome based on culture results at the end of treatment, regardless of early occurrence of failure (i.e., success-dominant algorithm).
METHODS
Among 2,525 patients enrolled in the multi-country endTB observational study, we calculated the frequencies of concordance using cross-tabulations of clinician-assigned and algorithm-assigned outcomes. We summarized the common discrepancies.
RESULTS
Treatment success calculated by algorithms had high concordance with treatment success assigned by clinicians (95.8 and 97.7% for failure-dominant and success-dominant algorithms, respectively). The frequency and pattern of the most common discrepancies varied by country.
CONCLUSION
High concordance was found between clinician-assigned and algorithm-assigned outcomes. Heterogeneity in discrepancies across settings suggests that using algorithms to calculate outcomes may minimize bias.
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 2023 January 1; Volume 27 (Issue 1); 41-48.; DOI:10.5588/ijtld.22.0138
Mansoor H, Hirani N, Chavan VV, Das M, Sharma J, et al.
Int J Tuberc Lung Dis. 2023 January 1; Volume 27 (Issue 1); 41-48.; DOI:10.5588/ijtld.22.0138
BACKGROUND
In high TB burden countries, access to drug susceptibility testing is a major bottleneck. Targeted next-generation sequencing (tNGS) is a promising technology for rapid resistance detection. This study assessed the role of tNGS for the diagnosis of drug-resistant TB (DR-TB).
METHODS
A total of 161 samples from bacteriologically confirmed TB cases were subjected to tNGS using the Deeplex® Myc-TB kit and sequenced using the MiSeq platform. These samples were also processed for conventional phenotypic DST (pDST) using 13 drugs on Mycobacteria Growth Indicator Tube and line-probe assays (MTBDR plus and MTBDRsl).
RESULTS
There were 146 DR-TB and 15 drug-susceptible TB (DS-TB) samples. About 70% of patients with DR-TB had no previous TB treatment history. Overall, 88.2% had rifampicin-resistant/multidrug-resistant TB (RR/MDR-TB), 58.5% pre-extensively drug-resistant TB (pre-XDR-TB) and 9.2% had XDR-TB as defined by the WHO (2020). Around 8% (n=13) of samples were non-culturable; however, identified 8 were resistant to first and second-line drugs using tNGS. Resistance frequency was similar across methods, with discordance in drugs less reliable using pDST or with limited mutational representation within databases. Sensitivities were aligned with literature reports for most drugs. We observed 10% heteroresistance, while 75% of strains were of Lineages 2 and 3.
CONCLUSIONS
Programme data supported tNGS in the diagnosis of DR-TB for early treatment using individualised regimens.
In high TB burden countries, access to drug susceptibility testing is a major bottleneck. Targeted next-generation sequencing (tNGS) is a promising technology for rapid resistance detection. This study assessed the role of tNGS for the diagnosis of drug-resistant TB (DR-TB).
METHODS
A total of 161 samples from bacteriologically confirmed TB cases were subjected to tNGS using the Deeplex® Myc-TB kit and sequenced using the MiSeq platform. These samples were also processed for conventional phenotypic DST (pDST) using 13 drugs on Mycobacteria Growth Indicator Tube and line-probe assays (MTBDR plus and MTBDRsl).
RESULTS
There were 146 DR-TB and 15 drug-susceptible TB (DS-TB) samples. About 70% of patients with DR-TB had no previous TB treatment history. Overall, 88.2% had rifampicin-resistant/multidrug-resistant TB (RR/MDR-TB), 58.5% pre-extensively drug-resistant TB (pre-XDR-TB) and 9.2% had XDR-TB as defined by the WHO (2020). Around 8% (n=13) of samples were non-culturable; however, identified 8 were resistant to first and second-line drugs using tNGS. Resistance frequency was similar across methods, with discordance in drugs less reliable using pDST or with limited mutational representation within databases. Sensitivities were aligned with literature reports for most drugs. We observed 10% heteroresistance, while 75% of strains were of Lineages 2 and 3.
CONCLUSIONS
Programme data supported tNGS in the diagnosis of DR-TB for early treatment using individualised regimens.
Journal Article > LetterFull Text
Int J Tuberc Lung Dis. 2022 December 1; Volume 26 (Issue 12); 1180-1182.; DOI:10.5588/ijtld.22.0335
Memani B, Furin J, Cox HS, Reuter A
Int J Tuberc Lung Dis. 2022 December 1; Volume 26 (Issue 12); 1180-1182.; DOI:10.5588/ijtld.22.0335