Background. 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. In animals, tenofovir alafenamide (TAF) has been found to have enhanced LT penetration compared with tenofovir disoproxil fumarate (TDF). No confirmatory or comparative human LT data, however, are available. The objective of this work was to compare the LT pharmacokinetics (PK) of TAF and TDF in HIV-infected persons.
Methods. Participants were HIV-infected persons enrolled in clinical studies of LT compartments and receiving TAF or TDF with other ARVs. PBMCs and mononuclear cells (MNCs) from LN, ileum and rectal tissues were obtained at steady-state. Intracellular concentrations of tenofovir-diphosphate (TFV-DP) were quantified by LC-MS/MS. Summary statistics were calculated.
Results. PK data were obtained from a total of 58 persons: TAF, n=13; TDF, n=45. The Table presents median and interquartile range values for TFV-DP in PBMCs (TAF, n=38; TDF, n=45), LN (TAF, n=9; TDF, n=43), ileum (TAF, n=9; TDF, n=22) and rectum (TAF, n=7; TDF, n=35). In PBMCs, median TFV-DP concentrations were 7-fold higher with TAF compared with TDF. In LN MNCs, TFV-DP concentrations were 4.7-fold higher with TAF vs. TDF.
Conclusions. TAF administration in HIV-infected persons produced higher TFV-DP concentrations in LN MNCs than did TDF. This finding confirms animal studies showing LN concentrations of TFV-DP were 5.7 to 15-fold higher with TAF, depending on the anatomical site of the LN. The 7-fold higher TFV-DP concentrations in PBMCs achieved with TAF vs. TDF, is consistent with other literature and known PK characteristics of TAF and TDF. TFV-DP concentrations in the ileum and rectum were lower with TAF compared with TDF; this may be due to better bioavailability of TAF vs. TDF and thus a lower fraction of unabsorbed drug in the gastrointestinal lumen. The higher LN concentrations of TFV-DP achieved with TAF demonstrate that drug penetration into this compartment can be modified in HIV-infected persons. This finding allows pharmacodynamic evaluations to investigate whether enhanced LN concentrations elicit a different virologic response.