Indian Pediatr 2010;47: 39-40
Physical Activity Assessment With
Accelerometers in Children
Senior Deputy Director, Tuberculosis Research Centre,
Chennai; and Coordinator, Neglected Priorities Research, TDR, WHO, Geneva.
hough an estimated 1 million new
cases of tuberculosis (TB) occur in children world-wide each year,
pediatric TB has not been given the same priority as its adult
counterpart(1). Advances in diagnosis and treatment are lagging behind –
the major limitation in performing treatment trials in children is the
lack of a definitive gold standard for diagnosis and monitoring. As a
result, regimens and dosages of anti-TB drugs tested in adults are often
extrapolated to children. The efficacy of short-course chemotherapy (SCC)
regimens for the treatment of pulmonary TB was first demonstrated in
adults in the1970s; this was followed by trials for extra-pulmonary and
childhood TB. Even before SCC became the norm, the phenomenon of "lag
phase" in mycobacteria exposed to anti-TB drugs in vitro was
described and led to the concept of intermittent treatment(2). Thrice,
twice and even once-weekly regimens were tested, most of the trials being
conducted at the UK Medical Research Council sites in Madras, Hongkong and
East Africa(3). The results with thrice-weekly treatment were encouraging;
lower dosing frequency led to higher failure and relapse, especially in
patients who were rapid acetylators of isoniazid. However, a Cochrane
review comparing daily and thrice-weekly treatment in adults identified
only one eligible trial and concluded that while cure rate was similar,
relapses were higher in the intermittent arm(4).
In this issue of the journal, Menon, et al.(5)
performed a meta-analysis of trials comparing daily and intermittent
treatment in children. The studies vary widely in terms of patient
profile, type of intermittent regimen tested (daily followed by
intermittent, thrice-weekly followed by twice-weekly, twice-weekly
throughout), drug dosages, use of directly observed treatment (DOT),
follow-up time and study end-points selected. Further, the use of
clinical/radiographic endpoints, unless validated and made as objective as
possible, leads to subjectivity in assessment of cure. Using the Jadad
score, which assesses the quality of trials based on the appropriate use
and reporting of randomization and patient losses, only 1 of the four
included trials scored 3 out of 5. Overall, favorable responses were high,
and death, relapse and adverse events low, with all the regimens used,
there was a trend to a lower "cure" rate with the use of twice-weekly
regimens. However, when one study was excluded during the sensitivity
analysis, the odds ratio approached 1.0 suggesting that this study was
driving the results. None of the studies tested a fully intermittent
thrice-weekly regimen, which is currently recommended for use in the
Indian Revised National TB Control Program. Perhaps, due to lack of
available baseline data, the authors have not attempted an analysis of the
other factors that predispose to poor outcomes – young age, associated
malnutrition, suboptimal dosage, non-compliance etc. Of course, HIV is
unlikely to have been a confounding factor as most of these studies were
conducted in the 1980s and 1990s in areas of low prevalence. HIV, however,
is an important factor to consider during analysis of trials being planned
or conducted now. Malabsorption of drugs has been documented in patients
with advanced HIV and could contribute to poor out-comes including higher
death, recurrence and acquisition of drug resistance(6). Recent pharmaco-kinetic
studies in children with TB, conducted mostly in south Africa, have
suggested that the dosage of the first line drugs, including isoniazid and
rifampicin, need to be critically reviewed(7,8).
This meta-analysis highlights the gaps in knowledge and
the lack of an evidence base to recommend a safe and efficacious
intermittent anti-TB regimen for children. Clinical trials performed now
need to conform to CONSORT guidelines and should follow preset case
definitions and endpoints. A more pragmatic approach may be to follow a
cohort of children being treated with the standard regimen, perform
pharmacokinetic studies at multiple time points, ensure adherence to
treatment and assess cure and relapses over 18-24 months. Such a study
would provide valuable information on the effectiveness of drug dosages
being used in the national program as well as provide an opportunity to
study the role of other factors like age, HIV infection, nutritional
status and acetylator status on patient outcomes.
Competing interests: None stated.
1. Nelson LJ, Wells CD. Global epidemiology of
childhood tuberculosis. Int J Tuberc Lung Dis 2004; 8: 636-647.
2. Fox W, Ellard GA, Mitchison DA. Studies on the
treatment of tuberculosis undertaken by the British Medical Research
Council Tuberculosis Units 1946-1986, with relevant subsequent
publications. Int J Tuberc Lung Dis 1999; 3: S231-S279.
3. Jawahar MS. Current trends in chemotherapy of
tuberculosis. Indian J Medical Res 2004; 120: 398-417
4. Mwandumba HC, Squire SB. Fully intermittent dosing
with drugs for treating tuberculosis in adults. Cochrane Database Syst Rev
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5. Menon P, Lodha R, Sivanandan S, Kabra SK.
Intermittent or daily short course chemotherapy for tuberculosis in
children: meta-analysis of randomized clinical trials. Indian Pediatr
2010; 47: 67-73.
6. Gurumurthy P, Ramachandran G, Hemanth Kumar AK,
Rajasekaran S, Padmapriyadarsini C, et al. Malabsorption of
rifampicin and isoniazid in HIV-infected patients with and without
tuberculosis. Clin Infect Dis 2004; 38: 230-233.
7. Schaaf HS, Parkin DP, Seifart HI, Werely CJ,
Hesseling PB, van Helden PD, et al. Isoniazid pharmacokinetics in
children treated for respiratory tuberculosis. Arch Dis Child 2005;
8. Schaaf HS, Willemse M, Cilliers K, Labadarios D,
Maritz JS, Hussey GD, et al. Rifampin pharmacokinetics in children,
with and without human immunodeficiency virus infection, hospitalized for
the management of severe forms of tuberculosis. BMC Med 2009; 7:19-29.