Journal Article > Meta-AnalysisFull Text
Lancet. 2018 September 8; Volume 392 (Issue 10150); 821-834.; DOI:10.1016/S0140-6736(18)31644-1
Ahmad N, Ahuja SD, Akkerman OW, Alffenaar JWC, Anderson LF, et al.
Lancet. 2018 September 8; Volume 392 (Issue 10150); 821-834.; DOI:10.1016/S0140-6736(18)31644-1
BACKGROUND
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.
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.
Journal Article > Meta-AnalysisFull Text
PLOS Med. 2012 August 28; Volume 9 (Issue 8); DOI:10.1371/journal.pmed.1001300
Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bayona J, et al.
PLOS Med. 2012 August 28; Volume 9 (Issue 8); DOI:10.1371/journal.pmed.1001300
Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB.
Journal Article > ResearchFull Text
Public Health Action. 2014 October 21; Volume 4 (Issue 2); S47-53.; DOI:10.5588/pha.14.0041
Kuksa L, Riekstina V, Leimane V, Ozere I, Skenders G, et al.
Public Health Action. 2014 October 21; Volume 4 (Issue 2); S47-53.; DOI:10.5588/pha.14.0041
SETTING
Drug-resistant tuberculosis (TB) is an important public health problem in Latvia.
OBJECTIVE
To document trends, characteristics and treatment outcomes of registered patients with multi-drug-resistant (MDR-) and extensively drug-resistant (XDR-) TB in Latvia from 2000 to 2010.
DESIGN
A retrospective national cohort study.
RESULTS
Of 1779 patients, 1646 (92%) had MDR- and 133 (8%) XDR-TB. Over 11 years, the proportion of XDR-TB among MDR-TB patients increased from 2% to 18%. Compared to MDR-TB patients, those with XDR-TB were significantly more likely to have failed MDR-TB treatment (OR 8.4, 95%CI 4.3-16.2), have human immunodeficiency virus infection (OR 3.2, 95%CI 1.8-5.7), be illegal drug users (OR 5.7, 95%CI 2.6-11.6) or have had contact with MDR-TB patients (OR 1.9, 95%CI 1.3-2.8). Cure rates for XDR-TB were 50%. Compared with MDR-TB patients, those with XDR-TB had a higher risk of treatment failure (29% vs. 8%, respectively, P < 0.001). Unfavourable treatment outcomes were significantly associated with being male; having smear-positive disease; pulmonary cavities; failure, default or relapse after previous MDR-TB treatment; and a history of incarceration.
CONCLUSION
More MDR-TB in Latvia is now also XDR-TB. This study identified several risk factors for XDR-TB and, for unfavourable treatment outcomes, highlighting the importance of early diagnosis and appropriate management of MDR-/XDR-TB.
Drug-resistant tuberculosis (TB) is an important public health problem in Latvia.
OBJECTIVE
To document trends, characteristics and treatment outcomes of registered patients with multi-drug-resistant (MDR-) and extensively drug-resistant (XDR-) TB in Latvia from 2000 to 2010.
DESIGN
A retrospective national cohort study.
RESULTS
Of 1779 patients, 1646 (92%) had MDR- and 133 (8%) XDR-TB. Over 11 years, the proportion of XDR-TB among MDR-TB patients increased from 2% to 18%. Compared to MDR-TB patients, those with XDR-TB were significantly more likely to have failed MDR-TB treatment (OR 8.4, 95%CI 4.3-16.2), have human immunodeficiency virus infection (OR 3.2, 95%CI 1.8-5.7), be illegal drug users (OR 5.7, 95%CI 2.6-11.6) or have had contact with MDR-TB patients (OR 1.9, 95%CI 1.3-2.8). Cure rates for XDR-TB were 50%. Compared with MDR-TB patients, those with XDR-TB had a higher risk of treatment failure (29% vs. 8%, respectively, P < 0.001). Unfavourable treatment outcomes were significantly associated with being male; having smear-positive disease; pulmonary cavities; failure, default or relapse after previous MDR-TB treatment; and a history of incarceration.
CONCLUSION
More MDR-TB in Latvia is now also XDR-TB. This study identified several risk factors for XDR-TB and, for unfavourable treatment outcomes, highlighting the importance of early diagnosis and appropriate management of MDR-/XDR-TB.
Journal Article > ResearchFull Text
Public Health Action. 2014 October 21; Volume 4 (Issue 2); S54-8.; DOI:10.5588/pha.14.0040
Lucenko I, Riekstina V, Perevoscikovs J, Mozgis D, Khogali MA, et al.
Public Health Action. 2014 October 21; Volume 4 (Issue 2); S54-8.; DOI:10.5588/pha.14.0040
SETTING
Latvia, an Eastern European country with a high burden of tuberculosis (TB).
OBJECTIVE
To describe treatment outcomes among new drug-susceptible TB patients and assess the association of treatment outcomes with selected social determinants and risk factors.
DESIGN
A retrospective cohort study of patients aged ⩾15 years registered during 2006-2010, with a review of records in the National Tuberculosis Registry.
RESULTS
Of 2476 patients, 1704 (69%) were male; the median age was 42 years. About two thirds of patients were unemployed or retired, 7% were human immunodeficiency virus (HIV) positive and 35% had a history of alcohol use. Treatment success was achieved in 2167 (88%) patients. Older age, unemployment, HIV infection and alcohol use were found to be independently associated with unsuccessful treatment (death, loss to follow-up, failure, transfer out and other). For many variables, including HIV infection, diabetes mellitus and tobacco use, it was not possible to distinguish between 'not recorded' and 'not present' in the registry.
CONCLUSION
The treatment success rate among new drug-susceptible TB patients exceeded the 85% global target for TB control. Additional attention and support is required for most vulnerable patients, such as those who are unemployed or retired, HIV infected and alcohol users. The National TB Registry should be revised to improve definitions and staff should be trained for proper data collection and recording.
Latvia, an Eastern European country with a high burden of tuberculosis (TB).
OBJECTIVE
To describe treatment outcomes among new drug-susceptible TB patients and assess the association of treatment outcomes with selected social determinants and risk factors.
DESIGN
A retrospective cohort study of patients aged ⩾15 years registered during 2006-2010, with a review of records in the National Tuberculosis Registry.
RESULTS
Of 2476 patients, 1704 (69%) were male; the median age was 42 years. About two thirds of patients were unemployed or retired, 7% were human immunodeficiency virus (HIV) positive and 35% had a history of alcohol use. Treatment success was achieved in 2167 (88%) patients. Older age, unemployment, HIV infection and alcohol use were found to be independently associated with unsuccessful treatment (death, loss to follow-up, failure, transfer out and other). For many variables, including HIV infection, diabetes mellitus and tobacco use, it was not possible to distinguish between 'not recorded' and 'not present' in the registry.
CONCLUSION
The treatment success rate among new drug-susceptible TB patients exceeded the 85% global target for TB control. Additional attention and support is required for most vulnerable patients, such as those who are unemployed or retired, HIV infected and alcohol users. The National TB Registry should be revised to improve definitions and staff should be trained for proper data collection and recording.