تعليقRecommendation 6.
People aged 12 years or older with drug-susceptible pulmonary TB, may receive a 4-month regimen of isoniazid, rifapentine, moxifloxacin and pyrazinamide⁸ (conditional recommendation, moderate certainty of evidence) - new recommendation.
Source of recommendation
This recommendation was developed following the advice of the GDG convened in April 2021 to review data from a randomized controlled trial that assessed the safety and effectiveness of 4-month regimens for the treatment of DS-TB.
Justification and evidence
Since 2010, the WHO guidelines have recommended treating persons with DS-TB with a 6-month regimen composed of four first line TB medicines - isoniazid, rifampicin, ethambutol and pyrazinamide - where rifampicin is used for 6 months (2HRZE/4HR)[4]. This regimen is based on seminal TB treatment studies conducted by the British Medical Research Council in the 1980s [5] and has been widely adopted worldwide. Using it, approximately 85% of patients will have a successful treatment outcome [1]. Despite its familiarity, safety and efficacy, many patients find the 6-month regimen difficult to complete due to its length. In fact, long treatment regimens present serious challenges both to patients and to the programmatic management of TB globally.
Since the discovery of first-line anti-TB medicines and treatment regimens, there has been a search for shorter and more effective treatments for TB disease. This has resulted in various trials and other studies designed to assess whether treatment can be shortened, while remaining highly effective. Three phase III trials (i.e. REMoxTB, OFLOTUB, RIFAQUIN) failed to demonstrate non-inferiority of shorter regimens to treat DS-TB [13, 14, 26]. A recent phase III trial (TBTC study 31/ACTG A5349, or S31/A5349, referred to below as "Study 31") assessed the safety and efficacy of two 4-month regimens for the treatment of DS-TB [27]. Study 31was the first and only phase III trial to demonstrate the non-inferiority of the 4-month regimen for treatment of DS-TB when compared to the standard of care. The dedicated Cochrane review⁹ in 2019 and the literature search for the period 2019-2021 performed prior to the GDG failed to identify any studies other than Study 31; therefore this was the only trial to provide evidence for this GDG review.
Study 31 was an international, multicentre, randomized, open-label, controlled, three-arm non-inferiority trial among adolescents and adults (aged 12 years and above) with smear-positive¹⁰ and culture-positive pulmonary DS-TB [27]. Study participants were recruited from 13 countries. The study objectives were to evaluate the efficacy of: 1) a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampicin makes it possible to reduce the duration of treatment for drug-susceptible pulmonary TB to four months; and 2) a rifapentine-containing regimen that additionally substitutes moxifloxacin for ethambutol and continues moxifloxacin throughout treatment, to determine whether the duration of treatment can be reduced, compared with the currently recommended 6-month regimen using a non-inferiority margin of 6.6 percentage points [27].
The rifapentine-moxifloxacin arm was the only arm to demonstrate non-inferiority when compared to the standard of care (the WHO recommended regimen of six months of treatment with rifampicin, isoniazid, pyrazinamide and ethambutol) and thus the regimen was the one reviewed by the GDG. This regimen consisted of eight weeks of daily isoniazid (H), rifapentine (P), moxifloxacin (M) and pyrazinamide (Z) , followed by nine weeks of daily isoniazid, rifapentine, and moxifloxacin (2HPMZ/2HPM). The dose of rifapentine used was 1200 mg daily. The primary efficacy end point of Study 31 was TB disease-free survival at 12 months after randomization, while the primary safety end point was the proportion of participants with grade 3 or higher adverse events during the study drug treatment.
In the trial, a total of 2 516 patients from 34 sites (in Brazil, China, Haiti, India, Kenya, Malawi, Peru, South Africa, Thailand, Uganda, USA, Viet Nam and Zimbabwe) were randomly assigned to a treatment group. The microbiologically eligible population¹¹ included 791 patients with TB in the rifapentine-moxifloxacin arm and 768 in the standard of care control arm. The GDG accepted the outcomes used by the Study 31 for analysis, using the microbiologically eligible population as defined by the study to minimize bias, and using the safety analysis population (as defined by the study protocol) for the review of all-cause mortality and adverse events. The proportion of patients who were cured¹² was similar in both arms (84.5% in the rifapentine-moxifloxacin arm versus 85.4% for the standard of care, relative risk (RR) 0.99, 95% CI: 0.95-1.03). Retention on treatment was high for both arms, namely: 99.7% for the rifapentine-moxifloxacin arm and 99.0% for the standard of care arm (RR: 1.01, 95% CI: 1.00-1.02). All-cause mortality recorded within 14 days after the end of treatment was reported for 0.4% of patients in the rifapentine-moxifloxacin arm versus 0.8% in the standard of care (RR 0.42, 95% CI: 0.11-1.61); and grade 3 or higher adverse events were noted in 18.8% of participants in the rifapentine-moxifloxacin arm versus 19.3% in the standard of care arm (RR 0.97, 95% CI: 0.76-1.24). There were no statistically significant differences in the proportion of patients who were cured when comparing the rifapentine-moxifloxacin arm to the standard of care arm for all four subgroups that were analysed (persons living with HIV infection; persons with extensive disease, based on extent of disease on chest radiography, persons with diabetes mellitus; and persons with a low body weight, less than 17.9 kg/m3). There was little or no difference in all-cause mortality and adverse events during treatment - a slight increase in retention on treatment was noted in the rifapentine-moxifloxacin arm (RR 1.01, 95% CI: 1-1.02) and the evidence was uncertain with regard to acquisition of drug resistance.
The GDG judged that the benefits of a shorter, 4-month regimen that is as effective as the currently recommended 6-month regimen would justify the introduction of the shorter regimen as an option for treating patients with DS-TB.
Certain contextual issues were discussed that resulted in a conditional recommendation, rather than a strong one. These included:
Resources: The costs related to the use of this regimen are currently high and further research is needed on resource implications (e.g. patient and health system savings) and cost-effectiveness of the 4-month regimen. In all, 90% of the cost of medicines for the 2HPMZ/2HPM regimen comes from the rifapentine component.
Equity: Shorter-term and longer-term equity considerations were raised by GDG members. The GDG considered that in the short term, issues such as access to rifapentine, the costs of rifapentine and increased pill burden (due to the lack of fixed-dose combinations for the 4-month regimen and the fact that rifapentine was dosed at 1200 mg) may decrease equity. However, in the longer term as costs reduce and access to rifapentine (including 300 mg tablets) increases, the shorter regimen is considered likely to increase equity for patients who will have a shorter period of time engaged with the health system, potentially reducing costs associated with TB treatment, and who would be able to return to work sooner.
Acceptability and feasibility: Although patients and health-care workers may prefer a regimen of shorter duration, GDG members were concerned at the pill burden relative to the standard 6-month regimen and the potential need for fluoroquinolone DST in some settings with a high background prevalence of fluoroquinolone resistance.
Subgroup considerations
Subgroup analyses were conducted for four patient groups in order to inform the GDG discussions. The subgroup analyses presented to the GDG included people living with HIV infection, people with diabetes mellitus, people with a low body weight (body mass index < 17.9 kg/m2) and people with extensive disease (using a cut-off of >50% lung area affected) on chest radiography. The reported risk differences for these subpopulations indicated no statistically significant differences when comparing the shorter regimen to the current standard of care; however, in some subgroups the overall numbers were small in both intervention and control groups (persons with HIV and those with diabetes mellitus).
Additional pharmacokinetic analyses being undertaken by the trial investigators will be available in the future and may provide more nuanced information on drug exposures in these groups. Other subgroup analyses that were part of the trial included analyses by age group, sex, presence of cavities on chest radiography, cavity size, WHO sputum smear grade, smoking history, Xpert Ct value and Mycobacterial Growth Indicator Tube liquid culture automated system TTP (days).
Subgroups included in the recommendation
The panel suggested that the shorter regimen can be used in the subgroups for which evidence was available for review (people living with HIV infection, persons with diabetes mellitus, those with a low body weight and those with extensive disease). However, the panel also emphasized that additional research on the use of the shorter regimen in these subgroups is desirable.
People living with HIV infection: The proportion of patients living with HIV infection in the intervention and control regimen arms was 8% and only patients with CD4 count above 100 cells/mm³ were enrolled. Of all the persons with HIV who participated in the trial (in all three arms), 95.4% were receiving antiretroviral treatment (ART). HIV-positive persons not on ART at enrollment, had planned initiation of efavirenz-based ART before or at study week 8. Persons with HIV were excluded from enrollment in the trial if, at the time of enrollment, their CD4-T cell count was known to be <100 cells/mm³. Overall, there were nine patients who were not on ART throughout the trial follow-up in the microbiologically-eligible analysis population (4.6%); the reasons for non-initiation of ART were not clear.
People with diabetes mellitus: Additional information from pharmacokinetic analyses will be available for this population in the future which may provide more nuanced evidence on the use of the intervention and control regimens in persons with diabetes mellitus.
People with extensive TB disease: The trial reported on the presence of cavitation on chest radiograph (CXR),the extent of disease on CXR as a percentage, and cavity size (absent, < or > = 4cm).
For patients with less severe and minimal forms of TB, such as lymph node TB there was limited or no evidence on the use of the shorter regimen. However, GDG members felt that the use of the shorter regimen could be considered because favourable outcomes were reported using the shorter regimen in patients with extensive disease.
Subgroups excluded from the recommendation
However, there were also subgroups for which there was no evidence (as they were not eligible for inclusion in the trial) and therefore the use of the shorter regimen outside the research environment is not indicated in these populations. These groups include:
- people weighing less than 40 kg;
- people with certain forms of extra-pulmonary TB (such as TB meningitis, disseminated TB, osteoarticular TB, abdominal TB);
- persons living with HIV infection with a CD4 count less than 100 cells/mm³ (NB: The trial did not include persons living with HIV infection if they had a CD4 count of less than 100 cells/mm³ and the GDG panel expressed concerns at an increased risk of relapse in this group (also because this group is at a higher risk of disseminated TB);
- children less than 12 years of age (NB: The trial aimed to recruit people aged 12 years and above. The youngest participant was 13 years of age. Therefore, no children were included in the trial. In the microbiologically-eligible population, there were 70 and 56 participants who were under 20 years of age in the rifapentine-moxifloxacin and control arms respectively); and
- pregnant, breastfeeding and postpartum women (NB: Pregnant or breast-feeding women were excluded from the study because of uncertainties about the safety of rifapentine, moxifloxacin, and pyrazinamide in these groups. Women who became pregnant while receiving study regimens were deregistered from the study and were treated according to national TB programme or local guidelines. The women continued to receive scheduled study follow-up, were classified as being on a non-study regimen, and did not receive study radiographs. Women who became pregnant while on study follow-up (but not on study treatment) continued to receive scheduled study follow-up and did not receive study radiographs. In all cases - i.e. whether pregnant during treatment or during follow up - the outcome of the pregnancy was reported on study forms).
Implementation considerations
A number of implementation considerations were discussed by the GDG. These included the following:
Drug susceptibility testing: The panel agreed that national TB programmes should strive for universal DST. The panel also acknowledged that universal DST is not always available but rapid DST for key medicines, including rifampicin, isoniazid and the fluoroquinolones is available and is expanding at an accelerated pace. Rapid genotypic testing for TB and rifampicin resistance is recommended by WHO as an initial test for TB and, if the same sputum sample can be tested for drug susceptibility for the fluoroquinolones and isoniazid, this can facilitate assignment of the most effective regimen. This would clearly have implications in terms of logistics, laboratory workload and cost. Balancing the desired situation of having the universal DST with reality, the panel considered that although desirable, baseline DST for fluoroquinolones would not be essential when patients with TB receive a WHO-recommended rapid molecular diagnostic test to detect rifampicin resistance. Fluoroquinolone resistance in new patients with DS-TB can reach up to 15% [1], although it is significantly lower in most settings [28-32]. In countries with high prevalence of resistance to fluoroquinolones in new patients DST for the fluoroquinolones would be highly recommended at baseline.
Directly observed treatment: Patients in the trial received daily treatment that was directly observed at least five days per week. However, this may not be possible in programmatic settings. Directly observed treatment may be important in view of the pill burden and the lack of a fixed-dose combination formulation, and also as a measure to prevent potential amplification of drug resistance. Current WHO recommendations support the use of directly observed treatment and also other forms of patient support and, overall, even though this regimen is a 4-month one and shorter than the current standard of care, patient support remains an important element of TB programming.
Pill burden: At present, the overall pill burden will be higher for patients who will receive this 4-month regimen¹³ because no fixed dose combination tablet exists for the regimen and the dose of rifapentine is high (1200 mg). This may affect acceptability by patients currently, however this situation may change in future as uptake of this regimen improves, creating a demand for the regimen and its component medicines. Wider availability of rifapentine formulation of 300 mg¹⁴ may decrease the pill burden and facilitate the implementation of this new regimen until the FDC tablet becomes available.
Cost of medicines: The current cost of the shorter regimen is substantially¹⁵ higher than the standard of care, mainly due to the inclusion of rifapentine. Again, this situation may change in future as uptake of the regimen improves, creating a demand for the regimen and for the medicines in it.
Administration of the shorter regimen with food may present a challenge in some settings. In the trial, a flat dose of 1200 mg of rifapentine was dosed daily, with food. This was based on: 1) demonstration of the safety of rifapentine at 1200 mg in phase I and phase II trials; 2) demonstration that body weight does not significantly affect rifapentine clearance; 3) recognition of an effect of food in increasing rifapentine absorption [33]; and 4) modelling predictions that the target rifapentine exposure (area under the curve [AUC] of approximately 500-600 mcg*h/L) is achievable using this strategy - see the supplementary appendix to reference 13).
As described in the trial's statistical analysis plan, pharmacokinetic/pharmacodynamic modelling predicted that a rifapentine dose of 1200 mg without food would yield an AUC approximately the same as that of a rifapentine dose of 900 mg with a very high fat meal. Since the target rifapentine AUC lies somewhere between that achieved with a very high fat meal and a rifapentine dose of 900-1200 mg, the strategy proposed was a rifapentine dose of 1200 mg with a modest food requirement. The rationale was that a very high fat meal may not be feasible under trial or routine TB care conditions, whereas dosing with food may be feasible.
Training of health-care workers was another implementation consideration that the panel discussed. Training will be necessary when introducing the 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 initial training investments.
Another implementation consideration discussed by the GDG concerned the choice of regimen to treat DS-TB. The GDG considered that, when choosing between the shorter 4-month regimen or the 6-month regimen, clinicians should consider eligibility criteria for the regimen and patient preference as well as local factors such as the availability of rifapentine.
Monitoring and evaluation
The current guidance on monitoring the response to DS-TB treatment stays the same. The panel did not recommend baseline electrocardiogram (ECG) monitoring for those receiving the shorter regimen (unless clinically indicated), and laboratory monitoring such as liver function tests would remain the same for both regimens. Some countries may have different requirements for liver function monitoring due to the "black box" warnings for moxifloxacin and these should be followed according to the country's policies.
Recommendation 7.
In children and adolescents between 3 months and 16 years of age with non-severe TB (without suspicion or evidence of MDR/RR-TB), a 4-month treatment regimen (2HRZ(E)/2HR) should be used (strong recommendation, moderate certainty of evidence) - new recommendation.
Remarks:
- Non-severe TB is defined as: 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;
- Children and adolescents who do not meet the criteria for non-severe TB should receive the standard six-month treatment regimen (2HRZE/4HR), or recommended treatment regimens for severe forms of extrapulmonary TB.
- The use of ethambutol in the first two months of treatment is recommended in settings with a high prevalence of HIV¹⁶, or of isoniazid resistance¹⁷.
Source of recommendation
This recommendation has been developed following advice from the Guidelines Development Group convened by the WHO Global Tuberculosis Programme in May-June 2021 on the topic of the management of TB in children and adolescents. The recommendation is also featured in the consolidated guidelines module on management of tuberculosis in children and adolescents.
Justification and evidence
The majority of children with TB have less severe forms of the disease than adults. Treatment regimens that are shorter than those for adults may be effective in treating children with TB, however solid evidence to substantiate this has been lacking to date. Shorter treatment regimens can result in lower costs to families and health services, potentially less toxicity, lower risks of drug-drug interactions in children living with HIV, and fewer problems with adherence. Shorter, safe and effective treatment regimens for children with both drug-susceptible and DR-TB benefit children with TB and their families and are a key intervention to achieve the WHO's End TB Strategy targets, as well as targets related to children set during the UNGA HLM on TB in 2018. New evidence from a recently completed trial on the shortened treatment of drug-susceptible TB in children and adolescents has paved the way for new recommendations on shorter regimens for this group.
The SHINE trial (Shorter Treatment for Minimal Tuberculosis in Children) was the first and only large phase three trial to evaluate the duration of TB treatment in children with non-severe drug-susceptible TB. Therefore, evidence from the trial rather than a systematic review, was used to answer this PICO question [34]. The SHINE trial was a multi-centre, open-label, parallel-group, non-inferiority, randomized, controlled, two-arm trial comparing four-month (16 weeks) versus the standard six-month (24 weeks) treatment durations in children under 16 years of age with symptomatic non-severe TB. Children and young adolescents aged below 16 years were treated with rifampicin, isoniazid, pyrazinamide with or without ethambutol using WHO recommended doses, appropriate for paediatric dosing [35].
PICO question: In children and adolescents with non-severe TB, should a four-month intervention regimen versus the standard six-month regimen conforming to WHO guidelines be used?
Evidence: In the SHINE trial, the primary efficacy outcome was a composite of treatment failure (including an extension of treatment beyond the replacement of missed doses, TB treatment drug changes or restarts due to suspected treatment failure), on-treatment loss-to-follow-up, TB recurrence or death by 72 weeks (from randomization), excluding children not reaching 16 weeks follow-up (modified-intention-to-treat). The non-inferiority margin for the primary efficacy outcome was 6%. The primary safety outcome was grade 3-5 adverse events recorded while on TB treatment.
The SHINE trial definition of non-severe TB was: peripheral lymph node TB or respiratory TB (including uncomplicated intrathoracic lymph node disease) confined to one lobe without cavities, no significant airway obstruction, uncomplicated pleural effusion, and no miliary TB.
The SHINE trial inclusion criteria were: children and young adolescents aged <16 years; weight >3 kg; no known drug-resistance; symptomatic but non-severe TB; smear negative on gastric aspirate or other respiratory sample (an Xpert MTB/RIF positive, rifampicin susceptible result was allowed);¹⁸ clinician's decision to treat with a standard first-line regimen; not treated for TB in the previous two years; known HIV status (positive or negative). Trial exclusion criteria were: respiratory sample acid fast bacilli smear-positive (a smear-positive peripheral lymph node sample was allowed); premature birth (<37 weeks) and aged under three months; miliary TB, spinal TB, TBM, osteoarticular TB, abdominal TB, congenital TB; pre-existing, non-tuberculous disease likely to prejudice the response to, or assessment of, treatment (such as liver or kidney disease, peripheral neuropathy or cavitation); any known contraindication to taking TB drugs; known contact with a drug-resistant adult source case (including mono-resistant TB); known drug-resistance in the child; being severely ill; pregnancy.
A total of 1204 children were enrolled in the trial between July 2016 and July 2018. The median age of enrolled children was 3.5 years (range: 2 months - 15 years), 52% were male, 11% had HIV-infection, and 14% had bacteriologically confirmed TB. Retention in the trial by 72 weeks and adherence¹⁹ to allocated TB treatment were 95% and 94%, respectively. Sixteen (2.8%) versus 18 (3.1%) children reached the primary efficacy outcome (treatment failure) in the 16- versus 24-week arms respectively, with an unadjusted difference of -0.3% (95% CI: -2.3, 1.6). Treatment success was reported in 97.1% of participants receiving the 16-week regimen versus 96.9% in those receiving the 24-week regimen (relative risk (RR): 1.00, 95% CI: 0.98-1.02). Non-inferiority of the 16-week regimen was consistent across all intention-to-treat, per-protocol and key secondary analyses. This included restricting the analysis to the 958 (80%) children that were independently adjudicated to have TB at baseline by the trial Endpoint Review Committee. A total of 7.8% of children experienced a grade 3-5 adverse event in the 16-week arm, versus 8.0% in the 24-week arm (RR: 0.98, 95% CI: 0.67-1.44). There were 115 on-treatment grade >3 adverse events in 95 (8%) children, 47 (8%) in the 16-week and 48 (8%) in the 24-week arm, most common being pneumonia or other chest infections (29 (25%)) or liver-related events (11 (10%)) across both arms. There were 17 grade 3 or 4 adverse reactions (considered possibly, probably or definitely) related to trial drugs, including 11 hepatic events; all adverse reactions except three occurred in the first eight weeks of treatment.
GDG considerations: The GDG judged that while the desirable effects related to this PICO question are related to treatment outcomes, shortening the duration of treatment is also important and desirable (as reducing the length of treatment could make treatment easier for children and caregivers as well as reduce cost for families and the health system). The GDG discussed that since the SHINE trial was a non-inferiority trial, no difference in unfavourable outcomes between the two arms is what the trial aimed to detect. Therefore, both desirable and undesirable effects were judged by most GDG members as trivial. Since non-inferiority of the 4-month regimen was demonstrated in the trial, the balance of effects was judged to not favour either the shorter or the longer duration of treatment. However, the GDG noted that treatment duration is a critical issue which was further considered in the context of issues such as cost, acceptability and feasibility.
The GDG also discussed that presumably, a shorter duration of treatment will reduce costs to both the health care system and to children with TB and their families. The GDG ultimately agreed on 'moderate savings' despite the varying views of the level of these savings. The GDG judged that equity was probably increased with a shorter duration of treatment. Despite no direct evidence on acceptability, the GDG judged that the shorter regimen was acceptable to stakeholders.
In addition, the GDG felt that, in the absence of exposure to DR-TB, access to CXR would help distinguish between non-severe and severe disease. However, the panel recognized that access to CXR is often limited or quality of CXR and capacity for interpretation is insufficient at lower levels of the health care system, which may have equity implications. Therefore, feasibility was judged to vary by setting. The GDG noted that it is critically important to clearly define "non-severe" disease and that NTPs be encouraged to scale up access to quality CXR and train health care providers in its interpretation. Overall, the GDG judged that if the severity of TB disease in children can be adequately determined under programmatic conditions, then implementation of a four-month regimen is highly feasible.
Subgroup considerations
Children with peripheral lymph node TB: Although the number 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 non-inferior compared to 24 weeks of treatment among 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 to clinicians regarding a seemingly delayed clinical response to TB treatment, frequently seen in children with peripheral lymph node TB (where lymph nodes remain enlarged even after treatment).
Children and adolescents living with HIV infection (CALHIV): CALHIV were eligible for enrolment in the SHINE trial; 65 (11%) CALHIV were enrolled in the 16-week arm and 62 (10%) in the 24-week arm. 49% of CALHIV in the 16-week arm and 43% in the 24-week arm were on antiretroviral treatment at the time of enrolment. 20% of CALHIV in both arms had a CD4 count of less than 200 cells per mm³. 51% of CALHIV in the 16-week arm and 63% in the 24-week arm were classified as severe as per the WHO immunological classification for established HIV infection [36]. In this subgroup, the 16-week regimen was non-inferior as compared to the 24-week regimen as well, although the 95% confidence interval for the difference in the unfavourable rate compared to the control arm was wide (risk difference -4.3, 95% CI -14.9 to 6.2).
In view of the limited evidence, clinicians may consider treating CALHIV with non-severe TB for four months, depending on the degree of immunosuppression and ART status, as well as the presence of other opportunistic infections. These children and adolescents will need to be monitored closely, especially at four months of treatment, and treatment extended to 6 months if there is insufficient progress.
Children with severe acute malnutrition (SAM): In the SHINE trial, SAM was defined as weight-for-height Z-score (WHZ) <-3 or MUAC <115 mm [37]. Thirty children with SAM (5%) were included in the 16-week arm and 33 (5%) in the 24-week arm. No separate sub-group analysis was therefore conducted for children with SAM. In view of the insufficient evidence on this subgroup, and as SAM is defined as a danger sign, children with SAM and non-severe TB should preferably receive 6 months of TB treatment.
Infants <3 months of age and/or weighing < 3kg: Infants <3 months of age and infants weighing <3 kg (including premature birth (<37 weeks) were not eligible for inclusion in the SHINE trial. No new data on the treatment of congenital TB and very young infants (aged 0-3 months) with TB disease was received following a call for data. Therefore, infants aged 0-3 months with suspected or confirmed PTB or tuberculous peripheral lymphadenitis should be promptly treated with the six-month treatment regimen (2HRZ(E)/4HR), as per the existing recommendation from the 2014 Guidance for national tuberculosis programmes on the management of tuberculosis in children [19]. Treatment may require dose adjustment to reconcile the effect of age and possible toxicity in young infants. The decision to adjust doses should be taken by a clinician experienced in the management of paediatric TB.
Children treated for TB in the past two years: Given the increased risk of treatment failure and of drug resistance, children and adolescents treated in the preceding two years were not eligible for inclusion in the SHINE trial; they should be treated with the six-month treatment regimen (2HRZ(E)/4HR).
Implementation considerations
Assessing severity of disease: The feasibility of assessing the severity of TB disease, particularly in settings without access to CXR or capacity for CXR interpretation and WHO-recommended diagnostic tests was identified as a major implementation consideration. Chest radiography was identified by the GDG as a critical tool to evaluate the severity of intrathoracic disease. As indicated under the recommendation remarks, non-severe intrathoracic or PTB disease refers to: 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. Extensive or advanced disease in children under 15 years of age is usually defined by the presence of cavities or bilateral disease on CXR [38]. NTPs are encouraged to scale up access to quality CXR and provide training to health care providers in its interpretation. Out-of-pocket expenses for CXR pose a potential barrier to TB diagnosis and access to shorter regimen for eligible children and young adolescents. In the SHINE trial, children who were Xpert MTB/RIF positive, but sputum smear-negative were eligible for inclusion. The 85 children (7%) who were Xpert MTB/RIF positive (45 in the four-month arm and 40 in the six-month arm), had very low or low semi-quantitative Xpert MTB/RIF results.
Detailed implementation guidance is provided in the Operational handbook on the management of tuberculosis in children and adolescents, taking into consideration differences in the health care system and country context, including the availability of diagnostic tools to make a diagnosis and to assess disease severity. While access to CXR is an important implementation consideration, it should not be a barrier for children and adolescents in lower resourced settings to benefit from the shorter regimen. The implementation guidance in the operational handbook comprises 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. Children with Xpert MTB/RIF or Ultra results that are trace, very low or low, who meet radiographical or clinical criteria for non-severe TB, can be treated with the four-month regimen.
Continuum between TB infection and disease: An additional implementation consideration is the concept that a continuum exists between TB infection, non-severe and more severe forms of TB disease in children. Shorter treatment regimens for drug-susceptible TB are now very similar to recently recommended shorter regimens for the treatment of TB infection, in terms of duration and composition, in particular the regimen that consists of three months of daily isoniazid and rifampicin (3HR) [39]. This implies that incorrectly diagnosing a child who has TB infection as having non-severe TB disease may not have severe consequences.
Contact investigation: Another implementation consideration is the scale up contact investigation approaches, which can improve early case detection of children with non-severe disease who may benefit from the 4-month regimen.
Use of ethambutol in the intensive phase of treatment: Children and young adolescents with non-severe TB who live in settings with low HIV prevalence or a low prevalence of isoniazid resistance and those who are HIV negative can be treated with a three-drug regimen (HRZ) for two months, followed by two months of HR. Children and young adolescents with non-severe TB who are living in settings where the prevalence of HIV is high²⁰ and/or the prevalence of isoniazid resistance is high²¹ should be treated with HRZE for two months followed by HR for two months. In the SHINE trial, ethambutol was used in line with these recommendations as per national guidelines and all CALHIV received ethambutol as part of their treatment. For the six-month regimen used to treat more severe forms of TB, it is recommended to add ethambutol to the regimen (i.e. 4HRZE/2HR).
Child-friendly formulations: NTPs are encouraged to prioritize the use of child-friendly fixed dose combination (FDC) formulations for TB treatment in children up to 25 kg body weight, such as: the 3-FDC HRZ 50/75/150 mg with or without the addition of dispersible ethambutol, and the 2-FDC HR 50/75 mg (available from the Stop TB Partnership's Global Drug Facility (GDF)). Capacity building of health care workers at all levels of the health system on diagnostic approaches (including treatment decision algorithms), eligibility for the four-month regimen and monitoring of children on first-line TB treatment will also be critical factors in the successful implementation of the shorter regimen.
Treatment of severe pulmonary TB in children and young adolescents: Children and young adolescents with forms of PTB that do not meet the eligibility criteria for the four-month regimen should be treated with a standard six-month regimen that includes a fourth drug (ethambutol) in the intensive phase (such as 2HRZE/4HR).
Treatment options for adolescents from 12 years of age: Another implementation consideration is that adolescents aged 12 years and above with TB can benefit from the four-month regimen that consists of isoniazid, rifapentine, moxifloxacin and pyrazinamide (HPMZ), which is now conditionally recommended by WHO (see Recommendation 6 in the current document). Adolescents aged between 12 and 16 years therefore have three options for treatment: the four-month HPMZ regimen, the four-month 2HRZ(E)/2HR regimen, and the standard six-month 2HRZ(E)/4HR regimen. Adolescents from 16 years of age were not included in the SHINE trial and therefore have two options: the four-month HPMZ regimen and the standard six-month 2HRZE/4HR regimen.
Choosing an appropriate regimen for this age group will depend on clinical factors (such as the presence of severe disease or if living with HIV, ART status and CD4 count) as well as contextual factors (including the availability of the HPMZ regimen in the country).
Monitoring and evaluation
The clinical monitoring requirements for the shorter regimen remain the same as for the six-month regimen and treatment outcomes are determined at the end of the four-month regimen.
Should there be insufficient clinical improvement after completion of the four-month regimen, the clinician may decide to extend treatment to six months while considering alternative diagnoses, including DR-TB.
Monitoring for potential relapse is a priority for shorter regimens especially when they are introduced into programmatic settings. Therefore, follow-up of children and young adolescents for up to 12 months after completion of the four-month regimen is important.
⁸ Two months of isoniazid, rifapentine, moxifloxacin, and pyrazinamide, followed by two months of isoniazid, rifapentine, and moxifloxacin
⁹ Grace AG, Mittal A, Jain S, Tripathy JP, Satyanarayana S, Tharyan P at al. Shortened treatment regimens versus the standard regimen for drug-sensitive pulmonary tuberculosis. Cochrane Database Syst Rev. 2019;(12):CD012918. doi: 10.1002/14651858.CD012918.pub2
¹⁰ Smear positive for acid-fast bacilli on smear microscopy or smear positive for M. tuberculosis by GeneXpert MTB/RIF® (“Xpert”, Cepheid Inc., Sunnyvale, CA) testing with semi-quantitative result of “medium” or “high”.
¹¹ The microbiologically eligible population excludes persons with resistance to the medicines used for treatment; those with no baseline positive TB culture and others that were not eligible to participate in the trial. The choice of a microbiologically eligible population for the analyses minimizes the chance of underestimating the effect of the rifapentine-moxifloxacin in view of the non-inferiority trial design.
¹² The outcome, named ‘cure’ or ‘favorable’ outcome in the Study 31, was chosen as it was prioritized by the GDG. The definition of the favorable outcome is detailed in the Study 31 protocol and the Evidence-to Decisions tables for this GDG review.
¹³ Based on estimates by the Global Drug Facility for an average weight of 55–70 kg: 1358 tablets versus 728 for whole course of treatment.
¹⁴ Rifapentine 150mg and 300mg are both included in the WHO Model list of essential medicines: 22nd list (2021). See: https://apps.who.int/iris/bitstream/handle/10665/345533/WHO-MHP-HPS-EML-2021.02-eng.pdf (accessed 28 February 2021).
¹⁵ Approximately 5 times (US$ 225–233 versus US$ 343), based on current estimates using weighted average prices of the Global Drug Facility.
16 Defined as countries, subnational administrative units, or selected facilities, where the HIV prevalence among adult pregnant women is ≥1% or among TB patients is ≥5% in the Guidance for national tuberculosis programmes on the management of tuberculosis in children (second edition) 2014.
17 WHO does not intend to establish thresholds for low, moderate or high levels of prevalence of isoniazid resistance: NTPs will establish definitions for their own countries
18 In the SHINE trial, children with Xpert MTB/RIF results had very low or low semi-quantitative results, or a negative result. Xpert Ultra was not used in the SHINE trial.
19 In the SHINE trial, adherence was defined as the proportion of children who received an adequate amount of treatment (as defined in the statistical analysis plan for both the intervention and control regimens; generally, a cut off of 80% of the allocated doses was used, within a certain time frame of starting each phase of treatment (i.e. intensive phase versus continuation phase)
20 This level of resistance was defined as countries, subnational administrative units, or selected facilities, where the HIV prevalence among adult pregnant women is ≥1% or among TB patients is ≥5% in the Guidance for national tuberculosis programmes on the management of tuberculosis in children (second edition) 2014.
21 WHO does not intend to establish thresholds for low, moderate or high levels of prevalence of isoniazid resistance; instead NTPs will establish definitions for their own countries