Isoniazid preventive therapy (IPT) for tuberculosis in pregnant women with HIV was associated with excess adverse pregnancy outcomes and may warrant a reassessment of the current World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) guidelines, according to a poster presented at CROI 2018, held from March 4-7 in Boston, Massachusetts.
The safety of IPT in pregnant women with HIV is unknown, especially with regard to its combination with highly active antiretroviral therapy (ART). Amita Gupta, MD, deputy director of the Johns Hopkins University Center for Clinical Global Health Education at the Johns Hopkins University School of Medicine, and colleagues hypothesized that IPT can be safely initiated during pregnancy in this population. In a phase 4 randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov Identifier: NCT01494038), 956 HIV-positive women on ART from tuberculosis-endemic areas in Africa, Asia, and Haiti were randomly assigned 1:1 to receive immediate/antepartum IPT (n=477) or deferred/postpartum IPT (n=479).
In the immediate/antepartum IPT group, women received isoniazid 300 mg at study entry through week 28 antepartum followed by an oral placebo once daily until week 40 postpartum. In the deferred/postpartum group, women received oral placebo once daily from study entry to week 12 postpartum followed by isoniazid 300 mg once daily through week 40 postpartum. Safety evaluation were performed every 4 weeks and mother-infant pairs were followed until 48 weeks postpartum.
The primary outcome measure was treatment-related maternal adverse events ≥ grade 3 or permanent discontinuation due to adverse reaction. Secondary outcome measures were maternal hepatotoxicity, maternal/infant death, tuberculosis, adverse pregnancy outcomes, and infant adverse events.
The noninferiority margin was an incidence rate of 5/100 person-years, assuming an incidence rate of 5/100 person-years in the deferred/postpartum group based on reports in nonpregnant women with HIV.
Among the 956 women enrolled, 93% were black, median age was 29 years, 34% were 14 weeks to less than 24 weeks pregnant, median CD4 count was 493 cells/µL, 30% had positive interferon-gamma release assays results, 955 were on ART with a majority on efavirenz-based therapy (85%), and 63% had undetectable HIV-1 RNA.
Primary outcome was reached in 15% of women (74 in the immediate/antepartum group vs 73 in deferred/postpartum group) with an incidence rate of 15.4/100 person-years and 14.9/100 person-years, respectively. There were no statistically significant differences in incidence rates of any maternal grade ≥3 adverse events (30% vs 28%), all-cause hepatotoxicity (6% vs 7%), or infant grade ≥3 adverse events (43% vs 41%) between the 2 groups. There was also no difference in maternal tuberculosis or infant tuberculosis between the 2 groups. However, adverse pregnancy outcomes were higher in the immediate/antepartum vs deferred/postpartum group (23% vs 17%; P =.009).
Of the 956 women, 171 discontinued the study prematurely, 6 died with 3 due to treatment-related hepatotoxicity, 77 withdrew consent (after data and safety monitoring boards and sponsor-required safety memo about risk of death from the treatment), and 75 were lost to follow-up.
“The current [WHO and CDC] recommendations to initiate IPT during pregnancy in HIV-positive women on ART needs re-evaluation,” concluded the researchers.
Gupta A, Montepiedra G, Aaron L, et al; IMPAACT P1078/TB APPRISE Study Team. Randomized trial of safety of isoniazid preventive therapy during or after pregnancy. Presented at: CROI 2018. Boston, MA; March 4-7, 2018. Abstract 142LB.