Rifampicin-resistant Tuberculosis Treatment Research Articles

Emerging bedaquiline resistance: A threat to the global fight against drug-resistant tuberculosis

Bedaquiline resistance is increasingly observed in the treatment of rifampicin-resistant tuberculosis (TB), yet standardized regimens for managing bedaquiline-resistant TB are lacking. Studies indicate a high proportion of bedaquiline-resistant cases have previously been treated for TB, and often involve strains resistant to quinolones. Regular monitoring of the culture status in patients receiving bedaquiline resistance treatment is advised. Methods such as experimental evolution, protein modeling, genome sequencing, and phenotypic analysis have been instrumental in identifying the mechanisms of bedaquiline resistance. Specifically, variants in the Rv0678 transcriptional repressor of the MmpS5-MmpL5 efflux system are linked to this type of resistance. Bayesian probability estimates show promise in determining the genotypic–phenotypic association for bedaquiline resistance, suggesting potential utility in clinical practice. Future research should explore the practical application of Bayesian probabilities in managing bedaquiline resistance. Sequencing-based technologies are anticipated to play a vital role in the early detection and management of drug-resistant TB strains.

Pharmacokinetics and Safety of Group A and B Anti-Tuberculosis Drugs Used in Treatment of Rifampicin-Resistant Tuberculosis during Pregnancy and Post-Partum: A Narrative Review.

Recommendations for treatment of rifampicin-resistant tuberculosis (RR-TB) during pregnancy and post-partum now include Group A and B antituberculosis drugs. While pharmacokinetic data for most of these drugs among adults receiving treatment for RR-TB are limited, the data from pregnant patients and their infants are extremely scarce. Existing data suggest that fluoroquinolones, bedaquiline, clofazimine and terizidone may be used safely in pregnancy. Pharmacokinetic exposures, particularly between trimesters, are potentially sub-optimal; however, there is currently no evidence to support dose adjustment during pregnancy. Linezolid poses a potentially serious toxicity risk, particularly as exposures appear to be high in the later stages of pregnancy and post-partum following extended use, but this should be considered alongside the benefits of this extremely effective drug in the treatment of this life-threatening disease. While plenty of questions remain regarding the exposure to Group A and B antituberculosis drugs through breastmilk, existing literature suggests minimal harm to the breastfed infant. Pregnant patients and their infants should be included in therapeutic trials and pharmacokinetic studies of effective antituberculosis drugs.

Optimizing dosing of the cycloserine pro-drug terizidone in children with rifampicin-resistant tuberculosis.

There are no pharmacokinetic data in children on terizidone, a pro-drug of cycloserine and a World Health Organization (WHO)-recommended group B drug for rifampicin-resistant tuberculosis (RR-TB) treatment. We collected pharmacokinetic data in children <15 years routinely receiving 15-20 mg/kg of daily terizidone for RR-TB treatment. We developed a population pharmacokinetic model of cycloserine assuming a 2-to-1 molecular ratio between terizidone and cycloserine. We included 107 children with median (interquartile range) age and weight of 3.33 (1.55, 5.07) years and 13.0 (10.1, 17.0) kg, respectively. The pharmacokinetics of cycloserine was described with a one-compartment model with first-order elimination and parallel transit compartment absorption. Allometric scaling using fat-free mass best accounted for the effect of body size, and clearance displayed maturation with age. The clearance in a typical 13 kg child was estimated at 0.474 L/h. The mean absorption transit time when capsules were opened and administered as powder was significantly faster compared to when capsules were swallowed whole (10.1 vs 72.6 min) but with no effect on bioavailability. Lower bioavailability (-16%) was observed in children with weight-for-age z-score below -2. Compared to adults given 500 mg daily terizidone, 2022 WHO-recommended pediatric doses result in lower exposures in weight bands 3-10 kg and 36-46 kg. We developed a population pharmacokinetic model in children for cycloserine dosed as terizidone and characterized the effects of body size, age, formulation manipulation, and underweight-for-age. With current terizidone dosing, pediatric cycloserine exposures are lower than adult values for several weight groups. New optimized dosing is suggested for prospective evaluation.

Estimating the effect of a rifampicin resistant tuberculosis diagnosis by the Xpert MTB/RIF assay on two-year mortality.

Studies assessing patient-centred outcomes of novel rifampicin resistant tuberculosis (RR-TB) diagnostics are rare and mostly apply conventional methods which may not adequately address biases. Even though the Xpert MTB/RIF molecular assay was endorsed a decade ago for simultaneous diagnosis of tuberculosis and RR-TB, the impact of the assay on mortality among people with RR-TB has not yet been assessed. We analysed data of an observational prospective cohort study (EXIT-RIF) performed in South Africa. We applied a causal inference approach using inverse odds of sampling weights to rectify survivor bias and selection bias caused by differing screening guidelines. We also adjusted for confounding using a marginal structural model with inverse probability of treatment weights. We estimated the total effect of an RR-TB diagnosis made by the Xpert assay versus the pre-Xpert diagnostic algorithm (entailing a targeted Line Probe Assay (LPA) among TB-confirmed patients) on two-year mortality and we assessed mediation by RR-treatment initiation. Of the 749 patients diagnosed with RR-TB [247 (33%) by the pre-Xpert diagnostic algorithm and 502 (67%) by the Xpert assay], 42.7% died. Of these, 364 (48.6%) patients died in the pre-Xpert group and 200 (39.8%) in the Xpert group. People diagnosed with RR-TB by the Xpert assay had a higher odds of RR-TB treatment initiation compared to those diagnosed by the targeted LPA-based diagnostic process (OR 2.79; 95%CI 2.19-3.56). Receiving an RR-TB diagnosis by Xpert resulted in a 28% reduction in the odds of mortality within 2 years after presentation to the clinic (ORCI 0.72; 95%CI 0.53-0.99). Causal mediation analysis suggests that the higher rate of RR-TB treatment initiation in people diagnosed by the Xpert assay explains the effect of Xpert on 2-year mortality [natural indirect effect odds ratio 0.90 (95%CI 0.85-0.96). By using causal inference methods in combination with high quality observational data, we could demonstrate that the introduction of the Xpert assay caused a 28% reduction in 2-year odds of mortality of RR-TB. This finding highlights the need for advocacy for a worldwide roll-out of rapid molecular tests. Because the effect is mainly caused by increased RR-TB treatment initiation, health care systems should also ensure timely initiation of effective treatment upon an RR-TB diagnosis.

Piloting a new method to estimate action thresholds in medicine through intuitive weighing

ObjectivesIn clinical decision-making, physicians take actions such as prescribing treatment only when the probability of disease is sufficiently high. The lowest probability at which the action will be considered, is...

Linezolid-related adverse effects in the treatment of rifampicin resistant tuberculosis: a retrospective study

Linezolid (LZD) is an effective drug in treating multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. This study aimed to evaluate the safety of LZD in the treatment of patients with rifampicin resistant tuberculosis. This was a multicenter retrospective study. A total of 184 patients of the rifampicin resistant tuberculosis patients treated with LZD from Jan 2018 to Apr 2020 in three hospitals were involved, and their clinical symptoms were recorded and analyzed. Meanwhile, the types and incidence of adverse effects associated with LZD were evaluated. It showed that peripheral neuritis (51, 27.7%) and hemochromatosis (42, 22.8%) were the most common adverse effects observed among these patients. The median time of symptoms after LZD treatment was 45.5 and 120.0 days, respectively. Furthermore, female patients had a significantly higher risk for leukopenia (P = 0.002) and hemochromatosis (P = 0.033) when compared with male patients. History of underlying disease was the risk factor for thrombocytopenia (P = 0.022). Patients with long duration of medication (RR = 1.004, 95%CI: 1.002–1.006, P < 0.001) and daily dosage ≥600mg (RR = 3.059, 95%CI: 1.238–7.558, P = 0.015) were at higher risk of hemochromatosis. Age was the risk factor for rash (P = 0.008) and nausea and vomiting (P = 0.018). In addition, LZD administration time was the risk factor for optic neuritis (P < 0.001) and peripheral neuritis (P < 0.001). LZD can cause adverse symptoms in patients with rifampicin resistant tuberculosis. Gender, history of underlying disease, LZD use time, LZD dosage, and age are the risk factors in the LZD treatment of these patients. During medication, bone marrow suppression and neuropathy should be closely monitored. This study could potentially provide useful information for the clinical practice.

Low Body Mass Index at Treatment Initiation and Rifampicin-Resistant Tuberculosis Treatment Outcomes: An Individual Participant Data Meta-Analysis.

The impact of low body mass index (BMI) at initiation of rifampicin-resistant tuberculosis (RR-TB) treatment on outcomes is uncertain. We evaluated the association between BMI at RR-TB treatment initiation and end-of-treatment outcomes. We performed an individual participant data meta-analysis of adults aged ≥18 years with RR-TB whose BMI was documented at treatment initiation. We compared odds of any unfavorable treatment outcome, mortality, or failure/recurrence between patients who were underweight (BMI <18.5 kg/m2) and not underweight. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using logistic regression, with matching on demographic, clinical, and treatment-related factors. We evaluated effect modification by human immunodeficiency virus (HIV) status and other variables using likelihood ratio tests. We also estimated cumulative incidence of mortality during treatment stratified by HIV. Overall, 5148 patients were included; 1702 (33%) were underweight at treatment initiation. The median (interquartile range) age was 37 years (29 to 47), and 455 (9%) had HIV. Compared with nonunderweight patients, the aOR among underweight patients was 1.7 (95% CI, 1.4-1.9) for any unfavorable outcome, 3.1 (2.4-3.9) for death, and 1.6 (1.2-2.0) for failure/recurrence. Significant effect modification was found for World Health Organization region of treatment. Among HIV-negative patients, 24-month mortality was 14.8% (95% CI, 12.7%-17.3%) for underweight and 5.6% (4.5%-7.0%) for not underweight patients. Among patients with HIV, corresponding values were 33.0% (25.6%-42.6%) and 20.9% (14.1%-27.6%). Low BMI at treatment initiation for RR-TB is associated with increased odds of unfavorable treatment outcome, particularly mortality.

Definitive outcomes in patients with rifampicin-resistant tuberculosis treated in Niger from 2012 to 2019: A retrospective cohort study.

Outcomes of retreatment for rifampicin-resistant tuberculosis (RR-TB) are rarely reported. We report 'definitive outcomes' after a cascade approach to RR-TB treatment. After a bacteriologically adverse outcome for the 9-months fluoroquinolone-based Short Treatment Regimen (STR), patients were retreated with a bedaquiline-based regimen (BDQ-regimen). A Retrospective cohort study of RR-TB patients treated with the STR during 2012-2019 and retreated with a BDQ-regimen in case of failure or relapse was conducted. Definitive relapse-free cure took into account BDQ-regimen outcomes. Of 367 patients treated with the STR, 20 (5.4%) experienced failure or relapse. Out of these 20 patients, 14 started a BDQ-regimen, of whom none experienced failure or relapse. Definitive end of treatment outcomes of STR after revising with third-line BDQ-regimen outcomes, 84.7% (311/367) were cured relapse-free, 10.6% (39/367) died during treatment and 3.0% (11/367) were lost to follow-up during treatment with either the STR or BDQ-regimen. Six patients (1.6%; 6/367) with STR failure/relapse died before starting a BDQ-regimen. No patient had definitive treatment failure or relapse and remained without treatment. If fluoroquinolone resistance is excluded or rare, it is beneficial to use fluoroquinolone as the core drug for a first RR-TB treatment regimen and to safeguard bedaquiline for those in need of retreatment.

Early mortality during rifampicin-resistant TB treatment.

SUMMARYBACK GROUND:Data suggest that treatment with newer TB drugs (linezolid [LZD], bedaquiline [BDQ] and delamanid [DLM]), used in Khayelitsha, South Africa, since 2012, reduces mortality due to rifampicin-resistant TB (RR-TB).METHODS:This was a retrospective cohort study to assess 6-month mortality among RR-TB patients diagnosed between 2008 and 2019.RESULTS:By 6 months, 236/2,008 (12%) patients died; 12% (78/651) among those diagnosed in 2008–2011, and respectively 8% (49/619) and 15% (109/738) with and without LZD/BDQ/DLM in 2012–2019. Multivariable analysis showed a small, non-significant mortality reduction with LZD/BDQ/DLM use compared to the 2008–2011 period (aOR 0.79, 95% CI 0.5–1.2). Inpatient treatment initiation (aOR 3.2, 95% CI 2.4–4.4), fluoroquinolone (FQ) resistance (aOR 2.7, 95% CI 1.8–4.2) and female sex (aOR 1.5, 95% CI 1.1–2.0) were also associated with mortality. When restricted to 2012–2019, use of LZD/BDQ/DLM was associated with lower mortality (aOR 0.58, 95% CI 0.39–0.87).CONCLUSIONS:While LZD/BDQ/DLM reduced 6-month mortality between 2012 and 2019, there was no significant effect overall. These findings may be due to initially restricted LZD/BDQ/DLM use for those with high-level resistance or treatment failure. Additional contributors include increased treatment initiation among individuals who would have otherwise died before treatment due to universal drug susceptibility testing from 2012, an effect that also likely contributed to higher mortality among females (survival through to care-seeking).

Treatment outcomes and safety in children with rifampicin-resistant TB.

BACKGROUND: The treatment of rifampicin-resistant TB (RR-TB) in children is evolving rapidly. As newer regimens are introduced into routine care, it is vital to compare their outcome and safety with well-characterised clinical cohorts treated with historical regimens.METHODS: Study sample comprised a prospective observational cohort of children on routine RR-TB treatment, enrolled from 2011 to 2015 in Cape Town, South Africa. Children were followed for safety, treatment response and outcome.RESULTS: Of 136 children included, 27 (19.9%) were living with HIV and 48 (37.8%) had severe TB. The median time-to-culture conversion in children with bacteriological confirmation (n = 44) was 28.5 days (IQR 14.5-45). Overall, 118/129 (91.5%) had favourable TB treatment outcomes. Of 106 (77.9%) children who received an injectable drug, 9 (8.5%) developed hearing loss and 7/136 (5.1%) developed other Grade 3 or higher adverse events likely related to treatment.CONCLUSIONS: In this cohort with a substantial proportion of children with severe manifestations of TB and with HIV, TB treatment outcomes were excellent. Apart from hearing loss, few children developed severe adverse events related to treatment. This study provides robust reference data for future evaluation of shorter, injectable-sparing regimens.

Implementing a Substance-Use Screening and Intervention Program for People Living with Rifampicin-Resistant Tuberculosis: Pragmatic Experience from Khayelitsha, South Africa.

Substance use (SU) is associated with poor rifampicin-resistant tuberculosis (RR-TB) treatment outcomes. In 2017, a SBIRT (SU screening-brief intervention-referral to treatment) was integrated into routine RR-TB care in Khayelitsha, South Africa. This was a retrospective study of persons with RR-TB who were screened for SU between 1 July 2018 and 30 September 2020 using the ASSIST (Alcohol, Smoking and Substance Involvement Screening Test). Here we describe outcomes from this program. Persons scoring moderate/high risk received a brief intervention and referral to treatment. Overall, 333 persons were initiated on RR-TB treatment; 38% (n = 128) were screened for SU. Of those, 88% (n = 113/128) reported SU; 65% (n = 83/128) had moderate/high risk SU. Eighty percent (n = 103/128) reported alcohol use, of whom 52% (n = 54/103) reported moderate/high risk alcohol use. Seventy-seven persons were screened for SU within ≤2 months of RR-TB treatment initiation, of whom 69%, 12%, and 12% had outcomes of treatment success, loss to follow-up and death, respectively. Outcomes did not differ between persons with no/low risk and moderate/high risk SU or based on the receipt of naltrexone (p > 0.05). SU was common among persons with RR-TB; there is a need for interventions to address this co-morbidity as part of “person-centered care”. Integrated, holistic care is needed at the community level to address unique challenges of persons with RR-TB and SU.

The Analysis of Missing Cases on the Treatment of Rifampicin-Resistant Tuberculosis

To describe the follow-up treatment of Resistant Rifampicin in health care facilities based on the results of the gene-Xpert examination. The study design was cross-sectional using data from "Evaluation study of detection of TB cases with the rapid molecular test in Indonesia in 2018". The data resources were from 42 hospitals and two primary health care facilities having conducted the gene-Xpert examination at least six months in 42 districts, 26 provinces in Indonesia. The number of TB diagnoses with gene-Xpert from health facilities was 33,630 cases, 31.6% of those cases were TB positive, namely rifampicin sensitivity of 89% (9,456) and rifampicin-resistant of 11% (1,171). 29% of resistant rifampicin tuberculosis cases were missing cases consisting of the untreated and unknown follow-up treatment of 18% and 11%, respectively. Missing cases were mostly found in males of 66.1%. Based on the age, 76.9% of the missing cases were in productive age, such as 15 to 54 years. Moreover, according to the TB treatment history and origin of the case, missing cases were found in new cases, 54.4%, and the existing health facility 51.2%. The most reason for missing the RR-TB case in the follow-up treatment was the refusal of treatment 40.3%. The high non-compliance to TB treatment was caused by inadequate general knowledge about TB, lack of social support, medication side effects, and long treatment period, which were posed as barriers to adherence to treatment.

Health care seeking patterns of rifampicin-resistant tuberculosis patients in Harare, Zimbabwe: A prospective cohort study.

Delays in seeking and accessing treatment for rifampicin-resistant tuberculosis (RR-TB) and multi-drug resistant (MDR-TB) are major impediments to TB control in high-burden, resource-limited settings. We prospectively determined health-seeking behavioural patterns and associations with treatment outcomes and costs among 68 RR-TB patients attending conveniently selected facilities in a decentralised system in Harare, Zimbabwe. From initial symptoms to initiation of effective treatment, patients made a median number of three health care visits (IQR 2-4 visits) at a median cost of 13% (IQR 6-31%) of their total annual household income (mean cost, US$410). Cumulatively, RR-TB patients most frequently first visited private facilities, i.e., private pharmacies (30%) and other private health care providers (24%) combined. Median patient delay was 26 days (IQR 14-42 days); median health system delay was 97 days (IQR 30-215 days) and median total delay from symptom onset to initiation of effective treatment was 132 days (IQR 51-287 days). The majority of patients (88%) attributed initial delay in seeking care to "not feeling sick enough." Total delay, total cost and number of health care visits were not associated with treatment or clinical outcomes, though our study was not adequately powered for these determinations. Despite the public availability of rapid molecular TB tests, patients experienced significant delays and high costs in accessing RR-TB treatment. Active case finding, integration of private health care providers and enhanced service delivery may reduce treatment delay and TB associated costs.

Data quality assessment of a South African electronic registry for drug-resistant TB, 2015-2016.

Assessment of bedaquiline roll-out in South Africa requires accurate patient data in EDRWeb, a national case-based rifampicin-resistant TB (RR-TB) surveillance register. To ensure EDRWeb data reflect programmatic DR-TB source data, we implemented a data quality improvement initiative. We conducted data quality assessments of EDRWeb data compared to paper patient folders at two South African RR-TB treatment facilities in 2015 and 2016. We assessed 80 patient records before the intervention for completeness of clinically relevant data fields, and 80 different records after the intervention for completeness and concordance. The intervention involved reviewing and updating EDRWeb along with data quality audits with direct feedback to sites. At baseline data completeness per site was lowest for variables related to electrocardiogram (ECG) data, adverse events, and concomitant medications (completeness for these fields ranged from 0% to 80%). Post-intervention data completeness and concordance were high for all fields except those related to ECG data (ECG-related field completeness ranged from 10% to 100%). After a data quality initiative, data completeness improved at each site with the exception of ECG data fields. Our findings suggest that data quality interventions may improve patient clinical registries, ultimately enabling better evidence-based decision making for TB programmes.

Preparing the healthcare workforce in South Africa for short-course rifampicin-resistant TB treatment: inter-professional training and task-sharing considerations

BackgroundTreatment for rifampicin-resistant Mycobacterium tuberculosis (RR-TB) is complex, however, shorter treatment, with newer antimicrobials are improving treatment outcomes. The South African National Department of Health (NDoH) recently accelerated the rollout of 9-month, all-oral, RR-TB short-course regimens. We sought to evaluate an inter-professional training program using pre-test and post-test performance of Professional Nurses (PNs), Advanced Practice Professional Nurses (APPNs) and Medical Officers (MOs) to inform: (a) training needs across cadres; (b) knowledge performance, by cadres; and (c) training differences in knowledge by nurse type.MethodsA 4-day didactic and case-based clinical decision support course for RR-TB regimens in South Africa (SA) was developed, reviewed and nationally accredited. Between February 2017 and July 2018, 12 training events were held. Clinicians who may initiate RR-TB treatment, specifically MOs and PN/APPNs with matched pre–post tests and demographic surveys were analyzed. Descriptive statistics are provided. Pre–post test evaluations included 25 evidence-based clinically related questions about RR-TB diagnosis, treatment, and care.ResultsParticipants (N = 842) participated in testing, and matched evaluations were received for 800 (95.0%) training participants. Demographic data were available for 793 (99.13%) participants, of whom 762 (96.1%) were MOs, or nurses, either PN or APPNs. Average correct response pre-test and post-test scores were 61.7% (range 7–24 correct responses) and 85.9% (range 12–25), respectively. Overall, 95.8% (730/762) of participants demonstrated improved knowledge. PNs improved on average 25% (6.22 points), whereas MOs improved 10% (2.89 points) with better mean test scores on both pre- and post-test (p < 0.000). APPNs performed the same as the MOs on post-test scores (p = NS).ConclusionsThe inter-professional training program in short-course RR-TB treatment improved knowledge for participants. MOs had significantly greater pre-test scores. Of the nurses, APPNs outperformed other PNs, and performed equally to MOs on post-test scores, suggesting this advanced cadre of nurses might be the most appropriate to initiate and monitor treatment in close collaboration with MOs. All cadres of nurse reported the need for additional clinical training and mentoring prior to managing such patients.

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.

BackgroundAt 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.MethodsWe 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.ResultsOur 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.ConclusionsAn 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.

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

BackgroundThe 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.MethodsFirstly, 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.ResultsCure 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.ConclusionFive 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.

Implementing novel regimens for drug-resistant TB in South Africa: what can the world learn?

Worldwide uptake of new drugs in the treatment of rifampicin-resistant tuberculosis (RR-TB) has been extremely low. In June 2018, ahead of the release of the updated WHO guidelines for the management of RR-TB, South Africa announced that bedaquiline (BDQ) would be provided to virtually all RR-TB patients on shorter or longer regimens. South Africa has been the global leader in accessing BDQ for patients with RR-TB, who now represent 60% of the global BDQ cohort. The use of BDQ within a shorter modified regimen has generated the programmatic data underpinning the most recent change in WHO guidelines endorsing a shorter, injectable-free regimen. Progressive policies on access to new drugs have resulted in improved favourable outcomes and a reduction in mortality among RR-TB patients in South Africa. This supported global policy change. The strategies underpinning these bold actions include close collaboration between the South African National TB Programme and partners, introduction of new TB diagnostic tools in closely monitored conditions and the use of locally generated programmatic evidence to inform country policy changes. In this paper, we summarise a decade´s work that led to the bold decision to use a modified, short, injectable-free regimen with BDQ and linezolid under carefully monitored programmatic conditions.

Translating drug resistant tuberculosis treatment guidelines to reality in war-torn Kandahar, Afghanistan: A retrospective cohort study.

IntroductionAfghanistan is affected by one of the world’s longest protracted armed conflicts, frequent natural disasters, disease outbreaks and large population movements and it suffers from a high burden of tuberculosis (TB), including rifampicin-resistant TB (RR-TB). The study shows Médecins Sans Frontières’ experiences with care for patients with RR-TB in Kandahar Province. We describe the uptake of RR-TB treatment, how World Health Organisation criteria for the choice between the short and an individualized regimen were implemented, and treatment outcomes.MethodsThis is a retrospective cohort analysis of routinely collected data from RR-TB patients enrolled in care from 2016 until 2019. Descriptive analysis was performed to present characteristics of patients and treatment outcomes. Multivariable Cox analysis was performed to identify risk factors for having an unfavourable treatment outcome.ResultsOut of 146 enrolled RR-TB patients, 112 (76.7%) started treatment: 41 (36.6%) and 71 (63.4%) with the short and individualized treatment regimen, respectively. Of 82 with results for fluoroquinolone susceptibility, 39 (47.6%) had fluoroquinolone-resistant TB. Seven patients with initially fluoroquinolone-resistant TB and three pregnant women started the short regimen and 18 patients eligible for the short regimen started the injectable-free individualized regimen. Overall, six-month smear and culture conversion were 98.7% and 97.1%, respectively; treatment success was 70.1%. Known initial fluoroquinolone resistance (aHR 3.77, 95%CI:1.53–9.27) but not choice of regimen predicted having an unfavourable outcome.ConclusionEven though criteria for the choice of treatment regimen were not applied strictly, we have achieved acceptable outcomes in this cohort. To expand RR-TB care, treatment regimens should fit provision at primary health care level and take patient preferences into account.

Injectable-free regimens containing bedaquiline, delamanid, or both for adolescents with rifampicin-resistant tuberculosis in Khayelitsha, South Africa

BackgroundLimited data exist on the use of bedaquiline and delamanid in adolescents with rifampicin-resistant tuberculosis (RR-TB). We describe RR-TB treatment of adolescents (10–19 years) with injectable-free regimens containing these drugs in Khayelitsha, South Africa. MethodsThis retrospective study included adolescents initiating injectable-free RR-TB treatment regimens containing bedaquiline and/or delamanid from February 2015 to June 2018. We report adverse events (AEs) of interest, sputum culture conversion (SCC), and final end-of-treatment outcomes. FindingsTwenty-two patients were included; median age at treatment initiation was 17 years (interquartile range [IQR] 15-18), and six (27%) were HIV-positive (median CD4 count 191 cells/mm3 [IQR 157-204]). Eight (36%) patients had RR-TB with fluoroquinolone resistance; ten (45%), eight (36%), and four (18%) patients received regimens containing bedaquiline, delamanid, or the combination of bedaquiline and delamanid, respectively. The median durations of exposure to bedaquiline and delamanid were 5·6 (IQR 5·5-8·4) and 9·4 (IQR 5·9-14·4) months, respectively. There were 49 AEs of interest which occurred in 17 (77%) patients. Fourteen (64%) patients had pulmonary TB with positive sputum cultures at bedaquiline and/or delamanid initiation; among these SCC at month 6 was 79%. Final end-of-treatment outcomes for the 22 adolescent were: 17 (77%) successfully treated, two (9%) lost-to-follow-up, two (9%) treatment failed, and one (5%) died. InterpretationThis study found that injectable-free regimens containing bedaquiline and/or delamanid in a programmatic setting were effective and well tolerated in adolescents and should be routinely provided for RR-TB treatment in this age group as recommended by the World Health Organisation.