Remarks

1. The recommendation also applies to extrapulmonary TB – except TB of the central nervous system, bone or joint, for which some expert groups suggest longer therapy.
2. WHO recommends that national TB control programmes (NTPs) provide supervision and support for all TB patients, to ensure completion of the full course of therapy.
3. WHO recommends drug-resistance surveys (or surveillance) for monitoring the impact of the treatment programme, and for designing standard regimens.

Source of recommendation

This recommendation was first put forward in 2010 and was considered valid in the 2017 guidelines update (see summary of recommendations in Annex 1). The recommendation is copied without modification into this consolidated document and appears exactly as in the 2010 guidelines.

Justification and evidence

A systematic review and meta-analysis included 21 472 participants in 312 arms of 57 randomized controlled trials (RCTs) conducted in various regions of the world since 1965 (7). In three of the 57 trials, patients were randomly assigned to either a 2-month rifampicin or a 6-month rifampicin arm; rates of failure, relapse and acquired drug resistance were compared “head-to-head” across the two study arms. In a multivariate regression analysis, each arm of the 57 trials was treated as a separate cohort and results were adjusted for potentially confounding patient and treatment factors.

The three studies with head-to-head comparisons showed that the risk of relapse after a 6-month rifampicin regimen was significantly lower than that after a 2-month rifampicin regimen. If a country were to change from a 2-month to a 6-month rifampicin regimen, the benefit would be an estimated 112 relapses averted per 1000 TB patients.

Regression analysis suggests that changing to a 6-month regimen would significantly reduce failure and acquired drug resistance rates, in addition to relapse rates.¹ This analysis found that regimens with 5–7 months of rifampicin have 0.43 times the failure rate, and 0.32 times the relapse rate of regimens with 1–2 months of rifampicin. Among the failures and relapses from regimens with 5–7 months of rifampicin, the rate of acquired drug resistance is 0.28 times that of the regimens with 1–2 months of rifampicin.

Patients with isoniazid resistance would realize major benefits if the 2-month rifampicin regimen were replaced with a 6-month regimen. Among patients with isoniazid monoresistance at the start of treatment, 38% relapsed after treatment with 2-month rifampicin regimens, which is significantly higher than the 5.5% relapse rate after treatment with 6-month rifampicin regimens. Thus, changing to the 6-month rifampicin regimen would avert 325 relapses per 1000 patients who start treatment with isoniazid resistance.

Even for patients with pansusceptible TB, the proportion who relapsed after the 2-month rifampicin regimen was 8.2%, which was significantly higher than the 3.1% for the 6-month rifampicin regimen.

When the first course of therapy is considered along with retreatment for patients who fail or relapse, it is estimated that the 6-month rifampicin regimen would avert between 3 and 12 deaths per 1000 compared with the 2-month rifampicin regimen across seven countries modelled with a range of drug resistance among new patients. In addition, 0.6–4.4 failures and relapses with drug resistance other than MDR-TB would be averted per 1000 TB patients, but an additional 0.6–1.3 MDR-TB cases would be generated.

Among patients who failed or relapsed after their first course of treatment containing 6 months of rifampicin, regression analysis found a reduction in overall acquired drug resistance; however, the pattern of acquired drug resistance was different from that in patients who received the 2-month rifampicin regimen. The risk of acquiring drug resistance other than MDR-TB is higher with the 2-month rifampicin regimen, but the risk of acquiring MDR-TB is higher with the 6-month rifampicin regimen. Among failures, the proportion with MDR-TB is predicted to be 4–56% after initial treatment with the 2-month rifampicin regimen but 50–94% after initial treatment with the regimen containing 6 months of rifampicin.

Subgroup considerations

The interactions of rifampicin with antiretroviral therapy (ART) are of concern. Switching to the 6-month rifampicin regimen means that these drug interactions must be taken into account for the full 6 months rather than for just the first 2 months of therapy. However, the 6-month rifampicin regimen has marked benefits for persons living with HIV, and the drug interactions can be managed (8).

Implementation considerations

To help minimize the acquisition of MDR-TB, it is critically important that national TB control programmes ensure adequate supervision of rifampicin. Implementing patient supervision for the 4-month continuation phase will require additional resources in areas where the continuation phase has been self-administered – an investment that may be offset by the savings from relapses (and therefore retreatments) averted. In 2008, 23 countries (including four that are considered high-burden) still used the 2-month rifampicin regimen for their new patients. These countries reported 706 905 new cases in 2007, or 13% of the global new TB notifications that year.

Monitoring and evaluation

This recommendation places high value on saving lives. Given both the high certainty of evidence for this benefit and the fact that the potential harm of acquired DR-TB can be mitigated by supervision of treatment. Periodic drug resistance surveys (or ongoing surveillance) in each country are essential for monitoring the impact of the regimen and the overall treatment programme.

Source of recommendation

This recommendation was first put forward in 2010 and considered valid in the 2017 guidelines update (see summary of recommendations in Annex 1). The recommendation is copied without modification into this consolidated document and appears exactly as in the 2010 guidelines.

Justification and evidence

A systematic review and meta-analysis included 21 472 participants in 312 arms of 57 RCTs conducted in various regions of the world since 1965 (7). In a multivariate regression analysis, each arm of the 57 RCTs was treated as a separate cohort, and results were adjusted for potentially confounding patient and treatment factors. Only one study of 223 patients evaluated a rifampicin-containing regimen administered twice weekly throughout therapy; this study was not included in the meta-analyses.

No significant increase in failure, relapse or acquired drug resistance was found when daily dosing throughout therapy was compared with the following intermittent regimens in new TB patients overall, namely: daily then thrice weekly; daily then twice weekly; or thrice weekly throughout therapy.

However, the regression analysis showed that patients being treated thrice weekly throughout therapy had rates of acquired drug resistance that were 3.3 times higher than those in patients who received daily drug administration throughout treatment.

The meta-analysis revealed no difference in rates of failure, relapse or acquired drug resistance in pan-susceptible new patients being treated with these dosing schedules. However, the use of a three times weekly intensive phase schedule in patients with pre-treatment isoniazid resistance was associated in another meta-analysis with a significantly higher risk of failure and acquired drug resistance (9).

Implementation considerations

When based in a health facility, daily administration of therapy places a larger burden on TB programmes and patients than does intermittent therapy. Intermittent regimens require stronger programmes with higher-quality patient supervision, but all regimens should be provided with full patient supervision and support.

Studies of patients’ preferences for dosing schedules were not systematically reviewed. The higher isoniazid dose used in intermittent therapy was not considered to have an increased incidence of adverse effects. The rifampicin dosage was unchanged when using intermittent therapy.

In an international, multicentre, randomized trial (Union Study A), Jindani, Nunn & Enarson found thrice weekly dosing resulted in significantly lower culture conversion rates at 2 months (10). In developing recommendations, this endpoint was ranked by the GDG as important but not critical for decision-making and was not part of the systematic review.

For new patients without HIV infection, high- certainty of evidence demonstrated no significant difference between regimens that were administered daily throughout treatment, daily initially and then intermittently in the continuation phase, or thrice weekly throughout treatment.

Daily dosing is optimal because it probably achieves better adherence under programme conditions. While the definition of the term varies across countries, “daily” is considered to mean at least five times per week. In addition, meta-analyses showed the superiority of daily (compared with thrice weekly) intensive-phase dosing for patients with pre-treatment isoniazid resistance and for preventing acquired drug resistance in patients overall.

Source of recommendation

This recommendation was first put forward in 2010 and then updated in the 2017 guidelines (see summary of recommendations in Annex 1). It is copied without modification into this consolidated document and appears exactly as in the 2010 guidelines.

Justification and evidence

The use of intermittent dosing of TB medications has been adopted in some geographical settings in an effort to improve treatment adherence and to reduce the burden on the health-care system due to daily treatment support. However, it was unclear how this intermittent dosing might affect treatment outcomes. In addition to the evidence from a systematic review conducted in 2009 of treatment regimens with intermittent dosing schedules (7), this systematic review was updated with the most recent RCTs (11–17).

Evidence showed that when thrice-weekly dosing throughout therapy was compared to daily dosing throughout therapy, patients who received thrice-weekly dosing had a higher risk of treatment failure, disease relapse and acquired drug resistance in both drug-susceptible disease and when the strain susceptibility was unknown. Consequently, thrice-weekly dosing in the intensive phase should never be used.

Likewise, when thrice-weekly dosing during the continuation phase only is compared to daily dosing throughout, there were higher rates of treatment failure and relapse in the patients that received thrice-weekly treatment during the continuation phase. In this case, acquired drug resistance rates did not differ. If thrice-weekly dosing during the continuation phase is used, it is essential to make sure that patients do not miss any dose of the medications and that treatment support is used.

In this review, the use of twice-weekly dosing in the continuation phase only was also reviewed. Twice-weekly dosing in the continuation phase only had higher rates of treatment failure, disease relapse and drug resistance than thrice-weekly dosing in the continuation phase only. As a result, twice-weekly dosing should never be used during any part of TB therapy.

Adherence to treatment was not adequately addressed in the reviewed studies to be included as an outcome. However, in most studies included in the systematic review, intermittent dosing used treatment support, while the use of treatment support during daily dosing was variable.

The GDG also considered that health equity would be adversely affected with intermittent dosing because more vulnerable populations would receive inferior treatment if intermittent dosing were used. This is because people living in more resource-constrained settings would be at greater risk of missing doses of medication, not only because of their difficulty in reaching a clinic but also because of the risk of medication stock-outs in clinics. Additionally, patients who are co-infected with HIV or have other comorbidities may not absorb TB medications well and therefore they may receive less medication than they are ingesting. In order for TB medication to be used as part of a treatment regimen, no doses may be missed with thrice-weekly intermittent dosing during the continuation phase because the rates of unfavourable outcomes may rise. Consequently, populations that are more vulnerable are at risk of missing doses of medication or of not absorbing the doses well, and intermittent dosing puts them in a situation where there is an increased risk of unfavourable outcomes.

Intermittent dosing may also create problems at national and international levels by resulting in requirements for different drug manufacturing and packaging and a reduced drug supply buffer, leading to an increased risk of TB medication stock-outs.

Given the findings in this review, all countries are encouraged to use daily dosing exclusively in both the intensive and the continuation phases of treatment. Although two separate evidence assessments were conducted on thrice-weekly dosing in the intensive phase and the continuation phase, both the formulated recommendations were conditional and there was very low certainty in the evidence. A combined recommendation for both intensive and continuation phases was formulated to make it more convenient for use by the end-users.

Subgroup considerations

This recommendation is the same for HIV-negative people and for people living with HIV.

The data used in this review examined only patients with drug-susceptible pulmonary TB who had no extenuating circumstances – such as adverse reactions which might require modification of the dosing schedule.

Children were not considered specifically in this review. However, there is no biologically plausible reason why this recommendation should not also apply to children. It is recommended that all children receive daily dosing of TB medications during the intensive and continuation phases of therapy for the same reason as adults. See WHO’s 2014 guideline Guidance for national tuberculosis programmes on the management of tuberculosis in children (18) for recommendations on the daily dosing of children with DS-TB.

Implementation considerations

There are no new implementation considerations as the recommended daily treatment is already widespread practice. However, intermittent dosing is still used in some countries. In such exceptional cases, implementation of the recommendation to use exclusively daily dosing in the intensive and continuation phases of TB therapy is likely to have implications for medication procurement, practitioner training, change of programme practice and patient support.

Monitoring and evaluation

There are no new monitoring and evaluation recommendations as the standard of care (daily dosing of medications during the intensive and continuation phases of therapy) is being recommended.

Source of recommendation

This recommendation was first put forward in the 2017 guidelines update (see summary of recommendations in Annex 1). It is copied without modification into this consolidated document and appears exactly as in the 2017 guidelines.

Justification and evidence

The evidence presented to the GDG was based on a systematic review of randomized controlled trials done by Albanna et al. (19) and by a recent Cochrane review (20). This evidence showed that the fixed-dose combination (FDC) tablets are non-inferior and equally effective as separate drug formulations in terms of treatment failure, death, treatment adherence and adverse events. There was a small increase in 2-month culture conversion with FDC treatment; however, there was no difference in culture conversion rates by the end of treatment. Patient satisfaction was higher among persons treated with FDCs. A slightly higher rate of disease relapse and acquired drug resistance among patients treated with FDCs compared with those treated with separate drug formulations was not statistically significant.

Patient treatment satisfaction with FDCs was considered the most important factor for making decisions on this recommendation.

Studies in these reviews did not evaluate bioavailability of the drugs in the FDCs, but previous studies did not indicate that the FDC formulations used had significant bioavailability issues (19). As no pharmacokinetic studies were done on these FDC formulations, the bioavailability of drugs within the FDCs versus the separate drug formulations remains an important consideration that indicates the need to procure FDCs of demonstrated bioavailability (21–23). This area requires further research.

FDCs may provide programme benefits by making the ordering of medication easier, simplifying supply chain management, reducing the occurrence of stock-outs, and facilitating drug delivery and prescription preparation. FDCs may also provide benefits – especially in settings with a large number of TB patients and a limited number of health-care workers – by reducing the need for additional health-care staff and training in the dosing and dispensing of medications, as well as by contributing to a lower pill burden for patients. Nevertheless, national TB programmes are advised to have a quantity of separate drug formulations available for certain treatment conditions. Having single drug formulations available would be beneficial to national TB programmes when designing MDR-TB regimens that include some first-line drugs (i.e. pyrazinamide, EMB, high-dose isoniazid), when providing preventive therapy, and in cases of adverse reactions to TB medications when drugs must be reintroduced one at a time.

The GDG acknowledged that greater patient satisfaction is an advantage of FDCs over separate drug formulations.

Subgroup considerations

The reduced pill burden as a result of using FDCs may be especially valuable in patients with co-morbidities (notably HIV infection) and paediatric patients (who may have some difficulty in swallowing large amounts of medications).

Patients with some specific medical conditions (e.g. intolerance to certain TB drugs, liver or renal function impairment) are likely to require individual medication dose adjustment which can be done only with separate drug formulations.

Implementation considerations

There are no specific implementation considerations as the use of FDC formulations is already widespread.

Monitoring and evaluation

There are no specific new recommendations for monitoring and evaluation as the use of both types of drug formulation is already widespread.

Source of recommendation

This recommendation was first put forward in 2010 and considered valid in the 2017 guidelines update (see summary of recommendations in Annex 1). It is copied without modification into this consolidated document and appears exactly as in the 2010 guidelines.

Justification and evidence

The systematic review identified only one relevant study (with results published in 2012). A study still under way (at moment of review) in Bangladesh of a 6-month rifampicin-containing regimen randomized 3775 new smear-positive patients who remained positive at 2 months to either the 1-month extension arm (extension of the intensive phase by 1 month) or the no-extension arm (24).

Preliminary results at 1 year of follow-up showed that patients in the 1-month extension arm had a significantly lower relapse rate (relative risk 0.37, 95% confidence interval [CI]: 0.21, 0.66) than patients in the no-extension arm. A smaller decrease in failure in the 1-month extension arm was not statistically significant. Given the preliminary nature of the results and the passive follow-up of patients, the evidence from the Bangladesh study was graded with moderate certainty.

In 1000 TB patients with a 7% risk of relapse, the Bangladesh study predicts that extending the treatment of 183 patients who are smear-positive at 2 months would avert 16 of the 70 expected relapses. However, to achieve this 23% reduction in relapses, 158 patients per 1000 would be incorrectly predicted to relapse; consequently their treatment would be extended unnecessarily.

While extending rifampicin beyond 6 months reduces the risk of relapse, there is insufficient evidence to determine which patients are most likely to benefit. Historically, when the new patient regimen included only 2 months of rifampicin, the extension of the intensive phase meant an extra month of supervised rifampicin. This extra month is less important now as the current recommended regimen is 6 months of supervised rifampicin. Given these considerations, together with preliminary results from one moderate-certainty study that showed only modest benefit, a conditional recommendation was made not to extend treatment on the basis of a positive smear at 2 months.

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) (2). This regimen is based on seminal TB treatment studies conducted by the British Medical Research Council in the 1980s (3) and has been widely adopted worldwide. Using it, approximately 85% of patients will have a successful treatment outcome (25). 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 (12, 13, 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 31 was 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 review (28) 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-positive³ 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 (2PHZM/2PHM). 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 population⁴ 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 cured⁵ 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).

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% (25), although it is significantly lower in most settings (29–33). 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 regimen⁶ 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 mg⁷ 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 substantially⁸ 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 (34); 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 (12)).

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.

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 (35). 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 (36).

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);¹¹ 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 adherence¹² 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 (37). 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 (38). 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 (18). 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. CXR 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 (39). 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) (40). 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 high¹³ and/or the prevalence of isoniazid resistance is high¹⁴ 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 2.1 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.

Source of recommendation

This recommendation was first put forward in 2010 and considered valid in the guidelines update of 2017 (see summary of recommendations in Annex 1). The recommendation is copied without modification into this consolidated document and appears exactly as in the 2010 guidelines.

Justification and evidence

A systematic review and meta-analysis of 6 randomized controlled trials and 21 cohort studies provided pooled estimates of failure, relapse and death by duration of rifampicin, and daily intensive phase versus intermittent throughout (41). The systematic review revealed a marked and significant reduction in failure and relapse in the arms where some or all patients received ART. In a regression model, treatment failure or relapse was 1.8–2.5 times more likely with intermittent rather than daily dosing in the intensive phase. Compared with 8 or more months of rifampicin, 2-month rifampicin regimens carried a 3-fold higher risk of relapse and 6-month regimens carried a 2.2 -fold higher risk. Extending treatment beyond 6 months is recommended by some expert groups in certain persons living with HIV and the meta-analysis showed that this is associated with significantly lower relapse rates. However, several other considerations were given greater weight. Separate regimens for TB patients living with or without HIV would be very challenging in operational terms and could create stigma. Other potential harms of extending treatment are acquired resistance to rifampicin, and a longer period during which ART options are limited (because of ART–rifampicin interactions).

Source of recommendation

This recommendation is from WHO’s Consolidated guidelines on HIV infection, testing, treatment, service delivery and monitoring: recommendations for a public health approach (42). The background and history of this recommendation is provided below, while the detailed rationale and supporting evidence can be found in the source document.

The recommendation applies to both children and adults but the strength of the recommendation and certainty of the evidence differ for each group because of the difference in the available data for the reviews. One specific exception that is highlighted in this recommendation relates to situations in which signs and symptoms of meningitis are present. Caution is needed regarding people who are living with HIV and who have TB meningitis because immediate ART is significantly associated with more severe adverse events. Thus, it might be a consideration to delay ART for 4–8 weeks after TB treatment is initiated in such situations.

The use of corticosteroids as adjuvant treatment for TB meningitis still applies in these situations.

Background

Since 2010, WHO has recommended that ART be started as soon as possible within eight weeks of initiating TB treatment (strong recommendation, high certainty of evidence) (43). In 2012, WHO added a recommendation to initiate ART within two weeks among those with a CD4 count less than or equal to 50 cells/mm³ (except for children for whom previous recommendations remained unchanged because of the lack of specific evidence) (11). In 2017, on the basis of a systematic review of evidence that earlier ART initiation resulted in reduced morbidity and mortality (44), WHO recommended offering rapid ART initiation within one week, and on the same day if ready, for all people diagnosed with HIV – including adults, adolescents and children (44) – with stated cautions for those with signs and symptoms of TB meningitis.

Source of recommendation

These recommendations were first put forward in the guidelines update of 2017 (see summary of recommendations in Annex 1). They are copied without modification into this consolidated document and appear exactly as in the 2017 guidelines.

Justification

In patients with tuberculous meningitis, evidence from randomized controlled trials in the systematic review (45–49) showed lower rates of mortality, death or severe disability, and disease relapse when patients were treated with steroids in addition to anti-TB treatment. The benefits in terms of mortality increased with the increasing TB meningitis stage (i.e. increasing severity of disease). Additionally, rates of adverse events and severe adverse events, including severe hepatitis, were lower in the patients receiving steroids.

In patients with tuberculous pericarditis, evidence from studies in the systematic review (50–56) showed a benefit to steroid treatment with regard to death, constrictive pericarditis and treatment adherence. When the studies were considered individually, the largest (1400 patients) and most recent study – the IMPI study (52) – showed no benefit with steroids. However, a complicating factor in these findings is HIV infection. In the IMPI study, 67% of subjects were HIV-positive and only 14% were on ART. This raises the question as to whether immunosuppressed patients may have had a different benefit from steroids when compared to HIV-negative people or persons living with HIV who are on ART. In the IMPI study, a supplemental analysis was done of the HIV-negative patients only and a small mortality benefit was shown with steroid treatment. However, the relationship between HIV infection and steroids is complex. In another smaller study of 58 subjects, all of whom were HIV-positive, steroids were found to reduce mortality (51). It is of note that the other studies in the review did not address HIV and mortality.

The panel considered that the benefit in preventing constrictive pericarditis outweighed the potential harms of corticosteroid therapy.

Subgroup considerations

Steroids should be given regardless of the severity of meningitis. With regard to the use of steroids in tuberculous pericarditis, in one study an increase in HIV-related cancers (non-Hodgkins’ lymphoma and Kaposi sarcoma) was observed (52). However, this increase appears to be caused by co-administration of immunotherapy (M. indicus pranii).

Implementation considerations

Practitioners should give oral steroids if intravenous formulations are not available.

Monitoring and evaluation

There are no additional recommendations beyond the standard of care.