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Paediatric Respiratory Reviews 12 (2011) 22–26

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Mini-symposium: Childhood TB in 2010

Treatment of paediatric TB: revised WHO guidelines


Stephen M. Graham 1,2,*
1
Centre for International Child Health, University of Melbourne Department of Paediatrics and Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Australia
2
Child Lung Health Division, International Union Against Tuberculosis and Lung Disease, Paris, France

EDUCATIONAL AIMS

 To describe the current recommendations for dosages of first-line TB treatment in children following recent revision
 To outline the rationale for these revisions
 To highlight clinical and pharmacokinetic data that helped inform the revised recommendations

A R T I C L E I N F O S U M M A R Y

Keywords: The World Health Organization has recently revised the recommended dosages of the main first-line
isoniazid anti-tuberculosis drugs for use in children. The recommended dosages and range of isoniazid, rifampicin,
rifampicin pyrazinamide and ethambutol have been increased from the previous recommended dosages.
pyrazinamide
Ethambutol is now recommended for use in children of all ages including those of less than 5 years
ethambutol
of age. This review explains the rationale for these recent revisions. Children require higher dosages than
dosages
toxicity adults to achieve the same serum concentrations. Available data in HIV-uninfected children suggest that
children the revised dosages are within limits that have a very low risk of toxicity. An important challenge will be
to examine the impact of higher dosages on clinical response, drug-drug interactions and risk of toxicity
in HIV-infected children.
ß 2010 Published by Elsevier Ltd.

INTRODUCTION has in the past primarily focused on the identification and effective
management of the most infectious cases of TB in order to reduce
The World Health Organization (WHO) has estimated that the transmission of infection with Mycobacterium tuberculosis.
around 10% of global tuberculosis (TB) caseload occurs in children These cases are usually adults or adolescents with sputum smear-
(0-14 years).1 Disease burden data in children is rarely reported positive pulmonary TB (PTB). Further, although there is evidence
from TB endemic countries. However, there are reports that that paediatric TB makes an important contribution to the global
children account for up to 40% of all cases being treated for TB.2–4 burden of TB, it has been difficult to accurately determine (and
Marked variability is expected because the reported burden of provide advocacy for) the burden of disease in children because
disease will depend on epidemiological and demographic differ- most cases are not confirmed. The burden of paediatric disease in
ences between communities5 as well as differences in diagnostic TB endemic settings is usually skewed towards the infants and
and notification practices. While there may be uncertainty of young children (< 5 years of age)2–5 from whom it is difficult to
actual disease burden, clinical and autopsy data from the sub- obtain sputum, and the nature of disease in this age group is
Saharan African region show that TB is a major cause of morbidity usually paucibacillary meaning that culture is required to improve
and mortality in children.6–9 Children are also susceptible to the yield of diagnostic confirmation. Therefore, most children with a
dual epidemic of TB/HIV. HIV-infected children are at 20-times diagnosis of TB are categorised by National TB Programmes (NTPs)
greater risk of TB disease than HIV-uninfected children and at as either ‘‘sputum smear-negative’’ PTB or extra-pulmonary TB
much higher risk of TB-related death.8–12 (EPTB) cases.3,4 These cases were not traditionally and are often
Paediatric TB has until recently not been a main priority of still not being routinely recorded and reported by NTPs.
global TB control efforts for various reasons. The control strategy
RECENT ATTENTION BY WHO TO THE CHALLENGES OF
PAEDIATRIC TB
* Centre for International Child Health, University of Melbourne Department of
Paediatrics, Royal Children’s Hospital, Flemington Rd, Parkville, Victoria 3052,
Australia. Tel.: +61 3 9345 4788; Fax: +61 3 9345 6667. The direct observed treatment strategy [DOTS] has recently
E-mail address: steve.graham@rch.org.au. been incorporated into WHO’s broader Stop TB Strategy13 which

1526-0542/$ – see front matter ß 2010 Published by Elsevier Ltd.


doi:10.1016/j.prrv.2010.09.005
S.M. Graham / Paediatric Respiratory Reviews 12 (2011) 22–26 23

Table 1
Treatment regimens for children recommended by WHO

TB cases and diagnostic category Anti-TB drug regimens

Intensive phase Continuation phase

New Patient Regimen


New smear-positive PTB 2HRZE 4HR
Smear-negative PTB with extensive parenchymal involvement
Severe forms of EPTB other than TB meningitis
New Patient Regimen
Smear-negative PTB without extensive parenchymal involvement 2HRZ 4HR
Less severe forms of EPTB (e.g TB cervical adenitis)
New Patient Regimen
TB meningitis 2HRZSa 4HR
Retreatment regimen
Previously treated smear-positive PTB (relapse, treatment after interruption or treatment failure) 2HRZES/1HRZE 5HRE
If low risk for MDR TB or risk unknown: continue with retreatment regimen
If high risk for MDR TB: use MDR TB regimen below
MDR Regimen
MDR-TB Individualized regimens

The Table represents WHO recommendations up until August 2010 which have since been changed (and approved by Guidelines Review Committee) and this process is
mentioned in text below. The main changes are that all TB types (except TBM and OA TB) in HIV endemic setting should receive a fourth drug in intensive phase 2RHZE/4RH,
that TBM and osteoarticular TB should receive 2 RHZE/10RH and that streptomycin is no longer recommended as first-line in children.
H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambutol; S: streptomycin
a
: Other regimens are recommended for treatment of TB meningitits that include replacing streptomycin with ethionamide and treating for 9-12 months

gives due emphasis to all types of TB disease and vulnerable at-risk Rifampicin and pyrazinamide (Z) are important first-line steriliz-
groups, thereby including TB in children. As part of this new ing drugs. Protection against emergence of drug-resistant organ-
strategy in response to the challenges of improving child TB isms is achieved by the combination of effective early bactericidal
management, the child TB subgroup of the DOTS Expansion activity to reduce microbial load combined with effective
Working Group of the Stop TB partnership was formed in 2003. sterilising activity of more slowly replicating organisms, and
This has facilitated a number of important initiatives aimed at strengthened by the addition of a fourth drug such as ethambutol
greater engagement by NTPs to address child TB issues: (E) or streptomycin (S).
The recommended treatment regimens for each TB diagnostic
1. Published guidelines for NTPs on TB management in children14 category are also generally the same for children as for adults.
2. Revision of recommended drug dosages of the four first-line Table 1 lists the regimens by disease category as currently
anti-TB drugs for children15,16 recommended by WHO in 2010.15 The most common TB diagnostic
3. The development of guidelines for national TB and HIV category in children is smear-negative PTB and so the commonest
programmes on TB management in HIV-infected children17 regimen used in children is 2HRZ 4HR: denotes a two-month
4. Recommendations to include routine reporting by NTPs of intensive phase of daily isoniazid, rifampicin and pyrazinamide
children receiving TB treatment in two age categories (0-4 years followed by a four-month continuation phase of daily isoniazid and
and 5-14 years)18 rifampicin. A fourth drug is important for cure of disease with a
5. A research agenda for child TB19 large microbial load such as sputum smear-positive PTB or PTB
with extensive parenchymal involvement, and to reduce the risk of
A major challenge that remains is to implement recent development of drug-resistance.21 These regimens are currently
guidelines and recommendations in resource-limited settings being reviewed by an expert panel and are likely to change before
through guidance and training of paediatric and NTP health end of 2010. The use of a fourth drug in the intensive phase for the
workers to increase effectiveness. This review aims to highlight the common forms in children, PTB and TB adenitis, may in the future
rationale and evidence base behind these initiatives, focusing be determined by epidemiological context i.e. population pre-
particularly on revised WHO guidelines for the treatment of valence of HIV and isoniazid resistance, rather than by extensive-
paediatric TB which relate to the first three points above. ness of pulmonary disease. The recommended treatment of TB
meningitis and osteoarticular TB are also under review and
PRINCIPLES OF TB TREATMENT treatment for 12 months may be the preferred option.
The WHO guidelines of 2003 included 6HE as an alternative to
The principles of TB treatment are the same for adults and 4HR for the continuation phase of new patient regimens.
children. The combination regimens used to treat active disease Rifampicin is important in the continuation phase to kill slowly
aim to eliminate actively replicating and dormant or near-dormant metabolizing organisms whilst isoniazid is less potent for
mycobacteria using a combination of drugs with different actions bactericidal activity in that context and when combined with
whilst preventing the emergence of drug-resistant organisms, and rifampicin, is added to provide protection against drug resis-
all being achieved with a minimum of toxicity.20 Bactericidal drugs tance.21 In the alternative combination of 6HE, isoniazid is used for
that kill actively metabolizing and replicating organisms are bactericidal activity but is less potent than rifampicin especially
important to achieve a rapid reduction in microbial load which against slowly metabolizing organisms, while ethambutol has less
leads to clinical improvement, contains disease progression and potent bactericidal activity and is used for protection against
terminates transmission.21 Isoniazid (H) and rifampicin (R) are development of drug resistance. A multi-centre randomised trial
important first-line bactericidal drugs with isoniazid having the that compared HR to HE in continuation phase in adults with TB
most potent early bactericidal activity. Sterilizing drugs aim to found that relapse was more common in those in the 6HE arm than
eradicate those organisms that are less active metabolically and for those in the 4HR.22 As a result, 4HR is now the only
those that are in an acidic environment in order to prevent relapse. recommended option for the continuation phase.
24 S.M. Graham / Paediatric Respiratory Reviews 12 (2011) 22–26

Table 2
Recommended first-line drug dosages for children as currently recommended and as previously recommended by WHO

Drug Currently recommended (Ref 15, 16) Previously recommended (Ref 23)

Daily dosage (dose range) in mg/kg Daily dosage (dose range) in mg/kg Thrice weekly dosage (dose range) in mg/kg

Isoniazid 10 (10-15) 5 (4-6) 10 (8-12)


Rifampicin 15 (10-20) 10 (8-12) 10 (8-12)
Pyrazinamide 35 (30-40) 25 (20-30) 35 (30-40)
Ethambutol 20 (15-25) 15 (15-20)* 30 (20-35)
Streptomycin 15 (12-18) 15 (12-18) 15 (12-18)
Thioacetazone No longer recommended 2.5 Not applicable
*
Was not recommended for children of less than 5 years of age in 2003

USE OF ETHAMBUTOL IN CHILDREN serum concentrations were at such low levels that they might be
inadequate for effective treatment. As a result, the review advised
The rationale for the addition of ethambutol in certain forms of that the recommended dosages for ethambutol be increased for
TB has been mentioned. Ethambutol was not recommended (or children being careful to ensure that the upper limit of
considered as contraindicated) for use in young children i.e. recommended dosage range had an excellent safety profile.16,36
children less than 5 years until recently. The need to reconsider the This initiative was followed by a review of the PK data in children
usage of ethambutol in young children with TB was largely for other first-line anti-TB drugs coupled with a thorough review of
prompted by toxicity problems with thiacetazone.23 Thiacetazone the data relating to the risk of major toxicity, i.e. hepatotoxicity, in
commonly caused severe and usually fatal mucocutaneous children at different dosages. Following review and consultation,
reactions in HIV-infected adults and children24,25 and had to be WHO has recently revised and increased recommended dosages
withdrawn from anti-TB regimens given the risk associated with for rifampicin, isoniazid and pyrazinamide to add to the earlier
its use in HIV-endemic settings where TB was also common. revision for ethambutol.16,17,28 The revised recommended dosages
Streptomycin was not considered an ideal alternative as a fourth are listed in Table 2 along with the previous dosage recommenda-
drug for most cases because it cannot be taken orally and therefore tions for comparison. The revised dosage is double that of the
its use often requires hospitalisation for at least two months. previous recommendation for isoniazid with less of a relative
The reasons for concern about the use of ethambutol in young increase for rifampicin, pyrazinamide and ethambutol. There has
children relate to the fact that the commonest form of drug-related been no change to the recommended dosage of streptomycin but
toxicity is optic neuritis which can lead to irreversible blindness if streptomycin is no longer recommended as a first-line therapeutic
ethambutol is not discontinued when visual symptoms occur. option. Dosage recommendations are no longer listed for inter-
Thus, young children would be at particular risk because they are mittent regimens. Daily regimens are preferred over thrice or twice
not able to report the early visual symptoms associated with optic weekly regimens. A valid concern with intermittent regimens is
neuritis. A number of extensive reviews report studies of that each missed dose represents a larger fraction of the total
ethambutol use in children of all ages, including infants, using a number of recommended treatment doses than it would for a daily
wide range of dosages and providing careful evaluation for visual regimen.
side-effects.16,26,27 These studies show that toxicity is dose-related The revised dosage recommendations are supported by recent
and related to the duration of therapy. Following review of the PK data from South African children with TB. Fifty-four South
data, it was concluded that ethambutol was safe and the risk of African children with severe forms of TB received rifampicin (mean
toxicity negligible for children of all ages if the recommended dosage of 9.6 mg/kg body weight) at 1 and 4 months after
dosages were adhered to. Further, the abovementioned removal of commencing anti-TB treatment.34 The mean area under the curve
6HE as an alternative to 4HR for the continuation phase (as was and 2-hour post-dosing concentrations were lower in HIV-infected
previously recommended23) also reduces the potential of toxicity children (n = 21) at 1 and 4 months compared to HIV-uninfected
because duration of ethambutol usage is now usually limited to the children but the difference was not significant. However, the main
initiation phase of two months. finding was that the values in all children were less than the
suggested lower limit for 2-hour rifampicin concentrations in
REVISION OF DRUG DOSAGES IN CHILDREN adults. Another study from the same group in South Africa found
that median peak concentrations of isoniazid in children receiving
The focus on the safety and dosage issues for ethambutol usage 4-6 mg/kg were 58% lower than in those in children receiving a
in children highlighted the general lack of pharmacokinetic (PK) dose of 8-10 mg/kg.35 Each increase in the dose by 1 mg/kg and
data in children. Dosage recommendations for anti-TB drugs in each increase in age by one year were associated with increases in
children have been the same in milligrams per kilograms of body peak concentrations of 21% (95% CI, 16%-25%) and 6% (95% CI, 3%-
weight as for adults, and the PK data that have informed these 10%), respectively. They concluded that a daily isoniazid dose of 8-
dosages have been from studies in adults. Yet, rates of drug 12 mg/kg should be recommended.
metabolism, distribution and clearance are likely to be different Clearly, the rationale for increasing drug dosages in children
especially in young children.28 A number of PK studies in children should not simply be directed by an aim to increase serum
show that age is a determinant of serum levels for all the first-line concentrations per se but also to improve treatment response. The
anti-TB drugs and that the infants and young children have lower poorer outcomes noted in children with TB/HIV co-infection7–10
peak serum levels than older children or adults.29–35 has increased attention on the need for dosages in children to
A very extensive review conducted by Peter Donald on behalf of achieve optimal serum levels. Treatment trials in HIV-uninfected
WHO included a careful examination of the pharmacokinetic data children with TB including using the higher dosages currently
of ethambutol in children.36 It was recognised that using the recommended have shown that treatment response is satisfactory
dosages recommended by WHO at the time23, the peak serum and that the drugs are well tolerated.37–43 However, survival is
concentrations of ethambutol were lower in children than in poorer for HIV-infected children receiving anti-TB treatment and
adults, especially in young children of less than 5 years.16 Peak deaths are particularly common during the initiation phase or first
S.M. Graham / Paediatric Respiratory Reviews 12 (2011) 22–26 25

two months of treatment.8,10,44 There is a need for PK data of anti- these studies have mainly been in the context of treatment of
TB drugs in children for comparison with clinical response. In HIV- severe disease such as TBM when there are other potential co-
infected children, this comparison will inevitably be confounded factors for toxicity such as disseminated disease involving the liver,
by other variables such as use of antiretroviral therapy (ART). the use of other anti-TB drugs and anticonvulsants.
Guidelines for the management of TB in HIV-infected children
CHILD-FRIENDLY THERAPY has recently been published by WHO.17 HIV-infected children
with TB are recommended to receive the same dosages of anti-TB
There are a number of ongoing challenges to the logistics of therapy as HIV-uninfected children. Some studies in adults have
providing anti-TB treatment for children.45 The production and found that HIV infection is associated with an increased risk of
provision of anti-TB drug preparations has largely focused on hepatotoxicity to anti-TB drugs.52 There are almost no published
therapy for adults. In many settings, children of all ages with TB data for children with HIV. A recent trial reported no increased risk
receive therapy as tablets or portions of tablets. Tablet portions are of hepatotoxicity associated with isoniazid (dosage around
well taken and tolerated by children and have some advantages in 10 mg/kg) use as preventive therapy in HIV-infected South
resource-poor setting as they are more readily transported and African children receiving ART.53 Peak serum levels of isoniazid,
stored than liquid preparations. However, the use of tablets means rifampicin, pyrazinamide and ethambutol were lower, though not
that a fixed dosage amount is supplied within a certain weight significantly, in HIV-infected compared to HIV-uninfected chil-
band and this can lead to a broad range of actual dose received in dren.33–35 However, the potential for toxicity also relates to drug-
mg/kg, especially in the younger children in the lower weight drug interactions and a greater likelihood of underlying liver
bands.46 Further, weight gain in response to anti-TB therapy can be disease and co-infections in HIV-infected children. Anti-TB drugs,
such that the child moves to another weight band during therapy mainly rifampicin, have important interactions with ART and have
requiring a higher dosage and this may not be noted. Neonates many similar side effects.17 In addition, HIV-infected children
deserve special attention. Neonates should be treated with with TB will routinely receive cotrimoxazole preventive therapy.
standard regimens but dosages need careful consideration and It is therefore difficult to distinguish which drug is responsible for
review. toxicity in this context.21,47 HIV and TB are frequent co-
The recent increase in dosages for children has provided morbidities in children in developing countries and with the
another challenge regarding fixed-dose combinations.45 Tablets of increasing use of ART, it will be important to monitor and to report
fixed-dose drug combinations have several advantages over adverse events.
individual drugs including less likelihood of prescription errors
and lesser pill burden. A more ideal combination has been SUMMARY
proposed by WHO because currently available fixed-dose combi-
nations are not optimal for use in children.16 For example, available This review explains the rationale for the recent revision by
fixed-dose combinations of RHZ for intensive phase have a dosage WHO of dosage recommendations for first-line anti-TB drugs in
ratio of rifampicin:isoniazid of 2:1 which means that extra single children. Children require higher dosages than adults to achieve
isoniazid tablets are required as well to reach optimal dosage the same serum concentrations. Available data in HIV-unin-
levels. fected children suggest that the revised dosages are within
limits that have a very low risk of causing serious toxicity. An
TOXICITY OF TB TREATMENT IN CHILDREN important challenge will be to examine the impact of higher
dosages on clinical response and risk of toxicity in HIV-infected
The increase in dosages raises the possibility of an increase in children.
adverse events due to drug-related toxicity. This is particularly
important to consider because the majority of children being
treated for TB live in settings where surveillance and reporting for PRACTICE POINTS
adverse events is poor or non-existent. It is well recognised that
children tolerate anti-TB drugs better than adults when using the  The recommended dosages and range for isoniazid,
same dosages in mg/kg of body weight.47 Reasons for this include a rifampicin, pyrazinamide and ethambutol have recently
lower prevalence of underlying liver disease and alcohol usage but been increased for children
the lower serum levels achieved in young children using these  Previous experience suggests that these drugs are well
dosages may be an additional important factor for fewer episodes tolerated with very low risk of toxicity when used in the
of toxicity. revised dosages, at least in HIV-uninfected children
Hepatotoxicity is the major drug-related adverse event of  Ethambutol is no longer contraindicated for use in young
concern. There are case reports in the literature of hepatic failure children of less than 5 years of age and is safe to use at
when recommended dosages are used.47,48 However, serious recommended dosages in all age groups
adverse events due to anti-TB drugs are rare in children and even
mild side effects are uncommon.47 The risk of hepatotoxicity using
a range of dosages of anti-TB drugs in children has been extensively
reviewed by Peter Donald on behalf of WHO. There is no evidence
RESEARCH DIRECTIONS
that the increased dosages now recommended (Table 2) are
associated with an increased risk of hepatotoxicity. There are data  The impact of revised dosages on treatment response and
available for a range of dosages especially of isoniazid because of outcome, especially in HIV-infected children
its frequent use for preventive therapy.47 Previous studies in  The risk of severe adverse events using revised dosages,
children have used the dosages of anti-TB drugs that are now especially in HIV-infected children
currently recommended following recent revision (e.g. isoniazid  The impact of HIV infection and malnutrition on pharma-
10-15 mg/kg/day) and report side-effects to be uncommon and cokinetic data
mild.37–42 Data from children using daily dosages of isoniazid  The relationship between pharmacokinetic data, treat-
higher than currently recommended (i.e. greater than 15 mg/kg) ment response and risk of toxicity
show a higher and significant risk of hepatotoxicity.49–51 However,
26 S.M. Graham / Paediatric Respiratory Reviews 12 (2011) 22–26

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