Conference Material > Slide Presentation
Guglielmetti L, Khan U, Velasquez GE, Gouillou M, Lachenal N, et al.
MSF Scientific Day International 2024. 2024 May 16; DOI:10.57740/HWpBuX
Conference Material > Slide Presentation
Yatskevich N, Hurevich H, Solodovnikova V, Garsevanidze E, Lachenal N, et al.
MSF Scientific Day International 2023. 2023 June 7; DOI:10.57740/3sk2-bf43
Journal Article > CommentaryFull Text
Int J Tuberc Lung Dis. 2020 October 1; Volume 24 (Issue 10); 1081-1086.; DOI:10.5588/ijtld.20.0141
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.; DOI:10.5588/ijtld.20.0141
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.
Journal Article > ProtocolFull Text
Trials. 2023 November 30; Volume 24 (Issue 1); 773.; DOI:10.1186/s13063-023-07701-6
Patil SB, Tamirat M, Khazhidinov K, Ardizzoni E, Atger M, et al.
Trials. 2023 November 30; Volume 24 (Issue 1); 773.; DOI:10.1186/s13063-023-07701-6
BACKGROUND
Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients.
METHODS
endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations.
DISCUSSION
This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen.
Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients.
METHODS
endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations.
DISCUSSION
This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen.
Journal Article > ProtocolFull Text
Trials. 2021 September 25; Volume 22 (Issue 1); 651.; DOI:10.1186/s13063-021-05491-3
Guglielmetti L, Ardizzoni E, Atger M, Baudin E, Berikova E, et al.
Trials. 2021 September 25; Volume 22 (Issue 1); 651.; DOI:10.1186/s13063-021-05491-3
BACKGROUND
Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings.
METHODS
endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations.
DISCUSSION
The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier NCT02754765.
Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings.
METHODS
endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations.
DISCUSSION
The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier NCT02754765.
Journal Article > ResearchFull Text
Clin Infect Dis. 2022 October 15; Volume 75 (Issue 8); 1307-1314.; DOI:10.1093/cid/ciac176
Huerga H, Khan UT, Bastard M, Mitnick CD, Lachenal N, et al.
Clin Infect Dis. 2022 October 15; Volume 75 (Issue 8); 1307-1314.; DOI:10.1093/cid/ciac176
BACKGROUND
Concomitant use of bedaquiline (Bdq) and delamanid (Dlm) for multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) has raised concerns about a potentially poor risk-benefit ratio. Yet, this combination is an important alternative for patients infected with strains of TB with complex drug resistance profiles or who cannot tolerate other therapies. We assessed safety and treatment outcomes of MDR/RR-TB patients receiving concomitant Bdq and Dlm, along with other second-line anti-TB drugs.
METHODS
We conducted a multi-centric, prospective observational cohort study across 14 countries among patients receiving concomitant Bdq-Dlm treatment. Patients were recruited between April 2015 and September 2018 and were followed until the end of treatment. All serious adverse events and adverse events of special interest (AESI), leading to a treatment change, or judged significant by a clinician, were systematically monitored and documented.
RESULTS
Overall, 472 patients received Bdq and Dlm concomitantly. A large majority also received linezolid (89.6%) and clofazimine (84.5%). Nearly all (90.3%) had extensive disease; most (74.2%) had resistance to fluoroquinolones. The most common AESI were peripheral neuropathy (134, 28.4%) and electrolyte depletion (94, 19.9%). Acute kidney injury and myelosuppression were seen in 40 (8.5%) and 24 (5.1%) of patients, respectively. QT prolongation occurred in 7 (1.5%). Overall, 78.0% (358/458) had successful treatment outcomes, 8.9% died and 7.2% experienced treatment failure.
CONCLUSIONS
Concomitant use of Bdq and Dlm, along with linezolid and clofazimine, is safe and effective for MDR/RR-TB patients with extensive disease. Using these drugs concomitantly is a good therapeutic option for patients with resistance to many anti-TB drugs.
Concomitant use of bedaquiline (Bdq) and delamanid (Dlm) for multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) has raised concerns about a potentially poor risk-benefit ratio. Yet, this combination is an important alternative for patients infected with strains of TB with complex drug resistance profiles or who cannot tolerate other therapies. We assessed safety and treatment outcomes of MDR/RR-TB patients receiving concomitant Bdq and Dlm, along with other second-line anti-TB drugs.
METHODS
We conducted a multi-centric, prospective observational cohort study across 14 countries among patients receiving concomitant Bdq-Dlm treatment. Patients were recruited between April 2015 and September 2018 and were followed until the end of treatment. All serious adverse events and adverse events of special interest (AESI), leading to a treatment change, or judged significant by a clinician, were systematically monitored and documented.
RESULTS
Overall, 472 patients received Bdq and Dlm concomitantly. A large majority also received linezolid (89.6%) and clofazimine (84.5%). Nearly all (90.3%) had extensive disease; most (74.2%) had resistance to fluoroquinolones. The most common AESI were peripheral neuropathy (134, 28.4%) and electrolyte depletion (94, 19.9%). Acute kidney injury and myelosuppression were seen in 40 (8.5%) and 24 (5.1%) of patients, respectively. QT prolongation occurred in 7 (1.5%). Overall, 78.0% (358/458) had successful treatment outcomes, 8.9% died and 7.2% experienced treatment failure.
CONCLUSIONS
Concomitant use of Bdq and Dlm, along with linezolid and clofazimine, is safe and effective for MDR/RR-TB patients with extensive disease. Using these drugs concomitantly is a good therapeutic option for patients with resistance to many anti-TB drugs.
Journal Article > LetterFull Text
Clin Infect Dis. 2024 August 15; Volume 79 (Issue 2); 569-570.; DOI:10.1093/cid/ciad767
Crocker-Buque T, Lachenal N, Narasimooloo C, Abdrasuliev T, Parpieva N, et al.
Clin Infect Dis. 2024 August 15; Volume 79 (Issue 2); 569-570.; DOI:10.1093/cid/ciad767
Journal Article > ResearchFull Text
Antimicrob Agents Chemother. 2024 June 6; Volume 68 (Issue 7); e0053624.; DOI:10.1128/aac.00536-24
Motta I, Cusinato M, Ludman AJ, Lachenal N, Dodd M, et al.
Antimicrob Agents Chemother. 2024 June 6; Volume 68 (Issue 7); e0053624.; DOI:10.1128/aac.00536-24
Regimens for the treatment of rifampicin-resistant tuberculosis currently rely on the use of QT-prolonging agents. Using data from the randomized controlled trial, TB-PRACTECAL, we investigated differences in QTcF among participants in the three interventional arms: BPaL (bedaquiline, pretomanid, and linezolid), BPaLC (BPaL with clofazimine), and BPaLM (BPaL with moxifloxacin). Additionally, we assessed whether age, body mass index, and country were causally associated with QTcF prolongation. The trial included participants from South Africa, Uzbekistan, and Belarus. A post hoc analysis of electrocardiogram data was undertaken. Random effects regression was used to model QTcF longitudinally over 24 weeks and causal frameworks guided the analysis of non-randomized independent variables. 328 participants were included in BPaL-based arms. The longitudinal analysis of investigational arms showed an initial QTcF steep increase in the first week. QTcF trajectories between weeks 2 and 24 differed slightly by regimen, with highest mean peak for BPaLC (QTcF 446.5 ms). Overall, there were 397 QTcF >450 ms (of 3,744) and only one QTcF >500 ms. The odds of QTcF >450 ms among participants in any investigational arm, was 8.33 times higher in Uzbekistan compared to Belarus (95% confidence interval: 3.25–21.33). No effect on QTcF prolongation was found for baseline age or body mass index (BMI). Clinically significant QTc prolongation was rare in this cohort of closely monitored participants. Across BPaL-based regimens, BPaLC showed a slightly longer and sustained effect on QTcF prolongation, but the differences (both in magnitude of change and trajectory over time) were clinically unimportant. The disparity in the risk of QTc prolongation across countries would be an important factor to further investigate when evaluating monitoring strategies.
Other > Pre-Print
medRxiv. 2024 January 29; DOI:10.1101/2024.01.29.24301679
Guglielmetti L, Khan U, Velasquez GE, Gouillou M, Abubakirov A, et al.
medRxiv. 2024 January 29; DOI:10.1101/2024.01.29.24301679
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
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
Conference Material > Abstract
Lachenal N, Hewison CCH, Berry C, Mitnick CD, Ahmed SM, et al.
MSF Scientific Days International 2022. 2022 May 11; DOI:10.57740/hs0k-1941
INTRODUCTION
Drug-resistant tuberculosis (DR-TB) carries significant morbidity and mortality risk. Care of DR-TB in pregnancy is even more challenging. A recent meta-analysis examining the impact of DR-TB on pregnancy outcomes found a higher than expected rate of maternal death, pregnancy loss, and a significant prevalence of low-birthweight infants. Anti-tubercular drugs such as bedaquiline and clofazimine have long half-lives and the impact of in-utero exposure is largely unknown. There is little information to help women, their family members, and clinicians make informed decisions about DR-TB treatment during pregnancy.
METHODS
Data on pregnancy outcomes were systematically collected as part of a pharmacovigilance programme supporting a clinical trial (TB-PRACTECAL; N=552) and a prospective cohort (endTB; N=2,906). We present the birth outcomes as reported to investigators by participants.
ETHICS
The endTB and TB-PRACTECAL studies were both approved by the local ethics committees in all recruiting countries and by the MSF Ethics Review Board. endTB was approved by the Partners Healthcare Human Research Committee, Boston, USA, and TB-PRACTECAL was approved by the London School of Hygiene and Tropical Medicine Ethics Committee, UK.
RESULTS
Between 01 April 2015 and 31 December 2021, 58 pregnancies in 53 women were notified from 10 different countries, predominantly Uzbekistan (14), Kazakhstan (13) and Pakistan (9). In 13 cases, pregnancy occurred after completion of tuberculosis treatment. Patients became pregnant a median of 260.5 (range, 0-727) days from treatment start; five women were 5-32 weeks pregnant at treatment start. There were no maternal deaths. 17.0% (9/53) of mothers changed or interrupted treatment during pregnancy. Treatment outcome was successful in 97.3% (36/37) of others in endTB and 100% (7/7) of mothers who completed follow-up in TB-PRACTECAL. Pregnancy outcome was known in 52 cases: 20 elective abortions, three miscarriages and 30 live births (one twin pregnancy). There were no stillbirths. Of the 30 live births, 29 occurred in mothers ever exposed to bedaquiline, 16 to clofazimine, 11 to a second-line injectable, 10 to pretomanid, and 7 to delamanid. Birth weight was known in 24/30 (80.0%) babies. Median weight was 3,015 (range, 1,270 to 4,200) grams. Two babies were born prematurely at 30 and 31 weeks. Low birthweight was reported in seven (29.2%; 7/24) babies. One low-birthweight baby died within four months of birth from complications unrelated to tuberculosis. One baby was treated for DR-TB. There were no reported birth malformations.
CONCLUSION
These results support evidence that effective DR-TB treatments may improve maternal outcomes and prevent perinatal transmission. How these perinatal outcomes compare to other cohorts not affected by TB in these settings or exposed to different TB treatments needs exploration. The factors contributing to low birthweight in babies born to mothers with DR-TB requires further research. A global registry is urgently needed to assist parents and clinicians with decision-making.
CONFLICTS OF INTEREST
The endTB project was funded by UNITAID (Geneva, Switzerland). Provision of delamanid within the endTB project was partially funded through a donation from Otsuka Company (Kyoto, Japan).
Drug-resistant tuberculosis (DR-TB) carries significant morbidity and mortality risk. Care of DR-TB in pregnancy is even more challenging. A recent meta-analysis examining the impact of DR-TB on pregnancy outcomes found a higher than expected rate of maternal death, pregnancy loss, and a significant prevalence of low-birthweight infants. Anti-tubercular drugs such as bedaquiline and clofazimine have long half-lives and the impact of in-utero exposure is largely unknown. There is little information to help women, their family members, and clinicians make informed decisions about DR-TB treatment during pregnancy.
METHODS
Data on pregnancy outcomes were systematically collected as part of a pharmacovigilance programme supporting a clinical trial (TB-PRACTECAL; N=552) and a prospective cohort (endTB; N=2,906). We present the birth outcomes as reported to investigators by participants.
ETHICS
The endTB and TB-PRACTECAL studies were both approved by the local ethics committees in all recruiting countries and by the MSF Ethics Review Board. endTB was approved by the Partners Healthcare Human Research Committee, Boston, USA, and TB-PRACTECAL was approved by the London School of Hygiene and Tropical Medicine Ethics Committee, UK.
RESULTS
Between 01 April 2015 and 31 December 2021, 58 pregnancies in 53 women were notified from 10 different countries, predominantly Uzbekistan (14), Kazakhstan (13) and Pakistan (9). In 13 cases, pregnancy occurred after completion of tuberculosis treatment. Patients became pregnant a median of 260.5 (range, 0-727) days from treatment start; five women were 5-32 weeks pregnant at treatment start. There were no maternal deaths. 17.0% (9/53) of mothers changed or interrupted treatment during pregnancy. Treatment outcome was successful in 97.3% (36/37) of others in endTB and 100% (7/7) of mothers who completed follow-up in TB-PRACTECAL. Pregnancy outcome was known in 52 cases: 20 elective abortions, three miscarriages and 30 live births (one twin pregnancy). There were no stillbirths. Of the 30 live births, 29 occurred in mothers ever exposed to bedaquiline, 16 to clofazimine, 11 to a second-line injectable, 10 to pretomanid, and 7 to delamanid. Birth weight was known in 24/30 (80.0%) babies. Median weight was 3,015 (range, 1,270 to 4,200) grams. Two babies were born prematurely at 30 and 31 weeks. Low birthweight was reported in seven (29.2%; 7/24) babies. One low-birthweight baby died within four months of birth from complications unrelated to tuberculosis. One baby was treated for DR-TB. There were no reported birth malformations.
CONCLUSION
These results support evidence that effective DR-TB treatments may improve maternal outcomes and prevent perinatal transmission. How these perinatal outcomes compare to other cohorts not affected by TB in these settings or exposed to different TB treatments needs exploration. The factors contributing to low birthweight in babies born to mothers with DR-TB requires further research. A global registry is urgently needed to assist parents and clinicians with decision-making.
CONFLICTS OF INTEREST
The endTB project was funded by UNITAID (Geneva, Switzerland). Provision of delamanid within the endTB project was partially funded through a donation from Otsuka Company (Kyoto, Japan).