Monocytes and macrophages represent a cell lineage integral to multiple aspects of HIV-1 infection, dissemination, and pathogenesis. They also play a fundamental role in innate host defense and may act as a tissue-privileged viral reservoir during all stages of infection. In the current ART-era of the HIV pandemic, HIV-seropositive patients can maintain undetectable viral loads for years. Nevertheless, this population faces central nervous system, cardiovascular, and other HIV-related co-morbidities, many of which are characterized by underlying monocyte/macrophage contributions. To investigate the regulation of the survival and activation profiles of monocytes/macrophages during HIV-1 infection in vivo, we performed the following sets of experiments: (1) we determined monocyte apoptosis profiles in previously uncharacterized highly viremic HIV (+) donors and assessed monocyte gene expression associated with monocyte apoptosis outcome; (2) we tested the impact of ART and CCR5 antagonism during advanced HIV-1 infection on the reversal of monocyte/macrophage activation; (3) we tested the impact of the interferon stimulated genes (ISGs) IFI6 and IFI27 as an underlying mechanism regulating monocyte apoptosis in the context of HIV-1 infection. Our results indicate both constitutive and oxidative stress-induced monocyte apoptosis are elevated in HIV (+) individuals with viral loads above 40,000 HIV-1 copies/mL and are associated with decreasing CD4 count. Furthermore, elevated apoptosis is associated with a shift in interferon stimulated gene and Bcl-2 family gene expression. Longitudinal analysis of ART treatment during advanced HIV-1 infection (nadir CD4 count < 100 cells/mm3) demonstrated differential reversal of cell-associated and soluble biomarkers of monocyte/macrophage activation. We show the addition of CCR5 antagonism (Maraviroc) does not impact the reversal of monocyte/macrophage activation beyond the impact of standard ART alone. Finally, we investigate the roles of the ISGs IFI6 and IFI27 in the regulation of monocyte apoptosis in vitro. Our work demonstrates the impact of viral and host pressures on monocyte survival/apoptosis and activation state during distinct stages of HIV-1 infection.