• 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.
    • 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.
    • 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.
    • The ethical imperative to relieve suffering for people with tuberculosis by ensuring access to palliative care

      Harding, R; Snyman, L; Ostgathe, C; Odell, S; Gwyther, L (International Union Against Tuberculosis and Lung Disease, 2020-05-01)
      Patients diagnosed with tuberculosis (TB) continue to experience clinical uncertainty and high mortality and to bear a high burden of symptoms and other concerns. Additional concerns may be family support needs and stigma, particularly the latter, as TB and human immunodeficiency virus (HIV) coinfection are common. Human rights covenants, global health policy and the End TB Strategy all recommend palliative care as an essential component of care services. As established in the resolution adopted by the World Health Assembly (WHA) on ‘‘Strengthening of palliative care as a component of comprehensive care throughout the life course’’, there is a ‘‘need for palliative care across disease groups (non-communicable diseases, and infectious diseases, including HIV and multidrug-resistant tuberculosis), and across all age groups’’. We address the ethical imperative to respect the dignity and fundamental rights of people with TB by providing palliative care. We review the evidence for the need for person-centred palliative care and highlight novel models that utilise the skills and training functions of specialist palliative care to achieve better care. We outline simple recommendations for the delivery of specialist and generalist palliative care, offer suggestions on how to ensure optimal coverage by enabling access to appropriate good-quality palliative care at all points of the health system, including alongside treatment. Finally, we set out the current priorities for research and policy to ensure that quality care is delivered to all who need it irrespective of treatment outcome, to minimise distress and to optimise engagement in treatment and care.
    • 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.
    • Impact of pyrazinamide resistance on multidrug-resistant tuberculosis in Karakalpakstan, Uzbekistan

      Kuhlin, J; Smith, C; Khaemraev, A; Tigay, Z; Parpieva, N; Tillyashaykhov, M; Achar, J; Hajek, J; Greig, J; du Cros, P; et al. (International Union Against Tuberculosis and Lung Disease, 2018-05-01)
      The World Health Organization (WHO) recommends the inclusion of pyrazinamide (PZA) in treatment regimens for multidrug-resistant tuberculosis (MDR-TB) unless resistance has been confirmed.
    • Implementing novel regimens for drug-resistant TB in South Africa: what can the world learn?

      Ndjeka, N; Hughes, J; Reuter, A; Conradie, F; Enwerem, M; Ferreira, H; Ismail, N; Kock, Y; Master, I; Meintjes, G; et al. (International Union Against Tuberculosis and Lung Disease, 2020-10-01)
      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.
    • Introducing new and repurposed TB drugs: the endTB experience

      Seung, KJ; Khan, U; Varaine, F; Ahmed, S; Bastard, M; Cloez, S; Damtew, D; Franke, MF; Herboczek, K; Huerga, H; et al. (International Union Against Tuberculosis and Lung Disease, 2020-10-01)
      n 2015, the initiative Expand New Drug Markets for TB (endTB) began, with the objective of reducing barriers to access to the new and repurposed TB drugs. Here we describe the major implementation challenges encountered in 17 endTB countries. We provide insights on how national TB programmes and other stakeholders can scale-up the programmatic use of new and repurposed TB drugs, while building scientific evidence about their safety and efficacy. For any new drug or diagnostic, multiple market barriers can slow the pace of scale-up. During 2015–2019, endTB was successful in increasing the number of patients receiving new and repurposed TB drugs in 17 countries. The endTB experience has many lessons, which are relevant to country level introduction of new TB drugs, as well as non-TB drugs and diagnostics. For example: the importation of TB drugs is possible even in the absence of registration; emphasis on good clinical monitoring is more important than pharmacovigilance reporting; national guidelines and expert committees can both facilitate and hinder innovative practice; clinicians use new and repurposed TB drugs when they are available; data collection to generate scientific evidence requires financial and human resources; pilot projects can drive national scale-up.
    • New TB drugs for the treatment of children and adolescents with rifampicin-resistant TB in Mumbai, India

      Das, M; Mamnoon, F; Mansoor, H; Meneguim, AC; Singh, P; Shah, I; Ravi, S; Kalon, S; Hossain, FN; Ferlazzo, G; et al. (International Union Against Tuberculosis and Lung Disease, 2020-12-01)
      SETTING: Médecins Sans Frontières (MSF) clinic in Mumbai, India. OBJECTIVE: To determine the final treatment outcomes, culture conversion and adverse events (AEs) during treatment among children and adolescents (0–19 years) with rifampicin-resistant tuberculosis (RR-TB) who received ambulatory injectable-free treatment, including bedaquiline (BDQ) and/or delamanid (DLM) during September 2014–January 2020. DESIGN: This was a retrospective cohort study based on review of routinely collected programme data. RESULTS: Twenty-four patients were included; the median age was 15.5 years (min-max 3–19) and 15 (63%) were females. None were HIV-coinfected. All had fluoroquinolone resistance. Twelve received treatment, including BDQ and DLM, 11 received DLM and one BDQ. The median exposure to BDQ (n = 13) and DLM (n = 23) was 82 (IQR 80–93) and 82 (IQR 77–96) weeks, respectively. Seventeen (94%) patients with positive culture at baseline (n = 18) had negative culture during treatment; median time for culture-conversion was 7 weeks (IQR 5–11). Twenty-three (96%) had successful treatment outcomes: cured (n = 16) or completed treatment (n = 7); one died. Eleven (46%) had 17 episodes of AEs. Two of 12 serious AEs were associated with new drugs (QTcF >500 ms). CONCLUSION: Based on one of the largest global cohorts of children and adolescents to receive new TB drugs, this study has shown that injectable-free regimens containing BDQ and/or DLM on ambulatory basis were effective and well-tolerated among children and adolescents and should be made routinely accessible to these vulnerable groups.
    • Setting up pharmacovigilance based on available endTB Project data for bedaquiline

      Lachenal, N; Hewison, C; Mitnick, C; Lomtadze, N; Coutisson, S; Osso, E; Ahmed, S; Leblanc, G; Islam, S; Atshemyan, H; et al. (International Union Against Tuberculosis and Lung Disease, 2020-10-01)
      SETTING: Active pharmacovigilance (PV) is recommended for TB programmes, notably for multidrug-resistant TB (MDR-TB) patients treated with new drugs. Launched with the support of UNITAID in April 2015, endTB (Expand New Drug markets for TB) facilitated treatment with bedaquiline (BDQ) and/or delamanid of >2600 patients in 17 countries, and contributed to the creation of a central PV unit (PVU). OBJECTIVE: To explain the endTB PVU process by describing the serious adverse events (SAEs) experienced by patients who received BDQ-containing regimens. DESIGN: The overall PV strategy was in line with the ‘advanced´ WHO active TB drug safety monitoring and management (aDSM) system. All adverse events (AEs) of clinical significance were followed up; the PVU focused on signal detection from SAEs. RESULTS and CONCLUSION: Between 1 April 2015 and 31 March 2019, the PVU received and assessed 626 SAEs experienced by 417 BDQ patients. A board of MDR-TB/PV experts reviewed unexpected and possibly drug-related SAEs to detect safety signals. The experts communicated on clusters of risks factors, notably polypharmacy and off-label drug use, encouraging a patient-centred approach of care. Organising advanced PV in routine care is possible but demanding. It is reasonable to expect local/national programmes to focus on clinical management, and to limit reporting to aDSM systems to key data, such as the SAEs.