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RANDOMIZED TRIAL OF SAFETY OF ISONIAZID PREVENTIVE THERAPY DURING OR AFTER PREGNANCY
Amita Gupta1, Grace Montepiedra2, Lisa Aaron2, Gerhard Theron3, Katie McCarthy4, Carolyne Onyango-Makumbi5, Tsungai Chipato6, Gaerolwe Masheto7, Katherine Shin8, Bonnie Zimmer9, Timothy R. Sterling10, Nahida Chakhtoura11, Patrick Jean-Philippe8, Adriana Weinberg12
1Johns Hopkins University, Baltimore, MD, USA,2Harvard University, Boston, MA, USA,3Stellenbosch University, Cape Town, South Africa,4FHI 360, Durham, NC, USA,5Makerere University–Johns Hopkins University Research Collaboration, Kampala, Uganda,6University of Zimbabwe, Harare, Zimbabwe,7Botswana Harvard AIDS Institute Partnership, Gabarone, Botswana,8NIAID, Bethesda, MD, USA,9Frontier Science & Technology Research Foundation, Inc, Amherst, NY, USA,10Vanderbilt University, Nashville, TN, USA,11National Institute of Child Health and Human Development, Bethesda, MD, USA,12University of Colorado Denver, Denver, CO, USA
The safety, efficacy, and optimal timing of isoniazid preventive therapy (IPT) for HIV-positive pregnant women on antiretroviral therapy (ART) is unknown. We hypothesized that IPT can be safely initiated during pregnancy.
A Phase IV randomized, double-blind, placebo-controlled trial compared initiation of 28 weeks of IPT in antepartum (AP; immediate) (arm A) versus at 12 weeks postpartum (PP; deferred) (arm B) in HIV-positive women from TB-endemic areas in Africa, Asia, and Haiti. Randomization 1:1 was stratified by gestational age [GA] (14-<24 weeks, 24-34 weeks); mother-infant pairs were followed to week 48 PP, with safety evaluations performed every 4 weeks. The primary safety endpoint was treatment-related maternal adverse events (AE) ≥ grade 3 or permanent drug discontinuation due to toxicity. The non-inferiority margin (NIM) was an incidence rate (IR) of 5/100 person-years (PY), assuming a 5/100 PY IR in arm B based on reports in non-pregnant HIV-positive adults. Secondary outcomes were maternal hepatotoxicity, maternal/infant death, TB, adverse pregnancy outcomes, and infant AE.
Among 956 enrolled, 93% were black, median age was 29 years, median CD4 was 493 cells/µL, 30% were IGRA+, 955 (>99%) were on ART (85% efavirenz-based), 63% had undetectable HIV-1 RNA, and 34% were 14-<24 weeks GA. Median follow-up was 58.6 weeks. 147 (15%) reached the primary outcome (74 in arm A, 73 in arm B), with IRs 15.4 and 14.9/100 PY, respectively (IR difference=0.5/100 PY, [95%CI: -4.4, 5.4]; Table).171 women discontinued the study prematurely; 6 died (2 in arm A, 4 in arm B), with 3 deaths due to treatment-related hepatotoxicity (1 in arm A, 2 in arm B) and one non-treatment-related hepatotoxicity in arm B; 77 withdrew consent (most after DSMB and sponsor-required safety memo about risk of death from IPT); 75 were lost to follow-up. There were no statistical differences in IRs of any maternal grade ≥3 AE, all-cause hepatotoxicity, or infant grade ≥3 AE between arms. There was no difference in maternal TB or infant TB by study arm. Adverse pregnancy outcomes however were significantly higher in arm A vs. B (23% vs 17%; p=0.009).
IR for the primary safety outcome was higher than expected and similar for immediate vs. deferred IPT, but did not meet the pre-specified NIM. TB incidence was low. Of note, immediate IPT was associated with excess adverse pregnancy outcomes. The recommendation to initiate IPT during pregnancy in HIV-positive women on ART needs re-evaluation.