New England Journal of Medicine – November 3, 2016 Vol. 375 No. 18

New England Journal of Medicine
November 3, 2016 Vol. 375 No. 18
http://www.nejm.org/toc/nejm/medical-journal

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Original Article
Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention
Mary G. Fowler, M.D., M.P.H., Min Qin, Ph.D., Susan A. Fiscus, Ph.D., Judith S. Currier, M.D., Patricia M. Flynn, M.D., Tsungai Chipato, M.B., Ch.B., M.C.E., James McIntyre, F.R.C.O.G., Devasena Gnanashanmugam, M.D., George K. Siberry, M.D., M.P.H., Anne S. Coletti, M.S., Taha E. Taha, M.D., Ph.D., Karin L. Klingman, M.D., Francis E. Martinson, M.B., Ch.B., Ph.D., Maxensia Owor, M.B., Ch.B., M.P.H., Avy Violari, M.D., Dhayendre Moodley, Ph.D., Gerhard B. Theron, M.D., Ramesh Bhosale, M.D., Raziya Bobat, M.B., Ch.B., M.D., Benjamin H. Chi, M.D., Renate Strehlau, M.B., Ch.B., Pendo Mlay, M.D., Amy J. Loftis, B.S., Renee Browning, R.N., M.S.N., Terence Fenton, Ed.D., Lynette Purdue, Pharm.D., Michael Basar, B.A., David E. Shapiro, Ph.D., and Lynne M. Mofenson, M.D., for the IMPAACT 1077BF/1077FF PROMISE Study Team*
N Engl J Med 2016; 375:1726-1737 November 3, 2016 DOI: 10.1056/NEJMoa1511691
Abstract
Background
Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking.
Full Text of Background…
Methods
We randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum “tail” of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir–ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir–ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety.
Full Text of Methods…
Results
The median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, −1.3 percentage points; repeated confidence interval, −2.1 to −0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P=0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P=0.03). Adverse events did not differ significantly between the ART groups (P>0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P<0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P=0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P<0.001). Tenofovir-based ART was associated with higher rates than zidovudine-based ART of very preterm delivery before 34 weeks (6.0% vs. 2.6%, P=0.04) and early infant death (4.4% vs. 0.6%, P=0.001), but there were no significant differences between tenofovir-based ART and zidovudine alone (P=0.10 and P=0.43). The rate of HIV-free survival was highest among infants whose mothers received zidovudine-based ART.
Full Text of Results…
Conclusions
Antenatal ART resulted in significantly lower rates of early HIV transmission than zidovudine alone but a higher risk of adverse maternal and neonatal outcomes. (Funded by the National Institutes of Health; PROMISE ClinicalTrials.gov numbers, NCT01061151 and NCT01253538.)

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Editorial
First-in-Human Clinical Trials — What We Can Learn from Tragic Failures
Sergio Bonini, M.D., and Guido Rasi, M.D.
N Engl J Med 2016; 375:1788-1789 November 3, 2016 DOI: 10.1056/NEJMe1609006
This article has no abstract; the first 100 words appear below.
On January 10, 2016, a healthy volunteer who had received 50 mg per day of a fatty acid amide hydrolase (FAAH) inhibitor for 5 days as part of a first-in-human phase 1 clinical trial was admitted to Rennes University Hospital with neurologic and gait disturbances. After a dramatic worsening of neurologic symptoms, the participant died on January 17. Another 5 participants who received the same drug dose for 6 days were subsequently admitted to the hospital, 4 of them with similar neurologic symptoms. In this issue of the Journal, Kerbrat et al.1 report the clinical and imaging findings of the…