Background:
Tenofovir disoproxil fumarate (TDF) when compared to tenofovir alafenamide (TAF) leads to lower body weight and plasma lipid concentrations; the mechanisms of these effects are unknown. TDF as opposed to TAF is processed into free tenofovir (TFV) within enterocytes when absorbed from proximal duodenum. The effect of TFV in enterocytes is unknown, but in kidney proximal tubular cells it may cause mitochondrial damage. We hypothesize that TDF may damage enterocytes leading to reduced absorption of nutrients from this anatomical site.
Methods:
People living with HIV without known gastrointestinal disease receiving stable TDF (n=12) or TAF (n=12) containing regimen underwent gastroscopy with biopsies from proximal and distal duodenum. Biopsies were scanned with Leica GT450 scanner and measurements taken in Neagen’s neaLink digital pathology solution. Serum intestinal fatty acid-binding protein (I-FABP) was measured as a circulating marker of enterocyte damage. Plasma/serum concentrations of nutrients absorbed from proximal duodenum were measured.
Results:
All participants were male. TDF and TAF groups were matched for third antiretroviral agent (58% integrase strand transfer inhibitor, 42% non-nucleoside reverse transcriptase inhibitor) and age (mean (SD) TDF group 55 (12) and TAF group 57 (16) years). Five patients in TDF group (celiac disease, helicobacter gastritis and 3 cases of esophagitis) and 2 patients in TAF group (2 cases of esophagitis) had a pathological macroscopic or histologic finding (p=0.178). The patient with newly diagnosed celiac disease was excluded from the rest of the analyses. Duodenal villi were flatter, crypts deeper, and villus height to crypt depth ratio was lower in TDF vs TAF group, especially in proximal duodenum (Table 1). I-FABP concentration was significantly higher in TDF vs. TAF group (3.0 (1.07) vs. 1.8 (0.53) ng/ml, p=0.003). TDF group had numerically lower plasma/serum concentrations of iron, folate, vitamins A, B1, D and E, whereas β-carotene concentration was lower in TAF group. None of these differences were statistically significant.
Conclusions:
TDF group displayed signs of villous damage especially in proximal duodenum when compared to TAF group. This together with increased I-FABP suggest enterocyte damage and may contribute to the clinical effect of TDF on lowering body weight and plasma lipid concentrations when compared to TAF. Larger studies are needed to evaluate concentrations of nutrients absorbed from proximal duodenum among TDF users.
