BACKGROUND
There are few data on the treatment of children and adolescents with multidrug-resistant (MDR) or rifampicin-resistant (RR) tuberculosis, especially with more recently available drugs and regimens. We aimed to describe the clinical and treatment characteristics and their associations with treatment outcomes in this susceptible population.
METHODS
We conducted a systematic review and individual participant data meta-analysis. Databases were searched from Oct 1, 2014, to March 30, 2020. To be eligible, studies must have included more than five children or adolescents (0-19 years of age) treated for microbiologically confirmed or clinically diagnosed MDR or RR tuberculosis within a defined treatment cohort, and reported on regimen composition and treatment outcomes. Abstracts were screened independently by two authors to identify potentially eligible records. Full texts were reviewed by two authors independently to identify studies meeting the eligiblity criteria. For studies meeting eligiblity criteria, anonymised individual patient data was requested and individiual level data included for analysis. The main outcome assessed was treatment outcome defined as treatment success (cure or treatment completed) versus unfavourable outcome (treatment failure or death). Multivariable logistic regression models were used to identify associations between clinical and treatment factors and treatment outcomes. This study is registered with Prospero (CRD42020187230).
FINDINGS
1417 studies were identified through database searching. After removing duplicates and screening for eligibility, the search identified 23 369 individual participants from 42 studies, mostly from India and South Africa. Overall, 16 825 (72·0%) were successfully treated (treatment completed or cured), 2848 died (12·2%), 722 (3·1%) had treatment failure, and 2974 (12·7%) were lost to follow-up. In primary analyses, the median age was 16 (IQR 13-18) years. Of the 17 764 (87·1%) participants with reported HIV status, 2448 (13·8%) were living with HIV. 17 707 (89·6%) had microbiologically confirmed tuberculosis. After adjusting for significant factors associated with treatment outcome, the use of two (adjusted odds ratio [OR] 1·41 [95% CI 1·09-1·82]; p=0·008) or three (2·12 [1·61-2·79]; p<0·0001) WHO-classified group A drugs (bedaquiline, moxifloxacin, levofloxacin, and linezolid) compared with the use of no group A drugs at all was positively associated with treatment success.
INTERPRETATION
Younger and clinically diagnosed children are underrepresented among those treated for MDR and RR tuberculosis and should be a focus for case-finding efforts. Overall treatment outcomes in our analysis were better than in adults but lower than the international targets of 90% or more individuals successfully treated. Treatment with more group A drugs was associated with better treatment outcomes in children and adolescents, highlighting the need for more rapid access to these drugs and improved regimens.
Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis.
METHODS
In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration.
FINDINGS
Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses.
INTERPRETATION
Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition.