What are the options for treating latent TB infection in children?
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You are looking after a previously well, HIV-negative 4-year-old boy who has recently migrated to Australia from Sudan. He is BCG-immunised and reports no history of TB contact. His tuberculin skin test (TST) is positive (16 mm induration) and his chest x-ray (CXR) is normal. You diagnose latent tuberculosis infection (LTBI) and wonder what would be the best treatment regimen.
Structured clinical question
In a child with LTBI [patient], what is the best treatment regimen [intervention] taking into account four criteria: treatment compliance, drug adverse effects, treatment efficacy and cost [outcomes]?
Search strategy and outcome
Medline and EMBASE were searched using the Ovid interface (1974 to current date) in December 2012. The following keywords were used: (latent tuberculosis/[drug therapy, therapy]) OR (latent AND *tuberculosis/[diet therapy, drug therapy, surgery, therapy]). Limit set: English-language. Studies of LTBI treatment that included children aged less than 15 years were selected. Case reports, brief reports, studies of LTBI treatment for drug-resistant TB, studies including less than five children and studies of HIV-infected children were excluded. Of the 78 articles identified by the original search, 10 were relevant. The references of these publications were then reviewed and two additional articles were identified giving a total of 12 relevant studies (table 1). We contacted the corresponding authors of 10 of the articles and obtained further paediatric data from two (Li and Cook).
Children with LTBI have a significant risk of developing active TB without treatment, including those that have been BCG-immunised.1 Progression to active TB has been reported in up to 40% of infected infants.2
Recommendations for the treatment of LTBI in children vary: the Centers for Disease Control and Prevention recommend 9 months of isoniazid monotherapy3; the UK NICE guidelines suggest 6 months of isoniazid monotherapy or 3 months of combination therapy with rifampicin plus isoniazid4; and Australian guidelines suggest 6–12 months of isoniazid monotherapy.5 Isoniazid preventive therapy (IPT) has been reported to have a protective efficacy of up to 90% in compliant patients.6 However, low treatment completion rates which have been reported as low as 65%, limit the effectiveness of IPT.7
Of the 12 studies that met our criteria, 10 compared isoniazid monotherapy with shorter courses of: (i) rifampicin plus isoniazid (RH); (ii) rifampicin plus pyrazinamide (RZ); and (iii) rifampicin monotherapy (R).
Treatment compliance and completion
Five studies compared isoniazid monotherapy with combination treatment with rifampicin or rifapentine plus isoniazid of shorter duration and found higher completion rates with the shorter regimens.8–12 However, two studies used directly observed therapy for the combination regimen but not for isoniazid monotherapy.10 ,12 Importantly, two prospective studies found significantly higher compliance rates with 3-12 and 4-month13 combination regimens of rifampicin/rifapentine plus isoniazid compared to a longer course of isoniazid alone. There was no difference in compliance between 3 and 4-month combination treatments.13
In a prospective randomised controlled trial (RCT), Tortajada et al14 found no difference in treatment completion or daily adherence between 2 months of rifampicin plus pyrazinamide and 6 months of isoniazid monotherapy. This contrasts with an observational study that showed improved completion rates for the shorter course combination regimen.11 Interestingly, this study found that completion rates were even higher in those taking 4 months of rifampicin monotherapy, although there were only 32 patients in this group.11 Consistent with this, three retrospective studies also found higher treatment completion rates with shorter duration rifampicin compared with longer course IPT.15–17
Drug adverse effects
Four studies (level 2 evidence) compared 4 and 6-month rifampicin monotherapy regimens with isoniazid monotherapy: three found higher rates of adverse effects, in particular hepatotoxicity, in those treated with isoniazid,11 ,15 ,16 while the fourth study found more adverse effects with rifampicin.17 Adverse effects led to differences in treatment discontinuation in two of these studies: Page et al15 reported lower treatment completion rates in the isoniazid group, while Li et al17 found higher discontinuation rates with rifampicin monotherapy.
Short-course combination therapy with rifampicin plus isoniazid was preferred by patients in one study,9 but this regimen has been associated with a higher incidence of hepatotoxicity compared with other treatment options.18 Of the seven studies that assessed combination therapy with rifampicin/rifapentine plus isoniazid, three were in children including one RCT.13 ,19 ,20 The RCT found fewer cases of hepatotoxicity when compared with IPT,13 and an observational study found no cases of hepatotoxicity with combination therapy.19 Despite this, patients taking combination therapy more frequently discontinued treatment due to an adverse drug effect, although the overall treatment discontinuation rate remained low (4.9% 3RH vs 3.7% 9H; p=0.009).10 ,12 Discontinuation in the combination therapy group was due to extra-hepatic adverse drug effects (gastrointestinal, neurological and hypersensitivity reactions).10 ,12 ,13
Two months of combination therapy with rifampicin plus pyrazinamide was compared to 6 months of isoniazid monotherapy in a prospective study which included 56 children.14 This combination did not cause hepatotoxicity in any patient, but higher rates of adverse effects occurred in all age groups (59% in 2RZ vs 41% in 6H).14 In contrast, in a small observational study of eight children receiving combination therapy with rifampicin plus pyrazinamide, one child developed hepatotoxicity but no extra-hepatic adverse effects were recorded.11
Two studies suggest that rifampicin monotherapy is as effective as isoniazid monotherapy in the prevention of pulmonary TB.15 ,16 Children receiving 2 months treatment with rifampicin plus pyrazinamide reported no cases of active TB, although patients were followed for only 24 weeks after treatment.14 Short course combination therapy with rifampicin/rifapentine plus isoniazid was found to be non-inferior and possibly more effective in preventing active TB in two RCTs and one observational study.12 ,13 ,19 One of these RCTs followed patients for up to 11 years and found a significant reduction in the number of patients who developed CXR changes suggestive of TB with the combination therapy compared to IPT.13
Only one study assessed cost. The cost per patient of 3 months of combination therapy with rifampicin plus isoniazid was found to be 1.6 times higher than isoniazid monotherapy.9
In eight of the studies, paediatric data were combined with adult data. The small number of children in many of the studies limits the generalisability of the findings. For example, it is difficult to draw firm conclusions from the two studies of combination therapy with 2 months of rifampicin plus pyrazinamide that included only 34 children in total. The results of some of the studies may not be directly comparable due to differences in their inclusion criteria, the populations sampled, drug doses and definitions of compliance and adverse effects.
Overall, short course combination therapy appears to be a safe option for the treatment of LTBI in children. The available evidence points to higher treatment completion rates with short course combination therapies with no increase in treatment failure, even with the shortest regimens. Combination therapy with rifampicin plus isoniazid has been the best-studied regimen. There is no evidence of increased rates of hepatotoxicity with combination therapy and there may be less hepatotoxicity compared to a longer course of isoniazid monotherapy. However, there is some evidence to suggest higher rates of non-hepatic adverse events with combination therapy, which could impact on treatment completion. There are insufficient studies to draw firm conclusions regarding the relative cost of short course combination therapies compared to isoniazid monotherapy.
Clinical bottom lines
▸ Higher completion rates are reported with a 3 or 4-month combination of rifampicin plus isoniazid than with 6 or 9 months of isoniazid monotherapy. (Grade B)
▸ There is no evidence of increased hepatotoxicity with rifampicin plus isoniazid combination therapy, although extra-hepatic drug adverse effects may be more common. (Grade B)
▸ Three or 4-month rifampicin plus isoniazid combination therapy is as effective as 6 or 9 months of isoniazid monotherapy. (Grade A)
▸ Four-month rifampicin monotherapy is as effective as 6 or 9 months of isoniazid monotherapy and associated with improved treatment completion, but it is unclear whether children on this regimen have more drug adverse effects. (Grade B)
▸ Data are limited for rifampicin plus pyrazinamide combination therapy and for economic assessment of any regimens in children.
We thank Jiehui Li and Paul Cook for providing us with paediatric data related to their studies. We also thank Stephen Graham for his helpful comments on the manuscript. We also thank Poh Chua for her assistance and Stephen Graham for his helpful comments on the manuscript.
Contributors AG, BC and NC: analysis and interpretation of data, drafting of the manuscript and critical revision of the manuscript for important intellectual content; NC: study supervision.
Competing interests None.
Provenance and peer review Commissioned; internally peer reviewed.
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