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Summary Background Bedaquiline improves outcomes of patients with rifampicin-resistant and multidrug-resistant (MDR) tuberculosis; however, emerging resistance threatens this success. We did a cross-sectional and longitudinal analysis evaluating the epidemiology, genetic basis, and treatment outcomes associated with bedaquiline resistance, using data from South Africa (2015–19). Methods Patients with drug-resistant tuberculosis starting bedaquiline-based treatment had surveillance samples submitted at baseline, month 2, and month 6, along with demographic information. Culture-positive baseline and post-baseline isolates had phenotypic resistance determined. Eligible patients were aged 12 years or older with a positive culture sample at baseline or, if the sample was invalid or negative, a sample within 30 days of the baseline sample submitted for bedaquiline drug susceptibility testing. For the longitudinal study, the first surveillance sample had to be phenotypically susceptible to bedaquiline for inclusion. Whole-genome sequencing was done on bedaquiline-resistant isolates and a subset of bedaquiline-susceptible isolates. The National Institute for Communicable Diseases tuberculosis reference laboratory, and national tuberculosis surveillance databases were matched to the Electronic Drug-Resistant Tuberculosis Register. We assessed baseline resistance prevalence, mutations, transmission, cumulative resistance incidence, and odds ratios (ORs) associating risk factors for resistance with patient outcomes. Findings Between Jan 1, 2015, and July 31, 2019, 8041 patients had surveillance samples submitted, of whom 2023 were included in the cross-sectional analysis and 695 in the longitudinal analysis. Baseline bedaquiline resistance prevalence was 3·8% (76 of 2023 patients; 95% CI 2·9–4·6), and it was associated with previous exposure to bedaquiline or clofazimine (OR 7·1, 95% CI 2·3–21·9) and with rifampicin-resistant or MDR tuberculosis with additional resistance to either fluoroquinolones or injectable drugs (pre-extensively-drug resistant [XDR] tuberculosis: 4·2, 1·7–10·5) or to both (XDR tuberculosis: 4·8, 2·0–11·7). Rv0678 mutations were the sole genetic basis of phenotypic resistance. Baseline resistance could be attributed to previous bedaquiline or clofazimine exposure in four (5·3%) of 76 patients and to primary transmission in six (7·9%). Odds of successful treatment outcomes were lower in patients with baseline bedaquiline resistance (0·5, 0·3–1). Resistance during treatment developed in 16 (2·3%) of 695 patients, at a median of 90 days (IQR 62–195), with 12 of these 16 having pre-XDR or XDR. Interpretation Bedaquiline resistance was associated with poorer treatment outcomes. Rapid assessment of bedaquiline resistance, especially when patients were previously exposed to bedaquiline or clofazimine, should be prioritised at baseline or if patients remain culture-positive after 2 months of treatment. Preventing resistance by use of novel combination therapies, current treatment optimisation, and patient support is essential. Funding National Institute for Communicable Diseases of South Africa.

BackgroundChildren and adolescents with household exposure to multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) are at high risk of developing TB disease. Tuberculosis preventive therapy (TPT) is recommended, but programmatic experience is limited, particularly for adolescents.MethodsWe conducted a prospective cohort study to describe MDR/RR-TB diagnosis and TPT provision for individuals aged ResultsBetween March 1, 2020 and July 31, 2021, 112 participants were enrolled; median age was 8.5 years, 57 (51%) were female, and 6 (5%) had human immunodeficiency virus. On screening, 11 (10%) were diagnosed with TB: 10 presumptive MDR/RR-TB and 1 drug-susceptible TB. Overall, 95 (94% of 101) participants started TPT: 79 with levofloxacin, 9 with isoniazid, and 7 with delamanid. Seventy-six (80%) completed TPT, 12 (13%) were lost to follow up, and 7 (7%) stopped TPT early due to adverse events. Potential adverse events were reported for 12 (13%) participants; none were serious. There were no further TB diagnoses (200 days median follow up).ConclusionsPost-MDR/RR-TB exposure management for children and adolescents resulted in significant MDR/RR-TB detection and both high TPT initiation and completion. Tuberculosis preventive monotherapy was well tolerated and there were no further TB diagnoses after initial assessment. Key factors supporting these outcomes included use of pediatric formulations for young children, monotherapy, and community-based options for assessment and follow up.

An estimated 19 million people are infected with rifampicin-resistant/multidrug-resistant strains of tuberculosis worldwide. There is little done to prevent these individuals from becoming sick with RR/MDR-TB, a disease that is associated with high rates of morbidity, mortality, and suffering. There are multiple phase III trials currently being conducted to assess the effectiveness of treatment of infection (i.e., “preventive therapy”) for RR/MDR-TB, but their results are likely years away. In the meantime, there is sufficient evidence to support a more comprehensive management of people who have been exposed to RR/MDR-TB so that they can maintain their health. We present a patient scenario and share our experience in implementing a systematic post-exposure management program in South Africa with the goal of inspiring similar programs in other high-burden RR/MDR-TB settings.

Summary Background South Africa has a high burden of rifampicin-resistant tuberculosis (including multidrug-resistant [MDR] tuberculosis), with increasing rifampicin-monoresistant (RMR) tuberculosis over time. Resistance acquisition during first-line tuberculosis treatment could be a key contributor to this burden, and HIV might increase the risk of acquiring rifampicin resistance. We assessed whether HIV during previous treatment was associated with RMR tuberculosis and resistance acquisition among a retrospective cohort of patients with MDR or rifampicin-resistant tuberculosis. Methods In this retrospective cohort study, we included all patients routinely diagnosed with MDR or rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa, between Jan 1, 2008, and Dec 31, 2017. Patient-level data were obtained from a prospective database, complemented by data on previous tuberculosis treatment and HIV from a provincial health data exchange. Stored MDR or rifampicin-resistant tuberculosis isolates from patients underwent whole-genome sequencing (WGS). WGS data were used to infer resistance acquisition versus transmission, by identifying genomically unique isolates (single nucleotide polymorphism threshold of five). Logistic regression analyses were used to assess factors associated with RMR tuberculosis and genomic uniqueness. Findings The cohort included 2041 patients diagnosed with MDR or rifampicin-resistant tuberculosis between Jan 1, 2008, and Dec 31, 2017; of those, 463 (22·7%) with RMR tuberculosis and 1354 (66·3%) with previous tuberculosis treatment. In previously treated patients, HIV positivity during previous tuberculosis treatment versus HIV negativity (adjusted odds ratio [OR] 2·07, 95% CI 1·35–3·18), and three or more previous tuberculosis treatment episodes versus one (1·96, 1·21–3·17) were associated with RMR tuberculosis. WGS data showing MDR or rifampicin-resistant tuberculosis were available for 1169 patients; 360 (30·8%) isolates were identified as unique. In previously treated patients, RMR tuberculosis versus MDR tuberculosis (adjusted OR 4·96, 3·40–7·23), HIV positivity during previous tuberculosis treatment (1·71, 1·03–2·84), and diagnosis in 2013–17 (1·42, 1·02–1·99) versus 2008–12, were associated with uniqueness. In previously treated patients with RMR tuberculosis, HIV positivity during previous treatment (adjusted OR 5·13, 1·61–16·32) was associated with uniqueness as was female sex (2·50 [1·18–5·26]). Interpretation These data suggest that HIV contributes to rifampicin-resistance acquisition during first-line tuberculosis treatment and that this might be driving increasing RMR tuberculosis over time. Large-scale prospective cohort studies are required to further quantify this risk. Funding Swiss National Science Foundation, South African National Research Foundation, and Wellcome Trust.

There is a need for short and safe all-oral treatment of rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after treatment initiation for patients with rifampicin-resistant tuberculosis in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable group).Patients with rifampicin-resistant tuberculosis, aged 18 years or older, eligible for a short regimen starting treatment between Jan 1 and Dec 31, 2017, with a bedaquiline-containing or WHO recommended injectable-containing treatment regimen of 9-12 months, registered in the drug-resistant tuberculosis database (EDRWeb), and with known age, sex, HIV status, and national identification number were eligible for study inclusion; patients receiving linezolid, carbapenems, terizidone or cycloserine, delamanid, or para-aminosalicylic acid were excluded. Bedaquiline was given at a dose of 400 mg once daily for two weeks followed by 200 mg three times a week for 22 weeks. To compare regimens, patients were exactly matched on HIV and ART status, previous tuberculosis treatment history, and baseline acid-fast bacilli smear and culture result, while propensity score matched on age, sex, province of treatment, and isoniazid-susceptibility status. We did binomial linear regression to estimate adjusted risk differences (aRD) and 95% CIs for 24-month outcomes, which included: treatment success (ie, cure or treatment completion without evidence of recurrence) versus all other outcomes, survival versus death, disease free survival versus survival with treatment failure or recurrence, and loss to follow-up versus all other outcomes.Overall, 1387 (14%) of 10152 patients with rifampicin-resistant tuberculosis treated during 2017 met inclusion criteria; 688 in the bedaquiline group and 699 in the injectable group. Four patients (1%) had treatment failure or recurrence, 44 (6%) were lost to follow-up, and 162 (24%) died in the bedaquiline group, compared with 17 (2%), 87 (12%), and 199 (28%), respectively, in the injectable group. In adjusted analyses, treatment success was 14% (95% CI 8-20) higher in the bedaquiline group than in the injectable group (70% vs 57%); loss to follow-up was 4% (1-8) lower in the bedaquiline group (6% vs 12%); and disease-free survival was 2% (0-5) higher in the bedaquiline group (99% vs 97%). The bedaquiline group had 8% (4-11) lower risk of mortality during treatment (17·0% vs 22·4%), but there was no difference in mortality post-treatment.Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months. This finding supports the use of short bedaquiline-containing regimens in eligible patients.WHO Global TB Programme.For the French translation of the abstract see Supplementary Materials section.

Children bear a substantial burden of suffering when it comes to tuberculosis. Ironically, they are often left out of the scientific and public health advances that have led to important improvements in tuberculosis diagnosis, treatment, and prevention over the past decade. This Series paper describes some of the challenges and controversies in paediatric tuberculosis, including the epidemiology and treatment of tuberculosis in children. Two areas in which substantial challenges and controversies exist (ie, diagnosis and prevention) are explored in more detail. This Series paper also offers possible solutions for including children in all efforts to end tuberculosis, with a focus on ensuring that the proper financial and human resources are in place to best serve children exposed to, infected with, and sick from all forms of tuberculosis.

We regret that this letter to the editor is behind a paywall. For more, please visit this page: https://www.ingentaconnect.com/content/iuatld/ijtld/2021/00000025/00000007/art00012;jsessionid=14ds6b542bebb.x-ic-live-02

Background: We compared outcomes up to 24 months after treatment initiation for rifampicin-resistant tuberculosis (RR-TB) patients in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable group). Methods: RR-TB patients eligible for a short regimen starting treatment between 1 January and 31 December 2017 with a bedaquiline-containing or WHO recommended injectable-containing treatment regimen of 9 to 12 months, registered with their national ID in the drug-resistant TB database and with known age, sex, and HIV status were eligible for study inclusion. To compare regimens, we exactly matched patients on HIV-infection, previous TB treatment history, baseline acid-fast bacilli smear and culture result, and propensity score matched patients on age, sex, and isoniazid susceptibility status, using logistic regression with generalized linear mixed models to estimate adjusted odds ratios (aOR) and 95% confidence intervals (95%CI). Results: Overall, 1,387 of the 10,152 RR-TB patients treated during 2017 met inclusion criteria, of whom 688 received the bedaquiline-containing regimen and 699 patients received the injectable-containing regimen. Four patients (0.6%) had treatment failure and/or recurrence, 44 (6.4%) were lost to follow-up, and 162 (23.5%) died in the bedaquiline group, compared to 17 (2.4%), 87 (12.4%), and 199 (28.5%), respectively, in the injectable group. Patients in the bedaquiline group had 1.8 (95%CI 1.4 to 2.4) times higher odds of treatment success at 24 months and 0.6 (0.4 to 0.8) times lower odds of loss to follow-up. This was consistent in stratified analyses on HIV-status, AFB smear positivity, and previous treatment history. The bedaquiline group had lower odds of mortality during treatment (0.5, 95%CI 0.4 to 0.7), but not post treatment (1.1, 95%CI 0.7 to 1.7). Conclusion: Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months compared to the injectable group. The analysis supports the use of short bedaquiline-containing regimens in eligible patients. Funding: WHO Global TB Programme. Declaration of Interest: We declare no competing interests. Ethical Approval: This analysis was approved by Human Research Ethics Committee, Medical of University of Witwatersrand (#M150340, March 2015).

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.

Purpose of review More than two billion people are infected with Mycobacterium tuberculosis and few of them are ever offered therapy in spite of such treatment being associated with reduced rates of morbidity and mortality. This article reviews the current recommendations on the diagnosis and treatment of TB infection (or what is commonly referred to as 'prophylaxis' or 'preventive therapy' of latent TB) and discusses barriers to implementation that have led to low demand for this life-saving therapeutic intervention. Recent findings Treatment of infection for both TB and drug-resistant TB is well tolerated and effective, and several new, shorter regimens - including rfiapenitine-based regimens of 1 month and 12 weeks duration - have been shown to be effective. Not all persons infected with TB go on to develop disease and the risk is the highest in the first 2 years after infection. Given this, additional work is needed to better identify those at the highest risk of developing active TB. Summary Practitioners should offer newer, shorter regimens to persons who are infected with TB and at high risk of developing disease, including people living with HIV and household contacts of people living with TB who are age 5 years and under. This includes individuals who have been exposed to drug-resistant forms of disease. Socioeconomic risk factors may play a key role in the development of TB disease and should also be addressed.

BACKGROUND: Completion of tuberculosis (TB) preventive treatment is important to optimize efficacy; treatment-related adverse events (AEs) sometimes result in discontinuation. This study describes the occurrence of AEs and their risk factors during a 6-month, 2-drug, fluoroquinolone-based preventive treatment for household contacts of patients with drug-resistant TB in Karachi, Pakistan. METHODS: The primary outcome was development of any clinical AE during preventive treatment. Adverse events were categorized using the AE grading tables of the National Institutes of Health. Time-to-event analysis with Kaplan-Meier curves and Cox proportional hazards models accounting for recurrence were used to analyze associated risk factors. RESULTS: Of the 172 household contacts on preventive treatment, 36 (21%) developed 64 AEs during 813 months of treatment. The incidence of AEs over 6 months of treatment was 7.9 per 100 person-months; 16 per 100 person-months with a fluoroquinolone and ethionamide, and 4.4 per 100 person-months with a fluoroquinolone and ethambutol. There were 53 (83%) grade 1 and 11 grade 2 AEs, with no grade 3 or 4 AEs. In multivariable analysis, the risk of AEs was higher in contacts prescribed ethionamide as compared to ethambutol adjusting for age, sex, and body mass index (adjusted hazard ratio, 2.1 [95% confidence interval {CI}, 1.2–3.6]). Overall, there was no notable difference in treatment completion among the contacts who experienced an AE and those who did not (crude odds ratio, 1.1 [95% CI, .52–2.5]). CONCLUSIONS: A fluoroquinolone-based preventive treatment regimen for drug-resistant TB exposure is well tolerated. Regimens with ethionamide are more likely to result in AEs.

Rifampicin-resistant tuberculosis (RR-TB) in a growing global health crisis. RR-TB and HIV co-infection is common, and this dual infection brings with it unique diagnostic and treatment challenges. Here, we review the most recent developments in the epidemiology, prevention, diagnoses, and treatment—including the use of novel antituberculosis drugs—for these diseases. We also review strategies to combat stigma and support adherence for people living with HIV and RR-TB. Advances in RR-TB diagnosis include genotypic tests, most notably Xpert MTB/RIF. Novel therapeutic advances in the treatment of RR-TB among people living with HIV include the use of new drugs (bedaquiline and delamanid), repurposed drugs (linezolid and clofazimine), and novel regimens (a shortened 9–12-month treatment). However, access to advances in diagnosis and treatment of RR-TB in people living with HIV is limited. Furthermore, there is a significant amount of stigma and discrimination against people with both HIV and RR-TB, and this could affect treatment outcomes via challenges with adherence. We conclude that with high-quality diagnostics, treatment, and support, people living with HIV and RR-TB have good treatment outcomes; thus, access to all of these interventions is an urgent global priority.

Little is known about the barriers to post-exposure management of rifampicin-resistant tuberculosis (RR-TB) in older children and adolescents. We report on implementation lessons from a pilot programme targeting household-exposed individuals aged 6-18 years in Khayelitsha, South Africa. Barriers included misperceptions regarding risk of exposure, multiple research and implementation stakeholders, additional workload for an overburdened healthcare system, logistical issues faced by families, and insufficient human and financial resources. Solutions to these barriers are possible, but creativity and persistence are required. Our experience can guide others looking to roll-out care for children and adolescents exposed to RR-TB.On connaît mal les entraves à la prise en charge post-exposition de la tuberculose résistante à la rifampicine (RR-TB) chez les enfants plus âgés et les adolescents. Nous rapportons les leçons de la mise en œuvre d'un programme pilote ciblant les individus exposés dans leurs foyers, âgés de 6–18 ans, à Khayelitsha, Afrique du Sud. Les obstacles ont inclus des perceptions erronées à propos du risque d'exposition, la multiplicité des partenaires de recherche et de mise en œuvre, la charge de travail supplémentaire pour un système de santé déjà surchargé, les problèmes logistiques auxquels sont confrontées les familles, et l'insuffisance des ressources humaines et financières. Il y a des solutions possibles à ces obstacles mais elles demandent de la créativité et de la détermination. Notre expérience peut guider ceux qui veulent lancer la prise en charge des enfants et des adolescents exposés à la RR-TB.Se conoce poco sobre los factores que obstaculizan la atención después de la exposición a un caso de tuberculosis resistente a rifampicina (RR-TB) en los niños mayores y los adolescentes. En el presente artículo se describen las enseñanzas aprendidas durante la ejecución de un programa piloto dirigido a los contactos domiciliarios expuestos entre los 6 y los 18 años de edad, en Khayelitsha, Suráfrica. Entre los obstáculos observados se pueden citar las percepciones equivocadas sobre el riesgo de exposición, la multiplicidad de interesados directos en la investigación y la ejecución, la carga de trabajo adicional en un sistema de salud sobresaturado, los problemas organizativos afrontados por las familias y la insuficiencia de recursos humanos y de financiamiento. Las soluciones a estos problemas son posibles, pero exigen creatividad y persistencia. Esta experiencia puede orientar a otros equipos que intenten poner en marcha la atención de los niños y los adolescentes expuestos a la RR-TB.

Zusammenfassung Vor dem Hintergrund der aktuellen Zuwanderung verscharft sich die Auspragung von Diversitat auch in der beruflichen Bildung. Dieser Praxisbeitrag widmet sich der Fragestellung, welche Gestaltungsaufgaben dadurch auf die beruflichen Schulen zukommen. Die Autorinnen kommen zu dem Schluss, dass die vorliegenden Berufsbildungskonzepte und ihre Instrumente eine geeignete Grundlage sein konnen, um Inklusion zu erreichen, wenn sie konsequent angewendet werden. Schlusselworter: Diversitat, Lernfeldkonzept, Migration, Berufsschule, Inklusion ----- Bibliographie: Boldajipour, Sigried/Mahlmann, Judith/Reuter, Anja: Diversitat als Chance nutzen – Gestaltungsaufgaben fur die berufliche Bildung, HiBiFo, 3-2017, S. 18-29. https://doi.org/10.3224/hibifo.v6i3.02

SETTING: Patients with rifampicin-resistant tuberculosis (RR-TB) in the township of Khayelitsha, South Africa, were offered delamanid (DLM) within a decentralised RR-TB treatment programme.OBJECTIVE: To describe adverse events (AEs) among HIV-positive and negative people receiving DLM for RR-TB in a programmatic setting.DESIGN: Patients were followed up monthly for blood, electrocardiography and clinical monitoring and AEs were assessed for severity grade, seriousness and relationship to DLM.RESULTS: Fifty-eight patients (55% male; median age 35 years, interquartile range [IQR] 28–42) started DLM; 46 (79%) were HIV-positive, median CD4 count 173 cells/mm3 (IQR 70–294). Fifty (86%) patients experienced ≥1 new or worsening AE after starting DLM, most commonly vomiting, QTcB >450 ms and/or myalgia. Serious and/or severe AEs were experienced by 22 (38%) patients; three HIV-positive patients died (not related to DLM). HIV status was not significantly associated with number (P = 0.089) or severity/seriousness (P = 0.11) of AEs during exposure to DLM. Two (3%) patients had DLM withdrawn due to AEs.CONCLUSION: AEs during RR-TB treatment, both before and during DLM exposure, were common, with relatively few serious/severe AEs considered related to DLM and no significant association with HIV status. Clinical and electrocardiography monitoring should be prioritised in the first two months after starting DLM.

Resistance to first-line anti-tuberculosis (TB) drugs continues to threaten global TB control with over 500 000 cases of rifampicin resistant (RR)-TB being reported in 2018. Treatment of RR-TB requires the use of toxic drugs often leading to adverse events, poor adherence and poor treatment outcomes. In order to address the toxicity of treatment and to improve treatment outcomes the World Health Organization has promoted the use of injection free regimens which include new and repurposed drugs: bedaquiline (BDQ), linezolid (LZD) and clofazimine (CFZ). In 2017, South Africa rolled out the inclusion of BDQ in the treatment of all pre-XDR- and XDR-TB cases as well as patients experiencing adverse events from kanamycin. In late 2018, South Africa included BDQ into three injection free regimens for treating RR-TB. This was done before routine drug susceptibility testing for BDQ could be implemented. Resistance to BDQ occurs primarily through mutations in Rv0678 (mmpR), pepQ and atpE. Understanding which mutations confer resistance and why they arise in a patient will be critical for early diagnosis as well as for preventing the emergence of resistance thereby ensuring successful treatment. Collation of the mutations identified in Rv0678 shows that BDQ resistance is largely driven by small insertions/deletions which disrupt the function of the repressor thereby leading to over expression of the efflux pump mmpL5 responsible for extruding BDQ from the cell. Understanding the association between gene mutation and phenotypic resistance remains critical for the development of new molecular diagnostics to rapidly diagnose resistance thereby affording the clinician the opportunity to adjust the regimen. Analysis of serial isolates collected from patients receiving BDQ (Access program pre-2017) has shown the emergence of mutations in Rv0678, atpE and pepQ during treatment in patients who remain culture positive after three months of treatment. Using targeted deep sequencing it is now possible to track the emergence of resistant sub-populations at the sub-phenotypic level (i.e., micro-heteroresistance) thereby affording the opportunity to study the association of the emergence of resistance with drug regimens, MIC distributions, PK and PD data and treatment outcomes. Our analysis showed that mutations conferring resistance occurred soon after the introduction of BDQ into the regimen and that clones harbouring these mutations were subsequently selected. Most surprising was the observation that different resistant sub-populations emerged during the period after the cessation of BDQ in the regimen. This demonstrates the continuing selective pressure as a result of the long half-life of BDQ. Although the origin of the distinct resistant clones is unknown, we hypothesize that resistance evolved independently in spatially separated lesions subsequently rupturing into the airways. A surprising observation was that concomitant emergence of different variants of the rpoC gene suggesting a compensatory mechanism to overcome the fitness cost of Rv0678 mutations.

Experience with delamanid (Dlm) is limited, particularly among HIV-positive individuals. We describe early efficacy and safety data from a programmatic setting in South Africa. This was a retrospective cohort study of patients receiving Dlm-containing treatment regimens between November 2015 and August 2017. We report 12-month interim outcomes, sputum culture conversion (SCC) by months 2 and 6, serious adverse events (SAEs) and QT intervals corrected using the Frederica formula (QTcF). Overall, 103 patients were initiated on Dlm; 79 (77%) were HIV positive. The main indication for Dlm was intolerance to second-line anti-tuberculosis (TB) drugs (n=58, 56%). There were 12 months of follow-up for 46 patients; 28 (61%) had a favourable outcome (cure, treatment completion or culture negativity). Positive cultures were found for 57 patients at Dlm initiation; 16 out of 31 (52%) had SCC within 2 months and 25 out of 31 (81%) within 6 months. There were 67 SAEs reported in 29 patients (28%). There were four instances of QTcF prolongation >500 ms in two patients (2%), leading to permanent discontinuation in one case; however, no cardiac arrhythmias occurred. This large cohort of difficult-to-treat patients receiving Dlm for rifampicin-resistant TB treatment in a programmatic setting with high HIV prevalence had favourable early treatment response and tolerated treatment well. Dlm should remain available, particularly for those who cannot be treated with conventional regimens or with limited treatment options., Patients with rifampicin-resistant TB treated with delamanid had good treatment response and cardiotoxicity was rare http://ow.ly/bVQu30jGPVJ

The novel coronavirus strain, SARS-CoV-2, was first reported from China in December 2019 [1]. As of the 14th May 2020, more than 4.4 million individuals have tested positive for SARS-COV-2 globally [2]. More than 300,000 individuals have died globally due to SARS-COV-2 [2]., Rapid adoption of new diagnostic tools, parallel process of research and implementation, decentralization of services, the use of personal protective equipment as well as strong partnership and collaboration could strengthen the fight against COVID-19.

Background: Limited data exist on 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. Methods: This 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. Findings: Twenty-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. Interpretation: This 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. Funding Statement: Medecins Sans Frontieres (MSF). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: Ethical approval was obtained from the University of Cape Town Human Research Ethics Committee (HREC 499/2011) for this study. Additionally this research fulfilled the exemption criteria set by the MSF Ethics Review Board for a posteriori analyses of routinely collected clinical data.

There is limited research investigating the possible mechanisms of how starting combination antiretroviral therapy (cART) at a higher CD4 cell count decreases mortality. This study investigated the association between initiating cART with short-term and long-term achievement of viral suppression; emergence of any drug resistance and of an AIDS-defining illness (ADI); long-term treatment adherence; and all-cause mortality.This retrospective cohort study included 4120 naive patients who initiated cART between 2000 and 2012. Patients were followed until 2013, death or until the last contact date (varied by outcome). The main exposure was the interaction between period of cART initiation (2000-2006 and 2007-2012) and CD4 cell count at cART initiation (500 versus ≥500 cells/μl). We considered both baseline and longitudinal covariates. We fitted different multivariable models using cross-sectional and longitudinal statistical methods, depending on the outcome.Patients who initiated cART with a CD4 cell count at least 500 cells/μl in 2007-2012 had an increased likelihood of achieving viral suppression at 9 months and of maintaining an adherence level of at least 95% over time, and the lowest probability of developing any resistance and an ADI during follow-up. These patients were not the ones with the highest likelihood of maintaining viral suppression over time, most likely due to viral load blips experienced during the follow-up.The outcomes in this study likely play an important role in explaining the positive impact of early cART initiation on mortality. These results should alleviate some of the concerns clinicians may have when initiating cART in patients with high CD4s as recommended by current treatment guidelines.

For decades, second-line injectable agents (IAs) have been the cornerstone of treatment for multidrug-resistant tuberculosis (MDR-TB). Although evidence on the efficacy of IAs is limited, there is an expanding body of evidence on the serious adverse events caused by these drugs. Here, we present the results of a structured literature review of the safety and efficacy of IAs. We review the continued widespread use of these agents in the context of therapeutic alternatives—most notably the newer TB drugs, bedaquiline and delamanid—and from the context of human rights, ethics and patient-centered care. We conclude that there is limited evidence of the efficacy of IAs, clear evidence of the risks of these drugs, and that persons living with MDR-TB should be informed about these risks and provided with access to alternative therapeutic options.

BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (–0·20, –0·23 to –0·16), levofloxacin (–0·06, –0·09 to –0·04), moxifloxacin (–0·07, –0·10 to –0·04), or bedaquiline (–0·14, –0·19 to –0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I(2) method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Experience with delamanid (Dlm) is limited, particularly among HIV-positive individuals. We describe early efficacy and safety data from a programmatic setting in South Africa.This was a retrospective cohort study of patients receiving Dlm-containing treatment regimens between November 2015 and August 2017. We report 12-month interim outcomes, sputum culture conversion (SCC) by months 2 and 6, serious adverse events (SAEs) and QT intervals corrected using the Frederica formula (QTcF).Overall, 103 patients were initiated on Dlm; 79 (77%) were HIV positive. The main indication for Dlm was intolerance to second-line anti-tuberculosis (TB) drugs (n=58, 56%). There were 12 months of follow-up for 46 patients; 28 (61%) had a favourable outcome (cure, treatment completion or culture negativity). Positive cultures were found for 57 patients at Dlm initiation; 16 out of 31 (52%) had SCC within 2 months and 25 out of 31 (81%) within 6 months. There were 67 SAEs reported in 29 patients (28%). There were four instances of QTcF prolongation >500 ms in two patients (2%), leading to permanent discontinuation in one case; however, no cardiac arrhythmias occurred.This large cohort of difficult-to-treat patients receiving Dlm for rifampicin-resistant TB treatment in a programmatic setting with high HIV prevalence had favourable early treatment response and tolerated treatment well. Dlm should remain available, particularly for those who cannot be treated with conventional regimens or with limited treatment options.

In their Lancet Review, Blake S Wilson and colleagues (July 10)1 describe the growing global burden of hearing loss caused by a range of possible factors. The use of ototoxic medication is a considerable contributor to hearing loss for both children and adults. The authors suggest a primary prevention strategy for reducing hearing loss, which includes the use of ototoxic drugs only when no alternatives are available and only for serious conditions.

Application designers are faced with a series of design decisions when considering the number of available cloud services that can be used nowadays to host one or more parts of the application. Each one of these services comes with a different pricing model, which results in additional complexity when trying to identify the most cost-efficient solution. Toward this goal, in this work we present our proposal for a design support process that covers both the migration of existing applications and the (re)design of new ones specifically for the cloud. Furthermore, we also discuss an architecture for the realization of this process, as well as our implementation of this architecture.

Location-based services (LBS) have gained enormous popularity, which imposes increasing query loads at the data tier of an LBS. Yet, the data access patterns of LBS typically possess high temporal and spatial locality. Therefore, a dedicated spatial cache which provides efficient access to the data currently needed may considerably reduce this load. To ensure high throughput, multiple cache nodes can collaborate in a distributed spatial cache overlay, which balances load among the nodes. However, load-balancing is a non-trivial task in this context, as load spreads unevenly in space and varies notably over time. This requires constant readjustment to shifting hot spots. We present an elastic load-balancing mechanism between cache nodes that is based on the physical model of a particle-spring system. Using spring contraction, nodes instantly form processing clusters in regions with high load and thus can easily work off accumulating queries. Our evaluation shows that our approach quickly adapts to rapidly changing hot spots and thereby ensures high throughput throughout the entire execution.