3425 - Ending the HIV Epidemic with Low Dose Total Body Irradiation in Combination with Anti-Microtubule Therapy

Purpose/Objective(s): We hypothesized combining low-dose total body radiation (LD-TBI) with anti-microtubule therapy (aMTT) could lead to high cure rates of HIV infection with a favorable long-term risk profile compared to indefinite antiretroviral therapy (ART). 25 cGy of ionizing radiation (IR) was shown to stimulate latently infected cells to actively replicate HIV. While high rates of T-cell death were seen, macrophages were more resistant. Macrophages appear to resist the major types of regulated cell death resulting from viral infection through viral-induced upregulation of surface receptors, leading to enhanced microtubular stabilization of the mitochondrial membrane. The objectives of our study were to perform mathematical modeling of HIV infection dynamics using a validated system of ordinary differential equations to predict cure rates by combining low-dose IR (LD-IR) with aMTT and to quantify the long-term safety of LD-TBI.

Materials/Methods: As is standard in assessing latent reservoir targeting strategies, we assumed ART highly effective at preventing reinfection. Thus, for 25 cGy fractions, an inter-fraction interval exceeding the time for marrow recovery could carry a negligible marrow failure risk. Secondly, we assumed effective combined therapy would have to achieve at least 90% cell kill. Using R Statistical Software (v4.2.0), we modeled the HIV dynamics through multiple phases and compartments to predict 95 and 99% cure rates. The NCI radiation risk assessment tool (RadRAT) v4.3.1 was used to predict lifetime cancer risk from a fraction of LD-TBI. Finally, we conducted an exhaustive literature search of observed rates of increased cancer risk from LD-TBI and long-term HIV infection treated continuously with ART.

Results: Our modeling predicts that six fractions of combined LD-IR and aMTT would be needed to achieve a 95% probability of cure. Seven fractions would be needed for a 99% cure rate (see Table). RadRAT predicted an all-organ exposure of 25 cGy would have excess lifetime cancer risks of 5.02% and 3.76% above baseline risks of 43.95% and 46.1% for a 30-year-old female and male, respectively. Data from 2019 found LD-TBI (2 – 4.5 Gy in 1-2 fractions) with fludarabine had a twofold higher risk of subsequent malignant neoplasms than the general population. In comparison, 2015 data found the cancer risk for people living with HIV was elevated by a factor of 3.89 with a 95% confidence interval of 2.92-5.19.