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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: HIV Infections; Weight Gain
• Intervention / Treatment: Procedure: gastroscopy

Detailed 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.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 4

Contacts and Locations

Study Locations

• Finland
  • Uusimaa
    • Helsinki, Uusimaa, Finland, 00290
      • Infectious Disease Clinic, Helsinki University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tenofovir disoproxil TDF; Participants who have used TDF as part of their stable antiretroviral regimen for at least past six months.	Procedure: gastroscopy; Gastroscopy to evaluate the effect of long term exposure of TDF or TAF on enterocytes
Active Comparator: Tenofovir alafenamide (TAF); Participants who have used TAF as part of their stable antiretroviral regimen for at least past six months.	Procedure: gastroscopy; Gastroscopy to evaluate the effect of long term exposure of TDF or TAF on enterocytes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mitochondrial respiratory chain function in situ	Cytochrome C Oxidase / Succinate Dehydrogenase (COX/SDH) activity analysis from cryosections	Baseline
Histopathology of duodenal biopsies	Modified Marsh Classification	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fasting plasma lipid concentrations	total, LDL and HDL cholesterol and triglycerides (all values in mmol/L)	Baseline
Fasting plasma calcium concentration (fP-Ca-ion)	mmol/l	Baseline
Fasting serum folate concentration (fS-folate)	nmol/l	Baseline
Fasting plasma iron concentration (fP-Fe)	umol/l	Baseline
Fasting serum beta carotene concentration (fS-beta carotene)	nmol/l	Baseline
Fasting blood thiamine concentration (fB-B1vit)	nmol/l	Baseline
Fasting serum intestinal fatty acid binding protein (fS-IFABP2)	ng/mL	Baseline

Collaborators and Investigators

• Sponsor: Jussi Sutinen
• Collaborators: Helsinki University Central Hospital; University of Helsinki
• Investigators: Principal Investigator: Jussi Sutinen, Helsinki University Hospital Infectious Disease Clinic

Study record dates

Study Major Dates

• Study Start (Actual): January 19, 2023
• Primary Completion (Anticipated): June 1, 2025
• Study Completion (Anticipated): June 1, 2025

Study Registration Dates

• First Submitted: March 27, 2022
• First Submitted That Met QC Criteria: April 6, 2022
• First Posted (Actual): April 14, 2022

Study Record Updates

• Last Update Posted (Actual): March 27, 2023
• Last Update Submitted That Met QC Criteria: March 23, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: mitochondria; tenofovir disoproxil fumarate; tenofovir alafenamide; gastroscopy
• Additional Relevant MeSH Terms: Body Weight; Body Weight Changes; Weight Gain
• Other Study ID Numbers: 1/2022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No