RetourAs in adults, TB treatment in children and adolescents includes an intensive phase of 2 months followed by a continuation phase of 2–4 months. In the intensive phase, tubercle bacilli are rapidly killed to prevent disease progression and transmission, and the development of drug resistance. In the continuation phase, dormant bacilli are eliminated to effect cure and prevent relapse. The choice of TB treatment regimen depends on the severity of disease and age. The decision on whether to include a fourth medicine – ethambutol – in the intensive phase depends on the patient’s HIV status, or on the prevalence of HIV or isoniazid resistance in the setting. In children and adolescents aged between 3 months and 16 years with non-severe TB, a 4-month treatment course is recommended. This recommendation is based on the evidence from the SHINE trial, a large phase III trial to evaluate duration of TB treatment in children with non-severe drug-susceptible TB. The trial showed that a 4-month treatment regimen (2 months of isoniazid, rifampicin and pyrazinamide, with or without ethambutol, followed by 2 months of isoniazid and rifampicin, 2HRZ(E)/2HR) was non-inferior to the standard 6-month regimen (2 months of isoniazid, rifampicin and pyrazinamide, with or without ethambutol, followed by 4 months of isoniazid and rifampicin, 2HRZ(E)/4HR) (1, 30).
5.1 Eligibility
The eligibility criteria in children and adolescents are summarized in Box 5.1 (31).
5.2 Composition and duration of the regimen
The regimen evaluated by the SHINE trial comprised 2 months of daily isoniazid, rifampicin and pyrazinamide, with or without ethambutol (2HRZ(E)), followed by daily isoniazid and rifampicin (2HR).
In the SHINE trial, ethambutol was included in the first 2 months of treatment, depending on the local policy in place at the recruitment site, for both the 4-month regimen and the comparator 6-month regimen. All CHILDREN AND ADOLESCENTS LIVING WITH HIV in the SHINE trial received ethambutol in the first 2 months of treatment (regardless of which regimen they received). It is therefore preferred that children and adolescents living with HIV who receive the 4-month regimen receive ethambutol for the first 2 months of treatment, irrespective of the background prevalence of HIV. In addition, it is recommended that ethambutol be added to the 4-month regimen for the first 2 months in settings with a high background prevalence of isoniazid resistance or HIV infection. Also, for this regimen, daily dosing (i.e. 7 days per week), ideally under direct observation, is suggested, taking advantage of a treatment supporter or VST.
The doses are the same as those recommended for the 6-month regimen 2HRZE/4HR (Annex 4).
Treatment should be continued for 6 months or should be modified in children and adolescents who have not responded clinically (i.e. have not demonstrated weight gain or resolution of TB symptoms) after 4 months of treatment. These people should be evaluated carefully for DR-TB, non-TB-related disease (e.g. malignancy or HIV-related lung disease) and poor treatment adherence. The first 2 months of treatment, which includes three or four drugs, is usually enough for the strong bactericidal activity of this regimen to be effective. If the patients are sputum smear negative (or paucibacillary) and no cavities are present in CXR, then the presence of one or more sputum smear results that are positive after 2 months may indicate undetected resistance to one or more drugs. If the patient is not improving clinically and radiologically (e.g. cavities appear), and drug resistance or potential failure are suspected, rapid diagnostics to exclude this should be done promptly together with culture and DST, to provide a basis for any adjustment of the treatment strategy.
5.3 Considerations for implementation
Assessing severity of disease
Access to CXR is an important implementation consideration for assessing the severity of TB disease in children and young adolescents, and is useful in making a decision about the duration of treatment (1). At lower levels of the health care system, access to CXR is often limited or the quality of CXR and the capacity for interpretation may be suboptimal; this can have equity implications, because of the out-of-pocket expenses it might cause. Therefore, the feasibility of CXR varies by setting. It is important to clearly define “non-severe” disease, and NTPs are encouraged to scale up access to quality CXR and train health care providers in its interpretation. If the severity of TB disease in children can be adequately determined under programmatic conditions, then implementation of a 4-month regimen is highly feasible.
The feasibility of assessing the severity of TB disease is a major consideration for implementation, particularly in settings without access to CXR or the capacity for CXR interpretation, and in settings without access to WHO-recommended diagnostic tests. CXR is a critical tool for evaluation of the severity of intrathoracic disease. Extensive or advanced pulmonary TB disease in children aged under 15 years is usually defined by the presence of cavities or bilateral disease on CXR (17). As indicated above, non-severe TB disease refers to peripheral lymph node TB; intrathoracic lymph node TB without airway obstruction; uncomplicated TB pleural effusion; or paucibacillary, non-cavitary disease, confined to one lobe of the lungs, and without a miliary pattern.
Detailed implementation guidance is provided in the operational handbook on the management of TB in children and adolescents (31). The guidance takes into consideration differences in the health care system and country context, including the availability of diagnostic tools for making a diagnosis and assessing disease severity. This guidance includes criteria for assessing disease severity (including clinical criteria in the absence of CXR or rapid diagnostics or other bacteriological tests) to determine eligibility for the shorter regimen.
Continuum between TB infection and disease
The continuum between TB infection and TB disease is an important consideration for implementation. Implementation of the 4-month regimen for the treatment of non-severe TB narrows the differences between recently recommended regimens for TB preventive treatment (TPT) (32) and treatment of non-severe forms of TB disease in children. This is particularly relevant to the TPT regimen that uses 3 months of daily isoniazid and rifampicin (3HR).
Contact investigation
The scale-up of contact investigation approaches is another implementation consideration. The scale-up can improve early case detection of children with non-severe disease who may benefit from the 4-month regimen.
Child-friendly formulations
NTPs are encouraged to prioritize the use of child-friendly FDC formulations for TB treatment in children up to 25 kg body weight; for example, the 3-FDC HRZ 50/75/150 mg (with or without the addition of dispersible ethambutol) and the 2-FDC HR 50/75 mg (19).
Training of health care workers
Another critical factor in successful implementation of the shorter regimen is capacity-building of health care workers at all levels of the health system on diagnostic approaches (including treatment decision algorithms), eligibility for the 4-month regimen and monitoring of children on first-line TB treatment. Training will be necessary when introducing this shorter regimen into a programmatic setting. However, this is a requirement for any new programmatic intervention and the ability to shorten treatment and potentially treat more patients may offset the initial investment in training.
5.4 Subgroups
5.4.1 Subgroups in which the regimen is recommended
Children with peripheral lymph node TB
Although the numbers of children with peripheral lymph node TB in the SHINE trial were small (N=19 in the 16-week arm and N=21 in the 24-week arm), there was no difference in the proportion of unfavourable outcomes between the two arms. The SHINE trial also found that 16 weeks of treatment was not inferior to 24 weeks of treatment in children with both peripheral lymph node disease and pulmonary disease (N=182 in the 16-week arm and N=171 in the 24-week arm). These results may provide reassurance for clinicians regarding a seemingly delayed clinical response to TB treatment, which is frequently seen in children with peripheral lymph node TB (where lymph nodes remain enlarged even after treatment).
Children and adolescents living with HIV
Children and adolescents living with HIV were eligible for enrolment in the SHINE trial; 65 (11%) children and adolescents living with HIV were enrolled in the 16-week arm and 62 (10%) in the 24-week arm, with 49% of children and adolescents living with HIV in the 16-week arm and 43% in the 24-week arm being on ART at the time of enrolment. Among children and adolescents living with HIV, 20% in both arms had a CD4 count of less than 200 cells/mm3, and 51% of children and adolescents living with HIV in the 16-week arm and 63% in the 24-week arm were classified as “severe” according to the WHO immunological classification for established HIV infection (33). In this subgroup, the 16-week regimen was again not inferior to the 24-week regimen, although the 95% confidence interval (CI) for the difference from the control arm in the unfavourable rate was wide (risk difference –4.3, 95% CI: –14.9 to 6.2).
Clinicians may consider treating children and adolescents living with HIV with non-severe TB for 4 months, depending on the degree of immunosuppression, ART status and presence of other opportunistic infections (34). These children and adolescents will need to be monitored closely, especially at 4 months of treatment, and treatment will need to be extended to 6 months if there is insufficient progress.
5.4.2 Subgroups in which the regimen is not recommended
Children with severe acute malnutrition
No separate subgroup analysis could be conducted for children with severe acute malnutrition (SAM)¹⁰ in the SHINE trial owing to the low numbers (30 children with SAM in the 16-week arm and 33 in the 24-week arm). Because SAM is defined as a danger sign, even if children with SAM have a non-severe form of TB, they should preferably receive 6 months of TB treatment.
5.5 Treatment monitoring
All children and adolescents initiated on TB treatment should undergo a monitoring assessment at the following intervals as a minimum:
- HIV-negative children and adolescents – 2 weeks and 4 weeks after the start of treatment, at the end of the intensive phase (after 2 months) and at completion of treatment at 4 months; and
- Children and adolescents living with HIV – 2 weeks and 4 weeks after the start of treatment, then every month until completion of treatment at 4 months or 6 months (depending on the regimen used).
Clinical monitoring requirements for the shorter regimen are the same as for the 6-month regimen. Treatment outcomes are determined at the end of treatment; that is, at 4 months for the shorter regimen.
Monitoring should include the following as a minimum:
- assess for resolution or persistence of TB-related symptoms, symptoms of side-effects of medicines and other symptoms;
- measure weight and adjust dosages as necessary, depending on weight gain;
- assess adherence; that is, review the treatment card and discuss with the patient, carers and other treatment supporters; and
- collect follow-up sputum samples for smear microscopy 2 months after the start of treatment and at treatment completion from any child who was Xpert MTB/RIF positive, Xpert Ultra positive, smear positive or culture positive at diagnosis, if the treatment site has the capacity to perform the test.
Symptomatic improvement and weight gain are the most valuable markers of treatment success or failure (29). If a follow-up smear is positive, the patient should complete additional investigations to assess for drug resistance (Xpert MTB/RIF or Ultra, TB culture and DST or molecular tests for drug resistance) and other causes of poor treatment response. Possible causes of a poor response include (29):
- incorrect dosage;
- adherence being compromised by AEs; or
- the child or adolescent:
- not taking the drugs as prescribed or having poor gastrointestinal absorption of one or more of the drugs;
- living with HIV and having developed immune reconstitution inflammatory syndrome (IRIS) or having an opportunistic infection;
- being (severely) malnourished, and SAM not being managed appropriately; or
- having another comorbidity or illness.
In children who cannot expectorate, a repeat specimen at the end of treatment is not necessary if the specimen collected at 2 months is negative. Repeat sample collection at 2 months in children with unconfirmed TB is not indicated unless there is an inadequate clinical response without symptomatic and nutritional improvement. Follow-up CXR is not needed if the child is responding well to TB treatment. Children commonly have a slow radiographic response to treatment and may have persistent radiographic abnormalities at treatment completion (29), but this does not mean they are not responding to treatment.
10 Defined as weight-for-height Z-score below −3 or mid-upper-arm circumference below 115 mm (33).