# Plausible Causative Mechanism for Dolutegravir Developmental Toxicity

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $674,574

## Abstract

Abstract
The human immunodeficiency virus (HIV) integrase inhibitors are increasingly being used for
antiretroviral therapy (ART), and dolutegravir (DTG) has emerged as a leading core agent. The
DTG/Tivicay manufacturer reports (09/2018) that animal reproduction studies showed no evidence of
adverse developmental outcomes, but an ongoing observational human cohort study in Botswana
initially reported a 9-fold increase for neural tube defect (NTD) risk in offspring from mothers receiving
DTG. With increased exposed births but no additional NTDs, a 6-fold increase for NTD risk in infants
with early gestational exposure to DTG still remains. Recent concerns about teratogenicity have led to
caution for DTG-based regimen use in women of child-bearing potential. We hypothesized that if DTG
is teratogenic, then embryonic exposure to DTG will result in changes to one or more essential
developmental processes, affecting functional mechanisms that have direct roles in neurulation and
NTDs. We report a mechanism of action (MOA) for DTG teratogenicity and demonstrate specificity of
this MOA in an animal model by rescue of DTG-induced developmental toxicity. Competitive binding
data indicates DTG is a partial antagonist of folate receptors at clinically relevant concentrations. Data
from the zebrafish model show developmental toxicity due to early embryonic exposure to DTG.
Specificity of DTG developmental toxicity is demonstrated via rescue of DTG-induced developmental
toxicity by supplemental folate. Folates and folate receptor are established modifiers of risk for NTDs,
and these data indicate DTG is an antagonist of folate receptor and developmental toxicant at clinically
relevant concentrations.

## Key facts

- **NIH application ID:** 10020423
- **Project number:** 5R01HD100229-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Robert M Cabrera
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $674,574
- **Award type:** 5
- **Project period:** 2019-09-18 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020423

## Citation

> US National Institutes of Health, RePORTER application 10020423, Plausible Causative Mechanism for Dolutegravir Developmental Toxicity (5R01HD100229-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10020423. Licensed CC0.

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