Mortality in Adults with MDR-TB and HIV by ART and TB Drug Use: Individual Patient Data Meta-Analysis

Background: HIV-infection is associated with increased mortality during multidrug-resistant tuberculosis (MDR-TB) treatment, but the extent to which the use of anti-retroviral therapy (ART) and anti-tuberculosis medications modify this risk are unclear.  Methods: We conducted an individual patient data meta-analysis of adults ≥18 years with confirmed or presumed MDR-TB initiating TB treatment between 1993 and 2016. Data included ART use and anti-tuberculosis medications grouped according to World Health Organization (WHO) effectiveness categorizations. The primary analysis compared HIV-positive versus HIV-negative patients in terms of death during MDR-TB treatment, excluding lost to follow up and stratified by ART use. Analyses used logistic regression after exact matching on country World Bank Income classification level and drug resistance and propensity-score matching on age, sex, geographic site, MDR-TB treatment year, previous TB treatment, directly observed therapy, and acid-fast-bacilli smear-positivity to obtain adjusted odds ratios (aORs) and 95% confidence intervals (CI). Secondary analyses were conducted among those with HIV-infection. Findings: Among 11,920 MDR-TB patients, 2,997 (25%) were HIV-positive on ART, 886 (7%) were HIV-positive not on ART, and 1,749 (15%) had extensively drug-resistant TB. Using HIV-negative patients as reference, the aOR of death for all patients with HIV-infection was 2.4 (95% CI 2.0-2.9), for HIV-positive patients on ART was 1.8 (95% CI 1.5-2.2), and for HIV-positive patients with no or unknown ART was 4.2 (95% CI 3.0-5.9). Among patients with HIV use of at least one WHO Group A drug and specific use of moxifloxacin/levofloxacin, bedaquiline and/or linezolid were associated with significantly decreased odds of death.  Interpretation: Use of ART and more effective anti-tuberculosis drugs lowers the odds of death among HIV-positive patients with MDR-TB. Access to these therapies should be urgently pursued.  Funding: American Thoracic Society, Canadian Institutes of Health Research, U.S. Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America. Declaration of Interests: W-JK reports consultation fees from Insmed Inc for work on the Insmed Advisory Board. CL reports receiving personal fees from Chiesi, Gilead, Janssen, Lucane, Novartis, Thermofisher, Oxfordimmunotec and Transgene. JR reports a grant from Janssen Pharmaceuticals. NV reports grants from Otsuka and Janssen Pharmaceuticals. W-WY reports consultation fees from Otsuka Pharmaceutical Co. All this work was declared by the authors to be outside the submitted work. All other authors declare no competing interests. Ethics Approval Statement: This study was approved by an ethics committee of the Research Institute of the McGill University Health Center. Ethics approval was also obtained at participating sites, as considered necessary.