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:
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. 作者: StephenW 时间: 2019-3-8 08:43
Courtney Fletcher（内布拉斯加大学）和明尼苏达大学的同事指出，HIV复制并维持潜伏池主要存在于淋巴结和肠道相关淋巴组织（GALT）中。弗莱彻观察到，抗逆转录病毒药物不能均匀地穿透所有组织。例如，淋巴结水平“特别低于”PBMC和其他组织中的水平。在动物研究中，TAF比TDF更好地穿透淋巴组织[2]。这是第一项比较人体中TAF和TDF组织穿透的研究。
据我所知，这在科学文献中尚未见报道。相反:
In pooled analyses of the HBsAg kinetics of TAF and TDF for 48 weeks, HBsAg change was similar for the TAF and TDF treatment regimens across HBV genotypes.35
在汇总分析TAF和TDF的HBsAg动力学48周时，TAF和TDF治疗方案的HBV基因型的HBsAg变化相似.35
[35] Marcellin P, Seto W-K, Hu CT, et al. Genotype-specific differences in magnitude of HBsAg reduction during tenofovir disoproxil fumarate or tenofovir alafenamide therapy in CHB patients [abstract no. 1858/poster] Hepatology. 2016;64(1 Suppl):918A.作者: StephenW 时间: 2019-3-20 15:26
