A hierarchical modeling approach for assessing the safety of exposure to complex antiretroviral drug regimens during pregnancy

Stat Methods Med Res. 2019 Feb;28(2):599-612. doi: 10.1177/0962280217732597. Epub 2017 Oct 3.


Combination antiretroviral regimens have achieved tremendous success in reducing perinatal HIV transmission, and have become standard of care in pregnant women with HIV. However, the large variety of combination antiretroviral regimens utilized in practice raises the question of whether some of these highly potent drugs pose other risks to the pregnancy or infant. While HIV-infected pregnant women are almost always exposed to multiple antiretrovirals concurrently, standard safety screening strategies typically consider each individual antiretroviral separately, which fails to account for potential confounding due to simultaneous exposure to other antiretrovirals. In this paper, we evaluate a hierarchical modeling approach which groups antiretrovirals by drug class to screen for the safety of antiretrovirals taken during pregnancy, while still providing individual antiretroviral drug effect estimates. In simulation studies, we observed that the hierarchical approach may be advantageous as compared to considering each antiretroviral drug separately or simultaneously evaluating all antiretrovirals in a fixed effect model, particularly when there is prior evidence suggesting drugs from the same class behave similarly on the outcome. The characteristics of the hierarchical approach are illustrated in an application evaluating risk of preterm birth using a study including over 2000 pregnancies representing over 100 antiretroviral combinations, each involving up to three drug classes.

Keywords: Hierarchical model; antiretroviral therapy; mixed effects model; pregnancy; safety; screening; simulation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Abnormalities, Drug-Induced / etiology
  • Adult
  • Anti-HIV Agents / adverse effects
  • Anti-HIV Agents / therapeutic use*
  • Drug Therapy, Combination
  • Female
  • HIV Infections / drug therapy*
  • Humans
  • Infant, Newborn
  • Infectious Disease Transmission, Vertical / prevention & control*
  • Models, Statistical*
  • Observational Studies as Topic
  • Pregnancy
  • Pregnancy Complications, Infectious / drug therapy*


  • Anti-HIV Agents