The recommendations in this section address one PICO (population, intervention, comparator and outcomes) question:
PICO question 1 (Hr-TB, 2018): In patients with isoniazid-resistant TB (other than MDR-TB), which treatment regimen composition and duration, when compared with 6 months or more of rifampicin–pyrazinamide–ethambutol, leads to a higher likelihood of success with least possible risk of harm?
Treatment with rifampicin, ethambutol and pyrazinamide – with or without isoniazid – has been used for the treatment of patients with rifampicin-susceptible, isoniazid-resistant TB (Hr-TB) (14–16). The evidence reviewed for this guideline compared treatment regimens with isoniazid, rifampicin, ethambutol, pyrazinamide ((H)REZ)¹⁸ of different durations (e.g. 6-month regimens versus longer duration ones). Additionally, the review of evidence focused on determining whether treatment outcomes in Hr-TB patients receiving (H)REZ treatment regimens of variable duration could be improved with the addition of a fluoroquinolone or streptomycin.
The evidence used to determine the composition and duration of regimens relied primarily on an analysis of IPD that comprised 33 databases with an analysable population of 5418 Hr-TB patients. All data used to develop these recommendations were derived from observational studies conducted in various settings (33% in Europe, 31% in the Americas, 26% in Asia and 6% in Africa) (17).¹⁹ In the IPD analysed, patient treatment regimens contained rifampicin, ethambutol, pyrazinamide, streptomycin, isoniazid and fluoroquinolones; thus, recommendations could be made only for regimens containing these anti-TB agents. Based on an assessment of the certainty of the evidence, carried out using predefined criteria, the certainty of the evidence was rated as very low.
Duration of (H)REZ. The analysis comparing (H)REZ treatment regimens for 6 months (6(H)REZ) and more than 6 months (>6(H)REZ) demonstrated that a 6(H)REZ regimen had a higher likelihood of treatment success than a >6(H)REZ regimen. Further analyses determined that there was no statistically significant difference in the treatment outcomes of patients receiving regimens of 6-month REZ (6REZ) and those receiving more than 6 months REZ (>6REZ). Since data were not included on intermittent dosing of the 6(H)REZ and >6(H)REZ regimens, no inferences could be drawn about the use of alternating 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 minimized to the shortest possible duration. The reduction in treatment with pyrazinamide to less than 3 months was associated with a worse treatment outcome, even with the addition of streptomycin (adjusted odds ratio [aOR]: 0.4; 95% confidence limits [CL]: 0.2–0.7). In 118 patients on fluoroquinolone-containing regimens who received pyrazinamide for less than 4 months, the odds of treatment success were higher than in those who received a 6(H)REZ regimen, although the difference was not statistically significant.
Duration of levofloxacin use. In a subsample of 241 patients on an (H)REZ plus fluoroquinolone regimen, the median duration of fluoroquinolone use was 6.1 months (interquartile range [IQR]: 3.5; 8.4), and for REZ it was 9 months (IQR: 7; 11). Hence, in the observational studies that informed the IPD, it seems that treatment length was based on the completion of 6 months of treatment with a fluoroquinolone.
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%) than in those receiving >6(H)REZ (4.3%). This observation could be due to the effect of selection and allocation of patients into specific regimens; for instance, the number of patients with extensive disease was slightly larger in those receiving >6(H)REZ. However, overall, the number of observations for each comparison was small and the effect was not statistically significant (aOR: 0.2; 95% CL: 0.02–1.70).
Adverse events. Data on adverse events were not evaluated owing to a of lack of standardization (dissimilar reporting). The GDG also considered two reports containing data from patients from the United States of America (USA) in whom a detailed assessment of adverse events suggested a risk of excess hepatotoxicity with the 6(H)REZ combination (18). Drug-induced hepatotoxicity is not uncommon with anti-TB drugs. It has also been reported in individuals receiving rifampicin and pyrazinamide for 2 months for the treatment of latent TB infection (LTBI) – in such individuals, a much higher occurrence of hepatotoxicity has been observed than in those receiving only isoniazid preventive therapy (19). It is not known whether the risk of hepatotoxicity differs 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 than when patients were treated with 6(H)REZ or >6(H)REZ without the addition of fluoroquinolones (aOR: 2.8; 95% CL: 1.1–7.3). With the addition of fluoroquinolones in patients receiving (H)REZ, the number of deaths was reduced (aOR: 0.4; 95% CL: 0.2–1.1). Acquisition of additional resistance with progression to MDR-TB was also reduced when fluoroquinolones were added to a ≥6(H)REZ regimen (aOR: 0.10; 95% CL: 0.01–1.2), albeit with small absolute numbers: 0.5% (1/221) of patients on ≥6(H)REZ plus fluoroquinolones acquired resistance to rifampicin compared with 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 because it was unclear whether fluoroquinolones were used at the beginning of treatment or only once drug susceptibility testing (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 an (H)REZ regimen with less than 4 months of pyrazinamide decreased the likelihood of treatment success (aOR: 0.4; 95% CL: 0.2–0.7), an effect that may in part be due to confounding. Addition of streptomycin did not reduce mortality significantly (see Annex 3 and Annex 4). There were no data on the use of other injectable agents (i.e. kanamycin, amikacin and capreomycin) for the 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. Those limitations were patient selection, allocation to treatment with specific regimens and their relationship with disease severity. Outcomes appeared to be worse in patients with cavitary disease, persistence of sputum smear positivity and previous history of TB treatment, who received a 6(H)REZ or >6(H)REZ regimen with an additional 3 months of pyrazinamide and 1–3 months of streptomycin (see Hr-TB, 2018 in Annex 3). However, the limited number of observations made it difficult to draw definitive conclusions based on the 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 an (H)REZ–levofloxacin regimen; they also considered 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 Annex 3 and Annex 4 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 the 6(H)REZ and >6(H)REZ regimens 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(H)REZ and >6(H)REZ regimens. As an example (although data on the extent of disease were not systematically captured for all patients), it is possible that a larger 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(H)REZ regimen.
The GDG acknowledged the safety implications of (H)REZ–levofloxacin, particularly for hepatotoxicity associated with prolonged use of pyrazinamide-containing multidrug regimens. However, reducing the duration of the treatment with pyrazinamide to 3 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 serious adverse events (20–22). On this basis, the GDG agreed that current data supported the use of the (H)REZ–levofloxacin regimen without streptomycin or any other injectable agent in Hr-TB cases, unless there is a compelling reason 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 6-month regimen, the likelihood of a 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 components is relatively low (compared with the recommended regimens for MDR/RR-TB) and the increased probability of cure in a substantial number of patients. In addition, the exclusion of streptomycin and other injectable agents reduces potential barriers to regimen administration.
Although patient costs were not factored into the analysis, the GDG agreed that improving diagnostic capacity to detect isoniazid resistance would be beneficial. A modelling analysis performed for the 2011 update of the WHO Guidelines for the programmatic management of drug-resistant tuberculosis estimated that the best strategy for averting deaths and preventing acquired MDR-TB was to undertake DST in all patients before treatment using a rapid test that detects resistance to isoniazid and rifampicin (23). The modelling work also showed that rapid testing for resistance to 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 the 6(H)REZ–levofloxacin regimen would be feasible in most drug-resistant TB treatment settings, and that 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 other end-users, the GDG reached overall agreement on the beneficial effect that the Hr-TB regimen may have, if used in conformity with these policy recommendations. Although there was no clear evidence to suggest that the addition of isoniazid to this regimen would be beneficial, the four-drug (H)REZ fixed-dose combination (FDC) may be more convenient for the patient and the health service because it removes the need to use single drugs.
Consistent with the overall framework for the management and care of patients diagnosed with drug-resistant TB, careful selection of patients is a fundamental principle. Ahead of starting the (H)REZ–levofloxacin regimen, it is essential that resistance to rifampicin be excluded, using WHOrecommended genotypic or phenotypic methods (24, 25). Ideally, resistance to fluoroquinolones (and, if possible, to pyrazinamide) should be similarly excluded before treatment, to help avert the acquisition of additional drug resistance (see Section 1.4).
Empirical treatment of Hr-TB is generally not advised. In cases where a diagnosis of Hr-TB is strongly presumed (e.g. close contacts of Hr-TB cases with active TB but without laboratory confirmation of Hr-TB), (H)REZ–levofloxacin may be introduced pending laboratory confirmation of isoniazid resistance, provided that rifampicin resistance has been reliably excluded. Should DST results eventually indicate susceptibility to isoniazid, levofloxacin is stopped, and the patient completes a 2HREZ/4HR regimen (i.e. 2 months of HREZ followed by 4 months of HR). For patients in whom Hr-TB is detected after the start of treatment with the 2HREZ/4HR regimen, the (H)REZ component drugs are continued (or pyrazinamide and ethambutol are reintroduced) and levofloxacin added, once rifampicin resistance has been excluded.
The duration of an (H)REZ–levofloxacin regimen is usually determined by the need to complete 6 months of a levofloxacin-containing regimen. 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 6 months of (H)REZ by the end of treatment. When the confirmation of isoniazid resistance arrives late into treatment with a 2HREZ/4HR regimen (e.g. 5 months after start during the continuation phase), the clinician would need to decide, based on an assessment of the patient’s condition, whether a 6-month course of (H)REZ–levofloxacin needs to be started at that point or not.
The addition of levofloxacin to (H)REZ is recommended in all patients with Hr-TB, with the exception of the following situations: resistance to rifampicin cannot be excluded; known or suspected resistance to levofloxacin; known intolerance to fluoroquinolones; known or suspected risk for prolonged QT interval; 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.
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.
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 acetylator²⁰ status at country or regional level will be useful, given that these may have implications for regimen design (26).
Under development are high-throughput diagnostic platforms (as an alternative to line probe assay [LPA]) that can simultaneously detect TB, and resistance to rifampicin and isoniazid. Evaluation studies of these diagnostics are underway.
¹⁸ “(H)” indicates that isoniazid is optional.
¹⁹ The number of patients highlighted in this section refers to the sample size of each study. However, the analysable sample size was later modified, depending on the availability of IPD for each analysable outcome (success and mortality).
²⁰ Decreased efficacy and toxicity of isoniazid have been related to its increased metabolism (acetylation) in certain individuals, as determined by mutations in the N-acetyltransferase type 2 (NAT2) gene.