WHO policy recommendations

Implementation considerations

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Case scenarios: The implementation of these recommendations requires that the (H)REZ-Lfx regimen is administered only in patients in whom resistance to isoniazid is confirmed and resistance to rifampicin has been excluded. Preferably, testing for resistance to fluoroquinolones, and if possible to pyrazinamide, is also done ahead of start of treatment. It is envisaged that the Hr-TB treatment regimen would apply in the following situations:

• Hr-TB is confirmed before TB treatment is started: treatment with the (H)REZ-Lfx is started immediately. If the diagnosis is strongly presumed (e.g. close contacts of a confirmed Hr-TB source case) but results of drug susceptibility testing are still pending the regimen may be introduced. Should drug susceptibility test results taken at start eventually show susceptibility to isoniazid, then levofloxacin is stopped and the patient continues treatment in order to complete a 2HREZ/4HR regimen.
• Hr-TB is confirmed after the start of treatment with 2HREZ/4HR regimen: This includes patients who had undiagnosed isoniazid resistance at the start or who developed isoniazid resistance later while on first-line regimen treatment. In such cases, rapid molecular testing for rifampicin resistance must be done (or repeated). Once rifampicin resistance is excluded, a full 6-month course of (H)REZ-Lfx is given. The duration is driven by the need to give levofloxacin for 6 months, which usually implies that the companion first-line medicines are taken for longer than this.

If rifampicin resistance is detected, the patient needs to be started on a recommended MDR-TB treatment regimen (4).

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Diagnostic capabilities: The overall aim of TB treatment is to achieve cure without relapse in all patients, interrupting M. tuberculosis transmission and preventing the acquisition (or amplification) of additional drug resistance. Globally, Hr-TB is more prevalent than MDR-TB. Efforts need to be made by all countries to move towards universal testing of both isoniazid and rifampicin at the start of TB treatment and to ensure the careful selection of patients eligible for the (H)RZE-Lfx regimen.¹⁴ The minimum diagnostic capacity to appropriately implement these recommendations requires rapid molecular rifampicin testing prior to the start of treatment with the Hr-TB regimen, and preferably, that fluoroquinolone resistance is ruled-out by WHO-recommended tests. Rapid molecular tests such as Xpert MTB/RIF and line probe assays (LPA) are preferred to guide patient selection for the (H)RZE-Lfx regimen.

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DR-TB surveillance indicates that fluoroquinolone resistance among patients with rifampicinsusceptible TB is generally low worldwide (20); however national data on the prevalence of fluoroquinolone resistance - including targeted or whole genome sequencing to detect specific mutations associated with resistance to fluoroquinolones (21) - could help guide testing policies when the Hr-TB treatment recommendations are implemented in countries.

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When additional resistance (e.g. to both fluoroquinolones and pyrazinamide) is suspected or confirmed, treatment regimens may have to be designed individually with other second-line TB medicines. The current review could not provide further evidence on effective regimens in patients with poly-resistant disease.

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Support and close monitoring of patients are needed in order to maximise treatment adherence and enable early detection of patients who are not responding to treatment (e.g. those with persistent sputum culture or smear positivity). Repeat DST to rifampicin and the fluoroquinolones, preferably with Xpert MTB/RIF or LPA, is indicated in the presence of nonresponse. Documented acquisition of resistance to rifampicin or a fluoroquinolone while on the Hr-TB regimen should alert the clinician to reviewing the entire clinical and microbiological status of the patient and change the regimen accordingly.

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Levofloxacin is proposed as the fluoroquinolone of first choice in the Hr-TB regimen for a number of reasons. Firstly, this medicine has a better-characterized safety profile compared to other fluoroquinolones and was the one most frequently used in the studies reviewed for this guidance. Secondly, levofloxacin has fewer known drug interactions with other medications as compared to moxifloxacin. For example, while plasma peak concentration and exposure to moxifloxacin decrease significantly when combined with rifampicin, (22) the same effect has not been reported for levofloxacin, attributed to the property of levofloxacin to undergo limited metabolism in humans and to be excreted unchanged in the urine (23). Additionally, although it may interfere with lamivudine clearance, unlike moxifloxacin there are no contraindications for its use with other antiretroviral agents (24).

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The addition of levofloxacin to (H)REZ is recommended in patients with Hr-TB, with the exception of the following:

(i)

in cases where resistance to rifampicin cannot be excluded (i.e. unknown susceptibility to rifampicin; indeterminate/error results on Xpert MTB/RIF);

(ii)

known or suspected resistance to levofloxacin;

(iii)

known intolerance to fluoroquinolones;

(iv)

known or suspected risk for prolonged QT-interval;¹⁵

(v)

if possible in pregnancy or during breastfeeding (not an absolute contraindication).

When the confirmation of isoniazid resistance arrives late (e.g. 5 months into a 2HRZE/4HR regimen), a decision to start 6 months of (H)REZ-Lfx at that point depends upon the patient’s clinical condition and microbiological status.

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If levofloxacin cannot be used because of toxicity or resistance, the patient may be given 6(H)REZ as an alternative. Based on the results of the evidence review conducted in preparation of these guidelines, it is not advised to replace levofloxacin with an injectable agent. The evidence review could not inform on the effect of other second-line TB medicines on treatment effectiveness.

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Addition of isoniazid: There was no clear evidence showing that the addition of isoniazid adds benefit or harms to patients. For patient convenience and ease of administration, the 4-drug HREZ FDCs¹⁶ may be used to deliver the Hr-TB regimen alongside levofloxacin.

Although the use of high-dose isoniazid (10-15mg/kg/day) was not evaluated in this review due to insufficiency of data, the GDG discussed the effect of increasing isoniazid dosing beyond that which is provided in weight-banded FDCs, depending on the type of molecular mutations identified. In vitro evidence seems to suggest that when specific inhA mutations are detected (and in the absence of any katG mutations), increasing the dose of isoniazid is likely to be effective; thus, additional isoniazid to a maximum dose of up to 15mg/kg per day could be considered. In the case of katG mutations, which more commonly confer higher-level resistance, the use of isoniazid even at higher-dose is less likely to be effective¹⁷. WHO plans to systematically review evidence related to phenotypic DST correlated with genotypic mutations associated with isoniazid resistance in late 2018 (25).

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Dosage: Although the IPD analysis did not provide evidence to address the frequency of dosing, intermittent or divided dosing of the 6(H)REZ-Lfx regimen is to be avoided (26, 27). In the absence of full information about optimal drug doses, a weight-band dosing scheme for levofloxacin is recommended.¹⁸

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Drug-drug interactions: levofloxacin may potentially interfere with lamivudine clearance (increasing levels of lamivudine), but is not contraindicated with other antiretroviral agents and no drug dosing adjustments are needed (24). Co-administration of levofloxacin with oral divalent cation-containing compounds (such as antacids) may impair its absorption and should be avoided (7). Restriction of concomitant use of milk products is not necessary.

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Treatment prolongation beyond 6 months: may be considered for patients with extensive cavitary disease or in patients slow to convert to negative smear/culture. In the latter, acquisition of additional resistance to rifampicin must be ruled-out, as well as resistance to fluoroquinolones and pyrazinamide if possible. Such patients require careful monitoring and follow-up.

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Cost: Cost-effectiveness analysis was not performed for this review. Table 4 presents approximate prices for a full course of medicines for the different regimens in adults based on the cost of products available from the Global Drug Facility(28). Use of FDCs, even for part of the regimen, reduces costs. Medicines needed for a 6HREZ-Lfx treatment cost about three times as much as a 2HREZ/4HR when using the HREZ FDC. The impact of treating Hr-TB according to these guidelines is not expected to increase operational costs significantly.

Table 4

Illustrative costs of regimens used to treat Hr-TB compared to the 6-month first-line TB regimen (price of medicines alone).

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Adherence: Although the IPD analysis contained limited data on treatment adherence strategies used (i.e. directly observed therapy, DOT; self-administered therapy), improved treatment success rates appeared to be associated with increased patient support, including medication adherence support (for example, by means of digital technologies) or other means as recommended by WHO (26). In contrast to regimens for drug-susceptible and MDR-TB, the recommended Hr-TB treatment regimen does not have an intensive and a continuation phase, which simplifies the delivery and monitoring of treatment.

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Monitoring and evaluation: Patients who receive the (H)REZ-Lfx regimen need to be monitored during treatment using schedules of clinical and laboratory testing. The definitions to use when assigning outcomes are the same ones in use for drug-susceptible TB (29). Signs of non-response or treatment failure should be followed up with DST to rifampicin and, if possible, to fluoroquinolones and pyrazinamide. In order to limit the risk of acquisition of additional resistance, the addition of single TB medicines should be avoided in patients who remain smear- or culture-positive after month 2 of treatment, who do not show a favourable clinical response and in those without recent DST results.

As with any other TB medicine and regimen, safety precautions to ensure the rapid identification and proper management of any serious adverse event (SAE) are required. Close clinical monitoring is essential for all patients receiving this regimen, particularly, liver function tests, given the hepatotoxic potential of prolonged pyrazinamide use. If possible, all patients should be tested each month for aspartate aminotransferase levels (AST or SGOT). If resources are not available to monitor all patients on the Hr-TB regimen, monthly monitoring of patients at high risk, such as patients co-infected with viral hepatitis or with a history of heavy alcohol use, is strongly advised. Additionally, in order to prevent and manage the potential toxic effects of ethambutol in children (e.g. retrobulbar neuritis), it is necessary to adhere to correct doses recommended for paediatric populations. Early signs of ethambutol toxicity can be tested in older children through red-green colour discrimination. Monitoring for retrobulbar neuritis can be sought early when appropriate (30).

Subgroup considerations

Children: In the IPD review, only 2% of Hr-TB patients were children, and therefore a separate estimate of effect for paediatric patients was not possible. However, there is no reason why the results and recommendations cannot be extrapolated from adults to children, considering that the regimen components have been standard paediatric TB medicines for many years.

Patients with extensive disease: Although the IPD analysis did not provide evidence for duration of treatment extension, the prolongation of the 6(H)REZ-Lfx to more than six months could be considered on an individual basis for patients with extensive disease, as determined by cavitary disease and persistence of bacteriologically positive sputum at or after month 3 (by culture or microscopy) (31). Prolongation of treatment may increase the risk of adverse events in some cases (See “Monitoring and Evaluation” above).

HIV-positive individuals: The effect of longer TB treatment duration among HIV-positive patients with and without antiretroviral therapy (ART) has been studied among patients with drug-susceptible TB (32). In these cases, relapse has been reported to be 2.4 times higher in HIV-infected patients who were not on ART and who received 6 months of treatment as compared to patients in whom treatment was prolonged up to nine months. In patients with drug-susceptible TB initiated on ART, no significant beneficial effect from prolonging rifampicin-containing regimens for over 6 months has been observed (26). In the current analysis, only a limited number of patients received ART; nonetheless, in TB patients with HIV co-infection, the first priority is to ensure that they are started on ART within 8 weeks of TB treatment initiation (regardless of CD4 count), in accordance with WHO guidelines (33). The 6-month (H)REZ-Lfx regimen is therefore recommended in HIV-positive patients.

Extrapulmonary disease: No data were available for patients with exclusive extrapulmonary Hr-TB. The regimen composition proposed is likely to be effective even in these patients. However, the treatment of patients with extrapulmonary TB should be designed in close consultation with appropriate specialists, such as infectious disease physicians and neurologists, to decide upon individual variations in treatment duration and supportive care as needed.

Justification

Treatment with rifampicin, ethambutol and pyrazinamide - with or without isoniazid - has been used in the last few years for the treatment of patients with Hr-TB (34-36). The evidence reviewed for this guideline compared treatment regimens with (H)REZ of different durations, i.e. six-month regimens versus longer duration. Additionally, the evidence review focused on determining whether treatment outcomes of Hr-TB patients receiving (H)REZ treatment regimens of variable duration could be improved with the addition of a fluoroquinolone or with the addition of streptomycin.

The evidence used to determine the composition and duration of regimens relied primarily on an IPD analysis, comprising 33 databases with an analysable population of 5418 Hr-TB patients (See also “Methods” above). All data used to develop these recommendations derived from observational studies conducted in various settings (26% in Asia; 33% in Europe; 31% in the Americas; and 6% in Africa) (Annex 4).¹⁹ Patient regimens analysed in the IPD contained rifampicin, ethambutol, pyrazinamide, streptomycin, isoniazid and fluoroquinolones. Thus, recommendations could only be made for regimens containing these anti-TB agents.

Duration of (H)REZ: The analysis comparing (H)REZ for 6- and >6-month treatment demonstrated that a 6-month (H)REZ regimen had a higher likelihood of treatment success compared with a regimen of >6 months. Further analyses determined that there was no statistically significant difference in treatment outcomes of patients receiving 6REZ and those receiving >6REZ regimens. Since data on intermittent dosing of the 6 months and >6 months (H)REZ regimens were not included, no inferences could be drawn about the use of alternating dosing versus daily regimens. The effect of length of pyrazinamide use in the (H)REZ regimen was assessed to investigate whether the use of this medicine could be minimised to the shortest possible duration. The reduction in treatment with pyrazinamide to less than 3 months was associated with worse treatment success, even with the addition of streptomycin (aOR, 0.4; 95%CI 0.2-0.7). In 118 patients on fluoroquinolone-containing regimens who received pyrazinamide for less than 4 months the odds of treatment success was higher than in those who received 6(H)REZ, although the difference was not statistically significant.

Duration of levofloxacin use: in a subsample of 241 patients on (H)REZ plus fluoroquinolones regimen, the median duration of fluoroquinolone use was 6.1 months (IQR 3.5; 8.4) and for REZ, it was 9.0 months (IQR 7; 11). It therefore appears that treatment length was premised upon the completion of 6 months of a fluoroquinolone in the observational studies that informed the IPD.

Acquisition of drug resistance: the analysis suggested that amplification of resistance to rifampicin was lower in patients receiving the 6(H)REZ regimen (0.6%) compared with those receiving >6(H)REZ (4.3%); this observation could be due to the effect of the selection and allocation of patients into specific regimens – for instance, the number of patients with extensive disease (cavities, bilateral disease of persistent smear positivity) was slightly higher in patients receiving longer regimens (>6(H)REZ); however, overall, the number of observations for each comparison were small and the effect was not statistically significant (aOR, 0.2; 95%CI 0.02-1.70).

Adverse events: Data on adverse events were not evaluated because of lack of standardization (dissimilar reporting). The GDG also considered two reports containing data from patients from the United States in whom a detailed assessment on adverse events indicated that there seemed to be a risk of excess hepatotoxicity with the 6(H)REZ combination (37). Drug-induced hepatotoxicity is not uncommon with anti-TB drugs. It has also been reported in persons receiving rifampicin and pyrazinamide during two months for LTBI treatment. In such individuals, a much higher occurrence of hepatotoxicity has been observed compared to persons receiving only isoniazid preventive therapy (38). It is unknown whether the risk of hepatotoxicity is different between 6REZ and 6HREZ.

Addition of a fluoroquinolone: In patients with Hr-TB, treatment success rates were higher when fluoroquinolones were added to (H)REZ regimens as compared to patients treated with six or more months of (H)REZ without the addition of fluoroquinolones (aOR, 2.8; 95%CI 1.1-7.3). With the addition of fluoroquinolones in patients receiving (H)REZ, the number of deaths was reduced (aOR, 0.4; 95%CI 0.2-1.1). Amplification to MDR-TB was also reduced when fluoroquinolones were added to a ≥6(H)REZ regimen (aOR, 0.10; 95%CI 0.01-1.2), albeit that absolute numbers were small with 0.5% (1/221) of patients on ≥6(H)REZ plus fluoroquinolones acquiring resistance to rifampicin versus 3.8% (44/1160) of patients who did not receive fluoroquinolones. Residual confounding could have increased this observed effect. The directness of the evidence was therefore downgraded as it was unclear whether fluoroquinolones were used at the beginning of treatment or only once DST results were available (in the second month or later).

Addition of streptomycin: the analysis showed that the addition of streptomycin (up to 3 months) to a HREZ regimen with <4 months of pyrazinamide decreased the likelihood of treatment success (aOR, 0.4; 95%CI 0.2-0.7), an effect that may in part be due to confounding. Addition of streptomycin did not reduce mortality significantly (see also Online Annexes 5 & 6). There were no data on the use of other injectable agents (i.e. kanamycin, amikacin, capreomycin) for treatment of Hr-TB.

Treatment outcomes: When analysing the overall treatment outcomes for each one of the regimens assessed for this review, other limitations, related to the characteristics of patients included in these studies, were evident and could not be controlled for (namely, patient selection, allocation to treatment with specific regimens and their relationship with disease severity). Outcomes of patients with cavitary disease, persistence of sputum smear positivity and past history of TB treatment who received ≥6(H)RE with an additional three months of pyrazinamide and one to three months of streptomycin appeared to result in worse outcomes when patients received this regimen (see Online Annex 5, GRADE table 5-3); however, the limited number of observations made it difficult to draw definitive conclusions based on severity of TB disease or the effect of other comorbidities on this regimen.

In formulating the recommendations, the GDG assessed the overall balance between benefits and harms of (H)REZ-Lfx regimen, as well as values and preferences, paying special attention to considerations of equity, acceptability and feasibility in addition to clinical outcomes and the potential risks of increasing toxicities (See Online Annexes 5 & 6 for more details). The conclusions of the GDG were that a regimen composed of 6 months of REZ plus fluoroquinolones was associated with higher treatment success rates (with or without the addition of isoniazid). The difference between 6(H)REZ and longer >6(H)REZ duration was modest, slightly favouring the 6-month regimen (not statistically significant). The GDG acknowledged that it was not possible to control for all possible confounding by indication when comparing the 6 months (H)REZ to the longer (H)REZ duration; as an example, though data on the extent of disease were not systematically captured for all patients, it is possible that a higher number of cases with extensive disease received >6(H)REZ regimens, resulting in poor outcomes for this group of patients (given the extent of disease) and possibly favouring the 6-month regimen.

The GDG acknowledged the safety implications of (H)REZ-Lfx, particularly for hepatotoxicity associated with prolonged use of pyrazinamide-containing multidrug regimens. However, reducing the duration of the treatment with pyrazinamide to three months or less was associated with worse treatment outcomes, at least in Hr-TB regimens without a fluoroquinolone. Furthermore, the use of streptomycin in these regimens was associated with no significant added benefit. The use of streptomycin and other injectable agents has also been associated with increased SAE (39-41). On this basis, the GDG agreed that current data supported the use of the (H)REZ-Lfx regimen without streptomycin or any other injectable agent in Hr-TB cases, unless there is a compelling reasons to do so (e.g. certain forms of polydrug resistance).

The GDG also noted that patients were likely to place a high value on a six-month regimen, the likelihood of relapse-free successful outcome, and especially, the implementation of a regimen without the use of injectable agents.. GDG members agreed that the use of the 6(H)REZ regimen would probably increase health equity given that the cost of the regimen components is relatively low (compared to recommended regimens for MDR/RR-TB) as well as the increased probability of cure in a substantial number of patients. In addition, potential barriers for regimen administration are curtailed with the exclusion of streptomycin and other injectable agents.

Although patient costs were not factored in during the analysis, the GDG agreed that improving diagnostic capacity to detect isoniazid resistance would be beneficial. According to a modelling analysis performed for the WHO guidelines for the programmatic management of drug-resistant tuberculosis (2011 update), performing DST in all patients before treatment using a rapid test that detects resistance to isoniazid and rifampicin was the best strategy for averting deaths and preventing acquired MDR-TB (42). The modelling work showed that rapid testing of both isoniazid and rifampicin at the time of diagnosis was the most cost-effective testing strategy for any patient group or setting, even at very low levels of resistance among TB patients (MDR- TB in >1% and isoniazid resistance (other than MDR-TB) in >2%).

In general, the GDG considered that the use of 6(H)REZ-Lfx regimen would be feasible in most DR-TB treatment settings. In addition, the use of a regimen based on medicines that are fully administered orally may increase feasibility. Altogether, based on present evidence, when discussing the balance between benefits and harms, preferences and values for patients and for other end-users, the GDG reached overall agreement on the beneficial effect that the Hr-TB regimen may have, should the regimen be used in conformity with these policy recommendations.

Research priorities

The development of the current recommendations was made possible by the availability of a global, Hr-TB, individual patient dataset. As in other IPD analyses conducted to inform WHO treatment guidelines in recent years, the Hr-TB IPD analysis facilitated the comparison of different patient groups, some adjustment for covariates and better interpretation of the results (43). It is important for researchers and national programmes to continue contributing patient records to the Hr-TB IPD to increase its value as a source of information for future treatment policy.

It should be noted that all recommendations were conditional and were based on very low certainty in the estimates of effect. Thus, further research is needed to inform the refinement of policies to optimize treatment of Hr-TB. The GDG identified a various research priorities, including:

• The need for randomized trials evaluating the efficacy, safety and tolerability of regimens for Hr-TB, and for cases with additional resistance to other medicines such as ethambutol or pyrazinamide (e.g. polydrug resistance);
• Research to clarify the potential benefits and risks of treatment with high-dose isoniazid;
• High-quality studies on the optimization of the regimen composition (e.g. reducing duration of pyrazinamide) and duration in children and adults, particularly the role of high-dose isoniazid, fluoroquinolones, and other second-line medicines;
• Modelling studies measuring the number-needed-to-treat for empirical use of an Hr-TB regimen, balancing risk to benefit;
• High-quality studies on treatment prolongation among HIV-positive individuals;
• High-quality studies evaluating regimens in which especial emphasis is placed on extrapulmonary or disseminated TB;
• Feasibility of developing FDCs for REZ alone (with or without integrating levofloxacin);
• Monitoring of patient response, by isoniazid resistance genotype (e.g. katG vs. inhA mutations), either in an individual-patient or distribution of genotypes in a population;
• Cost-effectiveness of different approaches to DST, including the rapid testing of all TB patients for both isoniazid and rifampicin resistance before start of treatment;
• Participatory action research within communities and other stakeholders (e.g. field practitioners, community workers) to explore and implement socio-cultural factors that can facilitate treatment adherence and influence outcomes;
• Effect of underlying fluoroquinolones/isoniazid polydrug resistance on treatment outcomes;
• Diagnostic accuracy of second-line line probe assays in rifampicin-sensitive patients.

Publication, dissemination, implementation, evalution and expiry

The recommendations contained in this policy guideline are published as a supplement to the 2016 WHO treatment guidelines for DR-TB (4), and made accessible on the WHO website (http://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/en/). “Frequently asked questions on the WHO treatment guidelines for isoniazid-resistant tuberculosis” are being released concurrently with the guidelines on the same website. The changes to the policy guideline will also be reflected in the Compendium of WHO guidelines and associated standards: ensuring optimum delivery of the cascade of care for patients with tuberculosis (44) and, in a forthcoming, revision of the Companion Handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis (7). The evidence reviews on Hr-TB as well as the specific recommendations for its management will be published in peer-reviewed journals and shared with key TB stakeholders and partners through various list serves to improve dissemination of the main messages.

WHO will work closely with its Regional and Country Offices, as well as with technical and funding agencies and partners, to ensure wide dissemination and translation of these recommendations through technical meetings and training activities. Implementation and impact of these guidelines will be assessed and monitored through the annual WHO Global TB Surveillance & Monitoring System as well as through technical assistance missions and National TB Programme Reviews.

WHO/GTB will review and update these policy recommendations within 4-5 years after their release, or earlier if new evidence becomes available.