Articles
Comparison of different treatments for isoniazid-resistant tuberculosis: an individual patient data meta-analysis

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Summary

Background

Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ.

Methods

Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study. Studies were identified from two relevant systematic reviews, an updated search of one of the systematic reviews (for papers published between April 1, 2015, and Feb 10, 2016), and personal communications. Individual patient data were obtained from authors of eligible studies. The individual patient data meta-analysis was performed with propensity score matched logistic regression to estimate adjusted odds ratios (aOR) and risk differences of treatment success (cure or treatment completion), death during treatment, and acquired rifampicin resistance. Outcomes were measured across different treatment regimens to assess the effects of: different durations of REZ (≤6 months vs >6 months); addition of a fluoroquinolone to REZ (fluoroquinolone plus 6 months or more of REZ vs 6 months or more of REZ); and addition of streptomycin to REZ (streptomycin plus 6 months of rifampicin and ethambutol and 1–3 months of pyrazinamide vs 6 months or more of REZ). The overall quality of the evidence was assessed using GRADE methodology.

Findings

Individual patient data were requested for 57 cohort studies and 17 randomised trials including 8089 patients with INH-R tuberculosis. We received 33 datasets with 6424 patients, of which 3923 patients in 23 studies received regimens related to the study objectives. Compared with a daily regimen of 6 months of (H)REZ (REZ with or without isoniazid), extending the duration to 8–9 months had similar outcomes; as such, 6 months or more of (H)REZ was used for subsequent comparisons. Addition of a fluoroquinolone to 6 months or more of (H)REZ was associated with significantly greater treatment success (aOR 2·8, 95% CI 1·1–7·3), but no significant effect on mortality (aOR 0·7, 0·4–1·1) or acquired rifampicin resistance (aOR 0·1, 0·0–1·2). Compared with 6 months or more of (H)REZ, the standardised retreatment regimen (2 months of streptomycin, 3 months of pyrazinamide, and 8 months of isoniazid, rifampicin, and ethambutol) was associated with significantly worse treatment success (aOR 0·4, 0·2–0·7). The quality of the evidence was very low for all outcomes and treatment regimens assessed, owing to the observational nature of most of the data, the diverse settings, and the imprecision of estimates.

Interpretation

In patients with INH-R tuberculosis, compared with treatment with at least 6 months of daily REZ, addition of a fluoroquinolone was associated with better treatment success, whereas addition of streptomycin was associated with less treatment success; however, the quality of the evidence was very low. These results support the conduct of randomised trials to identify the optimum regimen for this important and common form of drug-resistant tuberculosis.

Funding

World Health Organization and Canadian Institutes of Health Research.

Introduction

One of several major challenges impeding global tuberculosis control is the steady increase in the prevalence and severity of drug resistance.1 WHO has estimated that 17% of isolates from patients newly diagnosed with tuberculosis have some form of drug resistance.2 Globally, the most common form of drug-resistant tuberculosis is isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis, which is estimated to account for 8% of all new cases.3 In most low-income and middle-income countries, access to drug susceptibility testing is very limited, so both new and previously treated patients receive standardised regimens with first-line tuberculosis drugs. The expanded access to the Xpert MTB/Rif assay means that INH-R tuberculosis will continue to be missed because this test does not identify the mutations (in KatG and INHa)4 associated with INH-R tuberculosis. A 2016 systematic review5 estimated that treatment of patients with unrecognised INH-R tuberculosis with the standard regimen recommended for new cases6 would result in combined failure and relapse occurrence of 16%, and an 8% incidence of acquired rifampicin resistance.

Research in context

Evidence before this study

Drug-resistant tuberculosis is one of the major challenges impeding global tuberculosis control. Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug-resistant tuberculosis. In settings where drug susceptibility testing is not accessible or there is access only to Xpert MTB/RIF assay, INH-R tuberculosis will be missed and treated with standard regimens. Despite the frequent occurrence of INH-R tuberculosis and its major effect on outcomes, remarkably little research on therapy for INH-R tuberculosis has been done. As such, the optimum regimen for INH-R tuberculosis, including use of fluoroquinolones and duration of treatment, remains controversial. We built this individual patient data meta-analysis upon a 2017 systematic review and aggregate data meta-analysis, in which four electronic databases (Cochrane Database of Systematic Reviews and randomised trials, PubMed, Embase, and HealthStar) were searched with the terms “tuberculosis” AND “treatment” OR “therapy” AND “INH” OR “isoniazid resistance” for prospective or retrospective cohorts or randomised clinical trials published in English, French, or Spanish between Jan 1, 1948, and March 31, 2015. The systematic review found that treatment of patients with unrecognised INH-R tuberculosis with the standard regimen recommended for newly diagnosed patients would result in combined failure and relapse rates of 16%, and 8% of patients would acquire rifampicin resistance. All studies included in this review were deemed eligible for the individual patient data meta-analysis. We added previously excluded studies that might have been suitable for individual data analysis, plus studies included in a review on INH-R tuberculosis in children, and seven additional studies published after May 31, 2015, identified from an updated search finalised on Feb 10, 2016, using the same search terms and databases and eligibility criteria as the original review. Additionally, five of the authors contacted for papers identified during the systematic review provided other unpublished datasets (three now published), and three regional or national surveillance datasets were provided by authors responding to an invitation to all participants at a WHO European regional resistant tuberculosis surveillance meeting.

Added value of this study

To our knowledge, this is the first individual patient data meta-analysis on treatment outcome for INH-R tuberculosis. Individual-level data were compiled from 33 studies, and among 23 of these studies (21 cohorts and two randomised clinical trials), a total of 3923 patients received one of the regimens of interest. We assessed bias using an eight-item scale: two critical criteria (sampling method and outcome definition) and six important criteria (participation rate, attrition rate, completeness of information for age, HIV status, cavity at chest-x ray, and smear). On the basis of these criteria, the quality was judged low in one study, moderate in four, and high in the remainder. Compared with 6 months of REZ (rifampicin, ethambutol, and pyrazinamide), longer duration of REZ did not result in significantly improved treatment success or less acquired drug resistance. Addition of a fluoroquinolone to a core regimen of at least 6 months of REZ was associated with improved success and less acquired drug resistance, but no difference in mortality. Addition of a fluoroquinolone to a regimen with 2–3 months of pyrazinamide plus 6 or more months of rifampicin and ethambutol had no significant effect on success. The retreatment regimen (streptomycin added to 6 months of rifampicin and ethambutol plus 1–3 months of pyrazinamide) was associated with significantly worse success compared with at least 6 months of REZ.

Implications of all the available evidence

The findings of this study emphasise the importance of detecting INH-R tuberculosis and support the use of a fluoroquinolone in addition to a core regimen of 6 months of REZ. The addition of isoniazid, and prolongation of REZ beyond 6 months, seem to provide no benefits for this condition. Our results support a move away from the use of the streptomycin-containing retreatment regimens previously recommended. Because of the observational nature of the data, these results are graded very low quality evidence; as such, these results are insufficient to support strong treatment recommendations. However, the results do support the conduct of randomised trials to define the optimum treatment of this common and overlooked condition, particularly to assess the optimum type and duration of fluoroquinolone treatment and the optimum duration of pyrazinamide treatment.

Despite INH-R tuberculosis' frequent occurrence and major effect on outcomes, the disease has received remarkably little therapeutic research. The last randomised trial7 specifically investigating treatments for INH-R tuberculosis was published more than 20 years ago; in that trial, the best regimen, of three tested, resulted in failure or relapse in more than 11% of patients. The previously recommended retreatment regimen, designed to manage INH-R tuberculosis, was never tested in a randomised trial.8 As such, the optimum regimen composition, particularly regarding the use of fluoroquinolones, and duration of treatment remain controversial.3, 6, 9, 10, 11

We conducted a systematic review and meta-analysis of individual patient data of the treatment of patients with INH-R tuberculosis to address three main questions: (1) what is the optimum duration of a daily regimen of REZ (rifampicin, ethambutol, and pyrazinamide); (2) would the addition of a fluoroquinolone to 6 months or more of REZ be beneficial (and as a subquestion, would the addition of a fluoroquinolone to a regimen of 6 months or more of rifampicin plus ethambutol but only 1–3 months of pyrazinamide be beneficial); and (3) would the addition of streptomycin to a core regimen of 6 or more months of rifampicin plus ethambutol but only 1–3 months of pyrazinamide be beneficial (essentially the regimen formerly recommended by WHO for retreatment)? The benefit of including isoniazid in each of these regimens was also addressed. We assessed treatment success (cure or completion), death (from any cause) during treatment, failure or recurrence of disease after success, and acquired rifampicin resistance.

Section snippets

Search strategy and selection criteria

Randomised controlled trials and observational trials were eligible for inclusion in this systematic review. Only studies that were published after Jan 1, 1990, were eligible, reasoning that studies published before this date would be unlikely to have used fluoroquinolones, the effect of which was one of our main objectives. Other specific criteria for inclusion were that the study authors agreed to share their data; that the regimens and outcomes were known for individual patients; and at

Results

We considered all studies on INH-R tuberculosis that were included in a systematic review5 to be eligible for inclusion (33 trials and 19 cohort studies). We re-reviewed the 49 excluded studies from this systematic review, and identified 20 that had been excluded because regimens were individualised, multiple regimens had been used without stratifying results by regimen, some extra-pulmonary tuberculosis cases were included, or outcomes for INH-R tuberculosis were mixed with other resistance

Discussion

We assembled a large set of individual data of patients with INH-R tuberculosis, mostly from observational studies. This study fills an important knowledge gap on the relative efficacy of different regimens to treat INH-R-tuberculosis. Compared with a core regimen containing REZ, addition of a fluoroquinolone was associated with significantly higher odds of success, whereas a treatment regimen with streptomycin added in the first months of treatment and a shorter pyrazinamide treatment period

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