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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

The use of a fourth drug in the intensive phase for the workers to increase effectiveness. PTB and TB adenitis. 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. thereby including TB in children. 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. Recommendations to include routine reporting by NTPs of intensive phase of daily isoniazid. rather than by extensive- paediatric TB which relate to the first three points above. 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. sterilising activity of more slowly replicating organisms. while ethambutol has less leads to clinical improvement. children. The recommended treatment regimens for each TB diagnostic 1. and rifampicin. S. 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. 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. This review aims to highlight the common forms in children. and to reduce the risk of A major challenge that remains is to implement recent development of drug-resistance.16 recommended by WHO in 2010.15 The most common TB diagnostic 3. 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. 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. E: ethambutol. 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. is added to provide protection against drug resis- all being achieved with a minimum of toxicity.20 Bactericidal drugs tance. may in the future rationale and evidence base behind these initiatives. . 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. Published guidelines for NTPs on TB management in children14 category are also generally the same for children as for adults. 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. population pre- particularly on revised WHO guidelines for the treatment of valence of HIV and isoniazid 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.e. recommended option for the continuation phase. contains disease progression and potent bactericidal activity and is used for protection against terminates transmission. 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). ness of pulmonary disease. that TBM and osteoarticular TB should receive 2 RHZE/10RH and that streptomycin is no longer recommended as first-line in children. 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. focusing be determined by epidemiological context i.21 Isoniazid (H) and rifampicin (R) are development of drug resistance. As part of this new ing drugs. 4HR is now the only those that are in an acidic environment in order to prevent relapse.22 As a result. R: rifampicin.M. Z: pyrazinamide.21 In the alternative combination of 6HE. 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. 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. 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 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. 2.g TB cervical adenitis) New Patient Regimen TB meningitis 2HRZSa 4HR Retreatment regimen Previously treated smear-positive PTB (relapse. 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. H: isoniazid.

reactions in HIV-infected adults and children24. distribution and clearance are likely to be different Clearly. recommended dosage range had an excellent safety profile. 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. young children would be at particular risk because they are mittent regimens. the main initiation phase of two months. Dosage recommendations are no longer listed for inter- Thus. Fifty-four South data.37–43 However.16. 16%-25%) and 6% (95% CI.e. The revised dosage is double that of the its use often requires hospitalisation for at least two months. 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 15.17. including infants. option. 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. the peak serum and that the drugs are well tolerated.16. 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.e. especially in young children of less than 5 years. the rationale for increasing drug dosages in children especially in young children. A valid concern with intermittent regimens is neuritis. 3%- weight as for adults. 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.16 Peak deaths are particularly common during the initiation phase or first . isoniazid and pyrazinamide to add to the earlier its use in HIV-endemic settings where TB was also common. 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. 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. Following review of the PK data from South African children with TB. Yet.6 mg/kg body weight) at 1 and 4 months after dosages were adhered to. 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. and the PK data that have informed these 10%). Further.24 S. the abovementioned removal of commencing anti-TB treatment.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. in commonly caused severe and usually fatal mucocutaneous children at different dosages. 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.26.36 It was recognised that using the recommended have shown that treatment response is satisfactory dosages recommended by WHO at the time23. respectively.35 Each increase in the dose by 1 mg/kg and data in children.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. 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. 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. They concluded that a daily isoniazid dose of 8- dosages have been from studies in adults. However. hepatotoxicity. As a result.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. Daily regimens are preferred over thrice or twice not able to report the early visual symptoms associated with optic weekly regimens. previous recommendation for isoniazid with less of a relative The reasons for concern about the use of ethambutol in young increase for rifampicin. Ethambutol was not recommended (or children being careful to ensure that the upper limit of considered as contraindicated) for use in young children i.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. Following review and consultation.M.16. survival is concentrations of ethambutol were lower in children than in poorer for HIV-infected children receiving anti-TB treatment and adults.23 Thiacetazone the data relating to the risk of major toxicity.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.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. 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. 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. revision for ethambutol.36 children less than 5 years until recently. pyrazinamide and ethambutol. rates of drug 12 mg/kg should be recommended.27 These studies show that toxicity is dose-related The revised dosage recommendations are supported by recent and related to the duration of therapy. metabolism. i.

adverse events due to drug-related toxicity. However. 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. standard regimens but dosages need careful consideration and It is therefore difficult to distinguish which drug is responsible for review. Graham / Paediatric Respiratory Reviews 12 (2011) 22–26 25 two months of treatment. In HIV. greater than 15 mg/kg) ment response and risk of toxicity show a higher and significant risk of hepatotoxicity. Neonates should be treated with with TB will routinely receive cotrimoxazole preventive therapy. 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.21. treat- higher than currently recommended (i.37–42 Data from children using daily dosages of isoniazid  The relationship between pharmacokinetic data. There are data  The impact of revised dosages on treatment response and available for a range of dosages especially of isoniazid because of outcome. have important interactions with ART and have requiring a higher dosage and this may not be noted. toxicity in this context.46 Further. children of all ages with TB data for children with HIV. it will be important to monitor and to report fixed-dose drug combinations have several advantages over adverse events. 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.47 Previous studies in  The risk of severe adverse events using revised dosages.52 There are almost no published therapy for adults.44 There is a need for PK data of anti. Guidelines for the management of TB in HIV-infected children CHILD-FRIENDLY THERAPY has recently been published by WHO. this comparison will inevitably be confounded factors for toxicity such as disseminated disease involving the liver. in HIV-infected compared to HIV-uninfected chil- band and this can lead to a broad range of actual dose received in dren.17 In addition. children have used the dosages of anti-TB drugs that are now especially in HIV-infected children currently recommended following recent revision (e. Children require higher dosages than adults to achieve isoniazid tablets are required as well to reach optimal dosage the same serum concentrations. though not that a fixed dosage amount is supplied within a certain weight significantly. pyrazinamide and ethambutol were lower. HIV-infected children deserve special attention. fected children suggest that the revised dosages are within limits that have a very low risk of causing serious toxicity.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.g. especially in the younger children in the lower weight drug interactions and a greater likelihood of underlying liver bands. A more ideal combination has been SUMMARY proposed by WHO because currently available fixed-dose combi- nations are not optimal for use in children. 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.M. severe disease such as TBM when there are other potential co- infected children.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.53 Peak serum levels of isoniazid. these studies have mainly been in the context of treatment of TB drugs in children for comparison with clinical response.8.16 For example. revised dosages. same dosages in mg/kg of body weight.10. the use of tablets means rifampicin. It is well recognised that children tolerate anti-TB drugs better than adults when using the  The recommended dosages and range for isoniazid.e. In many settings.33–35 However. stored than liquid preparations.48 However. 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. Available data in HIV-unin- levels. the potential for toxicity also relates to drug- mg/kg. individual drugs including less likelihood of prescription errors and lesser pill burden. S. Neonates many similar side effects. 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. by other variables such as use of antiretroviral therapy (ART). such that the child moves to another weight band during therapy mainly rifampicin. There is no evidence RESEARCH DIRECTIONS that the increased dosages now recommended (Table 2) are associated with an increased risk of hepatotoxicity. 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. the use of other anti-TB drugs and anticonvulsants.45 Tablets of increasing use of ART. A recent trial reported no increased risk receive therapy as tablets or portions of tablets.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. Anti-TB drugs.47. weight gain in response to anti-TB therapy can be disease and co-infections in HIV-infected children. especially in HIV-infected children its frequent use for preventive therapy.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.47 Reasons for this include a rifampicin. Some studies in adults have providing anti-TB treatment for children.49–51 However. 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. . 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.

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