Safety and Effectiveness of an All-Oral, Bedaquiline-Based, Shorter Treatment Regimen for Rifampicin-Resistant Tuberculosis in High Human Immunodeficiency Virus (HIV) Burden Rural South Africa: A Retrospective Cohort Analysis.

BACKGROUND: At the end of 2018, South Africa updated its all-oral regimen, to include bedaquiline (BDQ) and 2 months of linezolid (LZD) for all patients initiating the shorter 9-12 months regimen for rifampicin-resistant tuberculosis (RR-TB). We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this treatment regimen under programmatic conditions. METHODS: We conducted a retrospective cohort analysis on RR-TB patients treated with a standardized all-oral short regimen between 1 July 2018 and 30 April 2019 in 3 facilities in King Cetshwayo District. An electronic register (EDR web) and facility-based clinical charts were used to collect variables, which were entered into an Epi-Info database. RESULTS: Our cohort included 117 patients; 68.4% (95% confidence interval [CI]: 59.3-76.3) tested positive for human immunodeficiency virus (HIV). The median time to culture conversion was 56 days (95% CI: 50-57). Treatment success was achieved in 75.2% (95% CI: 66.5-82.3) of patients. Mortality within the cohort was 12.8% (95% CI: 7.8-20.3). Anemia was the most frequent severe adverse event (AE). The median time to develop severe anemia was 7.1 weeks (interquartile range [IQR] 4.0-12.9) after treatment initiation. LZD was interrupted in 25.2% (95% CI: 17.8-34.5) of participants. CONCLUSIONS: An all-oral shorter regimen, including BDQ and LZD as core drugs for the treatment of RR-TB, shows good outcomes, in a high HIV burden rural setting. AEs are common, especially for LZD, but could be managed in the program setting. Support is needed when introducing new regimens to train staff in the monitoring, management, and reporting of AEs.

Refining MDR-TB treatment regimens for ultra short therapy (TB-TRUST): study protocol for a randomized controlled trial.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) are unsatisfied to treat, pressing more effective and innovative treatment regimens. New efficient regimens for MDR-TB have obtained high treatment success rates. However, those regimens without drug susceptibility testing (DST) are also likely to contribute to the emergence of resistance. Precision treatments guided by DST might optimize the patients' treatment outcome individually and minimize resistance amplification. METHODS: TB-TRUST is a phase III, multicenter, open-label, randomized controlled clinical trial of non-inferiority comparing the treatment success rate between the World Health Organization (WHO) shorter regimen and the refined ultra-short regimen for fluoroquinolones and second-line injectable drugs susceptible rifampicin-resistant TB. The control arm uses the WHO injectable-containing shorter regimen for 36-44 weeks depending on time of sputum smear conversion. The investigational arm uses a refined ultra-short regimen guided by molecular DST to pyrazinamide via whole-genome sequencing (WGS) to optimize the treatment of pyrazinamide-susceptible patients with levofloxacin, linezolid, cycloserine and pyrazinamide for 24-32 weeks and pyrazinamide-resistant with levofloxacin, linezolid, cycloserine and clofazimine for 36-44 weeks. The primary outcome is the treatment success rate without relapse at 84 weeks after treatment initiation. Secondary outcomes include the time of sputum culture conversion and occurrence of adverse events. Assuming α = 0.025 level of significance (one-sided test), a power of 80%, a < 10% difference in treatment success rate between control arm and investigational (80% vs. 82%), and a 5% lost follow-up rate, the number of participants per arm to show non-inferiority was calculated as 177(354 in total). DISCUSSION: Rapid molecular testing distinguishes patients who are eligible for shorter regimen with fluoroquinolone and the WGS-guided results shorten the treatment to 6 months for pyrazinamide susceptible patients. It's foreseeable that not only novel developed medicines, but also traditional powerful medicines with the susceptibility confirmed by DST are the key factors to ensure the effect of anti-MDR-TB drugs. As a DST-guided precision treatment, TB-TRUST are expected to optimize therapy outcome in more patients who cannot afford the expensive new medicines and minimize and even avoid resistance amplification with the rational use of anti-TB drugs. TRAIL REGISTRATION: ClinicalTrial.gov, NCT03867136 . Registered on March 7, 2019.

Investigation of the efficacy of the short regimen for rifampicin-resistant TB from the STREAM trial.

BACKGROUND: The STREAM trial demonstrated that a 9-11-month "short" regimen had non-inferior efficacy and comparable safety to a 20+ month "long" regimen for the treatment of rifampicin-resistant tuberculosis. Imbalance in the components of the composite primary outcome merited further investigation. METHODS: Firstly, the STREAM primary outcomes were mapped to alternatives in current use, including WHO programmatic outcome definitions and other recently proposed modifications for programmatic or research purposes. Secondly, the outcomes were re-classified according to the likelihood that it was a Failure or Relapse (FoR) event on a 5-point Likert scale: Definite, Probable, Possible, Unlikely, and Highly Unlikely. Sensitivity analyses were employed to explore the impact of informative censoring. The protocol-defined modified intention-to-treat (MITT) analysis population was used for all analyses. RESULTS: Cure on the short regimen ranged from 75.1 to 84.2% across five alternative outcomes. However, between-regimens results did not exceed 1.3% in favor of the long regimen (95% CI upper bound 10.1%), similar to the primary efficacy results from the trial. Considering only Definite or Probable FoR events, there was weak evidence of a higher risk of FoR in the short regimen, HR 2.19 (95%CI 0.90, 5.35), p = 0.076; considering only Definite FoR events, the evidence was stronger, HR 3.53 (95%CI 1.05, 11.87), p = 0.030. Cumulative number of grade 3-4 AEs was the strongest predictor of censoring. Considering a larger effect of informative censoring attenuated treatment differences, although 95% CI were very wide. CONCLUSION: Five alternative outcome definitions gave similar overall results. The risk of failure or relapse (FoR) may be higher in the short regimen than in the long regimen, highlighting the importance of how loss to follow-up and other censoring is accounted for in analyses. The outcome of time to FoR should be considered as a primary outcome for future drug-sensitive and drug-resistant TB treatment trials, provided sensitivity analyses exploring the impact of departures from independent censoring are also included.

Treatment Outcomes of Patients Switching From an Injectable Drug to Bedaquiline During Short Standardized Treatment for Multidrug-resistant Tuberculosis in Mozambique.

Bedaquiline was recommended by the World Health Organization as the preferred option in treatment of multidrug-resistant tuberculosis (MDR-TB) with long regimens. However, no recommendation was given for the short MDR-TB regimen. Data from our small cohort of patients who switched from injectable drug to bedaquiline suggest that a bedaquiline-based short regimen is effective and safe.

A Comprehensive Review on Long vs. Short Regimens in Multidrug-Resistant Tuberculosis (MDR-TB) Under Programmatic Management of Drug-Resistant Tuberculosis (PMDT).

This comprehensive review delves into the intricate landscape of multidrug-resistant tuberculosis (MDR-TB) treatment within the programmatic management of drug-resistant tuberculosis (PMDT) framework. MDR-TB poses a substantial global health threat, necessitating targeted approaches for effective management. The analysis explores the historical evolution, efficacy, safety profiles, and implementation challenges associated with long and short regimens. The findings underscore the importance of individualized clinical practices, considering patient-specific factors, and the need for ongoing monitoring within PMDT programs. Recommendations advocate for integrating advanced diagnostics, continuous surveillance, and training for healthcare professionals. The review concludes with a nuanced outlook on long versus short regimens, emphasizing a balanced approach and the imperative role of collaborative efforts in shaping the future of MDR-TB treatment. This synthesis contributes to the ongoing discourse, providing valuable insights for healthcare practitioners, policymakers, and researchers working toward optimizing outcomes for individuals afflicted with MDR-TB.

High Tuberculosis Preventive Treatment Uptake and Completion Rates Using a Person-Centered Approach among Tuberculosis Household Contact in Yogyakarta.

Coverage of tuberculosis preventive treatment (TPT) in Indonesia is inadequate, and persons who start TPT often do not complete treatment. In 2020, Zero TB Yogyakarta implemented person-centered contact investigation and shorter TPT regimen provision in collaboration with primary health care centers. Between 1 January 2020 and 31 August 2022, we assessed eligibility for TPT among household contacts of persons with bacteriologically confirmed TB (index cases) and offered them a 3-month TPT regimen (3RH or 3HP). A dedicated nurse monitored contacts on TPT for treatment adherence and side effects every week in the first month and every two weeks in the next months. Contacts were also able to contact a nurse by phone or ask for home visits at any point if they had any concerns. A total of 1016 contacts were eligible for TPT: 772 (78.8%) started short regimen TPT with 706 (91.5%) completing their TPT. Side effects were reported in 26 (39%) of the non-completion group. We conclude that high rates of TPT uptake and completion among contacts assessed as eligible for TPT can be achieved through person-centered care and the use of shorter regimens. Side-effect monitoring and management while on TPT is vital for improving TPT completion.

Adverse events using shorter MDR-TB regimens: outcomes from Port Moresby, Papua New Guinea.

Evidence increasingly indicates that standardised, shorter regimens (SR) for multidrug-resistant TB (MDR-TB) is effective in treating this global disease, but there is little published data on associated adverse events. We report outcomes from a cohort treated with the SR in Port Moresby, Papua New Guinea (PNG). Among 26 patients treated with a TB SR from September 2017 to September 2018, 10 (39%) were successful treatments, 12 (46%) were failures, 2 died, and 2 were lost to follow-up. Of those whose treatment failed, most (n = 10) changed their regimen due to adverse events, including seven from ototoxicity, suggesting this SR may not be suited to all patients in PNG and similar settings.

Les preuves disponibles montrent de plus en plus que des protocoles standardisés, plus courts (SR) de la TB multirésistante (MDR-TB) traitent efficacement cette maladie mondiale, mais il y a peu de données publiées sur les effets secondaires. Nous rapportons les résultats d'une cohorte traitée par SR à Port Moresby, Papouasie Nouvelle-Guinée (PNG). Parmi 26 patients traités par SR de TB de septembre 2017 à septembre 2018 : 10 (39%) ont été traités avec succès, 12 (46%) ont échoué, 2 sont décédés et 2 ont été perdus de vue. Parmi les échecs, la majorité (n = 10) a changé de protocole en raison d'effets secondaires, notamment sept patients pour ototoxicité, suggérant que ce protocole standardisé n'était pas forcément adapté à tous les patients en PNG et dans des contextes similaires.

Treatment success using novel and adapted treatment regimens in registered DR-TB children in Dushanbe, Tajikistan, 2013-2019.

INTRODUCTION: Approximately 3% of all pediatric TB cases develop MDR-TB, with only 3-4% of such children receiving MDR-TB treatment. In Tajikistan, children as a proportion of all DR-TB in the country increased from 4.3 to 7.5% during 2013-2018. Despite limited evidence on the use of new anti-TB drugs in children, WHO has updated its guidelines for DR-TB treatment for children, and Tajikistan did so in 2013 and 2017. Novel and adapted regimens included individual regimens for RR/MDR, XDR (with and without Bedaquiline and Delamanid) and short treatment regimens with and without injectables. It is important to document the outcomes of the treatment regimens. Therefore, the aim of this study was to describe characteristics of children receiving different treatment regimens for DR-TB, the culture conversion and treatment outcomes. METHODOLOGY: Cohort study of children enrolled in DR-TB treatment by the National Tuberculosis Program in Dushanbe, Tajikistan, January 2013 to July 2019. RESULTS: The study included 60 DR-TB children. The male to female ratio was 1:2 and mean age 13.6 years. Median time to culture conversion was 66 days [IQR:31-103; Range:2-232]. In children with treatment outcomes (N = 58), 93% had favorable outcomes. There were four children (7%) with unfavorable treatment outcomes, all of whom were female 15-17 years, on standard (RR/MDR) treatment during 2013-2015. Favorable outcomes by DR-TB type were 91%, 90%, and 100% in RR/MDR, PreXDR, and XDR-TB patients, respectively. CONCLUSIONS: All children enrolled after the introduction of modified guidelines for novel and adapted regimens for DR-TB showed positive TB treatment outcomes.

Short-Duration Prednisolone in Children with Nephrotic Syndrome Relapse: A Noninferiority Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: In children with nephrotic syndrome, steroids are the cornerstone of therapy for relapse. The adequate duration and dosage of steroids, however, have not been an active area of research, especially in children with infrequently relapsing nephrotic syndrome. This study investigated the efficacy of an abbreviated regimen for treatment of a relapse in this population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a single-center, open-label, randomized controlled trial, we evaluated the efficacy of prednisolone as a "short regimen" (40 mg/m2 on alternate days for 2 weeks) compared with "standard regimen" (40 mg/m2 on alternate days for 4 weeks) for children aged 1-16 years who achieved remission of a relapse. The primary outcome was the proportion of children developing frequent relapses or steroid dependence at 12 months. RESULTS: A total of 117 patients were enrolled and randomized to short (55) or standard (62) regimen. Fourteen (24%) patients in standard regimen and 12 (23%) in short regimen developed frequent relapses or steroid dependence over a period of 1 year (risk difference, -1%; 95% confidence interval, -15 to 16; P=0.90). A large 95% confidence interval crossed the proposed noninferiority margin. In a time to event analysis, there was no significant difference in the proportion of children developing frequent relapses or steroid dependence and time to outcome between the two groups (hazard ratio, 1.01; 95% confidence interval, 0.83 to 1.23; P=0.98). Time to relapse, relapse rate, and steroid-related adverse events were similar in both groups. Cumulative steroid exposure was significantly lower in the short regimen (risk difference, -541 mg/m2; 95% confidence interval, -917 to -164 mg/m2; P<0.001). CONCLUSIONS: In children with infrequently relapsing nephrotic syndrome, a short steroid treatment for relapse resulted in a similar proportion of patients developing frequent relapses or steroid dependence; however, noninferiority of a short regimen was not established. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: CTRI/2015/11/006345.

World Health Organization 2018 treatment guidelines for rifampicin-resistant tuberculosis: uncertainty, potential risks and the way forward.

The 2018 World Health Organization (WHO) treatment guidelines for multidrug-/rifampicin-resistant tuberculosis (MDR/RR-TB) give preference to all-oral long regimens lasting for 18-20 months. The guidelines strongly recommend combining bedaquiline, levofloxacin (or moxifloxacin) and linezolid, supplemented by cycloserine and/or clofazimine. The effectiveness of this combination in a long regimen has not been tested in any study to date, with corresponding uncertainty. The guidelines indicate that, ideally, all MDR-TB patients should have - as a minimum - the isolate tested for fluoroquinolones, bedaquiline and linezolid susceptibility before the start of treatment. Unfortunately, the capacity for drug susceptibility testing is insufficient in resource-limited settings. The risk of acquired bedaquiline resistance cannot be ignored, especially in patients with undetected resistance to fluoroquinolones. Both linezolid and cycloserine are known for their high frequency of serious adverse events. The combination of bedaquiline, moxifloxacin and clofazimine in the same regimen may excessively increase the QT interval. These expected adverse effects are difficult to monitor and manage in resource-limited settings, and may result in frequent modifications and a less effective regimen. The final STREAM results have confirmed the non-inferiority of the short regimen compared with the long regimen. Before evidence on the all-oral long and modified all-oral short treatment regimens is available, the WHO-recommended short MDR-TB regimens, with monitoring for ototoxicity, remain a better treatment option for the management of MDR/RR-TB patients who are eligible for short regimens in low- and middle-income countries. National tuberculosis programmes should also strengthen their capacity in the detection and management of fluoroquinolone-resistant MDR-TB following the WHO guidelines.

Outcomes of a nine-month regimen for rifampicin-resistant tuberculosis up to 24 months after treatment completion in nine African countries.

BACKGROUND: Treatment outcomes of the shorter regimen for rifampicin-resistant tuberculosis are not completely established. We report on these outcomes two years after treatment completion among patients enrolled in an observational cohort study in nine African countries. METHODS: 1,006 patients treated with the nine-month regimen were followed every six months with sputum cultures up to 24 months after treatment completion. The risk of any unfavourable outcome, of failure and relapse, and of death during and after treatment was analysed according to patient's characteristics and initial drug susceptibility by Cox proportional hazard models. FINDINGS: Respectively 67.8% and 57.2% patients had >=1 culture result six months and 12 months after treatment completion. Fourteen relapses were diagnosed. The probability of relapse-free success was 79.3% (95% confidence interval [CI] 76.6-82.0%) overall, 80.9% (95% CI 78.0-84.0%) among HIV-negative and 72.5% (95% CI 66.5-78.9%) among HIV-infected patients. Initial fluoroquinolone (adjusted hazard ratio [aHR] 6.7 [95% CI 3.4-13.1]) and isoniazid resistance (aHR 9.4 [95% CI 1.3-68.0]) were significantly associated with increased risk of failure/relapse and of any unfavourable outcome. INTERPRETATION: The close to 80% relapse-free success indicates the good outcome of the regimen in low-and middle-income settings. Results confirm the lesser effectiveness of the regimen in patients with initial resistance to fluoroquinolones and support the use of high-dose isoniazid, but do not support exclusion of patients for resistance to drugs other than fluoroquinolones. FUNDING: Expertise-France and Agence Française de Développement.