Oral Islatravir in Macaques Decreases Lymphocytes and Monocytes and Is Associated with Immune Alterations

Background: Islatravir (ISL) is a first-in-class nucleoside reverse transcriptase translocation inhibitor with high potency and long half-life in peripheral blood mononuclear cells (PBMCs). However, treatment and prevention of HIV with oral ISL in humans has been associated with decreases in total lymphocytes, CD4 T-cells, and B-cells in a dose-dependent manner. We investigated in macaques the effects of oral ISL on lymphocytes, monocytes, granulocytes, and gene expression in PBMCs. Methods: Female pig-tailed macaques (n = 5) received an HIV pre-exposure prophylaxis dose of oral ISL adjusted allometrically once a week for 12 weeks. Complete blood counts and B- and T-cells were monitored prior to, during, and after ISL treatment, and changes in counts were evaluated by using a repeated measures model. Changes in gene expression were investigated in PBMCs during treatment and following treatment discontinuation. Results: ISL treatment was associated with declines in lymphocytes (11.9%, p = 0.0015) and monocytes (22.4%, p = 0.0003), but not granulocytes (0.3%, p = 0.9781). Total lymphocytes and monocytes returned to pre-treatment levels 6 weeks after treatment cessation (p = 0.8244 and p = 0.4620, respectively). Lymphocyte subpopulation analyses showed a significant decline in CD8 (-18.4%, p = 0.0364) and CD20 (-35.3%; p = 0.0002) cells but not CD4 cells (-7.4%; p = 0.3470). Gene set enrichment analysis showed negative enrichment (p_adj < 0.05) of gene pathways associated with immune regulation, cell proliferation, and inflammation. Conclusions: ISL treatment resulted in significant reductions in lymphocytes reproducing clinical toxicity. This effect was reversed after treatment cessation as observed in humans. Our results highlight the value of the macaque model to study immune alterations at the preclinical stage.