Pediatric multidrug-resistant tuberculosis clinical trials: challenges and opportunities

McAnaw, Sarah; Hesseling, Anneke C.; Seddon, James A; Dooley, KE; Garcia-Prats, Anthony J.; Kim, S.; Jenkins, Helen E.; Schaaf, H. Simon; Sterling, TR; Horsburgh, C. Robert

doi:10.1016/j.ijid.2016.11.423

Cited by 14 publications

(9 citation statements)

References 29 publications

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“…36 There is an unmet need for TB treatment trials recruiting children and adolescents. 37 Urgent questions address efficacy, toxicity and prophylactic treatment of contacts to MDR TB. 37 A study from Tblisi, Georgia, described pulmonary surgery in 137 patients half with MDR/XDR TB.…”

Section: Tb Treatmentmentioning

confidence: 99%

“…37 Urgent questions address efficacy, toxicity and prophylactic treatment of contacts to MDR TB. 37 A study from Tblisi, Georgia, described pulmonary surgery in 137 patients half with MDR/XDR TB. 38 Whereas it was too early to describe outcomes in terms of mortality, the study found that "from the 98% of DS-TB cases presenting cavities or tuberculomas and considered bacteriology cured according to WHO definitions, 56% were AFB positive from samples from the surgical specimens".…”

Section: Tb Treatmentmentioning

confidence: 99%

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World TB Day 2017: Advances, Challenges and Opportunities in the “End-TB” Era

Petersen

Maeurer

Marais

et al. 2017

International Journal of Infectious Diseases

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World TB Day 2017: Advances, Challenges and Opportunities in the "End-TB" Era 4. Tackling TB Co-morbidities with infectious and noncommunicable diseases Co-infection with HIV greatly increases mortality and risk of treatment failure, 12 and diabetes mellitus also increases morbidity and mortality of TB. 13 These important co-morbidities clearly demonstrate that TB management needs an integrated approach and that every TB patient should be investigated for HIV and diabetes, and every patient with HIV and diabetes should be screened for active TB diseases and LTBI.Following a cohort of 1696 TB patients in Tanzania, Nagu and colleagues found that ART-näive TB/HIV patients had a seven-fold mortality risk (RR = 7.42; 95% CI: 3.87, 14.22; p < 0.0001), whereas TB/HIV patients on ART had a five-fold mortality risk (RR = 4.78; 95% CI: 2.41, 9.49; p < 0.0001). 12 The median time to death was shortest among ART-näive TB/HIV patients (thirty-six days). A thirty-day increase on ART duration associated with a 3% mortality reduction (RR = 0.97; 95% CI: 0.95, 0.99; p < 0.02), independent of CD4+ T lymphocyte count and ART regimen. 12 Diabetes mellitus, DM, increases the risk of developing TB by two to three fold and increases the risk of TB treatment failure, relapse and death. 13 Hypertension is an increasing problem

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Section: Tb Treatmentmentioning

confidence: 99%

Section: Tb Treatmentmentioning

confidence: 99%

World TB Day 2017: Advances, Challenges and Opportunities in the “End-TB” Era

Petersen

Maeurer

Marais

et al. 2017

International Journal of Infectious Diseases

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“…[2][3][4][5] Trials of multidrug-resistant tuberculosis (MDR-TB; defined as mycobacteria resistant to isoniazid and rifampicin) are necessary in children to confirm drug safety, inform appropriate dosing, and optimise treatment strategies and outcomes for children. [6][7][8] Literature on community engagement emphasises that it consists of a complex set of locally adaptive processes to foster active participation in research-related decisions through dialogue, multidirectionality and co-ownership-all of which are challenging to implement optimally, especially in paediatric populations. 3,[9][10][11] In addition, paediatric MDR-TB trials impose a unique combination of three additional complexities on community engagement:…”

mentioning

confidence: 99%

Community engagement for paediatric MDR-TB clinical trials: principles to support ethical trial implementation

Hoddinott

Staples²,

Brown

et al. 2018

int j tuberc lung dis

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The paediatric tuberculosis (TB) prevention and treatment landscape is moving into a new and exciting era, with knowledge from clinical trials offering real benefit to children. Community engagement is key to optimising the success of these trials. However, the clinical profile, epidemiology and social perceptions for paediatric multidrug-resistant TB (MDR-TB) complicate the operationalisation of this community engagement. We reflect on a diversity of recent experiences attempting to implement this type of research and the community engagement around it. We describe four recommendations and argue that these should guide the implementation of the community engagement agenda in the new landscape of paediatric MDR-TB clinical trials. Specifically, we argue for 1) dynamic, long-term continuity in community engagement platforms; 2) tiers of TB and research literacy; 3) multiple separate and joint platforms for holding 'stakes'; and 4) addressing the social/structural implications of family participation. We conclude that community-level stakeholders, such as health workers, parents and children, are willing to collaborate in paediatric MDR-TB clinical trials. Using these recommendations, there is considerable opportunity for effective community engagement in this new era of paediatric MDR-TB research.

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“…There is a need to reach global consensus on the optimal design of MDR-TB clinical trials. [5][6][7][8] Previous and some ongoing trials rely on large sample sizes and are of lengthy followup duration in order to produce convincing evidence base of efficacy of new TB drugs and regimens. Reducing large sample sizes and trialling more than one new TB drug in the same trial using the multi-arm, multi-stage (MAMS) design will allow maintaining flexibility to adapt to other data becoming available while trial in progress 6 .…”

mentioning

confidence: 99%

“…Several barriers exist in conduct RCTs in children and these need to be overcome. 7 Efficacy and safety from adult trials can be expanded to children after pilot pharmacokinetic and bioavailability studies. With the growing burden of MDR-TB in children and in HIVco-infected patients a range of trials are required to define optimal regimens for MDR-TB treatment and these will face the conventional issues of pharmacokinetics of new TB drugs; TB/HIV drug interactions, toxicity, and selection of the appropriate pediatric study population, case definition for TB in the absence of microbiological confirmation, and new strategies for integrating children into adult tuberculosis trials …”

mentioning

confidence: 99%