The Effect Tenofovir Disoproxil Fumarate (TDF) and Tenofovir Alafenamide (TAF) on Small Intestine Gut Wall

HIV Infections Clinical Trial

— TENENTOX  

Official title:

The Effect of Tenofovir Disoproxil Fumarate (TDF) Versus Tenofovir Alafenamide (TAF) on Proximal Small Intestine - a Potential Mechanism to Explain Opposing Effects on Body Weight

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05326971
• Other study ID #: 1/2022
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: January 19, 2023
• Est. completion date: June 1, 2025

Study information

• Verified date: March 2023
• Source: Helsinki University Central Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Several studies among people living with HIV (PLWH) have shown more weight gain with tenofovir alafenamide (TAF) than with tenofovir disoproxil fumarate (TDF). This difference could be due to weight increasing effect of TAF and / or weight decreasing effect of TDF.

When TDF is ingested, it gets absorbed in the beginning of the small intestine. TDF is processed into free tenofovir (TFV) within the enterocytes, whereas TAF is not. The effect of TFV on enterocytes is not known, but in kidney tubular cells TFV seems to damage mitochondria and that seems lead to TDF-associated kidney toxicity.

In the present cross sectional study the investigators hypothesize that TDF but not TAF causes damage in the small intestine gut wall and that may lead to poorer absorption of nutrients and opposing effects on body weigh.

Twelve stable PLWH who have been treated with TDF for at least past 6 months and 12 PLWH who have similarly been treated with TAF for at least past 6 months will be recruited. The participants will have a gastroscopy done with biopsies taken from the small intestine. These biopsies will be examined for mitochondrial damage and other potential pathological findings. In addition, blood concentrations of several nutrients absorbed from the same part of the small intestine as TDF and blood concentrations of some markers of intestinal damage will be measured.

Description:

Integrase inhibitors (INSTI) and tenofovir alafenamide (TAF) have been associated with increased weight gain in several randomized studies among people living with HIV (PLWH). In most of these studies, the control group received tenofovir disoproxil (TDF) which raises the question whether the difference in weight change is due to weight increasing effect of INSTI/TAF or weight decreasing effect of TDF.

When ingested, TDF is prone to chemical and enzymatic hydrolysis by intestinal esterases once pH rises above 3. Therefore, it has a narrow time window to be absorbed as an intact prodrug from the proximal small intestine, also the site of absorption of considerable proportion of lipids, lipid-soluble vitamins, folates, calcium, phosphate, iron, and other micronutrients.

TDF is metabolized within enterocytes in a two-step process of ester group cleavage into free phosphonate tenofovir (TFV). Neither TDF nor the monoester intermediate are detected in systemic circulation, indicating complete presystemic metabolism. The consequences of free TFV within enterocytes are not known, but TFV is cytotoxic in renal tubular cells.

TAF is more resistant than TDF to enzymatic hydrolysis. Due to the smaller amount of ingested prodrug and based on PK studies, it is suggested that ingestion of TAF leads to much smaller

• if any - intracellular concentration of TFV within enterocytes than that of TDF.

Mechanisms behind these clinical effects of TDF are not known. The investigators hypothesize these effects are mediated by reduced absorptive function of the proximal small intestine caused by intracellular accumulation of free TFV within enterocytes, a parallel mechanism to TFV-induced toxicity in proximal tubular cells.

This is a cross-sectional study comprising 24 adult PLW on stable antiretroviral therapy containing either TDF (n=12) or TAF (n=12) for at least the past six months. All participants will have a gastroduodenoscopy with biopsies from proximal and distal duodenum. Blood concentrations of nutrients absorbed from the proximal small intestine and related substances will be measured, as well as circulating markers of intestinal damage and function.

The primary objective is to compare pathology findings including mitochondrial studies in duodenal biopsies of PLWH receiving either TDF or TAF. The secondary objectives are to compare the effects of TDF versus TAF on absorption of selected nutrients absorbed from proximal duodenum and circulating markers of intestinal damage and function and microbiota.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 24
• Est. completion date: June 1, 2025
• Est. primary completion date: June 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years to 80 Years

Eligibility

Inclusion Criteria:

• Age = 18 year;

• HIV-positive on a stable ART including either TDF or TAF for > 6 months

• HIV viral load < 200 copies for = 6 months.

Exclusion Criteria:

• Known or suspected enteropathies (celiac disease, inflammatory bowel disease)

• Use of any of the following during the previous month: calcium, folic acid, iron, vitamin A, B, E supplements

• Pregnancy.

Related Conditions & MeSH terms

• HIV Infections
• Weight Gain

Intervention

Procedure:
• gastroscopy
Gastroscopy to evaluate the effect of long term exposure of TDF or TAF on enterocytes

Locations

Country	Name	City	State
Finland	Infectious Disease Clinic, Helsinki University Hospital	Helsinki	Uusimaa

Sponsors (3)

Lead Sponsor	Collaborator
Jussi Sutinen	Helsinki University Central Hospital, University of Helsinki

Country where clinical trial is conducted

Finland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mitochondrial respiratory chain function in situ	Cytochrome C Oxidase / Succinate Dehydrogenase (COX/SDH) activity analysis from cryosections	Baseline
Primary	Histopathology of duodenal biopsies	Modified Marsh Classification	Baseline
Secondary	Fasting plasma lipid concentrations	total, LDL and HDL cholesterol and triglycerides (all values in mmol/L)	Baseline
Secondary	Fasting plasma calcium concentration (fP-Ca-ion)	mmol/l	Baseline
Secondary	Fasting serum folate concentration (fS-folate)	nmol/l	Baseline
Secondary	Fasting plasma iron concentration (fP-Fe)	umol/l	Baseline
Secondary	Fasting serum beta carotene concentration (fS-beta carotene)	nmol/l	Baseline
Secondary	Fasting blood thiamine concentration (fB-B1vit)	nmol/l	Baseline
Secondary	Fasting serum intestinal fatty acid binding protein (fS-IFABP2)	ng/mL	Baseline