Second-generation HIV integrase inhibitors induce differentiation dysregulation and exert toxic effects in human embryonic stem cell and mouse models.

BACKGROUND: Each year, approximately 1.1 million children are exposed in utero to HIV antiretrovirals, yet their safety is often not well characterized during pregnancy. The Tsepamo study reported a neural tube defect signal in infants exposed to the integrase inhibitor (InSTI) dolutegravir from conception, suggesting that exposure during early fetal development may be detrimental.

METHODS: The effects of InSTIs on two human embryonic stem cell (hESC) lines were characterized with respect to markers of pluripotency, early differentiation, and cellular health. Additionally, fetal resorptions following exposure to InSTIs from conception were analyzed in pregnant mice.

RESULTS: At sub-therapeutic concentrations, second-generation InSTIs bictegravir, cabotegravir, and dolutegravir decreased hESC counts, pluripotency, and induced dysregulation of genes involved in early differentiation. At therapeutic concentrations, bictegravir induced substantial hESC death and fetal resorptions. Notably, first-generation InSTI raltegravir did not induce any hESC toxicity or differentiation, at any concentration tested.

CONCLUSIONS: Exposure to some InSTIs, even at sub-therapeutic concentrations, can induce adverse effects in hESCs and pregnant mice. Given the increasingly prevalent use of second-generation InSTIs, including in women of reproductive age, it is imperative to further elucidate the effect of InSTIs on embryonic development, as well as their long-term safety following in utero exposure.