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.

TI is an inhaled insulin with a more rapid absorption and a more rapid elimination than subcutaneously administered RHI, resulting in a quick onset and short duration of action. Insulin exposure following TI administration was found to be linear over the dose range of 25-100 U.

The World Health Organization guidelines recommend that individuals living with HIV receive ≥ 6 months of isoniazid preventive therapy, including pregnant women. Yet, plasma isoniazid exposure during pregnancy, in the antiretroviral therapy era, has not been well-described. We investigated pregnancy-induced and pharmacogenetic-associated pharmacokinetic changes and drug-drug interactions between isoniazid and efavirenz in pregnant women. Eight hundred forty-seven women received isoniazid for 28 weeks, either during pregnancy or at 12 weeks postpartum, and 786 women received efavirenz. After adjusting for NAT2 and CYP2B6 genotype and weight, pregnancy increased isoniazid and efavirenz clearance by 26% and 15%, respectively. Isoniazid decreased efavirenz clearance by 7% in CYP2B6 normal metabolizers and 13% in slow and intermediate metabolizers. Overall, both isoniazid and efavirenz exposures were reduced during pregnancy, but the main determinants of drug concentration were NAT2 and CYP2B6 genotypes, which resulted in a five-fold difference for both drugs between rapid and slow metabolizers.

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MKC253 is glucagon-like peptide 1 (GLP-1, 7-36 amide) adsorbed onto Technosphere microparticles for oral inhalation. The pharmacokinetics of inhaled GLP-1 and the pharmacokinetic-pharmacodynamic (PK-PD) relationship between inhaled GLP-1 and insulin were analyzed in two trials, one in healthy normal volunteers and the other in patients with type 2 diabetes. Inhaled GLP-1 was absorbed quickly, with peak concentrations occurring within 5 min, and levels returned to baseline within 30 min. Inhaled GLP-1 appeared to produce plasma levels of GLP-1 comparable to those of parenteral administration and sufficient to induce insulin secretion resulting in attenuation of postmeal glucose excursions in subjects with type 2 diabetes. An E(max) (maximum effect) model described the relationship between GLP-1 concentration and insulin release. The variability in the E(max) may be due to differences in baseline glucose levels, differences resulting from genetic polymorphisms in GLP-1 receptors (GLP-1Rs), or the stage of diabetes of the patient.