Isoniazid (H) is one of the most important first-line medicines for the treatment of active tuberculosis (TB) and latent TB infection (LTBI), with high bactericidal activity and a good safety profile. The emergence of TB strains resistant to isoniazid threaten to reduce the effectiveness of TB treatment (1). About 8% of TB patients worldwide are estimated to have rifampicin-susceptible, isoniazid-resistant TB (Hr-TB).
In April 2017, the World Health Organization (WHO) convened a Guideline Development Group (GDG) meeting to develop policy guidelines on the treatment of Hr-TB. The development of these policy guidelines was conducted in accordance with procedures established by the WHO Guideline Review Committee (2). This was the first time that Hr-TB treatment recommendations were developed following the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation) to review the evidence and formulate the recommendations (3). This method included an assessment of the quality of the evidence, a consideration of the overall balance of benefits and harms (at individual and population levels), health equity, resource use, acceptability and feasibility of interventions across a variety of settings, including those where access to drug-susceptibility testing (DST) is limited.
The new recommendations for the treatment of Hr-TB complement the 2016 update of the WHO treatment guidelines for DR-TB(4)10. The recommendations will also feature in a chapter of the forthcoming update of the Companion Handbook to the WHO guidelines for the programmatic management of drug-resistant TB and replace previous recommendations for the treatment of Hr-TB based on expert opinion (5-7).
Following an assessment of available evidence for the treatment of Hr-TB, including the evaluation of results from an analysis of individual patient data (IPD), and advice from members of the GDG, WHO made the following recommendations:
In patients with confirmed rifampicin-susceptible and isoniazid-resistant tuberculosis, treatment with rifampicin, ethambutol, pyrazinamide and levofloxacin is recommended for a duration of 6 months [Conditional recommendation, very low certainty in the estimates of effects ⊕○○○]
Notes.– The 4-drug “HREZ” fixed-dose combination (FDC) with isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) – may be used (as there is no approved REZ FDC available), to limit the need for using single drugs. Drug susceptibility to fluoroquinolones should preferably be confirmed ahead of start of treatment (See text below for other important remarks).
In patients with confirmed rifampicin-susceptible and isoniazid-resistant tuberculosis, it is not recommended to add streptomycin or other injectable agents to the treatment regimen [Conditional recommendation, very low certainty in the estimates of effects ⊕○○○]
Remarks11
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Although there was no clear evidence to suggest that the addition of isoniazid would add benefit to this regimen, the 4-drug HREZ FDC may be more convenient for the patient and the health service because it obviates the need to use single drugs.
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Consistent with the overall framework for the management and care of patients diagnosed with DR-TB, careful selection of patients is a fundamental principle. Ahead of starting the (isoniazid)-rifampicin-ethambutol-pyrazinamide plus levofloxacin (Lfx) regimen (henceforth abbreviated as (H)REZ-Lfx), it is essential that resistance to rifampicin be excluded by WHO-recommended genotypic or phenotypic methods (8, 9). Preferably, resistance to fluoroquinolones, and if possible to pyrazinamide, is similarly be excluded prior to treatment in order to help avert the acquisition of additional drug resistance. (See “Implementation considerations” in pg. 9).
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Empirical treatment of Hr-TB is not generally advised. In cases where Hr-TB diagnosis is strongly presumed (e.g. close contacts of Hr-TB cases with active TB but without laboratory confirmation of Hr-TB), (H)REZ-Lfx may be introduced pending laboratory confirmation of isoniazid resistance, so long as rifampicin resistance has been reliably excluded. Should DST results eventually indicate susceptibility to isoniazid, levofloxacin is stopped and the patient completes a 2HRZE/4HR regimen. For other patients, in whom Hr-TB is detected after the start of treatment with the 2HRZE/4HR regimen, the (H)REZ component drugs are continued (or pyrazinamide and ethambutol are re-introduced) and levofloxacin added once rifampicin resistance has been excluded.
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The (H)REZ-Lfx regimen is given for as long as it is necessary for the patient to receive levofloxacin for six months. Thus, in cases where the diagnosis of Hr-TB is made after first-line TB treatment has already been initiated, the patient may receive more than six months of (H)REZ by the end of treatment. When the confirmation of isoniazid resistance arrives late into treatment with a 2HRZE/4HR regimen (e.g. 5 months after start during the continuation phase), the clinician would need to decide, based on an assessment of patient condition and laboratory tests, whether a 6 months course of (H)REZ-Lfx needs to be started at that point or not.
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The addition of levofloxacin to (H)REZ is recommended in all patients with Hr-TB, with exception of the following: (i) in cases where resistance to rifampicin cannot be excluded; (ii) known or suspected resistance to levofloxacin; (iii) known intolerance to fluoroquinolones; (iv) known or suspected risk for prolonged QTc interval; and (v) pregnancy or during breastfeeding (not an absolute contraindication). In Hr-TB cases in whom a fluoroquinolone cannot be used, the patient may still be treated with 6(H)REZ.
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When additional resistance (especially to pyrazinamide) is suspected or confirmed, appropriate treatment regimens will have to be designed individually. The data reviewed for this guideline could not provide separate evidence-based recommendations for such cases.
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Where possible, isoniazid resistance testing should also include information on the specific mutations associated with resistance to isoniazid (katG or inhA). In addition, knowledge about overall host acetylator12 status) at country or regional level will be useful given that these may have implications for regimen design (10).
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High throughput diagnostic platforms are in development (as an alternative to LPA) that can simultaneously detect tuberculosis, and resistance to rifampicin and isoniazid. Evaluation studies of these diagnostics are underway and it is expected that WHO will review their operational and performance characteristics later in 2018.
- 10
Concurrent with the release of the Hr-TB treatment guidelines, and ahead of the update of this handbook, practical implementation issues are being provided in the document “Frequently asked questions on the WHO treatment guidelines for isoniazid-resistant tuberculosis”, available on the same website as the new guidelines.
- 11
See Implementation Considerations section (page 9) for more detailed information.
- 12
Decreased efficacy and toxicity of isoniazid has been related to its increased metabolism (acetylation) in certain individuals, as determined by mutations in the N-acetyltransferase type 2 (NAT2) gene.
