Abstract / Summary
Abstract Background and Aims Dolutegravir (DTG)-based regimens are widely used in HIV treatment, including during pregnancy, but the contribution of the nucleoside reverse transcriptase inhibitor (NRTI) backbone on maternal and foetal outcomes remains unclear. We examined this in a large mouse fetotoxicity study. Methods Pregnant C57BL/6J mice were randomized to control (water), DTG-alone, DTG+ Lamivudine (3TC), or DTG+tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), and treated daily from GD0.5 to GD15.5 at clinically relevant doses. Maternal weight gain, litter size, foetal and placental weights, and foetal anomalies were assessed. Kruskal-Wallis and generalized linear models were used for statistical comparisons. Results 472 litters were evaluated (115 control, 106 DTG, 101 DTG+3TC, 150 DTG+TDF/FTC). Foetal viability and resorptions were similar across groups. Maternal weight gain was significantly higher in the DTG and DTG+3TC groups compared to control, but lower in DTG+TDF/FTC. Foetal and placental weights were significantly lower in DTG+TDF/FTC and DTG+3TC groups versus controls, but not in DTG-alone. Nine neural tube defects occurred only in the DTG-exposed groups, most frequently in DTG+TDF/FTC. DTG was associated with higher rates of several foetal anomalies compared to controls, whether administered alone or in combination with NRTIs. Compared to DTG+TDF/FTC, cranial swelling and oedema rates were lower in DTG+3TC, and tail and limb defects were higher in the DTG-alone group. Conclusions TDF inclusion was associated with absence of DTG-associated excess maternal weight gain. NRTI inclusion was associated with lower foetal and placental weights. DTG-associated maternal and foetal outcomes in mice vary by NRTI backbone, highlighting the importance of considering each regimen component, and need for ongoing safety evaluation in pregnancy.