Isoniazid preventive therapy (IPT) for tuberculosis in pregnant women with HIV was associated with excess adverse pregnancy outcomes and may warrant a re-assessment of the current World Health Organisation (WHO) and the US Centres for Disease Control and Prevention (CDC) guidelines, according to a poster presented atthe Conference of Retroviruses and Opportunistic Infections (CROI 2018).
The safety of IPT in pregnant women with HIV is unknown, especially with regard to its combination with highly active antiretroviral therapy (ART). Dr Amita Gupta, deputy director of the Johns Hopkins University Centre for Clinical Global Health Education at the Johns Hopkins University School of Medicine, and colleagues at Harvard University, Stellenbosch University, FHI 360 in Durham, North Carolina, Makerere University–Johns Hopkins University Research Collaboration in Uganda, University of Zimbabwe, Botswana Harvard AIDS Institute Partnership, NIAID, Frontier Science & Technology Research Foundation, Vanderbilt University, National Institute of Child Health and Human Development and University of Colorado Denver, hypothesised that IPT can be safely initiated during pregnancy in this population. In a phase 4 randomised, double-blind, placebo-controlled trial, 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 non-pregnant 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.
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.
Amita Gupta, Grace Montepiedra, Lisa Aaron, Gerhard Theron, Katie McCarthy, Carolyne Onyango-Makumbi, Tsungai Chipato, Gaerolwe Masheto, Katherine Shin, Bonnie Zimmer, Timothy R Sterling, Nahida Chakhtoura, Patrick Jean-Philippe, Adriana Weinberg