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BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.

Grania Brigden,1 Cathy Hewison,2 Francis Varaine21Access Campaign, Médecins Sans Frontières, Geneva, Switzerland; 2Medical Department, Médecins Sans Frontières, Paris, France Abstract: 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. Keywords: MDR-TB, XDR-TB, tuberculosis drugs, group 5 drugs

1. Amlodipine is a novel calcium antagonist which, although pharmacologically similar to other dihydropyridine calcium antagonists, has a long plasma half-life, permitting steady state blood levels to be achieved with a once-daily dose regimen. 2. We have performed a study to examine the effects of this drug on the blood pressure of hypertensive patients over a 24 h period. After a placebo run-in, the drug was administered to 11 patients at a starting dose of 5 mg, and increased to 10 mg after 2 weeks of treatment if the cuff diastolic blood pressure response was unsatisfactory. Cuff measurements were made at entry, after 2 weeks treatment with placebo, after 2 weeks on amlodipine 5 mg once daily, and after a further 4 weeks on amlodipine 5 mg or 10 mg once daily. Intraarterial blood pressure recordings were made at the end of the placebo phase and at completion of the study. 3. Mean supine blood pressure measured sphygmomanometrically was 168/103 (n = 11) mm Hg at entry, 169/104 (n = 11) mm Hg at the end of the placebo phase, 153/95 (n = 11) mm Hg after 2 weeks of treatment and 146/92 (n = 11) mm Hg at the end of the study. Blood pressure curves plotted for each phase of the study revealed an effective 24 h duration of action. Mean daytime blood pressure was reduced from 165/103 to 147/89 mm Hg (P less than 0.05, n = 10), and mean night-time blood pressure was reduced from 137/79 to 121/69 mm Hg (P less than 0.05, n = 10).(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

1. The effects of fenoldopam, an orally active, specific dopamine-1 receptor agonist, were studied in eleven patients with essential hypertension, using intra-arterial blood pressure recording and equilibrium gated radionuclide angiography. 2. A single dose of fenoldopam 100 mg produced a fall in blood pressure (BP) starting after 20 min. The maximum BP reduction (23/25 mm Hg) occurred after 50 min and was accompanied by a heart rate (HR) increase of 10 beats min-1. The acute effects on BP lasted for 130 min. 3. After 8 weeks of fenoldopam 100 mg, twice daily, only a small, statistically insignificant, hypotensive effect was still apparent after each dose of drug. The duration of the effect was too short to be clinically useful. Tilt-testing produced a BP fall of 24/14 mm Hg and a HR increase of 17 beats min-1. Three patients experienced symptoms of postural hypotension during the study. 4. The drug attenuated the blood pressure rise produced by dynamic cycle exercise and isometric hand grip. 5. Acute administration of fenoldopam increased the left ventricular ejection fraction from 61% to 71% (P less than 0.005) and increased the peak filling rate from 2.52 to 3.86 end diastolic vol s-1 (P less than 0.002). After chronic fenoldopam administration, the left ventricular ejection fraction was 65% (P = NS) pre-dose, rising to 69% (P less than 0.02) post-dose and the peak filling rate was increased from 2.7 to 3.38 end diastolic vol s-1 (P less than 0.01) 60 min post- dose.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

Simpler, shorter, safer and more effective treatments for tuberculosis that are easily accessible to all people with tuberculosis are desperately needed. In 2016, the World Health Organization (WHO) developed target regimen profiles for the treatment of tuberculosis to make drug developers aware of both the important features of treatment regimens, and patient and programmatic needs at the country level. In view of recent ground-breaking advances in tuberculosis treatment, WHO has revised and updated these regimen profiles. We used a similar process as for the 2016 profiles, including a baseline treatment landscape analysis, an initial stakeholder survey, modelling studies estimating the impact and cost-effectiveness of novel tuberculosis treatment regimens, and an extensive stakeholder consultation. We developed target regimen profiles for the treatment of rifampicin-susceptible and rifampicin-resistant tuberculosis, as well as a pan-tuberculosis regimen that would be appropriate for patients with any type of tuberculosis. We describe the revised target regimen profile characteristics, with specific minimal and optimal targets to be met, rationale and justification, and aspects relevant to all target regimen profiles (drug susceptibility testing, adherence and forgiveness, treatment strategies, post-tuberculosis lung disease, and cost and access considerations). We discuss the trade-offs of proposed characteristics for decision-making at developmental or operational levels. We expect that, following these target regimen profile revisions, tuberculosis treatment developers will produce regimens that are quality-assured, affordable and widely available, and that meet the needs of affected populations., ((c) 2024 The authors; licensee World Health Organization.)

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., ((c) 2023 The authors; licensee World Health Organization.)

Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Aastha Gupta is a consultant to the Global Alliance for TB Drug Development (TB Alliance), a non-profit organization dedicated to the discovery and development of improved TB therapeutics. TB Alliance is funded by governments and foundations and developed pretomanid/BPaL. Sandeep Juneja is an employee of the Global Alliance for TB Drug Development (TB Alliance), a non-profit organization dedicated to the discovery and development of improved TB therapeutics. TB Alliance is funded by governments and foundations and developed pretomanid/BPaL.

In this article, we highlight technological pediatric TB research advances across the TB care cascade; discuss recently completed or ongoing work in adults and corresponding significant research gaps for children; and offer recommendations and opportunities to increase investments and accelerate pediatric TB R&D.

Objectives: To determine tuberculosis (TB) recurrence in previously successfully treated patients in a routine program setting and baseline characteristics associated with TB recurrence., Methods: A prospective longitudinal study in Jiangxi Province, China. Patients, ≥14 years old, were consecutively registered and were followed up for seven years to assess TB recurrence against a patients' individual baseline data that had been entered into a database at TB registration., Results: There were 800 TB patients registered at baseline, and 634 (79.2%) of them completed anti-TB treatments. Fifty-nine (9.3%) died, and 21 (3.3%) were lost to follow-up over the follow-up period. There were 96 patients with recurrent episodes (total incidence 15.2% or annual incidence 2,200/100,000). Of the recurrent cases, 53 (55.2%) happened within 2-year after completion of anti-TB treatments. After controlling confounding factors, the risk of TB recurrence was significantly higher in the age range 34-73 years (P<0.01) and current smokers (P<0.01)., Conclusions: Overall recurrence rate among previously treated TB patients was much higher than the initial incidence in the same population (61-98/100,000) and settings with similar TB incidence. TB programs should consider closer monitoring of these patients for early detection of recurrence. Particular attention should be given to those between 34-73 years and those who use tobacco products., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Tuberculosis (TB) treatment success rates are high in China, but there are still a considerable number of cases who have unfavourable treatment outcomes (UTO). We aimed to determine the proportion of TB patients with UTO and to assess whether baseline characteristics that included glycaemic status [normal fasting blood glucose (FBG), transient hyperglycaemia and diabetes mellitus (DM)] and vitamin D status were associated with UTO., Method: Prospective cohort study conducted between November 2015 and July 2016 at six clinics within routine TB services in Jilin province, where persons with TB were consecutively recruited. Data analysis was performed using the chi-squared test and multivariate logistic regression., Results: Of the 306 recruited TB patients, 96 (31.4%) had smear-positive pulmonary TB, 187 (61.1%) had smear-negative pulmonary TB and 23 (7.5%) had extrapulmonary TB (EPTB). Of these, 95 (31.1%) had normal blood glucose, 83 (27.1%) had transient hyperglycaemia and 128 (41.8%) had DM. 227 (74.2%) patients had vitamin D deficiency/severe deficiency. There were 125 (40.8%) patients with UTO of whom the majority were lost to follow-up (57.6%) or not evaluated (28.8%). UTO was significantly associated with smear-negative pulmonary TB (P = 0.009), EPTB (P < 0.001) and DM (P = 0.007)., Conclusion: The proportion of TB patients with UTO increased with smear-negative pulmonary TB, EPTB and DM. TB programmes need to pay more attention to these issues and ensure intensive patient support to those at risk and early detection of DM., (© 2019 John Wiley & Sons Ltd.)