Standards for clinical trials for treating TB.

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.

Should we consider a 'fourth 90' for tuberculosis?

The international community has committed to end the tuberculosis (TB) epidemic by 2030. To facilitate the meeting of the global incidence and mortality indicators set by the World Health Organization's End TB Strategy, the Stop TB Partnership launched the three 90-(90)-90 diagnostic and treatment targets in 2014. In this paper, we argue that a 'fourth 90'-Ensuring that 90% of all people successfully completing treatment for TB can have a good health-related quality of life'-should be considered. Many individuals who successfully complete anti-TB treatment are burdened with lifelong comorbidities-human immunodeficiency virus (HIV) and diabetes mellitus, obstructive and restrictive lung disease, involving lung destruction, cavitation, fibrosis and bronchiectasis, that either pre-existed or developed as a result of TB (e.g., chronic pulmonary aspergillosis), permanent disabilities such as hearing loss resulting from second-line anti-TB drugs, and mental health disorders. These need to be identified during TB treatment and appropriate care and support provided after anti-TB treatment is successfully completed. A 'fourth 90' has also been proposed for the UNAIDS 90-90-90 targets similar in scope to what is being suggested here for TB. Adoption by both HIV and TB control programmes would highlight the current focus on integrated person- and family-centred services.

Health care gaps in the global burden of drug-resistant tuberculosis.

The drug-resistant tuberculosis (DR-TB) cascade-from estimated or incident cases to numbers successfully treated or disease-free survival-has long been characterised by sharp declines at each step in the cascade. The losses along the cascade vary across different settings, and the reasons why some countries have a higher burden of DR-TB are complex and multifactorial; broadly, weak health systems, inadequate financing and poverty all impact differential access to DR-TB care. Within a human rights framework that mandates the right to health and the right to benefit from scientific progress, the aim of this review is to focus on describing inequities in access to DR-TB care at critical points in the cascade.

Global programmatic use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis.

SETTING: The World Health Organization recommended two new drugs, bedaquiline (BDQ) and delamanid (DLM), for the treatment of multidrug-resistant tuberculosis (MDR-TB) in 2013 and 2014, respectively. An estimated one third of patients with MDR-TB would benefit from the inclusion of these drugs in their treatment regimens. DESIGN: A convenience sample of 36 countries voluntarily reported monthly data on cumulative programmatic use of new drugs to the Drug-Resistant TB Scale-Up Treatment Action Team between 1 July 2015 and 31 June 2017. Programmatic use was defined as treatment for MDR-TB with newer drugs outside of clinical trials or compassionate use. RESULTS: A total of 10 164 persons were started on BDQ and 688 started on DLM during the reporting period. Only 15.7% of the 69 213 persons estimated to need newer drugs over the study period were reported to have received them. CONCLUSION: While there has been significant progress in some countries, uptake of the newer drugs has not kept pace with a conservative estimate of need; fewer than 20% of persons likely to benefit from either BDQ or DLM have received them. Concerted efforts are needed to ensure that the newer drugs are made available more widely for persons with MDR-TB in need of these therapeutic options.

A bitter pill to swallow: the need for better medications for drug-resistant tuberculosis in children.

The large and growing access gap between the number of children who become sick with drug-resistant tuberculosis (DR-TB) and those who are treated for the disease each year represents a significant health systems failure. While there are multiple reasons why children with DR-TB are not diagnosed and treated, a serious challenge is the medications used to treat the disease. This paper presents three child DR-TB cases who were treated incorrectly; the cases are used to illustrate some of the problems with existing second-line medications. Challenges, including the perception that the drugs are more dangerous than the disease, lack of proper dosing recommendations and formulations, and the high cost of current treatment, all contribute to a perverse situation in which the most vulnerable pediatric patients are provided with a lower standard of care. This situation can be reversed with novel partnerships and training models, pharmacokinetic studies of the relevant drugs, increased collaboration, and dedicated funding, grounded in a rights-based approach to DR-TB in children.

Novel pediatric delivery systems for second-line anti-tuberculosis medications: a case study.

Tens of thousands of children are sick with multidrug-resistant forms of tuberculosis (MDR-TB), but there are limited child-friendly delivery systems for second-line medications. This case study presents the development of a granular dosing spoon pediatric delivery system for para-aminosalicylic acid. This product is the first of its kind for MDR-TB and could serve as a model for the development of other urgently needed pediatric delivery systems for second-line anti-tuberculosis drugs.

Disappearing left atrial vegetation in an intravenous drug abuser.

Isolated left atrial mural endocarditis is rare. We report a case where the diagnosis was made clinically and supported by blood cultures and transoesophageal echocardiography. Appropriate intravenous antibiotics were administered and serial transoesophageal echocardiograms helped in monitoring the decrease in size and final disappearance of the vegetation, thus avoiding the need for surgical intervention.

Diurnal variation in pulmonary artery pressure.

Previous observations have suggested that pulmonary artery pressure rises during sleep, whereas systemic artery pressure falls. A system has been developed for careful and accurate recording of pulmonary arterial pressure, and applied it to two groups of subjects: patients with heart failure, and patients with chronic stable angina. The results have largely confirmed the nocturnal pressure rise in pulmonary arterial pressure. Detailed analysis strongly suggests that the same physiological mechanisms producing a fall in systemic pressure are responsible for the rise in pulmonary pressure. The precise mechanism remains to be elucidated.

Intra-arterial monitoring of the antihypertensive effects of once-daily amlodipine.

Amlodipine is a dihydropyridine calcium antagonist with a long elimination half life making it suitable for once-daily dosing. This study used sphygmomanometric and intra-arterial ambulatory blood pressure (BP) monitoring to confirm the antihypertensive effect of a once-daily dose of amlodipine over the dosing interval. After a 2-week single-blind placebo run in, amlodipine was administered to 11 patients at a starting dose of 5 mg daily for 2 weeks increasing to 10 mg daily for a further 4 weeks if diastolic blood pressure (DBP) measured sphygmomanometrically was not < 90 mmHg or decreased by > 10 mmHg from baseline values. Intra-arterial blood pressure recordings for 24-hour periods were made at the end of the placebo run in and on completion of the active treatment phase. The effects of isometric and dynamic exercise and head-up tilting (60 degrees) on BP and heart rate were measured during ambulatory monitoring. Mean supine cuff BP was 169/104 mmHg (n = 11) at the end of the placebo treatment period and was reduced to 153/95 mmHg (n = 11) after 2 weeks of amlodipine treatment and 146/92 mmHg (n = 11) after 6 weeks of amlodipine treatment. There was no significant change in heart rate. Intra-arterial ambulatory monitoring showed that BP was controlled for the whole dosing interval with once-daily doses of amlodipine. The normal circadian pattern of BP changes was not altered. BP was reduced by amlodipine during exercise and physiological tests, but there was no postural hypotension and the BP and heart rate responses to exercise were not blunted.(ABSTRACT TRUNCATED AT 250 WORDS)

Improvement in left ventricular function after rapid weight loss in obesity.

The effect of rapid weight reduction on left ventricular function and blood pressure was studied in 34 obese subjects, who all weighed more than 30% above their ideal body weight. Subjects with co-existing hypertension (N = 15) and proven coronary artery disease (N = 9) were included to assess contributions from these factors. Blood pressure (BP) was measured both indirectly and by direct ambulatory intra-arterial methods. Radionuclide ventriculography was performed at rest and at exercise, before and after dieting, which was supervised in hospital (daily intake 330 kCal day-1 for 4 weeks). Dieting induced a weight loss of (mean +/- SD) 9.6 +/- 3.5 kg (P less than 0.0001) in the whole group. The mean daytime intra-arterial blood pressure fell from 157 +/- 23/90 +/- 15 to 144 +/- 21/85 +/- 13 mmHg (P less than 0.0001). The fall in ambulatory intra-arterial diastolic blood pressure did not reach significance in the normotensive and ischaemic groups. The mean resting left ventricular ejection fraction (LVEF) in the whole group showed a significant reduction after weight loss from 61 +/- 10% to 56 +/- 6% (P less than 0.005). Although the individual groups showed a fall in LVEF, the effect was most marked in the hypertensive group, from 65 +/- 9% to 57 +/- 5% (P less than 0.002). Before dieting none of the groups achieved a 'normal' 5% rise in LVEF above basal in response to exercise, the hypertensive and the ischaemic groups both showing non-significant falls. This phenomenon was, however, reversed after weight loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood pressure changes during the game of squash.

The extent and pattern of the blood pressure response to the playing of squash was studied in five healthy volunteers using intra-arterial blood pressure recordings. Systolic pressure increased more than diastolic, but by only 18% of basal, peaking 5.2 +/- 2.3 min into the game (mean game duration 49 +/- 4 min). Thereafter there was a progressive decline, with reducing pulse pressure towards basal. There was a marked and significant increase in beat-by-beat blood pressure variability (P less than 0.01) and systolic peaks of up to 200 mmHg were recorded. A peak heart rate of 171 +/- 25 beats min-1 occurred at 20 min. These findings do not support the concept of a disproportionate and prolonged pressor response induced by playing squash. The possibility of high single-beat systolic peaks still justifies some caution in subjects at risk of arterial rupture.

Circadian variation and blood pressure: response to rapid weight loss by hypocaloric hyponatraemic diet in obesity.

Ambulatory intra-arterial blood pressure was monitored in 15 obese hypertensive and 10 obese normotensive subjects weighing more than 30% of their ideal body weight. Measurements were taken before and after 1 month in hospital on a diet of 330kCal/day designed to ensure 34 g protein and 65 mmol sodium. Mean +/- s.d. body mass index in the whole group fell from 40.8 +/- 7.6 to 37.2 +/- 7.4 kg/m2 (P less than 0.0001). Daytime intra-arterial blood pressure fell from 176 +/- 19/102 +/- 14 to 162 +/- 16/95 +/- 14 mmHg (P less than 0.0005 and P less than 0.002) in the hypertensive group and from 141 +/- 15/82 +/- 5 to 131 +/- 13/79 +/- 4 mmHg (P less than 0.005 for systolic pressure) in the normotensive group. Circadian variation of systolic intra-arterial blood pressure comparing the mean daytime with the mean night-time blood pressure recordings showed a day-night difference of 27 +/- 10 mmHg in the normotensive group compared with 12 +/- 13 mmHg in the hypertensive group (P less than 0.01). This trend was reversed after weight loss, when the normotensive group showed a day-night difference of 20 +/- 13 mmHg compared with 18 +/- 17 mmHg in the hypertensive group. Thus, circadian variation of systolic intra-arterial blood pressure in the hypertensive group was significantly (P less than 0.01) reduced compared with the normotensive group prior to, but not after, weight loss. These data show that, in obese subjects, weight loss produced a significant reduction in ambulatory intra-arterial blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolonged hypotensive effect of OPC-13340: a new, once-daily calcium channel blocking drug.

The duration and magnitude of the hypotensive effect of a new, once daily dihydropyridine calcium channel blocking drug, OPC-13340, was assessed in 14 patients with essential hypertension during normal daily activities and programmed exercise testing. Intra-arterial ambulatory blood pressure (BP) monitoring was performed before and after one month's treatment. Mean reduction in day-time BP was 27/14 mmHg and night-time BP 18/11 mmHg (P less than 0.001 and 0.05 respectively). There was no change in heart rate throughout the 24 h. Satisfactory day-time control of systolic and diastolic BP using the drug as monotherapy was achieved in 58% and 88% of patients respectively, although adequate control of nocturnal systolic and diastolic BP occurred in only 54% and 50% of patients respectively. No postural hypotension occurred during tilt testing, and there was a significant reduction in the peak BP observed during both dynamic and isometric exercise. Side effects were mild and transient. Thus OPC-13340, given once daily, is an effective and well tolerated anti-hypertensive drug, with a prolonged 24-h action.

24-hour blood pressure control with the once-daily calcium antagonist amlodipine.

The efficacy and toleration of once-daily amlodipine (5-10 mg) was studied in 11 patients with mild to moderate hypertension. Continuous intra-arterial blood pressure monitoring was used to study the effects of amlodipine over a 24-h period. Following a 2-week placebo run-in period, amlodipine was given initially as a single-blind 5-mg dose for 2 weeks and increased to 10 mg if required to control blood pressure for a further 4 weeks. Twenty-four-hour intra-arterial blood pressure recordings made after 6 weeks of treatment with amlodipine revealed that amlodipine effectively reduced blood pressure throughout the whole 24-h period without altering the normal circadian pattern. The mean daytime blood pressure was reduced from 165/103 to 147/89 mm Hg (p < 0.05) and the mean nighttime blood pressure was reduced from 137/79 to 121/69 mm Hg (p < 0.05). There was no significant change in heart rate. The mean supine blood pressure measured sphygmomanometrically was reduced from 169/103 mm Hg after placebo to 153/98 mm Hg after 2 weeks of treatment and to 145/92 mm Hg at the end of the study. The results of isometric and dynamic exercise testing showed that amlodipine decreased blood pressure, with no postural decrease on tilting and no change in the proportional increase in blood pressure at peak exercise. Amlodipine was well tolerated although one patient developed ankle edema that would have required discontinuation had she not already completed the study. This study has shown that amlodipine effectively reduced blood pressure for 24 h after once-daily dosing and was well tolerated.