HIV InfectionsPhase 4TENENTOXNCT05326971
The Effect Tenofovir Disoproxil Fumarate (TDF) and Tenofovir Alafenamide (TAF) on Small Intestine Gut Wall
A Phase 4 study testing gastroscopy in people with HIV Infections and Weight Gain, run by Jussi Sutinen at 1 site in Finland.
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. Read more about this study
- Who is it for?
- Ages 20 to 80 years
- Conditions the study is for
- HIV Infections, Weight Gain
- What is being tested?
- gastroscopy
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteFinland
- Study dates
- 19 Jan 2023to 1 Jun 2025
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
Finland1 site
Infectious Disease Clinic, Helsinki University Hospital
Helsinki, Uusimaa, 00290
About this study
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
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.
Read more
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.
Read the 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.
- Conditions
- HIV Infections, Weight Gain
- Being tested
- gastroscopy
- Keywords
- tenofovir disoproxil fumarate, tenofovir alafenamide, gastroscopy, mitochondria
- Medical subject headings
- HIV Infections, Weight Gain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
gastroscopyProcedure or surgery
Gastroscopy to evaluate the effect of long term exposure of TDF or TAF on enterocytes
| Study group | Role | What they receive |
|---|---|---|
| Tenofovir disoproxil TDF | Experimental | Participants who have used TDF as part of their stable antiretroviral regimen for at least past six months. Receives: Procedure: gastroscopy |
| Tenofovir alafenamide (TAF) | Active comparator | Participants who have used TAF as part of their stable antiretroviral regimen for at least past six months. Receives: Procedure: gastroscopy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mitochondrial respiratory chain function in situ
Cytochrome C Oxidase / Succinate Dehydrogenase (COX/SDH) activity analysis from cryosections
Measured: Baseline
Histopathology of duodenal biopsies
Modified Marsh Classification
Measured: Baseline
Secondary outcomes (7)
Fasting plasma lipid concentrations
total, LDL and HDL cholesterol and triglycerides (all values in mmol/L)
Measured: Baseline
Fasting plasma calcium concentration (fP-Ca-ion)
mmol/l
Measured: Baseline
Fasting serum folate concentration (fS-folate)
nmol/l
Measured: Baseline
Fasting plasma iron concentration (fP-Fe)
umol/l
Measured: Baseline
Fasting serum beta carotene concentration (fS-beta carotene)
nmol/l
Measured: Baseline
Fasting blood thiamine concentration (fB-B1vit)
nmol/l
Measured: Baseline
Fasting serum intestinal fatty acid binding protein (fS-IFABP2)
ng/mL
Measured: Baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Apr 2022
- Study start19 Jan 2023
- Primary completion1 Jun 2025 (estimated)
- Study completion1 Jun 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- A cross sectional study recruiting participants with their own regular home medication.
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 24 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Jussi Sutinen
- Sponsor type
- University, hospital or other
- Collaborators
- Helsinki University Central Hospital, University of Helsinki
- Responsible party
- Sponsor-investigator, Jussi Sutinen, Helsinki University Central Hospital
- Investigators
- Jussi Sutinen, Principal investigator, Helsinki University Hospital Infectious Disease Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05326971
- Sponsor's protocol ID
- 1/2022
- Acronym
- TENENTOX
- Status last verified
- Mar 2023
- First submitted
- 27 Mar 2022
- Last updated
- 27 Mar 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Kauppinen KJ, Aho I, Sjoblom N, Tynninen O, Suomalainen A, Schwab U, Zhao F, Arkkila P, Sutinen J. 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. Clin Infect Dis. 2025 Feb 24;80(2):381-388. doi: 10.1093/cid/ciae374.
PubMed 39039812
Study at a glance
From the registry record, last updated by the sponsor on 27 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT05326971
- Acronym / sponsor ID
- TENENTOX / 1/2022
- Conditions
- HIV Infections, Weight Gain
- Keywords
- tenofovir disoproxil fumarate, tenofovir alafenamide, gastroscopy, mitochondria
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 24 participants (estimated)
- Lead sponsor
- Jussi SutinenUniversity, hospital or other
- Collaborators
- Helsinki University Central Hospital, University of Helsinki
- Study start
- 19 Jan 2023 (actual)
- Primary completion
- 1 Jun 2025 (estimated)
- Study completion
- 1 Jun 2025 (estimated)
- First posted
- 14 Apr 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- Model description
- A cross sectional study recruiting participants with their own regular home medication.
| Arm | Type | Receives |
|---|---|---|
| Tenofovir disoproxil TDF | Experimental | Procedure: gastroscopyParticipants who have used TDF as part of their stable antiretroviral regimen for at least past six months. |
| Tenofovir alafenamide (TAF) | Active comparator | Procedure: gastroscopyParticipants who have used TAF as part of their stable antiretroviral regimen for at least past six months. |
Who may qualify
- Ages
- 20 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (3 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| gastroscopyGastroscopy to evaluate the effect of long term exposure of TDF or TAF on enterocytes | Procedure or surgery | Tenofovir alafenamide (TAF), Tenofovir disoproxil TDF |
Primary outcome
Mitochondrial respiratory chain function in situ
Time frame: Baseline
Cytochrome C Oxidase / Succinate Dehydrogenase (COX/SDH) activity analysis from cryosections
Histopathology of duodenal biopsies
Time frame: Baseline
Modified Marsh Classification
7 secondary outcomes
Fasting plasma lipid concentrations
Time frame: Baseline
Fasting plasma calcium concentration (fP-Ca-ion)
Time frame: Baseline
Fasting serum folate concentration (fS-folate)
Time frame: Baseline
Fasting plasma iron concentration (fP-Fe)
Time frame: Baseline
Fasting serum beta carotene concentration (fS-beta carotene)
Time frame: Baseline
Fasting blood thiamine concentration (fB-B1vit)
Time frame: Baseline
Fasting serum intestinal fatty acid binding protein (fS-IFABP2)
Time frame: Baseline
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Mar 2023.
- Derived from this study: PubMed 39039812Kauppinen KJ, Aho I, Sjoblom N, Tynninen O, Suomalainen A, Schwab U, Zhao F, Arkkila P, Sutinen J. 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. Clin Infect Dis. 2025 Feb 24;80(2):381-388. doi: 10.1093/cid/ciae374.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jussi Sutinen principal investigator
Helsinki University Hospital Infectious Disease Clinic
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing gastroscopy in people with HIV Infections and Weight Gain, run by Jussi Sutinen at 1 site in Finland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 27 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Finland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mitochondrial respiratory chain function in situ (time frame: Baseline). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05326971, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Mar 2023.