Journal Article > ResearchFull Text
Bull World Health Organ. 1 November 2023; Volume 101 (Issue 11); 730-737.; DOI:10.2471/BLT.23.290901
Gupta-Wright A, den Boon S, MacLean E, Cirillo DM, Cobelens F, et al.
Bull World Health Organ. 1 November 2023; Volume 101 (Issue 11); 730-737.; DOI:10.2471/BLT.23.290901
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The World Health Organization has developed target product profiles containing minimum and optimum targets for key characteristics for tests for tuberculosis treatment monitoring and optimization. Tuberculosis treatment optimization refers to initiating or switching to an effective tuberculosis treatment regimen that results in a high likelihood of a good treatment outcome. The target product profiles also cover tests of cure conducted at the end of treatment. The development of the target product profiles was informed by a stakeholder survey, a cost-effectiveness analysis and a patient-care pathway analysis. Additional feedback from stakeholders was obtained by means of a Delphi-like process, a technical consultation and a call for public comment on a draft document. A scientific development group agreed on the final targets in a consensus meeting. For characteristics rated of highest importance, the document lists: (i) high diagnostic accuracy (sensitivity and specificity); (ii) time to result of optimally ≤ 2 hours and no more than 1 day; (iii) required sample type to be minimally invasive, easily obtainable, such as urine, breath, or capillary blood, or a respiratory sample that goes beyond sputum; (iv) ideally the test could be placed at a peripheral-level health facility without a laboratory; and (v) the test should be affordable to low- and middle-income countries, and allow wide and equitable access and scale-up. Use of these target product profiles should facilitate the development of new tuberculosis treatment monitoring and optimization tests that are accurate and accessible for all people being treated for tuberculosis.
Journal Article > ReviewFull Text
Clin Microbiol Infect. 21 July 2023; Volume S1198-743X (Issue 23); 00339-7.; DOI:10.1016/j.cmi.2023.07.013
Motta I, Boeree M, Chesov D, Dheda K, Günther G, et al.
Clin Microbiol Infect. 21 July 2023; Volume S1198-743X (Issue 23); 00339-7.; DOI:10.1016/j.cmi.2023.07.013
BACKGROUND
Tuberculosis is a global health challenge and one of the leading causes of death worldwide. In the last decade, the tuberculosis treatment landscape has dramatically changed. After long years of stagnation, new compounds entered the market (bedaquiline, delamanid and pretomanid) and phase III clinical trials have shown promising results towards shortening duration of treatment for both drug-susceptible (Study 31/A5349, TRUNCATE-TB, SHINE) and drug-resistant tuberculosis (STREAM, NiX-TB, ZeNix, TB-PRACTECAL). Dose optimization of rifamycins and repurposed drugs have also brought hopes of further development of safe and effective regimens. Consequently, international and World Health Organization clinical guidelines have been updated multiple times in the last years to keep pace with these advances.
OBJECTIVES
This narrative review aims to summarize the state-of-the-art on treatment of drug-susceptible and drug-resistant tuberculosis, as well as recent trials results and an overview of ongoing clinical trials.
SOURCES
A non-systematic literature review was conducted in PubMed and MEDLINE, focusing on the treatment of tuberculosis. Ongoing clinical trials were listed according to the authors' knowledge, and completed consulting clinicaltrials.gov and other publicly available websites (www.resisttb.org/clinical-trials-progress-report, www.newtbdrugs.org/pipeline/trials).
CONTENT
This review summarizes the recent, major changes in the landscape for drug-susceptible and drug-resistant treatment, with a specific focus on their potential impact on patient outcomes and programmatic TB management. Moreover, insights in host-directed therapies, and advances in pharmacokinetic and pharmacogenomics are discussed. A thorough outline of ongoing therapeutic clinical trials is presented, highlighting different approaches and goals in current TB clinical research.
IMPLICATIONS
Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selection of drug resistance and providing widespread, affordable, patient-centered access to new treatment options for all people affected by tuberculosis.
Tuberculosis is a global health challenge and one of the leading causes of death worldwide. In the last decade, the tuberculosis treatment landscape has dramatically changed. After long years of stagnation, new compounds entered the market (bedaquiline, delamanid and pretomanid) and phase III clinical trials have shown promising results towards shortening duration of treatment for both drug-susceptible (Study 31/A5349, TRUNCATE-TB, SHINE) and drug-resistant tuberculosis (STREAM, NiX-TB, ZeNix, TB-PRACTECAL). Dose optimization of rifamycins and repurposed drugs have also brought hopes of further development of safe and effective regimens. Consequently, international and World Health Organization clinical guidelines have been updated multiple times in the last years to keep pace with these advances.
OBJECTIVES
This narrative review aims to summarize the state-of-the-art on treatment of drug-susceptible and drug-resistant tuberculosis, as well as recent trials results and an overview of ongoing clinical trials.
SOURCES
A non-systematic literature review was conducted in PubMed and MEDLINE, focusing on the treatment of tuberculosis. Ongoing clinical trials were listed according to the authors' knowledge, and completed consulting clinicaltrials.gov and other publicly available websites (www.resisttb.org/clinical-trials-progress-report, www.newtbdrugs.org/pipeline/trials).
CONTENT
This review summarizes the recent, major changes in the landscape for drug-susceptible and drug-resistant treatment, with a specific focus on their potential impact on patient outcomes and programmatic TB management. Moreover, insights in host-directed therapies, and advances in pharmacokinetic and pharmacogenomics are discussed. A thorough outline of ongoing therapeutic clinical trials is presented, highlighting different approaches and goals in current TB clinical research.
IMPLICATIONS
Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selection of drug resistance and providing widespread, affordable, patient-centered access to new treatment options for all people affected by tuberculosis.
Journal Article > ReviewFull Text
PLOS One. 25 May 2016; Volume 11 (Issue 5); e0155968.; DOI:10.1371/journal.pone.0155968
Mitnick CD, Rodriguez CA, Hatton ML, Brigden G, Cobelens F, et al.
PLOS One. 25 May 2016; Volume 11 (Issue 5); e0155968.; DOI:10.1371/journal.pone.0155968
INTRODUCTION
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.
METHODS
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.
RESULTS
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.
DISCUSSION
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.
CONCLUSION
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.
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.
METHODS
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.
RESULTS
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.
DISCUSSION
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.
CONCLUSION
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.
Journal Article > ResearchFull Text
PLOS Med. 6 November 2007; Volume 4 (Issue 11); DOI:10.1371/journal.pmed.0040302
Schluger N, Karunakara U, Lienhardt C, Nyirenda T, Chaisson RE
PLOS Med. 6 November 2007; Volume 4 (Issue 11); DOI:10.1371/journal.pmed.0040302
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 1 March 2016; Volume 20 (Issue 3); 290-294.; DOI:10.5588/ijtld.15.0490
Furin J, Alirol E, Allen E, Fielding K, Merle CS, et al.
Int J Tuberc Lung Dis. 1 March 2016; Volume 20 (Issue 3); 290-294.; DOI:10.5588/ijtld.15.0490
Drug-resistant tuberculosis (DR-TB) is a growing public health problem, and for the first time in decades, new drugs for the treatment of this disease have been developed. These new drugs have prompted strengthened efforts in DR-TB clinical trials research, and there are now multiple ongoing and planned DR-TB clinical trials. To facilitate comparability and maximise policy impact, a common set of core research definitions is needed, and this paper presents a core set of efficacy and safety definitions as well as other important considerations in DR-TB clinical trials work. To elaborate these definitions, a search of clinical trials registries, published manuscripts and conference proceedings was undertaken to identify groups conducting trials of new regimens for the treatment of DR-TB. Individuals from these groups developed the core set of definitions presented here. Further work is needed to validate and assess the utility of these definitions but they represent an important first step to ensure there is comparability in clinical trials on multidrug-resistant TB.
Journal Article > ResearchFull Text
Emerg Infect Dis. 1 May 2019 (Issue 5); DOI:10.3201/eid2505.181823.
Mbuagbaw L, Guglielmetti L, Hewison CCH, Bakare N, Bastard M, et al.
Emerg Infect Dis. 1 May 2019 (Issue 5); DOI:10.3201/eid2505.181823.
Bedaquiline is recommended by the World Health Organization for the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). We pooled data from 5 cohorts of patients treated with bedaquiline in France, Georgia, Armenia, and South Africa and in a multicountry study. The rate of culture conversion to negative at 6 months (by the end of 6 months of treatment) was 78% (95% CI 73.5%-81.9%), and the treatment success rate was 65.8% (95% CI 59.9%-71.3%). Death rate was 11.7% (95% CI 7.0%-19.1%). Up to 91.1% (95% CI 82.2%-95.8%) of the patients experienced >1 adverse event, and 11.2% (95% CI 5.0%-23.2%) experienced a serious adverse event. Lung cavitations were consistently associated with unfavorable outcomes. The use of bedaquiline in MDR and XDR TB treatment regimens appears to be effective and safe across different settings, although the certainty of evidence was assessed as very low.
Journal Article > ReviewFull Text
Int J Tuberc Lung Dis. 1 February 2013; Volume 17 (Issue 2); DOI:10.5588/ijtld.12.0017
Horsburgh Jr CR, Haxaire-Theeuwes M, Lienhardt C, Wingfield C, McNeeley D, et al.
Int J Tuberc Lung Dis. 1 February 2013; Volume 17 (Issue 2); DOI:10.5588/ijtld.12.0017
Journal Article > ReviewFull Text
PLOS Med. 2 March 2016; Volume 13 (Issue 3); e1001965.; DOI:10.1371/journal.pmed.1001965
Lienhardt C, Lonnroth K, Menzies D, Balasegaram M, Chakaya JM, et al.
PLOS Med. 2 March 2016; Volume 13 (Issue 3); e1001965.; DOI:10.1371/journal.pmed.1001965
Journal Article > CommentaryFull Text
J Infect Dis. 15 May 2012; Volume 205 (Issue suppl_2); S199-S208.; DOI:10.1093/infdis/jis008
Graham SM, Ahmed T, Amanullah F, Browning R, Cardenas V, et al.
J Infect Dis. 15 May 2012; Volume 205 (Issue suppl_2); S199-S208.; DOI:10.1093/infdis/jis008
There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis.