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Programmatic Management of Drug-Resistant Tuberculosis: An Updated Research Agenda

Programmatic Management of Drug-Resistant Tuberculosis: An Updated Research Agenda

  • Carole D. Mitnick, 
  • Carly A. Rodriguez, 
  • Marita L. Hatton, 
  • Grania Brigden, 
  • Frank Cobelens, 
  • Martin P. Grobusch, 
  • Robert Horsburgh, 
  • Christoph Lange, 
  • Christian Lienhardt, 
  • Eyal Oren



There are numerous challenges in delivering appropriate treatment for multidrug-resistant tuberculosis (MDR-TB) and the evidence base to guide those practices remains limited. We present the third updated Research Agenda for the programmatic management of drug-resistant TB (PMDT), assembled through a literature review and survey.


Publications citing the 2008 research agenda and normative documents were reviewed for evidence gaps. Gaps were formulated into questions and grouped as in the 2008 research agenda: Laboratory Support, Treatment Strategy, Programmatically Relevant Research, Epidemiology, and Management of Contacts. A survey was distributed through snowball sampling to identify research priorities. Respondent priority rankings were scored and summarized by mean. Sensitivity analyses explored weighting and handling of missing rankings.


Thirty normative documents and publications were reviewed for stated research needs; these were collapsed into 56 research questions across 5 categories. Of more than 500 survey recipients, 133 ranked priorities within at least one category. Priorities within categories included new diagnostics and their effect on improving treatment outcomes, improved diagnosis of paucibacillary and extra pulmonary TB, and development of shorter, effective regimens. Interruption of nosocomial transmission and treatment for latent TB infection in contacts of known MDR−TB patients were also top priorities in their respective categories. Results were internally consistent and robust.


Priorities retained from the 2008 research agenda include shorter MDR-TB regimens and averting transmission. Limitations of recent advances were implied in the continued quest for: shorter regimens containing new drugs, rapid diagnostics that improve treatment outcomes, and improved methods of estimating burden without representative data.


There is continuity around the priorities for research in PMDT. Coordinated efforts to address questions regarding shorter treatment regimens, knowledge of disease burden without representative data, and treatment for LTBI in contacts of known DR-TB patients are essential to stem the epidemic of TB, including DR-TB.


Drug-resistant tuberculosis (DR-TB) threatens global TB control and is a major public health concern. The World Health Organization (WHO) estimates that 480,000 new cases of multidrug-resistant tuberculosis (MDR-TB), tuberculosis resistant to at least isoniazid and rifampicin, occurred in 2014.[1] Of these, an estimated 8.7% had extensively drug-resistant tuberculosis (XDR-TB), defined as MDR- TB with additional drug resistance to at least one fluoroquinolone and a second-line injectable drug. Effective management of drug-resistant tuberculosis (DR-TB) requires prevention, case detection, care and treatment, surveillance, drug management, and monitoring and evaluation of program performance. These activities should be coordinated by national TB control programs, and are referred to collectively as the "programmatic management of drug-resistant tuberculosis" (PMDT).

Guidance from WHO on PMDT has been available since 2006, and updated guidance based on new research, technology, and expert opinion has become available over the past decade.[25] Unfortunately, progress on the scale up of PMDT has been decidedly slow. Despite an increase in the number of persons with MDR-TB detected, from 46,897 in 2009 to 122,618 in 2014, approximately 75% of TB patients estimated to have MDR-TB were still not detected in 2014.[1, 6] Treatment scale up lags far behind the Stop TB Partnership's Global Plan targets to treat 1.6 million MDR-TB and XDR-TB patients by 2015, with only 110,803 (23.0%) of estimated incident cases of MDR-TB and 4,044 (8.7%) of estimated incident cases of XDR-TB reported to be enrolled on treatment during 2014.[1] The diagnostic and treatment “gaps” mean that many cases of MDR-TB are neither being identified nor treated, contributing to the further spread of MDR-TB. The consequences of these gaps can be seen in regions reporting increasing rates of MDR-TB among new TB patients.[7] Although evidence from resource-limited settings on the effectiveness and feasibility of PMDT has provided a foundation for guidance, many knowledge gaps still remain.

Two previously published research agendas (2003, 2008) highlighted research gaps affecting the operation of PMDT pilot projects, and identified research questions that needed to be addressed in order to inform the scale up of PMDT.[8, 9] Publications citing the last research agenda spanned all topics in the 2008 publication including Laboratory Support,[10] Epidemiology,[11] Programmatically Relevant Research,[1215] Treatment Strategy,[1619] and Management of Contacts,[2022] as well as those that were cross-cutting through multiple priority areas.[23, 24] These publications included both original research articles and reviews summarizing existing evidence. Here, we update the pending research questions, systematically identify new knowledge gaps, and determine the relative priority of these research questions through a consultative process among research stakeholders in PMDT.


Development of research questions

A group consisting of members from the former Research Subgroup of the MDR-TB Working Group of the Stop-TB Partnership (merged with the Research Task Force of the Global Drug-Resistant TB Initiative [GDI,]), Core Group of the GDI, and RESIST-TB (Research Excellence to Stop TB Resistance) ( prepared the present manuscript. The group first reviewed the 2008 research agenda on PMDT to classify the previously published research priorities as still relevant and unresolved, relevant and only partially resolved, or no longer relevant.[9] To identify additional knowledge gaps, we reviewed resources including guidelines, documents, websites and publications published between January 2008 and August 2013 from relevant organizations and authorities such as the US Centers for Disease Control and Prevention (CDC), the National Institute of Allergy and Infectious Diseases (NIAID), the WHO, European Centre for Disease Prevention and Control (ECDC), Médecins Sans Frontières (MSF), and others (See Table 1). In addition, we reviewed all PubMed-indexed documents that cited the 2008 publication. We extracted statements about knowledge gaps and/or explicit research questions from these documents. Overlapping statements were consolidated and formulated into 56 research questions that were categorized into 34 subcategories. These were organized into the 5 main research categories, established in the 2008 research agenda on PMDT: Laboratory Support, Epidemiology, Programmatically Relevant Research, Treatment Strategy, and Management of Contacts.[9] From this extensive list of research questions, an online survey to establish priorities among the questions was constructed using Qualtrics (Provo, UT).

Table 1. List of documents, websites, and articles citing the 2008 research agenda reviewed for statements on research needs.

Format and distribution of survey

The survey comprised two primary sections: 1) selection and ranking of specific research questions within each of the five main categories; and 2) global ranking of subcategories. For the first section, respondents were instructed to select 5 priority research questions in each main category identified in the 2008 research agenda on PMDT.[9] Within each main category, they were asked to rank the 5 selected research questions from 1–5, with 1 being the highest priority. Respondents could also choose to select, but not rank research questions. In the second part, respondents were instructed to select and rank 5 priority subcategories from the complete list of subcategories. This second ranking served to assess internal consistency. Additionally, it provided respondents the chance to prioritize not only within a main category but across main categories.

Snowball sampling was used to select survey respondents: the survey was distributed by email to PMDT research stakeholders including RESIST-TB, Treatment Action Group, TB CARE I, TB TEAM, Stop TB Partnership’s New Diagnostics Working Group, the former MDR-TB Working Group, and GDI. These groups, in turn, shared the survey with their own distribution lists and with other groups. The number of recipients was estimated to be at least 500.

Analysis of survey

For each main category, we designated the subset of the survey respondents who selected at least one research question. We calculated the proportion who selected each individual question. Questions that were selected but not ranked were recoded at the intermediate value of 3, and any questions that were unselected by a participant were coded as 6, to reflect their priority as lower than the lowest possible ranking for selected research questions. We then scored each research question as the mean rank, on a scale of 1 to 6, with 1 representing the highest possible priority and 6 the lowest. Because there were different numbers of questions in each category, numeric priority ranking could be compared within, but not between, categories. We performed two different sensitivity analyses to assess the robustness of the rankings. In one, we excluded (rather than recoded) the questions that were not ranked (which comprised <20% of responses). In another, we separately coded unselected questions as missing and weighted the mean by response rate [].

For the subcategory ranking, we included responses from individuals who completed this section as instructed, selecting 4, 5, or 6 subcategories from the complete list of 34 subcategories. Selected subcategories were ranked on a scale of 1 to 6, with 1 as the highest priority and 6 as the lowest priority. Subcategories selected but not ranked were recoded to an intermediate value of 3, as for the research questions within the main categories. If a respondent selected or ranked more than 6 subcategories, we excluded the response from the analysis.

Ethics statement

Ethics approval was not sought for this study. Surveys were completed anonymously and no data (identifiers or otherwise) were collected on respondents.


We identified and reviewed 30 sources for statements on knowledge gaps in PMDT (Table 1): 15 were normative documents or websites; and a PubMed search for peer-reviewed publications that cited the 2008 research agenda returned an additional 15 sources. Over 100 calls for research on topics related to PMDT were extracted from these documents and consolidated into 56 distinct research questions. Since all 5 research categories from the 2008 research agenda were judged to still be relevant, (i.e., none was thought to be completely resolved), the unique research questions were classified across these five categories: 10 in Laboratory Support; 7 in Treatment Strategy; 18 in Programmatically Relevant Research; 13 in Epidemiology; and 8 in Management of Contacts. Survey participants selected priority questions within and across these categories. Among more than 500 survey recipients, 133 (approximately 27%) answered at least one question (Fig 1).

In the Laboratory Support main category, the questions “Do results of new diagnostic tests improve patient-relevant outcomes OR treatment outcomes?” and “How can we reliably identify forms of tuberculosis that are not easily diagnosed by examination of sputum (e.g., meningitis, pediatric TB, TB in HIV-coinfected persons)?” were selected as top priorities, with scores of 3.33 and 3.69, respectively (Fig 2). These were selected over questions that focused on refining drug susceptibility testing (DST), markers of fitness, and evaluating treatment response.

Fig 2. Laboratory support–mean of priority ranking assigned by respondents (N = 132), 1 representing the highest priority and 6 representing the lowest priority.

In the Treatment Strategy category, the questions: “How do we develop effective and shorter treatment regimens that can be used for special populations (e.g., pregnant/lactating women, children, HIV-coinfected individuals)?”, “What are the optimal combinations and duration of treatment to prevent drug resistance?” and “Is the Bangladesh regimen (a 9-month gatifloxacin-based regimen) effective in countries with high prevalence of resistance to second-line drugs (SLDs)? What modifications would be necessary?” ranked as the top priorities (scores: 2.76, 2.84, 2.87) (Fig 3). The lowest priorities in this category were questions related to optimization and further individualization of treatment with SLDs (with or without antiretroviral therapy) and toxicity.

Fig 3. Treatment strategy—mean of priority ranking assigned by respondents (N = 126), 1 representing the highest priority and 6 representing the lowest priority.

In the Programmatically Relevant Research category, the highest ranked research question was “What are options for short-course treatment and how can they be used to expand MDR-TB treatment?”. Distant second and third priorities were the questions: “What are barriers to treatment initiation and completion?” (4.28) and “Which groups at risk for MDR-TB should be targeted for DST in settings of limited resources and which diagnostic algorithms should be used to identify patients within risk groups?”(4.49). These were all ranked in the top 5 by those who ranked at least one question, as were “Operationally, what are the best methods to ensure optimal treatment, including guidelines; reliable drug supply; staff appropriately trained; adequate health facilities?” with a score of 4.75 and “What infection control measures exist with proven evidence to reduce transmission?” (4.81) (Fig 4).

Fig 4. Programmatically relevant research—mean of priority ranking assigned by respondents (N = 119), 1 representing the highest priority and 6 representing the lowest priority.

In the Epidemiology category the question “What interventions are effective at reducing nosocomial infection? What is the impact of these interventions?” was highest ranking, with a score of 3.74. The questions “In countries without current, representative data on the burden of drug-resistant TB, what is the burden? (How) can non-representative data be used to improve estimates of DR-TB?” and “What ecologic or population-level characteristics predict incidence, resistance acquisition and/or amplification, transmission, or outcomes?” were also high ranking, with scores of 4.18 and 4.52, respectively (Fig 5). In addition, the research question “What is the frequency of resistance to PZA, moxifloxacin, and injectables?” also arose as a priority (score: 4.52). The topics with the fewest selections and lowest rankings included the role of strain and resistance patterns as predictors of epidemiologic indicators.

Fig 5. Epidemiology—mean of priority ranking assigned by respondents (N = 115), 1 representing the highest priority and 6 representing the lowest priority.

Lastly, among 113 respondents to the Management of Contacts category, “What are optimal drugs, combinations, and durations for latent tuberculosis infection (LTBI) in known contacts of MDR-TB patients?” was the top priority with a score of 3.17 (Fig 6). Also high priorities were “What are the best methods for preventing household transmission” and “What biomarkers can be used to distinguish infection from disease?” with scores of 3.66 and 3.74, respectively. In contrast, topics on post-exposure vaccines, averting nosocomial transmission, and individualization of prophylactic treatment were lower priorities.

Fig 6. Management of contacts—mean of priority ranking assigned by respondents (N = 113), 1 representing the highest priority and 6 representing the lowest priority.

Only 58% of respondents who initiated the survey completed the second part according to instructions (see S1 Appendix). We note, however, that priorities selected across subcategories were generally consistent with those within categories. Results from the Subcategory ranking are available in the Appendix (See S2 Appendix).

Rare exceptions included “vaccines (as a strategy for management of contacts)”, which was selected as the 3rd ranked subcategory overall while the related questions ranked in the middle within the Management of Contacts category. How to optimize access to MDR-TB diagnosis and treatment was selected as 4th in the Programmatically Relevant Research category and 4th overall. Despite these exceptions, the similarity between the rankings of subcategories and main categories supports the internal consistency of survey results. Results from the sensitivity analyses, both when we performed the analysis with results weighted by response rate and when we excluded selections that were not ranked, were similar to those from the primary analysis.


This third research agenda informing PMDT is the result of a multistep, systematic, consultative approach to identify current research priorities. It builds on the pioneering efforts that led to publications in 2003 and 2008.[8, 9] For the present effort, we added an extensive literature review and stakeholder survey to the previous strategy of identifying and grouping priorities by the writing groups.

Certain research questions emerged consistently across categories. Shortened regimens, which would be effective in a range of patient populations, were clearly perceived as a high priority within and across categories. This topic has been the subject of some research in the interim, and the need for advancement in this area was noted in the 2008 research agenda and the 2011 WHO guidelines,[2, 3] the latter calling for further investigation on optimizing treatment regimens, including in special populations such as children. Observational studies of 9-month regimens, variations on that known as the "Bangladesh regimen,” have been successfully implemented in several settings.[2527] Moreover, the recent conditional approval of bedaquiline and delamanid, two new anti-TB drugs [28, 29], has induced additional interest in shortened, and now all-oral, regimens. Ongoing research efforts to advance the evidence base in this area include the STREAM trial;[26] three trials sponsored by the Global Alliance for TB Drug Development explore shortened regimens for DR-TB: NC-005, Identifier: NCT02193776; STAND, Identifier: NCT02342886; and NIX-TB, Identifier: NCT02333799. Additionally, groups such as the AIDS Clinical Trials Group through ACTG5343, and MSF through TB-PRACTECAL ( Identifier: NCT02589782) and endTB, together with Partners In Health,[30, 31] are exploring shorter, simpler regimens that depend less on second-line drugs with extensive prior use. Instead, these efforts will use combinations of new drugs or repurposed drugs with less prior population exposure. Interestingly, developing effective shorter regimens—rather than reducing toxicity of treatment—emerged as the priority within the Treatment Strategy category, despite the development of treatment for toxicity linked to second-line drugs appearing as a gap in the 2011 WHO guidance. This may be because shortened regimens with toxicity profiles similar to the current regimen would still be considered an advance if they are effective. Or, this preference may reflect expectations that shorter regimens will reduce exposure to less toxic drugs (e.g., eliminating injectable, shortening exposure to ethionamide).

Treatment of latent Mycobacterium tuberculosis infection (LTBI) in contacts of DR-TB patients was also highlighted, as were other measures to prevent or rapidly detect active disease—pre-exposure vaccines, averting nosocomial transmission, and active case finding. Relative to efforts to produce shorter, more efficacious regimens and in contrast to improved LTBI treatment after exposure to drug susceptible TB,[32] there has been limited activity in this domain since the 2008 publication and the 2011 WHO guidelines[3] which also identified this research gap and called for advances in this area. Recent exceptions include case series and observational studies of treatment of LTBI in household contacts of patients with MDR-TB, often children, with regimens containing fluoroquinolones.[3337] Trials being planned at this writing include V QUIN and TB-CHAMP, which will test levofloxacin for prophylaxis, and PHOENIx (ACTG A5300), which is likely to test delamanid.[38, 39]

Changes from the 2008 research agenda are notable. These include a refinement of the priority placed on new DST methods. In the current research agenda, the call is for better evidence on the impact of new methods on improved treatment outcomes. Research to date has not supported the hypothesis that introduction of rapid molecular tests (GeneXpert MTB/RIF or GenoType MTBDR) is leading to improved treatment outcomes. [4044] It appears unlikely that diagnostics alone—in the absence of other interventions that improve the timely, programmatic management of MDR-TB—can realistically be expected to have an impact on outcomes or epidemiology of MDR-TB.[42, 45] The current priorities also highlight the need for diagnostic tools that result in improved sensitivity for traditionally difficult-to-diagnose TB (extra pulmonary TB, TB in HIV-coinfected or pediatric populations). The emphasis on programmatic research to select algorithms for screening sub-populations for MDR-TB persists from the 2008 research agenda, but as a relatively low priority in the area of programmatically relevant research. Its decline in perceived importance may be because such risk profiles are already being incorporated in algorithms that guide the use of GeneXpert MTB/RIF and other rapid tests in populations, and, WHO guidelines released in 2011 call for universal screening for rifampin resistance in all TB patients. Working toward this standard obviates the need for refined identification of these risk groups.

Respondents revealed some interest in improved estimates of the prevalence of drug resistance, even in the absence of fully representative national data. This may reflect the reality that even 20 years into the project on Anti-TB Drug Resistance Surveillance, only a limited number of countries have recent, national, representative data from surveys or ongoing surveillance of drug resistance. This is particularly salient for the Africa region in which 19 (40%) of 47 countries have no data and only 28 (60%) countries have or are undertaking national surveys or surveillance. Only 9 (20%) have relatively current data, that is, results from 2010–2014.[1] The absence of recent representative data does not necessarily correspond to the absence of resistance;[46] countries require tools for planning and treating even in the absence of such data.[14]


As noted, the changes in priorities since 2008 reflect, in part, exciting advances in rapid diagnostics—GeneXpert and GenoType MTBDRplus—and treatment options, the Bangladesh regimen and new anti-TB drugs, bedaquiline and delamanid. Some changes also reflect a pragmatism about the current state of affairs—that there would be interest in developing methodologies for drawing inference from non-representative anti-TB drug resistance surveys, for example—and the paucity of resources for TB research.[47] For the same reason, many of the 2008 priorities appear again as priorities eight years later. Also it is important to note that the priorities emerging from these consultative efforts are not necessarily reflected in the choices made by industry. For example, both bedaquiline and delamanid were conditionally approved based on trials whose designs added these drugs to the currently recommended long, weak and toxic standard of DR-TB treatment. This reflects the companies’ priority of getting the drugs approved, and the way regulatory authorities make approval decisions. While short, all-oral regimens emerge here as a top priority, these were not addressed in the sponsors’ trials. Fortunately, non-industry researchers have begun to address these questions, frequently supported by public funding (e.g., South African Medical Research Council, USAID, US National Institutes of Health, UNITAID).[31] Continued advocacy around ensuring adequate resources for research and accelerated testing of new interventions, and support of new initiatives, such as the 3P project, that use open-collaboration frameworks and incentives to promote regimen development early in the clinical development of products is essential.[48] To this end, the engagement of GDI and RESIST-TB, as well as activists, researchers, donors and policymakers will be key to continued research advocacy.


First, the representativeness of survey respondents is not known. The survey sought input from an extensive list of individuals that included clinical researchers, policy makers, clinicians and other service providers, activists, patients, and donors. Only approximately 20% of these individuals responded, and information about geographical and professional distribution of respondents is not available. Nevertheless, since the priorities identified represent progressions—not dramatic deviations—from those identified in the previous documents, the results are credible as a reflection of the perspective of individuals involved in or affected by PMDT. Second, stakeholder input was sought only on issues that were raised in the sources consulted. Although every attempt was made to review an exhaustive body of relevant sources, other knowledge gaps and new areas of important research that were not mentioned in the sources reviewed were not submitted to survey respondents for ranking. This may result in a bias, especially toward applied research, which was prioritized in the previous research agenda on which the current exercise was based. Nevertheless, the systematic, transparent, and inclusive process that resulted in the present document represents a strength of the agenda.


Longstanding evidence gaps plague the scale-up of programmatic management of MDR-TB. A systematic effort to assess the priorities for evidence necessary to expand treatment access yielded internally consistent, robust results. Coordinated efforts to address questions regarding shorter treatment regimens, distribution of disease where representative data do not exist, and treatment for LTBI in household contacts of known DR-TB patients are essential to stem the epidemic of TB, including DR-TB.

Supporting Information

S1 Appendix. Survey on research priorities in the programmatic management of DR-TB.



Drs. Christian Lienhardt and Fraser Wares are staff members of the WHO, and Laura Jean Podewils is a staff member at the Centers for Disease Control and Prevention. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions or policies of the WHO or the official position of the Centers for Disease Control and Prevention. RESIST-TB’s Steering Committee includes: Grania Brigden, Francesca Conradie, Margareth Dalcolmo, Stefan Goldberg, Martin Grobusch, Salim Hamid, Mark Harrington, Robert Horsburgh, Salmaan Keshavjee, Christoph Lange, Erica Lessem, Christian Lienhardt, Carole Mitnick, Susan van den Hof, and Andy Vernon. The Core Group of the Global Drug-Resistant Tuberculosis Initiative includes: Heather Alexander, Amy Bloom, Sarabjit Chadha, Chen-Yuan Chiang, Daniela Cirillo, Charles Daley, Essam Elmoghazy, Jennifer Furin, Agnes Gebhard, Sirinapha Wungmanee Jitimanee, Saira Khowaja, Rafael Laniado Laborin, Andrey Maryandyshev, Fuad Mirzayev, Subrat Mohanty, Kuldeep Singh Sachdeva, Hind Satti, Kwonjune Justin Seung, Carrie Tudor, Jacques van den Broek, and Andre Zagorski.

Author Contributions

Conceived and designed the experiments: CDM FC LJP EO SvdH C. Lange MPG. Performed the experiments: CDM CAR GB FC MPG RH C. Lange C. Lienhardt EO LJP BS SvdH CLD ACG FW. Analyzed the data: MH. Wrote the paper: CDM CAR MH. Designed the survey to collect data: CAR.


  1. 1. Global tuberculosis report 2015. Geneva: World Health Organization; 2015 (WHO/HTM/TB/2015.22).
  2. 2. Guidelines for the programmatic management of drug-resistant tuberculosis. Emergency update 2008. Geneva: World Health Organization; 2008 (WHO/HTM/TB/2008.402).
  3. 3. Guidelines for the programmatic management of drug-resistant tuberculosis. 2011. Geneva: World Health Organization; 2011 (WHO/HTM/TB/2011.6).
  4. 4. Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. Geneva: World Health Organization; 2014. (WHO/HTM/TB/2014.11).
  5. 5. Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, World Health Organization, 2006 (WHO/HTM/TB/2006.361).
  6. 6. Global tuberculosis report 2013. Geneva: World Health Organization; 2013 (WHO/HTM/TB/2013.11)
  7. 7. Global tuberculosis report 2014. Geneva: World Health Organization; 2014 (WHO/HTM/TB/2014.08).
  8. 8. Gupta R, Espinal M. A prioritised research agenda for DOTS-Plus for multidrug-resistant tuberculosis (MDR-TB). Int J Tuberc Lung Dis. 2003;7(5):410–4. pmid:12757039
  9. 9. Cobelens FG, Heldal E, Kimerling ME, Mitnick CD, Podewils LJ, Ramachandran R, et al. Scaling up programmatic management of drug-resistant tuberculosis: a prioritized research agenda. PLoS Med. 2008;5(7):e150. pmid:18613746
  10. 10. Lessells RJ, Cooke GS, Newell ML, Godfrey-Faussett P. Evaluation of tuberculosis diagnostics: establishing an evidence base around the public health impact. J Infect Dis. 2011;204 Suppl 4:S1187–95. pmid:21996701
  11. 11. Becerra MC, Appleton SC, Franke MF, Chalco K, Arteaga F, Bayona J, et al. Tuberculosis burden in households of patients with multidrug-resistant and extensively drug-resistant tuberculosis: a retrospective cohort study. Lancet.377(9760):147–52. pmid:21145581
  12. 12. Cobelens F, van Kampen S, Ochodo E, Atun R, Lienhardt C. Research on implementation of interventions in tuberculosis control in low- and middle-income countries: a systematic review. PLoS Med. 2012;9(12):e1001358. pmid:23271959
  13. 13. Marais BJ, Raviglione MC, Donald PR, Harries AD, Kritski AL, Graham SM, et al. Scale-up of services and research priorities for diagnosis, management, and control of tuberculosis: a call to action. Lancet.375(9732):2179–91. pmid:20488521
  14. 14. Mitnick CD, Keravec J, Cohen T. Planning for the invisible: projecting resources needed to identify and treat all patients with MDR-TB. Int J Tuberc Lung Dis. 2013;17(4):427–8. pmid:23485374
  15. 15. Getahun H, Sculier D, Sismanidis C, Grzemska M, Raviglione M. Prevention, Diagnosis, and Treatment of Tuberculosis in Children and Mothers: Evidence for Action for Maternal, Neonatal, and Child Health Services. J Infect Dis. 2012.
  16. 16. Chiang C-Y, Centis R, Migliori GB. Drug-resistant tuberculosis: Past, present, future. Respirology. 2010;15(3):413–32. pmid:20337989
  17. 17. Gammino VM, Taylor AB, Rich ML, Bayona J, Becerra MC, Bonilla C, et al. Bacteriologic monitoring of multidrug-resistant tuberculosis patients in five DOTS-Plus pilot projects. Int J Tuberc Lung Dis. 2011;15(10):1315–22. pmid:22283887
  18. 18. Horsburgh CR, Shea KM, Phillips P, Lavalley M. Randomized clinical trials to identify optimal antibiotic treatment duration. Trials. 2013;14:88. pmid:23536969
  19. 19. Lienhardt C, Davies G. Methodological issues in the design of clinical trials for the treatment of multidrug-resistant tuberculosis: challenges and opportunities. Int J Tuberc Lung Dis. 2010;14(5):528–37. pmid:20392344
  20. 20. Becerra MC, Franke MF, Appleton SC, Joseph JK, Bayona J, Atwood SS, et al. Tuberculosis in Children Exposed at Home to Multidrug-resistant Tuberculosis. Pediatr Infect Dis J. 2013;32(2):115–9. pmid:22926210
  21. 21. Seddon JA, Godfrey-Faussett P, Hesseling AC, Gie RP, Beyers N, Schaaf HS. Management of children exposed to multidrug-resistant Mycobacterium tuberculosis. Lancet Infect Dis. 2012;12(6):469–79. pmid:22373591
  22. 22. van der Werf MJ, Langendam MW, Sandgren A, Manissero D. Lack of evidence to support policy development for management of contacts of multidrug-resistant tuberculosis patients: two systematic reviews. Int J Tuberc Lung Dis. 2012;16(3):288–96. pmid:22640442
  23. 23. Rylance J, Pai M, Lienhardt C, Garner P. Priorities for tuberculosis research: a systematic review. Lancet Infect Dis. 2010;10(12):886–92. pmid:21050822
  24. 24. Grange J, Mwaba P, Dheda K, Höelscher M, Zumla A. World TB Day 2010 –New innovations are required for enhancing the global fight against Tuberculosis: the ‘Captain of all these men of death’. Trop Med Int Health. 2010;15(3):274–6. pmid:20070628
  25. 25. Van Deun A, Maug AK, Salim MA, Das PK, Sarker MR, Daru P, et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 2010;182(5):684–92. pmid:20442432
  26. 26. Nunn AJ, Rusen I, Van Deun A, Torrea G, Phillips PP, Chiang CY, et al. Evaluation of a standardized treatment regimen of anti-tuberculosis drugs for patients with multi-drug-resistant tuberculosis (STREAM): study protocol for a randomized controlled trial. Trials. 2014;15(1):353.
  27. 27. Aung KJ, Van Deun A, Declercq E, Sarker MR, Das PK, Hossain MA, et al. Successful '9-month Bangladesh regimen' for multidrug-resistant tuberculosis among over 500 consecutive patients. Int J Tuberc Lung Dis. 2014;18(10):1180–7. pmid:25216831
  28. 28. Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I, et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014;371(8):723–32. pmid:25140958
  29. 29. Skripconoka V, Danilovits M, Pehme L, Tomson T, Skenders G, Kummik T, et al. Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis. Eur Respir J. 2013;41(6):1393–400. pmid:23018916
  30. 30. Médecins Sans Frontières. endTB, Expand New Drug Markets for TB 2014 [November 6, 2015]. Available from:
  31. 31. Partners in Health. PIH among Groups Bringing New TB Treatment to Those in Need 2015 [November 6, 2015]. Available from:
  32. 32. Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, Bliven-Sizemore E, et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med. 2011;365(23):2155–66. pmid:22150035
  33. 33. Seddon JA, Hesseling AC, Finlayson H, Fielding K, Cox H, Hughes J, et al. Preventive therapy for child contacts of multidrug-resistant tuberculosis: a prospective cohort study. Clin Infect Dis. 2013;57(12):1676–84. pmid:24065321
  34. 34. Thee S, Garcia-Prats AJ, McIlleron HM, Wiesner L, Castel S, Norman J, et al. Pharmacokinetics of ofloxacin and levofloxacin for prevention and treatment of multidrug-resistant tuberculosis in children. Antimicrob Agents Chemother. 2014;58(5):2948–51. pmid:24550337
  35. 35. Adler-Shohet FC, Low J, Carson M, Girma H, Singh J. Management of latent tuberculosis infection in child contacts of multidrug-resistant tuberculosis. Pediatr Infect Dis J. 2014;33(6):664–6. pmid:24445837
  36. 36. Bamrah S, Brostrom R, Dorina F, Setik L, Song R, Kawamura LM, et al. Treatment for LTBI in contacts of MDR-TB patients, Federated States of Micronesia, 2009–2012. Int J Tuberc Lung Dis. 2014;18(8):912–8. pmid:25199004
  37. 37. Williams B, Ramroop S, Shah P, Anderson L, Das S, Riddell A, et al. Management of pediatric contacts of multidrug resistant tuberculosis in the United Kingdom. Pediatr Infect Dis J. 2013;32(8):926–7.
  38. 38. Clayden P, Collins S, Frick M, Harrington M, Horn T, Jefferys R, et al. 2015 Pipeline Report: HIV, hepatitis C visus (HCV), and tuberculosis (TB). Drugs, diagnostics, vaccines, preventive technologies, research towards a cure, and immune-based and gene therapies in development New York, NY: HIV i-Base/Treatment Action Group; 2015 [November 6, 2015]. Available from:
  39. 39. Network I. IMPAACT 2003B: (PHOENIx) (DAIDS ID 12041): Protecting Households on Exposure to Newly Diagnosed Index Multidrug-Resistant TB Patients 2015 [cited 2015 December 14]. Available from:
  40. 40. Hanrahan CF, Selibas K, Deery CB, Dansey H, Clouse K, Bassett J, et al. Time to Treatment and Patient Outcomes among TB Suspects Screened by a Single Point-of-Care Xpert MTB/RIF at a Primary Care Clinic in Johannesburg, South Africa. PLoS ONE. 2013;8(6):e65421. pmid:23762367
  41. 41. Lawn SD, Kerkhoff AD, Vogt M, Ghebrekristos Y, Whitelaw A, Wood R. Characteristics and Early Outcomes of Patients With Xpert MTB/RIF-Negative Pulmonary Tuberculosis Diagnosed During Screening Before Antiretroviral Therapy. Clin Infect Dis. 2012;54(8):1071–9. pmid:22318975
  42. 42. Mupfumi L, Makamure B, Chirehwa M, Sagonda T, Zinyowera S, Mason P, et al. Impact of Xpert MTB/RIF on Antiretroviral Therapy-Associated Tuberculosis and Mortality: A Pragmatic Randomized Controlled Trial. Open Forum Infect Dis. 2014;1(1):ofu038. pmid:25734106
  43. 43. Trajman A, Durovni B, Saraceni V, Menezes A, Cordeiro-Santos M, Cobelens F, et al. Impact on Patients’ Treatment Outcomes of XpertMTB/RIF Implementation for the Diagnosis of Tuberculosis: Follow-Up of a Stepped-Wedge Randomized Clinical Trial. PLoS ONE. 2015;10(4):e0123252. pmid:25915745
  44. 44. Yoon C, Cattamanchi A, Davis JL, Worodria W, den Boon S, Kalema N, et al. Impact of Xpert MTB/RIF testing on tuberculosis management and outcomes in hospitalized patients in Uganda. PLoS One. 2012;7(11):e48599. pmid:23139799
  45. 45. Durovni B, Saraceni V, van den Hof S, Trajman A, Cordeiro-Santos M, Cavalcante S, et al. Impact of replacing smear microscopy with Xpert MTB/RIF for diagnosing tuberculosis in Brazil: a stepped-wedge cluster-randomized trial. PLoS Med. 2014;11(12):e1001766. pmid:25490549
  46. 46. Zignol M, Sismanidis C, Falzon D, Glaziou P, Dara M, Floyd K. Multidrug-resistant tuberculosis in children: evidence from global surveillance. Eur Respir J. 2013;42(3):701–7. pmid:23222872
  47. 47. Frick M. Tuberculosis Research and Development: 2014 Report on Tuberculosis Research Funding Trends, 2005–2013. Treatment Action Group Stop TB Partnership, 2014.
  48. 48. Médecins Sans Frontières. The 3P Project: A new approach to developing better treatments for TB 2015 [November 6, 2015]. Available from: