A Randomized Controlled Trial of Isoniazid to Prevent Mycobacterium tuberculosis Infection in Kenyan Human Immunodeficiency Virus-Exposed Uninfected Infants

Abstract

Background: Human immunodeficiency virus (HIV)-exposed uninfected (HEU) infants in endemic settings are at high risk of tuberculosis (TB). For infants, progression from primary Mycobacterium tuberculosis (Mtb) infection to TB disease can be rapid. We assessed whether isoniazid (INH) prevents primary Mtb infection.

Methods: We conducted a randomized nonblinded controlled trial enrolling HEU infants 6 weeks of age without known TB exposure in Kenya. Participants were randomized (1:1) to 12 months of daily INH (10 mg/kg) vs no INH. Primary endpoint was Mtb infection at end of 12 months, assessed by interferon-γ release assay (QuantiFERON-TB Gold Plus) and/or tuberculin skin test (TST, added 6 months after first participant exit).

Results: Between 15 August 2016 and 6 June 2018, 416 infants were screened, with 300 (72%) randomized to INH or no INH (150 per arm); 2 were excluded due to HIV infection. Among 298 randomized HEU infants, 12-month retention was 96.3% (287/298), and 88.9% (265/298) had primary outcome data. Mtb infection prevalence at 12-month follow-up was 10.6% (28/265); 7.6% (10/132) in the INH arm and 13.5% (18/133) in the no INH arm (7.0 vs 13.4 per 100 person-years; hazard ratio, 0.53 [95% confidence interval {CI}, .24-1.14]; P = .11]), and driven primarily by TST positivity (8.6% [8/93] in INH and 18.1% [17/94] in no INH; relative risk, 0.48 [95% CI, .22-1.05]; P = .07). Frequency of severe adverse events was similar between arms (INH, 14.0% [21/150] vs no INH, 10.7% [16/150]; P = .38), with no INH-related adverse events.

Conclusions: Further studies evaluating TB preventive therapy to prevent or delay primary Mtb infection in HEU and other high-risk infants are warranted.

Clinical trials registration: NCT02613169.

Keywords: HIV-exposed; infant; isoniazid; prevention; tuberculosis.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Detailed trial profile. †Mycobacterium tuberculosis (Mtb) infection by interferon-γ release assay (QuantiFERON-TB Gold Plus) or tuberculin skin test. aExcludes 2 children diagnosed with human immunodeficiency virus and 23 without primary Mtb infection endpoint. bExcludes 4 infants in the isoniazid (INH) arm with a primary outcome who did not receive INH. cExcludes 1 infant in the no INH arm who received INH due to tuberculosis exposure. Abbreviations: HIV, human immunodeficiency virus; INH, isoniazid; Mtb, Mycobacterium tuberculosis; TB, tuberculosis.

Figure 2.

Primary, secondary, and exploratory outcomes including subgroup analyses. The primary outcome is Mycobacterium tuberculosis (Mtb) infection (either tuberculin skin test or QuantiFERON-TB Gold Plus) 12 months after randomization utilizing a modified intention-to-treat approach including all participants who underwent randomization irrespective of receipt of trial medication with at least 1 measure of Mtb infection, excluding 2 children found to be human immunodeficiency virus DNA positive in the no isoniazid arm during the study. Exploratory composite outcome of Mtb infection, death, or tuberculosis includes all infants with known vital or tuberculosis status at the end of the trial. Subgroup analyses are based on baseline characteristics at the trial entry and include only participants with available primary outcome Mtb assessment. aInteraction between study group and subgroup. bBy Fisher exact test due to zero cases in the isoniazid arm. Abbreviations: ART, antiretroviral therapy; CI, confidence interval; HIV, human immunodeficiency virus; INH, isoniazid; IPT, isoniazid preventive therapy; Mtb, Mycobacterium tuberculosis; PY, person-years; QFT, QuantiFERON-TB Gold Plus; TB, tuberculosis; TST, tuberculin skin test.