In utero exposure to zidovudine and heart anomalies in the ANRS French perinatal cohort and the nested PRIMEVA randomized trial

Clin Infect Dis. 2015 Jul 15;61(2):270-80. doi: 10.1093/cid/civ260. Epub 2015 Apr 1.

Abstract

Background: Antiretroviral (ARV) regimens during pregnancy are highly effective in preventing mother-to-child transmission of human immunodeficiency virus (HIV). Congenital heart defects (CHDs) and anomalies in cardiac function have been reported in zidovudine (ZDV)-exposed uninfected children. We explored these associations in a large observational cohort and a randomized clinical trial.

Methods: Since 1986, the French Perinatal Cohort prospectively enrolled all HIV-infected women in 90 centers and collected follow-up on their children through 2 years of age. All CHDs were reviewed by a specialist blinded to exposures. Additionally, in a randomized trial (PRIMEVA ANRS 135) of 2 ARV regimens during pregnancy, 1 of which was without nucleoside reverse transcriptase inhibitors, infants had a specific follow-up including echocardiography at 1 month and 12 months.

Results: Among 12 888 children included, ZDV exposure in the first trimester was significantly associated with CHD (1.5% vs 0.7%; adjusted odds ratio, 2.2 [95% confidence interval, 1.3-3.7]; P < .001). This association was significant for ventricular septal defects (1.1% vs 0.6%; P = .001) and other CHDs (0.31% vs 0.11%; P = .02). In the randomized trial, among 50 infants, girls (but not boys) exposed in utero to ZDV/lamivudine/ritonavir-boosted lopinavir (LPV/r) had a higher left ventricular shortening fraction at 1 month (40% vs 36%; P = .008), and an increased posterior wall thickness at 1 year (5.4 mm vs 4.4 mm; P = .01) than the LPV/r group.

Conclusions: This study confirms a specific association between in utero exposure to ZDV and CHDs, and a long-lasting postnatal myocardial remodeling in girls. A potential common mechanism, including the involvement of mitochondrial dysfunction, must be explored, and long-term consequences on cardiac function warrant specific attention.

Clinical trials registration: NCT00424814.

Keywords: PMTCT; congenital heart defects; heart function; randomized trial; zidovudine.

Publication types

  • Clinical Trial
  • Observational Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-HIV Agents / adverse effects*
  • Anti-HIV Agents / therapeutic use
  • Drug Combinations
  • Echocardiography
  • Female
  • Follow-Up Studies
  • France
  • HIV Infections / drug therapy*
  • HIV Infections / prevention & control
  • HIV Infections / transmission
  • Heart Defects, Congenital / diagnosis
  • Heart Defects, Congenital / epidemiology
  • Heart Defects, Congenital / etiology*
  • Heart Septal Defects, Ventricular / diagnosis
  • Heart Septal Defects, Ventricular / epidemiology
  • Heart Septal Defects, Ventricular / etiology
  • Humans
  • Infant
  • Infectious Disease Transmission, Vertical / prevention & control*
  • Lamivudine / administration & dosage
  • Lamivudine / adverse effects
  • Male
  • Pregnancy
  • Pregnancy Complications, Infectious / drug therapy*
  • Pregnancy Complications, Infectious / virology
  • Pregnancy Trimester, First
  • Sex Factors
  • Uterus
  • Young Adult
  • Zidovudine / administration & dosage
  • Zidovudine / adverse effects*
  • Zidovudine / therapeutic use

Substances

  • Anti-HIV Agents
  • Drug Combinations
  • lamivudine, zidovudine drug combination
  • Lamivudine
  • Zidovudine

Associated data

  • ClinicalTrials.gov/NCT00424814