Tenofovir alafenamide (TAF), a pro-drug of tenofovir (TFV), has higher intracellular penetration and lower plasma concentrations than tenofovir disoproxil fumarate (TDF). Intraindividual comparisons of plasma and intracellular pharmacokinetics (PK) of TFV and its intracellular metabolite, tenofovir-diphosphate (TFV-DP) have not been described in patients switching from TDF to TAF.
We conducted a prospective, non-randomized, cross-over, PK study in participants receiving a TDF-based antiretroviral therapy (ART) regimen (TDF 300mg/FTC 200mg/COBI 150mg/EVG 150mg) who were switching to a TAF containing regimen (TAF 10mg/FTC 200mg/COBI 150mg/EVG 150mg). Single, sparse plasma and PBMC samples were collected prior to switching therapy and 4 to 8 weeks post-switch to TAF. Plasma TFV and cell associated TFV-DP concentrations were determined with validated liquid chromatography tandem mass spectrometry methods. PBMC cell enumeration was performed by quantification of RNase P (RPP30) copy numbers by a highly sensitive droplet digital PCR assay. Patient characteristics are summarized as median (interquartile range, IQR); PK data are summarized as geometric mean (IQR), and compared pre- and post- switch using a geometric mean ratio (GMR) of TAF:TDF, and Wilcoxon signed rank test.
30 participants completed both study visits: 4 (13%) female, 10 (33%) black non-hispanic, and 39 (25-58) years of age. All participants had undetectable (<20cpm) HIV-1 RNA prior to switching ART and median CD4+ count of 632 (429-713) cells/mm3. Time of blood sampling post dose was 11.2 (4.1-18.6) hrs during TDF-based ART and 10.8 (2.7-17.4) hrs during TAF-based ART. TFV plasma concentrations during TDF-based ART were 100.0 (57.1-147.3) ng/mL and 10.2 (9.8-13.7) ng/mL during TAF-based ART (GMR 0.10; p<0.001). TFV-DP concentrations during the TDF-based regimen were 346.9 (149.3-617.4) fmol/million cells and 834.7 (526.0-1110.9) fmol/million cells in participants receiving TAF-based ART (GMR = 2.4, p=0.004).
Plasma TFV concentrations significantly decreased after switching to TAF, coinciding with the lower dose of tenofovir contained in the TAF-based ART regimen. Conversely, intracellular TFV-DP concentrations were significantly increased with the TAF-based regimen. This study provides the first intraindividual plasma and intracellular PK data in virologically suppressed HIV+ individuals switching from TDF to TAF.