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In 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.

OBJECTIVE: To systematically screen older rural populations in Cambodia for tuberculosis (TB) and develop an effective active case-finding (ACF) model for this TB high-risk group.DESIGN: A retrospective study using routinely collected programmatic data on community-based ACF among people aged ≥55 years using TB symptoms and systematic chest radiography (CXR) screening, followed by Xpert® MTB/RIF testing for participants with positive screening results and TB culture for certain Xpert-negative specimens.RESULTS: Of 22 101 participants included in the analysis, 7469 (33.8%) were screening-positive and 5960 (27.0%) underwent Xpert testing. Pulmonary TB was identified in 482 (2.2%) individuals: 288 (1.3%) were bacteriologically confirmed (253 using Xpert, 35 using culture) and 194 (0.9%) were clinically diagnosed. Eighty-seven people needed to be screened in order to diagnose one Xpert-positive case. Among the Xpert-positive cases, only 31.6% (80/253) reported cough ≥2 weeks, and 39.9% (101/253) were asymptomatic but had a CXR suggestive of active TB. Treatment uptake was 97.3% (469/482), and treatment success was 88.0% (424/482).CONCLUSIONS: Community-based ACF was effective in detecting and successfully treating older TB patients, most of whom might otherwise have remained undiagnosed. Mobile CXR appears to be crucial in identifying a high number of asymptomatic, bacteriologically confirmed cases.

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.

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.

We assessed effectiveness and safety of concomitant chronic hepatitis C virus (HCV) treatment with direct-acting antivirals (DAAs) and multidrug-resistant tuberculosis (MDR-TB). Of 322 MDR-TB patients (19.4% HCV), 30 were treated concomitantly (23.3% human immunodeficiency virus-positive). Overall, 76.7% achieved HCV treatment success (95.8% among tested). One patient (3.3%) experienced a serious adverse event.

We regret that this article is behind a paywall., Background Bedaquiline and delamanid offer the possibility of more effective and less toxic multidrug-resistant tuberculosis (MDR-TB) treatment. With this treatment, however, some patients, remain at high risk for an unfavorable treatment outcome. The endTB observational study is the largest multicountry cohort of patients with rifampin-resistant/MDR-TB treated in routine care, according to WHO guidance, with delamanid- and/or bedaquiline-containing regimens. We report frequency of sputum culture conversion within six-months of treatment initiation and risk factors for non-conversion. Methods We included patients with a positive baseline culture who initiated a first endTB regimen prior to April 2018. Two consecutive negative cultures collected > 15 days apart constituted culture conversion. We used generalized mixed models to derive marginal predictions for the probability of culture conversion in key subgroups. Findings 1,109 patients initiated a multidrug treatment containing bedaquiline (63%), delamanid (27%) or both (10%). Of these, 939 (85%) experienced culture conversion within six months. In adjusted analyses, patients with HIV had a lower probability of conversion (0·73 [95% CI: 0·62, 0·84]) than patients without HIV (0·84 [95% CI: 0·79, 0·90]; p=0·03). Patients with both cavitary disease and highly positive sputum smear had a lower probability of conversion (0·68 [95% CI: 0·57, 0·79]) relative to patients without either (0·89; 95% CI: 0·84, 0·95; p=0·0004). Hepatitis C infection, diabetes mellitus/glucose intolerance, and baseline resistance were not associated with conversion. Interpretation Frequent sputum conversion in patients with rifampin-resistant/MDR-TB who were treated with bedaquiline and/or delamanid underscores the need for urgent expanded access to these drugs. There is a need to optimize treatment for patients with HIV and extensive disease.

BACKGROUND AND SETTING Bedaquiline (BDQ) was initially only available through compassionate use programmes. OBJECTIVE To assess the effectiveness and safety of multidrug-resistant tuberculosis (MDR-TB) treatment containing BDQ. METHOD Retrospective analysis of data from patients receiving BDQ through compassionate use in Armenia and Georgia from April 2013 to April 2015. Logistic regression was used to assess the risk factors associated with unsuccessful treatment outcomes. RESULTS Of 82 patients included, 84.2% (69/82) had fluoroquinolone-resistant MDR-TB and 43.4% (23/53) were seropositive for the hepatitis C virus (HCV). The culture conversion rate was 84.4% (54/64), and 18.5% (10/54) reverted back to positive. In total, 79.3% (65/82) of the patients reported at least one adverse event. Serious adverse events were reported in 14 patients, with 10/14 patients experiencing fatal outcomes-6/10 related to advanced TB and 2/10 assessed as possibly related to BDQ. Treatment outcomes were as follows: 58.5% treatment success, 12.2% deaths, 7.3% failures and 21.9% lost to follow-up. HCV coinfection was associated with unsuccessful outcomes (adjusted OR 4.45, 95%CI 1.23-16.13). CONCLUSION BDQ through compassionate use showed relatively good success rates and safety profiles in a cohort with difficult-to-treat MDR-TB. High rates of reversion may indicate that >24 weeks of BDQ is necessary in some cases. HCV coinfection should be diagnosed and treatment considered in MDR-TB patients.

Phase II trials for bedaquiline (BDQ) and delamanid (DLM) were completed by 2011 and the drugs were approved by stringent regulatory authorities for the treatment of multidrug-resistant tuberculosis (MDR-TB) between 2012 and 2014. Manufacturers established 'early access' mechanisms to provide drugs before local registration.To inform improvements in early access, we explored experiences of providers and advocates in accessing BDQ and DLM before the end of 2015 using a mixed-methods design.We examined barriers and facilitators to early access through an electronic survey. Barriers and facilitators were classified as occurring at the manufacturer- or country-level. We identified themes using inductive content analysis and illustrated themes through case studies.We analysed 41 survey responses from 36 respondents reporting on 22 countries; early access was attempted in 30 (73%) survey responses. Eligibility restrictions (11/30, 37%) and complicated and slow processes (8/30, 27%) were manufacturer-level barriers; access to companion drugs (10, 33%) and importation difficulties (4, 13%) were country-level barriers. Previous experience with manufacturer (3/30, 10%) and country processes (2/30, 7%) facilitated access. Eight case studies show the human impact of barriers and facilitators.Manufacturers and countries should develop transparent processes to permit early access, particularly for diseases that largely affect the poor, such as MDR-TB. Developers should plan for this need and rapidly register drugs with proven benefit, prioritizing high-burden settings.La bédaquiline (BDQ) et le delamanide (DLM) ont terminé leurs essais de Phase II en 2011 et ont été approuvés par des autorités réglementaires strictes pour le traitement de la tuberculose multirésistante (TB-MDR) entre 2012 et 2014. Les fabricants ont mis en place des mécanismes d’accès anticipé afin de fournir les médicaments avant les enregistrements au niveau national.Pour mettre en lumière les améliorations nécessaires en matière d’accès anticipé, nous avons examiné les expériences des fournisseurs et des promoteurs de l’accès à la BDQ et au DLM avant fin de 2015 en utilisant un modèle multi-méthodes.Nous avons analysé les obstacles et les facteurs facilitants de l’accès rapide via un sondage électronique. Les obstacles et les facteurs facilitants ont été classés comme survenant au niveau du fabricant ou du pays. Nous avons identifié des thèmes à l’aide d’une analyse inductive de contenu et les avons illustrés à l’aide d’études de cas.Nous avons analysé 41 réponses à une enquête auprès de 36 répondants de 22 pays; l’accès anticipé a été tenté dans 30 (73%) des réponses au sondage. Les restrictions d’éligibilité (11/30, 37%) et la complexité et la lenteur des démarches (8/30, 27%) étaient des obstacles au niveau du fabricant ; l’accès aux médicaments associés (10, 33%) et les difficultés d’importation (4, 13%) constituaient des obstacles au niveau des pays. Une expérience préalable avec les démarches au niveau du fabricant (3/30, 10%) et du pays (2/30, 7%) étaient des facteurs facilitants. Huit études de cas illustrent l’impact humain des obstacles et des facteurs facilitants.Les fabricants et les pays doivent mettre au point des procédures transparentes permettant un accès rapide, en particulier pour les maladies qui touchent principalement les personnes pauvres, telles que la TB-MDR. Les développeurs doivent planifier la réponse à ce besoin et enregistrer rapidement les médicaments dont les bénéfices sont avérés, en donnant la priorité aux régions les plus touchées.La fase II de los ensayos clínicos con bedaquilina (BDQ) y delamanid (DLM) se completaron en el 2011 y estos fármacos recibieron la aprobación por parte de organismos de regulación rigurosos para el tratamiento de la tuberculosis multirresistente (TB-MDR) entre el 2012 y el 2014. Los fabricantes crearon mecanismos de ‘acceso precoz’ destinados a proveer los fármacos antes de haber obtenido su registro local.Con el propósito de documentar los progresos en el acceso precoz, se examinaron las experiencias de los proveedores de atención y los facilitadores del acceso a la BDQ y el DLM antes de fines del 2015 en un estudio de métodos mixtos.Mediante una encuesta electrónica se analizaron los obstáculos y los factores que facilitaron el acceso precoz. Estos factores se clasificaron según que se presentaran a nivel del fabricante o del país. Se reconocieron los temas principales mediante un análisis inductivo de contenido y se ejemplificaron los temas con estudios de casos.Se analizaron 41 respuestas a las encuestas aportadas por 36 entrevistados con experiencias de 22 países; el intento de obtención de un acceso precoz se refirió en 30 de las respuestas (73%). Entre los obstáculos a nivel del fabricante se encontraron las restricciones de las condiciones exigidas (11/30, 37%) y la complejidad y la lentitud de los procedimientos (8/30, 27%); las barreras referidas a escala nacional fueron el acceso a los medicamentos utilizados en asociación (10, 33%) y las dificultades de importación. La experiencia previa con el fabricante (3/30, 10%) y con los procedimientos del país (2/30, 7%) facilitó el acceso. Ocho estudios de casos aclaran el impacto humano de los obstáculos y los factores facilitadores.Es primordial que los fabricantes y los países elaboren procedimientos transparentes que faciliten el acceso precoz, en especial para las enfermedades que afectan en gran medida a las personas pobres como es el caso de la TB-MDR. Los encargados del desarrollo galénico deberían prever esta necesidad y acelerar el registro de los medicamentos cuyo beneficio se ha demostrado, dando prioridad a los entornos con alta carga de morbilidad.

INTRODUCTION: Identification of good prognostic marker for tuberculosis (TB) treatment response is a necessary step on the path towards a surrogate marker to reduce TB trial duration.METHODS: We performed a retrospective analysis on routinely collected data in 6 drug-resistant TB (DRTB) programs. Culture conversion, defined as two consecutive negative cultures, was assessed, and performance of culture conversion at Month 2 and Month 6 to predict treatment success were explored. To explore factors associated with positive predicted value (PPV) and the specificity of culture conversion, a multinomial logistic regression was fitted.RESULTS: This study included 634 patients: 68.5% were males; the median age was 35 years, 75.2% were previously treated for TB, 59.4% were resistant only to isoniazid and rifampicin and 18.1% resistant to fluoroquinolones. Culture conversion at Month 2 and 6 showed similar PPV while specificity was much higher for culture conversion at Month 2: 91.3% (95%CI 86.1–95.1). PPV of culture conversion at Month 2 did not vary strongly according to patients' characteristics, while specificity was slightly higher among patients with fluoroquinolone-resistant strains.CONCLUSION: Culture conversion at Month 2 is an acceptable prognostic marker for MDR-TB treatment. Considering the advantage of using an earlier marker, further evaluation as a surrogate marker is warranted to shorten TB trials.

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The current treatment for drug-resistant tuberculosis (TB) is long, complex, and associated with severe and life-threatening side effects and poor outcomes. For the first time in nearly 50 years, there have been two new drugs registered for use in multidrug-resistant TB (MDR-TB). Bedaquiline, a diarylquinoline, and delamanid, a nitromidoxazole, have received conditional stringent regulatory approval and have World Health Organization interim policy guidance for their use. As countries improve and scale up their diagnostic services, increasing number of patients with MDR-TB and extensively drug-resistant TB are identified. These two new drugs offer a real opportunity to improve the outcomes of these patients. This article reviews the evidence for these two new drugs and discusses the clinical questions raised as they are used outside clinical trial settings. It also reviews the importance of the accompanying drugs used with these new drugs. It is important that barriers hindering the use of these two new drugs are addressed and that the existing clinical experience in using these drugs is shared, such that their routine-use programmatic conditions is scaled up, ensuring maximum benefit for patients and countries battling the MDR-TB crisis.

International audience; Prevalence of nontuberculous mycobacteria (NTM) disease is poorly documented in countries with high prevalence of tuberculosis (TB). We describe prevalence, risk factors, and TB program implications for NTM isolates and disease in Cambodia. A prospective cohort of 1,183 patients with presumptive TB underwent epidemiologic, clinical, radiologic, and microbiologic evaluation, including \textgreater12-months of follow-up for patients with NTM isolates. Prevalence of NTM isolates was 10.8% and of disease was 0.9%; 217 (18.3%) patients had TB. Of 197 smear-positive patients, 171 (86.8%) had TB confirmed (167 by culture and 4 by Xpert MTB/RIF assay only) and 11 (5.6%) had NTM isolates. HIV infection and past TB were independently associated with having NTM isolates. Improved detection of NTM isolates in Cambodia might require more systematic use of mycobacterial culture and the use of Xpert MTB/RIF to confirm smear-positive TB cases, especially in patients with HIV infection or a history of TB.

Background 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. Methods A qualitative assessment of country TB programs in which more than 5% of MDR-TB patients were started on BDQ under program conditions. Results National TB programs in Belarus, France, Georgia, South Africa, and Swaziland all started sizeable cohorts of patients on BDQ in 2015. Common factors observed in these programs included experience with compassionate use/expanded access, support from implementing partners, and adequate national or donor-supported budgets. Barriers to introduction included restriction of BDQ to the in-patient setting, lack of access to companion drugs, and the development of systems for pharmacovigilance. Conclusion The five countries in this paper are examples of the introduction of new therapeutic options for the treatment of TB.

The success of the current treatment regimen for multidrug-resistant (MDR) tuberculosis is poor partly owing to a high default rate. Many studies have explored predictors of poor outcomes, but very few have assessed the effects of treatment interruptions on treatment outcomes for MDR tuberculosis.We conducted a retrospective analysis among patients with MDR tuberculosis enrolled in 2 MDR tuberculosis programs using regimens recommended by the World Health Organization under directly observed therapy. Treatment outcomes were defined as successful if the patient was cured or completed treatment and unsuccessful if the patient died or defaulted from treatment or if treatment failed. The effect of patterns of interruptions on treatment outcomes was assessed through multivariate logistic regression.A total of 393 patients with MDR tuberculosis were included in the study; 171 (43.5%) had a successful outcome, and 222 (56.5%) an unsuccessful outcome: 39 (9.9%) died, 56 (14.3%) had failed treatment, and 127 (32.3%) defaulted from treatment. In multivariate analysis, long interruptions (≥3 days) (adjusted odds ratio, 3.87; 95% confidence interval, 1.66-8.98) and short gaps (10 days) between interruptions (3.94; 1.76-8.81) were independently associated with an unsuccessful treatment outcome.This study shows that in a directly observed therapy-based MDR tuberculosis program, treatment interruptions at short intervals of ≥3 days directly affect treatment outcome.

BACKGROUND: The World Health Organization recommends adding bedaquiline or delamanid to multi drug-resistant tuberculosis (MDR-TB) regimens for which four effective drugs are not available, and delamanid for patients at high risk of poor outcome. OBJECTIVE: To identify patients at risk of unfavourable outcomes who may benefit from the new drugs. METHODS: Retrospective cohort study of treatment outcomes involving four to five effective drugs for 1524 months in programmes in Uzbekistan, Georgia, Armenia, Swaziland and Kenya between 2001 and 2011. RESULTS: Of 1433 patients, 48.5% had body mass index (BMI)

Background The emergence of resistance to anti-tuberculosis (DR-TB) drugs and the HIV epidemic represent a serious threat for reducing the global burden of TB. Although data on HIV-negative DR-TB treatment outcomes are well published, few data on DR-TB outcomes among HIV co-infected people is available despite the great public health importance. Methods We retrospectively reported and compared the DR-TB treatment outcomes of HIV-positive and HIV-negative patients treated with an individualized regimen based on WHO guidelines in seven countries: Abkhazia, Armenia, Colombia, Kenya, Kyrgyzstan, Swaziland and Uzbekistan. Results Of the 1,369 patients started DRTB treatment, 809 (59.1%) were multi-drug resistant (MDR-TB) and 418 (30.5%) were HIV-positive. HIV-positive patients were mainly from African countries (90.1%) while HIV-negative originated from Former Soviet Union (FSU) countries. Despite a higher case fatality rate (19.0% vs 9.4%), HIV-positive MDR-TB patients had a 10% higher success rate than HIV-negative patients (64.0% vs 53.2%, p = 0.007). No difference in treatment success was found among polydrug-resistant (PDR-TB) patients. Overall, lost to follow-up rate was much higher among HIV-negative (22.0% vs. 8.4%). Older age and not receiving ART were the only factors associated with unfavorable treatment outcome among HIV-positive patients. Conclusions As already known for HIV-negative patients, success rate of DR-TB HIV-positive patients remains low and requires more effective DR-TB regimen using new drugs also suitable to HIV-infected patients on ART. The study also confirms the need of ART introduction in HIV co-infected patients.

Objective: To assess the safety and effectiveness of eflornithine as first line treatment for human African trypanosomiasis. Design: Cohort study. Setting: Control programme in Ibba, southern Sudan. Participants: 1055 adults and children newly diagnosed with second stage disease in a 16 month period. Main outcome measures: Deaths, severe drug reactions, and cure at 24 months. Results: 1055 patients received eflornithine for 14 days (400 mg/kg/day in adults and 600 mg/kg/day in a subgroup of 96 children). Overall, 2824 drug reactions (2.7 per patient) occurred during hospital stay, 1219 (43.2%) after the first week. Severe reactions affected 138 (13.1%) patients (mainly seizures, fever, diarrhoea, and bacterial infections), leading to 15 deaths. Risk factors for severe reactions included cerebrospinal fluid leucocyte counts ≥100x109/l (adults: odds ratio 2.6, 95% confidence interval 1.5 to 4.6), seizures (adults: 5.9, 2.0 to 13.3), and stupor (children: 9.3, 2.5 to 34.2). Children receiving higher doses did not experience increased toxicity. Follow-up data were obtained for 924 (87.6%) patients at any follow-up but for only 533 (50.5%) at 24 months. Of 924 cases followed, 16 (1.7%) died during treatment, 70 (7.6%) relapsed, 15 (1.6%) died of disease, 403 (43.6%) were confirmed cured, and 420 (45.5%) were probably cured. The probability of event free survival at 24 months was 0.88 (0.86 to 0.91). Most (65.8%, 52/79) relapses and disease related deaths occurred after 12 months. Risk factors for relapse included being male (incidence rate ratio 2.42, 1.47 to 3.97) and cerebrospinal fluid leucocytosis: 20-99x109/l (2.35, 1.36 to 4.06); ≥100x109/l (1.87, 1.07 to 3.27). Higher doses did not yield better effectiveness among children (0.87 v 0.85, P=0.981). Conclusions: Eflornithine shows acceptable safety and effectiveness as first line treatment for human African trypanosomiasis. Relapses did occur more than 12 months after treatment. Higher doses in children were well tolerated but showed no advantage in effectiveness., Funding: French section of Médecins Sans Frontières.

Simple tuberculosis (TB) treatment monitoring tools are needed. We assessed the performance of fluorescein-diacetate (FDA) smear microscopy for detection of viable Mycobacterium tuberculosis in sputum specimens ( n = 288) of TB cases under treatment compared to culture (17.4% culture positivity). FDA sensitivity was moderate (83.7% [95% confidence interval {CI}, 70.3 to 92.6]), and specificity was low (66.1% [59.5 to 72.2]). The good negative predictive value (94.8% [90.1 to 97.8]) and negative likelihood ratio (0.2) suggest using this method to rule out treatment failure in settings without access to culture.

Introduction: As part of a programme providing care for patients with drug-resistant tuberculosis (DR-TB) in Armenia, participation in therapeutic patient education (TPE) is proposed to patients when they start treatment. Objectives: To assess the usefulness, reliability and ease of use of a patient skills evaluation system, and to determine whether and how these skills change after TPE. Methods: A total of 70 patients were assessed before TPE and after a minimum of one TPE session using a pedagogical evaluation tool. A structured questionnaire was administered to 10 educators who participated in the patient skills evaluation Results: The evaluation system was perceived by educators as well-adapted to identifying further learning needs, and as reliable and easy to use. After TPE we observed a 23.7% mean gain in knowledge (p DR-TB patients’ skills, other than self-efficacy, improved after TPE. Recommendations to improve the quality of the evaluation system are given.

The work challenges faced by doctors, nurses and other health professionals in the humanitarian field are overwhelming.This article highlights the psychological effects on humanitarian workers and the support available, both while on a 'mission' and on return home.It is impossible not to be psychologically affected by witnessing gross acts of violence, starvation, epidemics, displacement and despair, or hearing tales of slaughter, rape and killing. Just as those populations who are subjected to traumatic experiences develop post-traumatic psychological problems, so too can those humanitarian workers who assist them.