The initiation of isoniazid for the prevention of tuberculosis was associated with a greater risk for adverse pregnancy outcomes among HIV-infected pregnant women compared with HIV-infected women given the medication after birth, according to results from a study published in the New England Journal of Medicine.
Researchers conducted a multicenter, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier, NCT01494038) to assess the safety, efficacy, and correct timing of isoniazid preventive treatment in pregnant women receiving antiretroviral therapy.
Pregnant women with HIV were randomly assigned to receive 28 weeks of isoniazid treatment (300 mg/d) started either during pregnancy (immediate cohort) or at 12 weeks after delivery (deferred group). All mothers and infants were followed through 48 weeks after delivery. The primary outcome measured the combined treatment-related adverse events (≥ grade 3) or the permanent discontinuation of the trial regimen as a result of toxic effects.
Of the 956 women included in the study, 477 were assigned to the immediate group and 479 were assigned to the deferred group. The vast majority of participants were African American (90.5%) and the mean age was 29 years. The median CD4 count among the women was 493 cell/cm2 and all but 1 patient was receiving antiretroviral therapy.
Approximately 25% of patients in both the immediate and deferred groups did not complete the trial. Fifteen percent of women in both the immediate and deferred groups experienced primary outcome adverse events (incidence rates, 15.03 and 14.93 events per 100 person-years, respectively; rate difference, 0.10). Abnormal laboratory findings were the most common adverse events, including elevated liver enzymes and abnormal chemical and hematologic levels. The most common clinical adverse events included weight loss and events related to pregnancy.
There were a total of 6 deaths in the study, 2 in the immediate cohort and 4 in the deferred group. All the deaths occurred in the postpartum portion of the analysis (incidence rates, 0.40 and 0.78 per 100 person-years, respectively; rate difference, -0.39). Four of the mortalities were caused by liver failure (1 in the immediate group and 3 in the deferred group). Two of women who died of liver failure had received isoniazid (1 woman from each group) and 4 were receiving efavirenz-emtricitabine-tenofovir. In addition, tuberculosis developed in 3 women in both the immediate and deferred cohorts (incidence rates, 0.60 and 0.59 per 100 person-years, respectively; rate difference, 0.01).
Adverse pregnancy outcomes including stillbirth or spontaneous abortion, infant low birth weight, preterm delivery, and infant congenital abnormalities. These outcomes were more prevalent among women in the immediate group compared with women in the deferred group (23.6% vs 17.0%, respectively; difference, 6.7 percentage points).
“In women with HIV infection who were receiving [antiretroviral therapy], the initiation of isoniazid preventive therapy during pregnancy was noninferior to initiation during the postpartum period with respect to maternal treatment-related adverse events,” the authors wrote. “However, our finding of a greater incidence of adverse pregnancy outcomes in the immediate group than in the deferred group without any additional benefit with respect to the risk of tuberculosis or maternal or infant death is a cause for concern.”
The authors noted that shorter courses of tuberculosis prevention (ie, 1 or 3 months) during pregnancy may have a different risk-benefit profile, but further study is needed. “Our trial highlights the need to include pregnant women in clinical trials to inform global health policy,” the investigators concluded.
Gupta A, Montepiedra G, Aaron L, et al. Isoniazid preventive therapy in HIV-infected pregnant and postpartum women. N Engl J Med. 2019;381(14):1333-1346.