The majority of persistently HIV-infected cells in patients on suppressive antiretroviral therapy (ART) are in lymphoid tissue. Limited drug uptake by lymphoid tissues may contribute to sustained viral persistence. Identifying tissue sources with differential drug uptake may help guide future HIV eradication strategies.
We measured plasma, gut mucosa, and peripheral lymph node drug concentrations from HIV-infected participants with plasma HIV RNA<40 copies/mL for ≥12 months on integrase (raltegravir, RAL) or protease inhibitor (daranavir, DRV, or atazanavir, ATV)-based regimens. Tissue samples were collected in duplicate, homogenized, and quantified using a validated liquid chromatography-mass spectrometry assay. We developed compartmental plasma-tissue PK models used nonlinear mixed effects modeling incorporating previously reported PK parameters for these drugs. Monte Carlo simulations were performed to estimate plasma and tissue PK profiles, and reported IC95 (RAL) or IC90 (DRV, ATV) values were used to calculate Ctrough:IC95/90 ratios.
Rectal biopsies were collected from 19 participants (8 RAL, 7 DRV, 4 ATV), with a subset with ileal (2 RAL, 1 DRV, 1 ATV) and lymph node (2 RAL, 1 DRV) samples. The median age was 44 years and median duration of ART suppression was 4.4 years. Tissue:plasma concentration ratios (TPRs) were higher in ileum vs. rectum for RAL and ATV (Table 1A). Median Ctrough:IC95/90 ratios for RAL, DRV, and ATV were: 97.9, 1622, and 2.67, respectively (Table 1B), corresponding to a predicted 100% of RAL and DRV and 80% of ATV participants with rectal concentrations >IC95/90. Adequate lymph node samples were only available for RAL (1 DRV participant demonstrated evidence of nonadherence). Among RAL participants, median Ctrough:IC95 ratios for rectum, ileum, and lymph node were 97.9, 99.9, and 3.20, suggesting lower drug penetration in lymphoid vs. gut tissues. Based on this model, we predict ~15% of patients will have lymph node concentrations
The relative concentrations of both integrase (RAL) and protease (ATV) inhibitors were higher in ileum compared to rectum. In a limited number of participants, concentrations of RAL were significantly lower in lymph nodes compared to gut mucosa, confirming prior observations. These results support and add to the current limited data on tissue ART drug concentrations and have potential implications on HIV cure strategies.