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Abstract
Background/setting Treatment for 3 months with rifampicin (R) and isoniazid (H) (3RH) for latent tuberculosis infection (LTBI), defined as an inappropriately positive tuberculin skin test with no clinical or x-ray evidence of disease, has been used locally since 1989. The efficacy of this regimen in children in the UK has only been studied indirectly. The long-term outcome of those children treated with 3RH, in the Chest Clinic of this high tuberculosis (TB) incidence district, has been studied to derive a more direct assessment of effectiveness.
Methods All children treated with 3RH for LTBI from 1989 to 2004 inclusive were matched with the local patient administration system (PAS), GP registration and local TB notification databases. Only those persons still registered locally on PAS, or locally GP registered were then checked for subsequent TB notification.
Results A total of 334 patients were identified, of whom 252 remained locally, with 82 lost to follow-up; 3 cases of clinical TB developed in the 252 (1.19%), with 3113 years observation (mean 12.35 years) giving 0.964/1000 person years (95% CI 0.199 to 2.816). Sensitivity analyses showed a ‘best case’ scenario of 0.727/1000 person years (95% CI 0.15 to 2.12), and if 10% of those lost to follow-up developed clinical TB of 2.66/1000 person years (95% CI 1.33 to 4.77).
Conclusions Follow-up of those cases treated with 3RH, for a mean of 12.35 years, and over 3100 patient years observation, shows a rate of active TB of under 1/1000 patient years. This suggests that 3RH has very high efficacy when used to treat LTBI in children in the UK and compares favourably with the expected untreated TB rate.
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Introduction
Treatment for latent tuberculosis infection (LTBI) for children aged 0–15 years, with tuberculin skin tests inappropriately positive for their Bacille Calmette-Guérin (BCG) vaccine status (Heaf grade 2–4 without prior BCG; Heaf grades 3–4 with prior BCG), was advised by the Joint Tuberculosis Committee (JTC) of the British Thoracic Society from 1990 onwards.1,–,3 The regimens advised were either isoniazid for 6 months (6H) or rifampicin (R) and isoniazid (H) for 3 months (3RH).4 5 The protective efficacy of 3RH prophylaxis in adults is known to be 60% to 65%,6 but could well be higher in children below age 16. The efficacy of 3RH was analysed in the National Institute for Clinical Excellence (NICE) guidelines as significant,6 with an ‘A’ level recommendation based mainly on adult studies on patients who were silicotic in Hong Kong.7 There was no high level evidence in children, so the recommendations for them were based on clinical experience.
What is already known on this topic
▶. Preventive treatment of 6 months isoniazid (6H) has a protective efficacy for tuberculosis (TB) disease of 65% but this is largely derived from adult data.
▶. Preventive treatment of 3 months rifampicin and isoniazid has a protective efficacy of 60% in adult data.
What this study adds
▶. Preventive treatment of 3 months rifampicin and isoniazid is very well tolerated in children with no significant hepatitis over a 15-year treatment period.
▶. The derived protective efficacy in this cohort study, with a mean follow-up of 12.35 years, has at least the 60% protective efficacy found in adult studies and probably greater than 80% efficacy.
We have previously demonstrated that the introduction of rifampicin and isoniazid prophylaxis locally significantly reduced the incidence of paediatric tuberculosis (TB),8 and that the reduction in incidence was maintained on 3RH between 1987 and 1996,9 in the Blackburn, Hyndburn and Ribble Valley areas (BHRV) of East Lancashire. Detailed local records allow a potential assessment of all patients treated with 3RH between 1989 and 2004 inclusive. This should give a more direct assessment of the potential long-term effectiveness of 3RH prophylaxis. The aim of the study was to ascertain how many of the children treated for LTBI between 1989 and 2004 went on to develop active disease. It should be noted however, that:
Infants born to South Asian parents locally had a consistently high (average 95%) neonatal BCG rate. Children entering the UK were screened on entry, and had generally not had prior BCG vaccination.
This report does not cover the use of primary preventive treatment with isoniazid monotherapy for those children under age 2, without prior BCG, who were contacts of sputum smear-positive pulmonary disease.1,–,3
In the local South Asian community, isoniazid resistance has consistently run at between 7% and 10% for the last 40 years.10,–,12 Contacts of known isoniazid resistant cases were treated with rifampicin for 6 months, in line with JTC recommendations,1,–,3 and not included in this study.
Our hypothesis was that the protective efficacy of 3RH prophylaxis would be high, and only a small proportion of these children would go on and develop active disease.
Methods
Details were obtained from the local TB contact and new entrant registers of all patients aged under 16 years when treated with 3RH between 1989 and 2004 inclusive. These names were matched with the current patient administration system (PAS) hospital database and the general practice (GP) database for the BHRV areas to ascertain whether patients were still locally registered. Those patients who were still locally registered, with either recent hospital PAS contact (2007–2008) confirming continuing local residence, or GP registration confirmed via their patient details for those without recent PAS contact, were then matched to the local TB notifications database for 1989 to the end of 2008. All cases of TB locally, paediatric and adult, were treated via the local chest clinic throughout the entire period with 100% ascertainment, and the database has been prospectively maintained since 1981 to date. As an additional check, the notification database also has a field for those with known prior chemoprophylaxis and this was also crosschecked. We were unable to follow up children who moved outside our local government areas, as data were not then stored by National Health Service (NHS) identification number.
The duration of follow-up for those remaining locally was calculated from the cessation of chemoprophylaxis to the end of 2008. For those treated at the beginning of 1989 this potentially was a maximum of 19 years 9 months, and for those treated at the end of 2004, a minimum of 3 years 9 months. No child died of any form of TB for the years 1989–2008 inclusive.
Results
Examination of the data revealed that 334 patients were treated with 3RH prophylaxis between 1989 and 2004 inclusive. Of these 252 patients were still registered with a GP in the BHRV area, of whom 3 (1.19%) patients developed TB. These were 6 months, 6 years 11 months and 7 years 10 months after the commencement of prophylaxis, with further details in table 1. A total of 82 cases were not locally registered and thus lost to follow-up. No patient developed significant hepatitis on 3RH requiring cessation of treatment during the active treatment period of 1989–2004. In a few cases antiemetics were needed for nausea/vomiting with normal liver function. All children had monthly compliance assessments throughout their 3-month course of treatment, with no significant non-compliance detected.
Clinical cases of tuberculosis (TB) post chemoprophylaxis
The three cases of clinical TB occurred during a total of 3113 years follow-up, with a mean follow-up of 12.35 years. The rate of clinical TB was therefore 3/3113 years or 0.964/1000 person years (95% CI 0.0199 to 2.816). A sensitivity analysis was performed. The best case scenario would be that none of the 82 cases lost to follow-up developed clinical TB, giving an estimated person years rate of 0.727/1000 person years (95% CI 0.15 to 2.12). If it was assumed that 5% of those 82 lost to follow-up (n=4) developed clinical TB, this would give a rate of 1.697/1000 person years (95% CI 0.682 to 3.496). If it was assumed that 10% of those 82 lost to follow-up (n=8) developed clinical TB, this would give a rate of 2.66/1000 person years (95% CI 1.33 to 4.77). Scenarios with more than 10% of those lost to follow-up developing clinical TB were thought unlikely.
Discussion
The UK guidance on treatment of LTBI in children recommends either 6H or 3RH, derived largely from adult data, with 6H (60% to 65%13) and 3RH (60%7) protective efficacy quoted. In most developed countries, the protective efficacy of prophylactic drug treatment for LTBI is derived rather than direct, because trials with a non-treatment arm would be held unethical. The risk of active TB developing in infected subjects, as defined by a positive tuberculin skin test, is estimated at a 10% whole lifetime risk, but this is higher in children,14 and is maximal in the first 2 years after infection but decreases over time.15,–,18
Since NICE guidelines, which stopped evidence analysis in November 2004, were published,6 two studies comparing treatment with isoniazid and rifampicin/isoniazid regimens have been published. The one from Spain19 showed better adherence with 3RH (n=51) compared with 6H (n=45), and a lower discontinuation rate. One case of clinical TB was found in the 6H group over a 5-year follow-up compared with none in the 3RH arm. A study in Greece,20 over 11 years, initially compared 9H (n=232) and 4RH (n=238), and then 4RH (n=236) and 3RH (n=220) with 3-year follow-up. They concluded that 3RH and 4RH were superior to 9H. A meta-analysis from 2005,21 too late to be included in NICE guidance,6 comparing rifampicin and isoniazid with isoniazid alone, confirmed equivalence of the two regimens in terms of efficacy, proportion of severe side effects and mortality.21
Given that the predicted rate of clinical TB in children after an initial positive tuberculin test, is between 5% and 10% in the next 10 years,15,–,18 the rate of clinical TB in this study, with a mean observation period of over 12 years was under 1%, consistent with a protective efficacy in excess of 80%. One factor that may lower this apparently high efficacy a little is the issue of false positive tuberculin tests, because of prior BCG in the majority of our cohort. This cohort received their diagnoses before confirmatory interferon γ release assays (IGRAs) were available. The 2006 NICE guidelines6 recommended a confirmatory IGRA test, to exclude false positive tuberculin responses from either prior BCG or environmental mycobacterial exposure, before treating for LTBI. Our local experience of IGRA testing, in children and adults, suggests that up to 28% of positive tuberculin skin tests are ‘falsely positive’ due to the above reasons22. If that had applied to this cohort, it would reduce the denominator of 252 by up to 28%, but not the numerator of 3 cases, lowering the overall effectiveness by up to 28%. Even with this caveat, this cohort and long-term follow-up data, suggests that 3RH in children is well tolerated and has a protective efficacy of at least the 60% demonstrated in adult trials.
Acknowledgments
The authors would like to thank Mrs Elaine Williams, TB team clerk, for her help in tracing GP registrations of the individuals in the study.
References
Footnotes
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Competing interests None.
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Ethics approval Ethics approval not required (Cumbria and Lancashire Ethics Board 2006).
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Provenance and peer review Not commissioned; externally peer reviewed.