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
试验速览
- 阶段
- 4 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 24
- 试验地点
- 2
- 主要终点
- Mitochondrial respiratory chain function in situ
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
Pathologist and mitochondrial researchers performing biopsy studies are blinded for the study groups.
入排标准
- 年龄范围
- 20 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
结局指标
主要结局
Mitochondrial respiratory chain function in situ
时间窗: Baseline
Cytochrome C Oxidase / Succinate Dehydrogenase (COX/SDH) activity analysis from cryosections
Histopathology of duodenal biopsies
时间窗: Baseline
Modified Marsh Classification
次要结局
- Fasting serum folate concentration (fS-folate)(Baseline)
- Fasting serum intestinal fatty acid binding protein (fS-IFABP2)(Baseline)
- Fasting plasma lipid concentrations(Baseline)
- Fasting serum beta carotene concentration (fS-beta carotene)(Baseline)
- Fasting blood thiamine concentration (fB-B1vit)(Baseline)
- Fasting plasma calcium concentration (fP-Ca-ion)(Baseline)
- Fasting plasma iron concentration (fP-Fe)(Baseline)
研究者
Jussi Sutinen
Infectious Disease Consultant
Helsinki University Central Hospital