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  Conference on Retroviruses
and Opportunistic Infections
Seattle, Washington
March 4-7, 2019
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Lymphoid tissue PKs of tenofovir-alafenamide vs. -disoproxil fumarate / Tenofovir levels in human PBMCs and lymph nodes higher with TAF than TDF
  Conference on Retroviruses and Opportunistic Infections (CROI), March 4-7, 2019, Seattle
Mark Mascolini
Tenofovir-diphosphate (TFV-DP) levels in peripheral blood mononuclear cells (PBMCs) of humans lay 7-fold higher with tenofovir alafenamide (TAF) than with the older tenofovir disoproxil fumarate (TDF), according to results of a 58-person pharmacokinetic study [1]. Lymph node levels of TFV-DP, the active form of TAF and TDF, were 6-fold higher with TAF than with TDF. But TFV-DP levels in ileum (small intestine) and rectum were lower with TAF than with TDF.
Courtney Fletcher (University of Nebraska) and University of Minnesota colleagues noted that HIV replicates and maintains latent pools mainly in lymph nodes and gut-associated lymphoid tissue (GALT). Antiretrovirals do not penetrate all tissues uniformly, Fletcher observed. For example, lymph node levels are "particularly lower" than levels in PBMCs and other tissues. TAF penetrated lymphoid tissue better than TDF in animal studies [2]. This is the first study to compare TAF and TDF tissue penetration in humans.
Study participants were already enrolled in lymphoid compartment analyses. People on TAF took it as part of a stable regimen, had a viral load below 50 copies, and will undergo lymph node and GALT biopsies at baseline, month 12, and month 30. People on TDF were either part of this TAF study or people starting antiretroviral therapy (ART) for the first time.
This analysis compared TFV-DP levels in 13 people taking TAF and 45 taking TDF. Participants in both groups gave multiple samples of PBMCs, lymph node mononuclear cells, ileum mononuclear cells, and rectal mononuclear cells. Median TFV-DP concentrations (fmol/million cells) proved higher in PBMCs and lymph nodes with TAF than with TDF, but lower with TAF in ileum and rectum:
-- PBMCs: TAF 497, TDF 63
-- Lymph nodes: TAF 136, TDF 22
-- Ileum: TAF 82, TDF 3056
-- Rectum: TAF 47, TDF 441
In PBMCs TAF yielded TFV-DP concentrations about 7-fold higher than TDF, and in lymph nodes TFV-DP was about 6-fold higher with TAF. The lymph node findings confirm results of animal studies, Fletcher noted. The lower rectal TFV-DP levels with TAF than TDF, he added, are consistent with findings in nonhuman primates [3] and women [4]. He suggested two possible explanations of lower TFV-DP concentrations in ileum and rectum:
-- Better bioavailability of TAF than TDF and thus a lower fraction absorbed in gut -- Intestinal efflux and/or metabolism of tenofovir
Fletcher proposed that the lymph node finding "allows pharmacodynamic evaluations to investigate whether enhanced lymph concentrations elicit a different virologic response" with TAF. The findings could also inform ongoing studies of TAF for PrEP.
1. Fletcher CV, Thorkelson A, Campbell K, et al. Lymphoid tissue PKs of tenofovir-alafenamide vs. -disoproxil fumarate. Conference on Retroviruses and Opportunistic Infections (CROI). March 4-7, 2019. Seattle. Abstract 103.
2. Lee WA, He GX, Eisenberg E, et al. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents Chemother. 2005;49:1898-1906.
3. Massud I, Mitchell J, Babusis D, et al. Chemoprophylaxis with oral emtricitabine and tenofovir alafenamide combination protects macaques from rectal simian/human immunodeficiency virus infection. J Infect Dis. 2016;214:1058-1062.
4. Cottrell M, Garrett KL, Prince HMA, et al. Single-dose pharmacokinetics of tenofovir alafenamide and its active metabolite in the mucosal tissues. J Antimicrob Chemother. 2017;72:1731-1740