• Access to paediatric formulations for the treatment of childhood tuberculosis

      Nash, M; Perrin, C; Seddon, JA; Furin, J; Hauser, J; Marais, B; Kitai, I; Starke, J; McKenna, L (Elsevier, 2020-12-01)
    • Barriers and solutions to finding rifampicin-resistant tuberculosis cases in older children and adolescents

      Mohr-Holland, E; Apolisi, I; Reuter, A; de Azevedo, V; Hill, J; Matthee, S; Seddon, JA; Isaakidis, P; Furin, J; Trivino-Duran, L (International Union Against Tuberculosis and Lung Disease, 2019-12-21)
      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.
    • Bedaquiline and delamanid result in low rates of unfavourable outcomes among TB patients in Eswatini

      Vambe, D; Kay, AW; Furin, J; Howard, AA; Dlamini, T; Shabangu, A; Hassen, F; Masuku, S; Maha, O; Wawa, C; et al. (International Union Against Tuberculosis and Lung Disease, 2020-10-01)
      SETTING: Since 2015, Eswatini has been scaling up bedaquiline (BDQ) and delamanid (DLM) based drug-resistant TB treatment regimens under programmatic conditions. OBJECTIVE: Identification of factors associated with treatment outcomes in patients receiving BDQ and/or DLM either as a new treatment initiation or drug substitution. DESIGN: This is a retrospective cohort study of patients receiving BDQ and/or DLM in Eswatini between March 2015 and October 2018. We describe factors associated with unfavourable treatment outcomes (death, lost to follow-up, treatment failure and amplification of resistance) and culture conversion using multivariable flexible parametric survival and competing-risks regression analyses. RESULTS: Of 352 patients receiving BDQ and/or DLM, 7.8% and 21.2% had an unfavourable treatment outcome at 6 and 24 months, respectively. Predictors were age ≥ 60 years (adjusted hazard ratio aHR 4.49, 95%CI 1.61–12.57) vs. age 20–39 years, and a treatment regimen combining both drugs (aHR 4.49, 95%CI 1.61–12.57) vs. BDQ only. The probability of culture conversion was increased for two health facilities and patients with a poly resistance profile (adjusted sub-hazard ratio 2.01, 95%CI 1.13–3.59) vs. multidrug resistance. CONCLUSION: Single use of BDQ or DLM was associated with low rates of unfavourable outcomes, suggesting that these medications may be effectively adopted at scale under routine programmatic conditions. Combined use of BDQ and DLM was a risk factor for unfavourable outcomes and should prompt for collection of more data on the combined use of these medications.
    • Calling tuberculosis a social disease--an excuse for complacency?

      Isaakidis, P; Smith, S; Majumdar, S; Furin, J; Reid, T (Elsevier, 2014-09-20)
    • Challenges and controversies in childhood tuberculosis

      Reuter, A; Hughes, J; Furin, J (Elsevier, 2019-09-14)
      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.
    • Clinical perspectives on treatment of rifampicin-resistant/multidrug-resistant TB

      Cox, V; McKenna, L; Acquah, R; Reuter, A; Wasserman, S; Vambe, D; Ustero, P; Udwadia, Z; Trivino-Duran, L; Tommasi, M; et al. (International Union Against Tuberculosis and Lung Disease, 2020-11-01)
      Rapid diagnostics, newer drugs, repurposed medications, and shorter regimens have radically altered the landscape for treating rifampicin-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB). There are multiple ongoing clinical trials aiming to build a robust evidence base to guide RR/MDR-TB treatment, and both observational studies and programmatic data have contributed to advancing the treatment field. In December 2019, the WHO issued their second ‘Rapid Communication´ related to RR-TB management. This reiterated their prior recommendation that a majority of people with RR/MDR-TB receive all-oral treatment regimens, and now allow for specific shorter duration regimens to be used programmatically as well. Many TB programs need clinical advice as they seek to roll out such regimens in their specific setting. In this Perspective, we highlight our early experiences and lessons learned from working with National TB Programs, adult and pediatric clinicians and civil society, in optimizing treatment of RR/MDR-TB, using shorter, highly-effective, oral regimens for the majority of people with RR/MDR-TB.
    • Compassionate Use of New Drugs in Children and Adolescents with Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis: Early Experiences and Challenges

      Tadolini, M; Garcia-Prats, AJ; D'Ambrosio, L; Hewison, C; Centis, R; Schaaf, HS; Marais, BJ; Ferreira, H; Caminero, JA; Jonckheere, S; et al. (European Respiratory Society, 2016-06-23)
    • Correspondence regarding "Delamanid for rifampicin-resistant tuberculosis: a retrospective study from South Africa".

      Mohr-Holland, E; Reuter, A; Hughes, J; Daniels, J; Beko, B; Makhanda, G; De Avezedo, V; Kock, Y; Cox, H; Furin, J; et al. (European Respiratory Society, 2020-07-23)
    • Delamanid for rifampicin-resistant tuberculosis: a retrospective study from South Africa.

      Mohr, E; Hughes, J; Reuter, A; Trivino Duran, L; Ferlazzo, G; Daniels, J; De Azevedo, V; Kock, Y; Steele, SJ; Shroufi, A; et al. (European Respiratory Society, 2018-06-14)
      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.
    • Demanding an end to tuberculosis: treatment of tuberculosis infection among persons living with and without HIV

      Fargher, J; Reuter, A; Furin, J (Lippincott, Williams & Wilkins, 2019-01-01)
      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.
    • The devil we know: is the use of injectable agents for the treatment of MDR-TB justified?

      Reuter, A; Tisile, P; von Delft, D; Cox, H; Cox, V; Ditiu, L; Garcia-Prats, A; Koenig, S; Lessem, E; Nathavitharana, R; et al. (International Union Against Tuberculosis and Lung Disease, 2017-11-01)
      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.
    • Direct Observation (DO) for Drug-Resistant Tuberculosis: Do We Really DO?

      Benbaba, S; Isaakidis, P; Das, M; Jadhav, S; Reid, T; Furin, J (2015-12-29)
      Directly-observed therapy (DOT) is recommended for drug-resistant tuberculosis (DR-TB) patients during their entire treatment duration. However, there is limited published evidence on implementation of direct observation (DO) in the field. This study aims to detail whether DO was followed with DR-TB patients in a Médecins Sans Frontières (MSF) tuberculosis program in Mumbai, India.
    • Early safety and efficacy of the combination of bedaquiline and delamanid for the treatment of patients with drug-resistant tuberculosis in Armenia, India, and South Africa: a retrospective cohort study

      Ferlazzo, G; Mohr, E; Laxmeshwar, C; Hewison, C; Hughes, J; Jonckheere, S; Khachatryan, N; De Avezedo, V; Egazaryan, L; Shroufi, A; et al. (Elsevier, 2018-02-13)
      Bedaquiline and delamanid have been approved for treatment of multidrug-resistant (MDR) tuberculosis in the past 5 years. Because of theoretical safety concerns, patients have been unable to access the two drugs in combination. Médecins Sans Frontières has supported the use of combination bedaquiline and delamanid for people with few treatment options since 2016. We describe early safety and efficacy of regimens containing the bedaquiline and delamanid combination in patients with drug-resistant tuberculosis in Yerevan, Armenia; Mumbai, India; and Khayelitsha, South Africa.
    • The Epidemiology, Pathogenesis, Transmission, Diagnosis, and Management of Multidrug-Resistant, Extensively Drug-Resistant, and Incurable Tuberculosis

      Dheda, K; Gumbo, T; Maartens, G; Dooley, KE; McNerney, R; Murray, M; Furin, J; Nardell, EA; London, L; Lessem, E; et al. (Elsevier. We regret that this article is behind a paywall., 2017-03-15)
      Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.
    • Examples of Bedaquiline Introduction for the Management of Multidrug-Resistant Tuberculosis in Five Countries

      Guglielmetti, L; Hewison, C; Avaliani, Z; Hughes, J; Kiria, N; Lomtadze, N; Ndjeka, N; Setkina, S; Shabangu, A; Sikhondze, W; et al. (International Union Against Tuberculosis and Lung Disease, 2017-02-01)
      For the first time in almost 50 years, there are new drugs available for the treatment of tuberculosis (TB), including bedaquiline (BDQ) and delamanid (DLM). The rate of introduction, however, has not kept pace with patient needs. It is estimated that as many as 23% of multidrug-resistant TB (MDR-TB) patients have an indication for receiving BDQ. As this is the first time the MDR-TB community is introducing new medications, it is important to understand how implementation can be developed in a variety of settings.
    • The Experience of Bedaquiline Implementation at a Decentralised Clinic in South Africa

      Cariem, R; Cox, V; de Azevedo, V; Hughes, J; Mohr, E; Durán, LT; Ndjeka, N; Furin, J (International Union Against Tuberculosis and Lung Disease, 2016-09-21)
    • Global programmatic use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis

      Cox, V; Brigden, G; Crespo, RH; Lessem, E; Lynch, S; Rich, ML; Waning, B; Furin, J (International Union Against Tuberculosis and Lung Disease, 2018-04-01)
      The World Health Organization recommended two new drugs, bedaquiline (BDQ) and delamanid (DLM), for the treatment of multidrug-resistant tuberculosis (MDR-TB) in 2013 and 2014, respectively. An estimated one third of patients with MDR-TB would benefit from the inclusion of these drugs in their treatment regimens.
    • A home-based care programme for rifampicin-resistant TB.

      Douglas-Jones, B; Mohr-Holland, E; Mema, N; Mathee, S; Mathews, G; Hurribance, S; Scott, V; Reuter, A; Furin, J; Pfaff, C (Ingenta, 2021-07-01)
    • How COVID-19 could benefit tuberculosis and HIV services in South Africa.

      Keene, C; Mohr-Holland, E; Cassidy, T; Scott, V; Nelson, A; Furin, J; Trivino-Duran, L (Elsevier, 2020-08-03)