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

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] mu m; P = .016), crypts nonsignificantly deeper (200 [46] vs 176 [27] mu m; 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. People with stable HIV receiving tenofovir disoproxil fumarate (TDF) versus tenofovir alafenamide (TAF) exhibited shorted duodenal villi, decreased villous-to-crypt ratio, and higher plasma I-FABP. These findings may explain the different effect of TDF versus TAF on body weight and plasma lipids.