Isoniazid Preventive Therapy in HIV-Infected Pregnant and Postpartum Women

Abstract

Background: The 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.

Methods: In 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.

Results: A 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 person-years 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).

Conclusions: The 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. (Funded by the National Institutes of Health; IMPAACT P1078 TB APPRISE ClinicalTrials.gov number, NCT01494038.).

Figure 1.. Enrollment, Randomization, and Analysis.

Participants were assigned to receive 28 weeks of isoniazid preventive therapy initiated either during pregnancy (immediate group) or at 12 weeks after delivery (deferred group). Participants were excluded from the per-protocol analysis for one or more of the following reasons: they withdrew consent, they were lost to follow-up, they did not complete the trial regimen according to the protocol, or they had been found after randomization to be ineligible.

Figure 2.. Hepatotoxicity and Adverse Pregnancy Outcomes.

Hepatotoxicity (Panel A) was defined as a grade 3 or higher elevation in liver-enzyme levels (alanine aminotransferase [ALT], aspartate aminotransferase, or total bilirubin), a grade 2 or higher elevation in total bilirubin and ALT levels, or a grade 2 or higher elevation in ALT level with symptomatic clinical hepatitis. Grading of hepatotoxicity was determined on the basis of criteria specified in the protocol. The composite adverse pregnancy outcome (Panel B) was stillbirth (fetal death at 20 weeks of gestation or later) or spontaneous abortion (loss of pregnancy before 20 weeks of gestation), low birth weight (<2500 g) in an infant, preterm delivery (delivery before 37 weeks of gestation, with duration of gestation determined with the use of the Ballard examination when available or by obstetrical estimate), or major congenital anomalies in an infant (defined according to the criteria of the Metropolitan Atlanta Congenital Defects Program of the Centers for Disease Control and Prevention). The composite severe adverse pregnancy outcome was stillbirth or spontaneous abortion, very low birth weight (<1500 g) in an infant, very preterm delivery (delivery before 34 weeks of gestation), or major congenital anomalies in an infant. The risk difference (RD) is the between-group difference in percentage points.