World Health Organization guidance on the treatment of isoniazid-resistant tuberculosis

Background: isoniazid is a critical component of first-line tuberculosis (TB) treatment regimens. Even in the absence of resistance to rifampicin – another key anti-TB medicine - isoniazid-resistance (Hr-TB) lowers the effectiveness of these regimens. Evidence-based treatment recommendations for Hr-TB (present in ~8% of TB cases worldwide) are thus important. Methods: in 2017, the World Health Organization (WHO) convened a multidisciplinary Guideline Development Group to advise it on Hr-TB treatment policy. The guidelines were prepared using the GRADE approach (www.gradeworkinggroup.org/). Individual patient data from ~5,500 Hr-TB cases in 33 observational studies worldwide were analysed. Recommendations were developed by the Guideline Development Group based on this evidence and on consideration of the balance of benefits and harms of different therapeutic options for the patients and caregivers. Findings: upon the expert advice, WHO recommends that Hr-TB patients be treated with a 6-month regimen composed of rifampicin, ethambutol, pyrazinamide and levofloxacin (6REZLfx). Levofloxacin is only added to the regimen if rifampicin resistance has been reliably excluded. If the fluoroquinolone is contraindicated, treatment with a 6-month course of REZ alone is recommended. Streptomycin or other injectable agents are not usually recommended. All recommendations are conditional and based on a very low certainty in the estimates of effect. Interpretation: the production of these guidelines has highlighted a shortage of high-quality evidence about the treatment of Hr-TB. Implementation research and trials of regimen effectiveness and safety (e.g. to limit duration of pyrazinamide use) would be desirable.