Clinical trial NCT05326971: The Effect Tenofovir Disoproxil Fumarate (TDF) and Tenofovir Alafenamide (TAF) on Small Intestine Gut Wall
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: HIV Infections
Weight Gain
Keywords: tenofovir disoproxil fumarate
tenofovir alafenamide
gastroscopy
mitochondria
Lead sponsor: Helsinki University Central Hospital
Sponsor class: OTHER
Collaborators: name: Helsinki University Central Hospital
name: University of Helsinki
First posted: 2022-04-14
Enrollment: 24
Sex: ALL
Minimum age (years): 20
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A cross sectional study recruiting participants with their own regular home medication.
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Mitochondrial respiratory chain function in situ
timeFrame: Baseline
measure: Histopathology of duodenal biopsies
timeFrame: Baseline
Secondary outcomes:
measure: Fasting plasma lipid concentrations
timeFrame: Baseline
measure: Fasting plasma calcium concentration (fP-Ca-ion)
timeFrame: Baseline
measure: Fasting serum folate concentration (fS-folate)
timeFrame: Baseline
measure: Fasting plasma iron concentration (fP-Fe)
timeFrame: Baseline
measure: Fasting serum beta carotene concentration (fS-beta carotene)
timeFrame: Baseline
measure: Fasting blood thiamine concentration (fB-B1vit)
timeFrame: Baseline
measure: Fasting serum intestinal fatty acid binding protein (fS-IFABP2)
timeFrame: Baseline
Other outcomes:
Locations:
city: Helsinki
country: Finland
facility: Infectious Disease Clinic, Helsinki University Hospital
state: Uusimaa
Study officials:
affiliation: Helsinki University Hospital Infectious Disease Clinic
name: Jussi Sutinen
role: PRINCIPAL_INVESTIGATOR
References: