Effect of 2 Forms of Tenofovir on Duodenal Enterocytes-A Hypothesis for Different Effect of Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide on Body Weight and Plasma Lipids

Abstract

Background: Tenofovir disoproxil fumarate (TDF), compared to tenofovir alafenamide (TAF), leads to lower body weight and plasma lipids by an unknown mechanism. We hypothesize that TDF, when absorbed, may damage enterocytes of the proximal duodenum, leading to reduced absorption of nutrients.

Methods: People with human immunodeficiency virus, without significant gastrointestinal symptoms, receiving a regimen containing TDF (n = 12) or TAF (n = 12), underwent esophagogastroduodenoscopies. Plasma/serum concentrations of nutrients absorbed from proximal duodenum and serum intestinal fatty acid-binding protein (I-FABP), a marker of enterocyte damage, were measured. Cytochrome c oxidase/succinate dehydrogenase (COX/SDH) staining and electron microscopy (EM) were conducted to evaluate mitochondria.

Results: Five patients in the TDF group (1 celiac disease [excluded from further analyses], 1 Helicobacter gastritis, and 3 esophagitis) and 2 in the TAF group (2 esophagitis) had a pathological finding in esophagogastroduodenoscopy. Villi were flatter (337 [59] vs 397 [42] μm; P = .016), crypts nonsignificantly deeper (200 [46] vs 176 [27] μm; P = .2), and villus-to-crypt ratio lower (1.5 [0.42] vs 2.5 [0.51]; P = .009) in the TDF versus TAF group (mean [standard deviation]). I-FABP concentration was higher in the TDF versus TAF group (3.0 [1.07] vs 1.8 [0.53] ng/mL; P = .003). The TDF group had numerically but not statistically significantly lower concentrations of folate and vitamins A, B1, D, and E. COX/SDH staining and EM showed similar mitochondrial damage in both groups.

Conclusions: Duodenal villous alterations may explain TDF-associated decrease in body weight and plasma lipids. Larger studies are needed to evaluate concentrations of nutrients absorbed from duodenum among TDF users..

Clinical trials registration: NCT05326971; EudraCT 2022-000849.

Keywords: duodenal villus; enterocyte; intestinal fatty acid–binding protein; tenofovir alafenamide; tenofovir disoproxil fumarate.

Figure 1.

Cytochrome c oxidase (COX) and succinate dehydrogenase double staining of duodenal mucosa. A, Normal COX activity in villous epithelial cells and crypts (brown staining). B, COX activity is absent in villus epithelial cells (blue staining); <50% of epithelial cells are COX deficient. C, COX deficiency in >50% of epithelium of villi and crypts. Scale bar = 100 µm. Insets in B and C show high-power magnification of COX-deficient epithelium.

Figure 2.

Electron microscopic samples of a participant receiving tenofovir disoproxil fumarate (A), a participant receiving tenofovir alafenamide (B), and a human immunodeficiency virus–negative control (C). Scale bar = 5 µm. Black arrows = myelin figures, white arrows = damaged mitochondria with smudged cristae, black asterisk = mitochondrial fusion.