Fetal Defects in Mice Treated with Integrase Strand Transfer Inhibitors: Comparison of Dolutegravir, Raltegravir, Bictegravir and Cabotegravir.

Background: Integrase strand transfer inhibitors (INSTIs) are preferred for treatment of HIV. However, safety data in pregnancy are limited for newer INSTIs.

Methods: Pregnant C57BL/6 mice were randomly allocated to control (water), dolutegravir, raltegravir, bictegravir, or cabotegravir at clinically relevant doses, administered orally with tenofovir disoproxil fumarate and emtricitabine, once daily from gestational day (GD) 0.5 to sacrifice (GD15.5). Fetuses were assessed for gross anomalies. Descriptive statistics were used to compare proportions of gross anomalies.

Findings: 550 litters (115 control, 150 dolutegravir, 113 raltegravir, 79 bictegravir, 93 cabotegravir) were assessed. Raltegravir was associated with the highest fetal weight, placental weight, and fetal weight/placenta weight ratio (placental efficiency). Fetal weight, placental efficiency, and litter size, were lowest in bictegravir and cabotegravir. Neural tube defects were only observed in INSTI groups with litter prevalence rates of 0.66% in raltegravir, 0.45% in dolutegravir, 0.39% in bictegravir, 0.15% in cabotegravir, and 0% in control. Tail defects, eye defects, bleeding defects, cranial swelling, and growth restriction were significantly more common in all INSTI groups versus control. Overall rates of defects were lowest in dolutegravir. Compared to dolutegravir, limb and tail defects (indicative of spinal dysraphism) were significantly more prevalent in the raltegravir group, while bleeding defects were significantly more prevalent in the bictegravir and cabotegravir groups.

Interpretation: While INSTIs represent a critical advance in the management of HIV infection, the findings of this study demonstrate a link between INSTI therapy and adverse fetal outcomes. This highlights the need for continued surveillance of pregnancy outcomes in women exposed to INSTIs.