The secondary lymphoid tissues (LT), lymph nodes (LN) and gut-associated lymphoid tissue (GALT), are the primary sites of HIV replication and where the latent pool of virus is maintained. In HIV-infected persons with undetectable plasma HIV-RNA, an association has been reported between low concentrations of antiretroviral drugs (ARVs) in LT and measures of persistent viral production. None of those individuals, however, were receiving an INSTI-based regimen. The objective of this work was to compare the LT PK of the INSTIs, dolutegravir (DTG), elvitegravir EVG) and raltegravir (RAL).
Study participants were HIV-infected persons receiving DTG, EVG (with cobicistat), or RAL, with other ARVs. PBMCs and mononuclear cells (MNCs) from LN, ileum and rectal tissues were obtained, and intracellular concentrations of INSTIs were quantified by LC-MS/MS. Inhibitory quotients (IQ) as the ratio of intracellular concentrations to the protein-binding corrected 90 or 95% inhibitory concentration (IC90-95) of the respective INSTIs were determined. Summary statistics were calculated.
PK data were obtained from a total of 27 persons: DTG, n=10; EVG, n=11; RAL, n=6. NRTIs were: TDF/FTC, n=20; ABC/3TC, n=4; ABC/3TC/TDF, n=1; TDF/3TC, n=1; and TAF/FTC, n=1. Median (and interquartile range) IQ values for the INSTIs in PBMCs, LN, ileum and rectum are given in the Table.
In PBMCs, the median IQ values for DTG, EVG and RAL were 5-fold or more above the IC90-95. This is consistent with clinical trial results showing these INSTIs produce rapid and potent decreases in plasma HIV RNA. In LT, however, all median IQ values were lower than those in PMBCs, except for EVG in the ileum and rectum, which were greater or equivalent, respectively. Only EVG had a median IQ value in the LN (1.85) above the IC90-95. As shown for other ARVs, these INSTIs achieved lower concentrations particularly in the LN, than in peripheral blood. Plasma concentrations of DTG, EVG and RAL have been linked with virologic response; the standard doses of these INSTIs achieve plasma IQ values of 8 or greater. Pharmacodynamic evaluations are needed to determine whether the low concentrations observed in LT create conditions in LT that allow persistent viral production.