Isoniazid Preventive Therapy in HIV-Infected Pregnant and Postpartum Women

Abstract

BACKGROUNDThe safety, efficacy, and appropriate timing of isoniazid therapy to prevent tuberculosis in pregnant women with human immunodeficiency virus (HIV) infection who are receiving antiretroviral therapy are unknown. METHODSIn this multicenter, double-blind, placebo-controlled, noninferiority trial, we randomly assigned pregnant women with HIV infection to receive isoniazid preventive therapy for 28 weeks, initiated either during pregnancy (immediate group) or at week 12 after delivery (deferred group). Mothers and infants were followed through week 48 after delivery. The primary outcome was a composite of treatment-related maternal adverse events of grade 3 or higher or permanent discontinuation of the trial regimen because of toxic effects. The noninferiority margin was an upper boundary of the 95% confidence interval for the between-group difference in the rate of the primary outcome of less than 5 events per 100 person-years. RESULTSA total of 956 women were enrolled. A primary outcome event occurred in 72 of 477 women (15.1%) in the immediate group and in 73 of 479 (15.2%) in the deferred group (incidence rate, 15.03 and 14.93 events per 100 person-years, respectively; rate difference, 0.10; 95% confidence interval [CI], −4.77 to 4.98, which met the criterion for noninferiority). Two women in the immediate group and 4 women in the deferred group died (incidence rate, 0.40 and 0.78 per 100 person-years, respectively; rate difference, −0.39; 95% CI, −1.33 to 0.56); all deaths occurred during the postpartum period, and 4 were from liver failure (2 of the women who died from liver failure had received isoniazid [1 in each group]). Tuberculosis developed in 6 women (3 in each group); the incidence rate was 0.60 per 100 person-years in the immediate group and 0.59 per 100 personyears in the deferred group (rate difference, 0.01; 95% CI, −0.94 to 0.96). There was a higher incidence in the immediate group than in the deferred group of an event included in the composite adverse pregnancy outcome (stillbirth or spontaneous abortion, low birth weight in an infant, preterm delivery, or congenital anomalies in an infant) (23.6% vs. 17.0%; difference, 6.7 percentage points; 95% CI, 0.8 to 11.9). CONCLUSIONSThe risks associated with initiation of isoniazid preventive therapy during pregnancy appeared to be greater than those associated with initiation of therapy during the postpartum period.

New opportunities in tuberculosis prevention: implications for people living with HIV

“…One of the few PK studies conducted in pregnant women showed only modest changes with rifampin, so dose adjustment is not needed . A randomized trial of IPT during or after pregnancy in 956 HIV‐infected women on ART showed higher than expected rates of treatment‐related adverse events, and excess adverse pregnancy outcomes in the immediate IPT arm . However, in a post‐hoc analysis of 3HP in 112 pregnant women, the rates of spontaneous abortion and birth defects were similar to those in the general US population .…”

“…Treatment guidelines generally recommend use of the same regimens and dosages for pregnant women and non‐pregnant adults. However, the safety, efficacy, and appropriate timing of TPT in pregnant women living with HIV remain uncertain . One of the few PK studies conducted in pregnant women showed only modest changes with rifampin, so dose adjustment is not needed .…”

TB prevention strategies and unanswered questions for pregnant and postpartum women living with HIV: the need for improved evidence

“…While early data from India suggested high negative predictive value in postpartum women [7], newer prospective data from multiple sub-Sahara African countries suggests performance may be lower during pregnancy.Once active TB is excluded, WHO recommends providing isoniazid preventive therapy (IPT) for people living with HIV, including pregnant women to prevent TB disease [1]. This recommendation has been called into question since the recently published TB-APPRISE study found IPT initiation during pregnancy among PWLHIV increased the risk of adverse pregnancy outcomes [8]. (see details in "Treatment" section below).While some national programmes opt to first screen for LTBI, the optimal diagnostic test and timing remain unclear.…”

“…Once active TB is excluded, WHO recommends providing isoniazid preventive therapy (IPT) for people living with HIV, including pregnant women to prevent TB disease [1]. This recommendation has been called into question since the recently published TB-APPRISE study found IPT initiation during pregnancy among PWLHIV increased the risk of adverse pregnancy outcomes [8]. (see details in "Treatment" section below).…”

“…The first randomized control trial of IPT in pregnancy (TB-APPRISE), demonstrates the importance of including pregnant and postpartum women in TB trials [8]. Gupta et al reported PWLHIV on ART initiating IPT during pregnancy (in line with WHO recommendations), had a significantly increased risk of composite adverse pregnancy outcomes (e.g.…”