Background:
Antiretroviral therapy (ART) successfully inhibits HIV replication but cannot eradicate the viral reservoir in various anatomic compartments. This is partially due to differential antiretroviral (ARV) drug penetration in different compartments. In humans, ARVs measurement in reservoirs is complicated by technical and ethical obstacles in performing tissue biopsies in vivo. Here we present a map of ARVs penetration across different post-mortem tissue homogenates from altruistic participants recruited in the Last Gift program.
Methods:
People with HIV with terminal illness who gave written informed consent were enrolled. All participants were on suppressive ART until the time of death. Tissue samples were collected through rapid research autopsy (<6h after death) and immediately snap frozen in liquid nitrogen. Non-nucleosidic ARVs intra-tissue concentrations were determined through an UHPLC-MS/MS validated method, with accuracy and precision within the requirements of FDA guidelines, after homogenization of 2 aliquots (about 30 mg) of tissue for each sample. The results were normalized by weight and the mean values were reported as results.
Results:
21 tissue biopsies per participant were isolated from different anatomical sites in 6 volunteers on different ART regimens: 3 on tenofovir alafenamide/emtricitabine (TAF/FTC) and dolutegravir (DTG), 1 on TAF/FTC+DTG plus rilpivirine (RPV), 1 on DTG and darunavir/cobicistat (DRV/c) and 1 on abacavir/lamivudine (ABC/3TC)/DTG. DTG had a higher exposure in intestine, kidney, and liver and lower in central nervous system (CNS) and pancreas (p<0.001 and p=0.012 compared to intestine, respectively). DRV, RPV and cobicistat (COBI), in a lower sample size (1 participant/drug), showed a higher exposure in liver and intestine, compared with other anatomical sites as reported in Fig.1. No statistical differences were observed in the overall ARVs penetration in different areas in the brain (p=0.971) and intestine tracts (p=0.941).
Conclusions:
Scarce data on human intra-tissue ARV penetration are reported in literature. This is the first study to report different ARV concentrations in different anatomical sites in humans. Previous studies on non-human primates showed similar results about the poor, but rather uniform, concentrations of DTG in all the districts of the CNS, and higher concentrations in kidney and intestine.
