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

Abstract

Background HIV-exposed uninfected (HEU) infants in endemic settings are at high risk of tuberculosis (TB). For infants, progression from primary M. tuberculosis infection to TB disease can be rapid. We assessed whether isoniazid (INH) prevents primary Mtb infection. Methods We conducted a randomized non-blinded controlled trial enrolling HEU infants 6 weeks of age without known TB exposure in Kenya. Participants were randomized (1:1) to 12 months daily INH (10 mg/kg) vs. no INH. Primary endpoint was Mtb infection at end of 12 months, assessed by interferon-gamma release assay QuantiFERON-TB Gold Plus (QFT-Plus) and/or tuberculin skin test (TST, added 6 months after first participant exit). Results Between August 15, 2016 and June 6, 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-months follow-up was 10.6% (28/265); 7.6% (10/132) in INH and 13.5% (18/133) in no INH arms (7.0 vs. 13.4 per 100PY, HR 0.53 [95%CI 0.24-1.14], p=0.11]), and driven primarily by TST positivity (8.6% [8/93] in INH and 18.1% [17/94] in no INH arms; RR 0.48 [95%CI 0.22-1.05], p=0.07). Frequency of severe adverse events was similar between arms (INH 14.0% [21/150] vs. no INH 10.7% [16/150], p=0.38), 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.

Non-IFNγ Whole Blood Cytokine Responses to Mycobacterium tuberculosis Antigens in HIV-exposed Infants

“…When we measured Mtb infection by the presence of Mtbantigen specific immune responses (either QFT-Plus or non-IFNγ cytokines) and excluded TST results, we did not detect a trend toward protection against Mtb infection in BCG-vaccinated HEU infants who received IPT as was seen in the iTIPS study, which used a combined TST/IGRA endpoint. 17,18 However, we did detect a trend for IPT protection against Mtb infection when using a composite infection endpoint of a positive TST or any ESAT6/CFP10 cytokine response to define positivity. As the relationship between Mtb infection outcome and IPT was driven by the non-Mtb specific TST, the possibility remains that the association between IPT and TST size reflects either NTM infection or an effect of IPT administration on BCG efficacy (despite initiating IPT 6 weeks of postvaccination) rather than Mtb infection.…”

“…Further study information has been previously published. 17,18 Infants were randomized 1:1 to 12 months of INH (10 mg/kg dose) with pyridoxine or no INH. Primary endpoint was Mtb infection 12 months after randomization (approximately 14 months old) assessed by QuantiFERON-TB Gold Plus (QFT-Plus) and/or TST.…”

“…15 Isoniazid (INH) preventive therapy (IPT) is routinely used to prevent TB in people living with HIV (PLHIV) >1 year old 16 but limited data exists on whether IPT protects from primary Mtb infection in high-risk HEU infants living where widespread antiretroviral therapy and IPT for PLHIV is common. 7,17 The Infant TB Infection Prevention Study (iTIPS) was a randomized nonblinded trial in western Kenya, an area of high HIV and TB burden. 17,18 HEU infants were randomized to receive IPT or no IPT for the first year of life with cumulative incidence of Mtb infection measured at 12 months postrandomization using TST and Quantiferon-Gold Plus (QFT-Plus).…”

“…7,17 The Infant TB Infection Prevention Study (iTIPS) was a randomized nonblinded trial in western Kenya, an area of high HIV and TB burden. 17,18 HEU infants were randomized to receive IPT or no IPT for the first year of life with cumulative incidence of Mtb infection measured at 12 months postrandomization using TST and Quantiferon-Gold Plus (QFT-Plus). IPT was not associated with a significant difference in risk of Mtb infection (hazard ratio = 0.53, P = 0.11), though there was a trend toward lower risk of positive TST among HEU infants randomized to IPT (hazard ratio = 0.46, P = 0.07).…”

A CD4+ TNF+ monofunctional memory T-cell response to BCG vaccination is associated with Mycobacterium tuberculosis infection in infants exposed to HIV

“…Details of trial design and procedures have been previously published including the study power calculations (ClinicalTrials.gov NCT02613169). 12 , 13 Eligible infants 6–10 weeks of age, born to mothers living with HIV, with birth weight >2·5 kilograms, and >37 weeks gestation, were enrolled from prevention of maternal-to-child transmission of HIV (PMTCT) clinics. Infants were provided prophylactic antiretrovirals through PMTCT clinics.…”