The aim of anti-TB treatment (ATT) in adults and children alike is to cure the patient of TB, reduce spread to others and avoid the development of drug resistance within the community. For the first time in three decades there is a promising pipeline of new anti-TB agents at various stages of development, and several have already entered clinical trials.134
Clinical trials of ATT are usually carried out in adults with microbiologically proven pulmonary TB, allowing objective microbiological case definitions and treatment outcomes. The difficulty achieving a clear microbiological diagnosis in the majority of paediatric cases severely hampers trials in children, as microbiological case definitions and treatment endpoints are impractical. As a result few randomised controlled trials have been conducted in children to establish optimum ATT regimens134
and current treatment guidelines are largely inferred from adult data. Furthermore, although first line drugs have scarcely changed for over three decades, there is still a lack of pharmacokinetic studies in children, particularly in the context of HIV infection and malnutrition.
TB treatment consists of two phases - an intensive phase, using a combination of bactericidal drugs to kill the rapidly growing bacilli and a continuation phase using fewer drugs to eradicate the slower growing persistent bacilli.135
National recommendations still vary considerably in treatment duration and drug regimens used.136
In keeping with studies in adults, observational data in children suggest that for drug-susceptible pulmonary TB (PTB), 6 months’ isoniazid and rifampicin combined with 2 months’ pyrazinamide initially has a 99 % cure rate; however quadruple therapy with the addition of ethambutol or streptomycin in the intensive phase is generally recommended where there is high risk of INH-drug resistance. Although some authorities have recommend longer treatment courses for TBM, disseminated TB or bone TB, evidence of their superiority is lacking. The adjunctive use of steroids in TBM has been shown to reduce death and severe disability.137
DOTS may also improve treatment outcomes in paediatric settings.138
Fixed dose combination tablets contribute to increased adherence to treatment regimens, but the significant differences in absorption, distribution and excretion of pharmacological agents in children of various ages might require dose-adjustments. Existing fixed dose combinations contain 4-6 mg of isoniazid per kilogram, but published pharmacokinetic studies in children support a standard dose of 10 mg/kg or even 20 mg/kg isoniazid as younger children acetylate this drug more quickly.139
Pyrazinamide similarly has a lower half-life in children140
who also have lower peak serum levels of ethambutol than adults.141
Equally toxicity may vary in children, both in a beneficial and negative fashion. This emphasizes the importance of specific paediatric pharmacokinetic studies of all ATT, new and old.
Treatment of TB in HIV co-infected children
HIV co-infection is increasingly common in TB endemic areas, often requiring simultaneous therapy. Pharmacokinetic interactions between ATT (in particular rifampicin) and ART, and similar side-effects profiles of many of the drugs pose special challenges. Latest WHO recommendations advise starting ART once ATT is established (after a period of 2-8 weeks) for all WHO clinical stage 4 HIV-infected children and stage 3 children with advanced or severe immunosuppression; for children in WHO clinical stage 3 with mild or no immunosuppression, ART may be deferred until 6 months of ATT are completed.142
On-going prospective trials involving adults and children in TB/HIV endemic countries, wish to inform future guidelines for the ideal timing of the initiation of anti-retroviral therapy (ART) in patients with HIV receiving TB therapy. Unpublished results from prospective trials show that high mortality is associated with TB in advanced stages of HIV-disease in children who do not receive ART promptly. However, these findings have to be considered in the light of developing IRD, which is particularly common in this group. Further research is required to improve our understanding of IRD in children.87
Where available, therapeutic drug monitoring (TDM) should be undertaken when children are receiving concomitant ART and ATT. TDM data from ethnically similar children in resource-rich countries may in the future inform dosing recommendations in resource-poor settings where TDM is not available.
Treatment of LTBI
Treatment of LTBI, also known as chemoprophylaxis, is important to prevent future disease activation. The fact that over 50% of hospitalized children with culture-confirmed TB have a reported close TB contact and do not receive chemoprophylaxis, is an indication of the important missed opportunities using existing public health interventions. For the last 20 years WHO guidelines recommend all children under 5 years in close contact with an infectious (usually smear positive) case receive 6 months isoniazid once active disease has been excluded. Isoniazid monotherapy for 6-9 months has been proven to reduce the TB risk in exposed children by >90% with good adherence.143
More recent studies suggest that 3 months of combined isoniazid and rifampicin are equally effective.144
In a recent study with very short follow-up, continuous isoniazid prophylaxis for HIV-infected children without documented evidence of latent infection, but living in an environment of high exposure, has also been shown to reduce overall morbidity and mortality from TB and other infections.145
Further trials in HIV-infected children receiving ART are ongoing. Recommendations for chemoprophylaxis will continue to differ in TB-endemic and non-endemic settings, because of the perceived risk of exposure. Whilst most paediatricians in Europe and North America would advocate chemoprophylaxis for HIV infected, TB-exposed children only, this needs to be interpreted with caution if the exposure is potentially ongoing or recurrent, and the ability to distinguish LTBI from active disease is limited. In this context, many colleagues in TB-endemic settings are reluctant to place children on chemoprophylaxis because of the potential emergence of resistant strains, if indeed the child has active disease instead of LTBI.