What are the most efficacious treatment regimens for isoniazid-resistant tuberculosis? A systematic review and network meta-analysis.
BACKGROUND
Consensus on the best treatment regimens for patients with isoniazid-resistant TB is limited; global treatment guidelines differ. We undertook a systematic review and meta-analysis using mixed-treatment comparisons methodology to provide an up-to-date summary of randomised controlled trials (RCTs) and relative regimen efficacy.


METHODS
Ovid MEDLINE, the Web of Science and EMBASE were mined using search terms for TB, drug therapy and RCTs. Extracted data were inputted into fixed-effects and random-effects models. ORs for all possible network comparisons and hierarchical rankings for different regimens were obtained.


RESULTS
12 604 records were retrieved and 118 remained postextraction, representing 59 studies-27 standalone and 32 with multiple papers. In comparison to a baseline category that included the WHO-recommended regimen for countries with high levels of isoniazid resistance (rifampicin-containing regimens using fewer than three effective drugs at 4 months, in which rifampicin was protected by another effective drug at 6 months, and rifampicin was taken for 6 months), extending the duration of rifampicin and increasing the number of effective drugs at 4 months lowered the odds of unfavourable outcomes (treatment failure or the lack of microbiological cure; relapse post-treatment; death due to TB) in a fixed-effects model (OR 0.31 (95% credible interval 0.12-0.81)). In a random-effects model all estimates crossed the null.


CONCLUSIONS
Our systematic review and network meta-analysis highlight a regimen category that may be more efficacious than the WHO population level recommendation, and identify knowledge gaps where data are sparse.
PROSPERO CRD42014015025.
Research Department of Infection and Population Health, University College London, London, UK.
H R
HR
Stagg
Statistics, Modelling and Economics Department, Public Health England, London, UK.
R J
RJ
Harris
Research Department of Infection and Population Health, University College London, London, UK UCL CoMPLEX, Faculty of Mathematics and Physical Sciences, University College London, London, UK.
H-A
HA
Hatherell
Research Department of Infection and Population Health, University College London, London, UK.
D
D
Obach
Respiratory Diseases Department, National Infections Service, Public Health England, London, UK.
H
http://orcid.org/0000-0002-1148-6240
H
Zhao
Department of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
N
N
Tsuchiya
National and Supranational Mycobacterium Reference Laboratory, Research Centre Borstel, Borstel, Germany.
K
K
Kranzer
National Mycobacterium Reference Laboratory, Public Health England, London, UK Department of Medicine, Imperial College London, London, UK.
V
V
Nikolayevskyy
Research Department of Infection and Population Health, University College London, London, UK Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.
J
J
Kim
UCL Respiratory, Division of Medicine, University College London, London, UK Royal Free London National Health Service Foundation Trust, London, UK.
M C
MC
Lipman
Research Department of Infection and Population Health, University College London, London, UK MRC Clinical Trials Unit, University College London, London, UK.
I
I
Abubakar
D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology / Q000627:therapeutic use*; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D017594:Publication Bias; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D014376:Tuberculosis / Q000188:drug therapy*
D000995:Antitubercular Agents; D007538:Isoniazid
Clinical Epidemiology; Tuberculosis