Abacavir Sulfate

The use of antiretroviral (ART) treatment during pregnancy has dramatically reduced rates of perinatally-acquired human immunodeficiency virus 1 (HIV-1) infection to <1% in the United States. Despite this success, we have limited knowledge of how ART drugs that cross the placental barrier affect fetal development, particularly in the central nervous system (CNS). During gestation, large populations of oligodendroglia are produced that are responsible for critical postnatal CNS myelination enabling appropriate neurological function. Previous studies have shown that antiretrovirals impair oligodendrocyte (OL) differentiation leading us to hypothesize that OL maturation might be inhibited by exposure to a frontline ART drug cocktail (Triumeq®) prescribed during pregnancy containing dolutegravir (DTG), abacavir (ABC), and lamivudine (3TC). In this study, we demonstrated that exposing primary rat oligodendrocyte precursor cells (OPCs) and OLs to the Triumeq drug combination decreased OL maturation and myelin protein production in a concentration-dependent manner, and that DTG was solely responsible. Regardless of the timing of exposure during OL development, a high concentration of DTG inhibited OL maturation. Bulk RNA sequencing revealed transcriptional changes after DTG exposure related to a variety of cellular mechanisms, including cellular responses to stress pathways, amino acid starvation, and mitochondrial dysfunction. Although we found that DTG robustly activated the integrated stress response (ISR), attempted rescue experiments showed that DTG primarily inhibits OL maturation independently of the ISR. Collectively, our novel data on DTG underscore the necessity of investigating how ART drugs that are administered during pregnancy and cross the placental barrier can affect fetal CNS development.

Cyclin‐dependent kinase 4 and 6 inhibitors (CDK4/6i) combined with endocrine therapy are the preferred choice for first‐line treatment of patients with HR + /HER2 − locally advanced/metastatic breast cancer (aBC). The CDK4/6i ribociclib in combination with an aromatase inhibitor (AI) or fulvestrant (FUL) has demonstrated significant progression‐free survival (PFS) and overall survival (OS) benefits for pre‐ and postmenopausal aBC patients who were enrolled in the three pivotal MONALEESA trials. Following the initial approval of ribociclib in 2017, the non‐interventional RIBANNA study was initiated to evaluate the effectiveness and safety of ribociclib plus AI/FUL therapy among patients with aBC in a real‐world setting. Two additional treatment cohorts (endocrine monotherapy [ET] and chemotherapy [CT]) were included to extend the knowledge about current aBC treatments. A total of 2567 patients were enrolled in 279 study centers, of whom 1852 were treated with ribociclib+AI/FUL, 183 were treated with ET, and 139 were treated with CT, who were available for effectiveness analyses. Median PFS (mPFS) and median OS (mOS) on first‐line treatment with ribociclib+AI/FUL were 35.0 and 76.0 months, respectively. Adjustment for differences in demographic and baseline characteristics resulted in a longer mPFS on ribociclib+AI/FUL (34.7 months) compared to ET (26.4 months) or CT (19.2 months). Adverse events (AEs) on ribociclib were consistent with those seen in the pivotal trials, and no new safety signals were observed. The RIBANNA study confirmed the PFS and OS benefit seen in the MONALEESA trials. Together with the safety data, this large real‐world dataset supports the favorable risk/benefit profile of ribociclib in large scale patient populations.