The Effectiveness of Isoniazid Preventive Treatment among Contacts of Multidrug-Resistant Tuberculosis: A Systematic Review and Individual-Participant Meta-Analysis

Rationale: Recent empirical research suggests isoniazid may lead to a risk reduction of incident tuberculosis among close tuberculosis contacts of multi-drug resistant (MDR) tuberculosis. Objectives: To evaluate the association between isoniazid tuberculosis preventive treatment (TPT), compared to no treatment, upon incident tuberculosis in household contacts of MDR tuberculosis cases using a large global consortium of tuberculosis contact tracing studies. Methods: We conducted a systematic review and individual-participant meta-analysis among observational studies of household contact tracing studies. Participants were included if they were exposed to someone with MDR-tuberculosis and were given either 6 months of isoniazid TPT or no TPT. Our primary outcome was incident tuberculosis in contacts exposed to tuberculosis. We derived adjusted hazard ratios (aHRs) using mixed-effects, multivariable survival regression models with study-level random effects. The effectiveness of isoniazid TPT against incident tuberculosis was estimated through propensity score matching. We stratified our results by contact age, background tuberculosis burden, and Mycobacterium tuberculosis infection status. Measurements and Main Results: We included participant-level data from 6,668 contacts exposed to multidrug-resistant tuberculosis from 17 countries. The effectiveness of isoniazid TPT against incident tuberculosis in contacts of multidrug-resistant tuberculosis was 57% (aHR, 0.43; 95% CI, 0.26–0.71) and did not appreciably change with adjustment for additional potential confounders. The reduction in incident tuberculosis was marginally greater among child (<20 years old) contacts (0.51; 95% CI, 0.28–0.92) compared to adult contacts (0.69; 95% CI, 0.22–2.20). The reduction in incidence was 73% (0.27; 95% CI, 0.11–0.70) in the first year of follow-up; effectiveness dropped to 60% (0.40; 95% CI, 0.15–1.06) from 12–23 months of follow-up and was non-significant after two years (28% effectiveness; 0.72; 95% CI, 0.33–1.54). Conclusions: Among over 6,500 contacts of MDR-tuberculosis, isoniazid TPT was highly effective in preventing incident tuberculosis. The reduction was greatest in high-burden countries and waned after 2 years of follow-up