A Pathogenesis Pilot Study to Evaluate the Impact of Switching to Tenofovir/lamivudine/doravirine on Adipose Tissue (AT) Morphology and Functions in Suppressed Patients with Weight Gain on an INSTI-based Regimen
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 22
- 试验地点
- 1
- 主要终点
- Measure the phenotype and alterations in adipose tissue to assess the impact of this weight gain
研究概览
简要总结
Integrase-strand-transfer-inhibitors (INSTIs) based regimens have been associated with body weight gain and increase in total body adipose tissue (AT). Whereas there is by now no clear understanding of the mechanisms that induce these changes, we have observed modifications of AT in vitro, in animals models or in vivo in obese patients with raltegravir (RAL) and dolutegravir (DTG) with the presence of increased peri-adipocyte fibrosis and high levels of collagen VI that have been associated with poor metabolic prognoses together with cellular insulin resistance and decreased adiponectin secretion.
One major clinical question is whether such AT abnormalities are reversible.
Doravirine (DOR), the most recent available Non-Nucleosidic Reverse Transcriptase Inhibitor (NNRTI) drug, has an excellent metabolic profile and as a NNRTI is expected to induce neither changes in fat tissue distribution nor changes in body weight. Tenofovir disoproxil fumarate (TDF) is associated with a protective lipid profile and, unlike tenofovir alafenamide (TAF) which seems to potentiate weight gain in combination with INSTI, has not been associated with weight gain.
One major clinical question is whether such AT abnormalities are reversible.
Doravirine, the most recent available NNRTI drug, has an excellent metabolic profile and as a NNRTI is expected to induce neither changes in fat tissue distribution nor changes in body weight. Tenofovir DF is associated with a protective lipid profile and, unlike TAF which seems to potentiate weight gain in combination with INSTI, has not been associated with weight gain.
We hypothesized that modifications in morphology and function of the adipose tissue in patients with significant weight gain under an INSTI-based regimen could be improved after switching to the triple drug TDF/Emtricitabine/DOR and that fat increase and body weight will be stopped or reversed.
This pathogenesis study aimed to evaluate potential changes in adipose tissue after switching from an INSTI-based regimen (Raltegravir or Dolutegravir or Bictegravir) to TDF/Emtricitabine/DOR. Each patient will be evaluated with an adipose tissue biopsy performed before (D0) and after a 48 week switch (W48) from an INSTI-based regimen to the non INSTI-based regimen combining TDF/3TC/Doravirine.
With a number of 22 patients at D0, a total of 20 patients with paired adipose tissue biopsies are expected at W48.
The antiretroviral therapy with TDF/emtricitabine/Doravirine will be used as routine practice recommends.
详细描述
Integrase-strand-transfer-inhibitors (INSTIs) represent the most largely prescribed antiretroviral therapy as recommended either as first-line antiretroviral treatment or as switch strategy due to their high efficacy, good tolerability and high genetic barrier to resistance for the latest compounds.
Recently, weight/fat gain has been reported in INSTIs-exposed patients, raising concerns on possible deleterious clinical outcome. Several studies performed in naïve or in Antiretroviral Therapy-suppressed individuals, revealed that dolutegravir (DTG), raltegravir (RAL) or bictegravir (BIC) based therapy resulted in weight gain.
In the large ADVANCE trial, which has compared in Africa three Antiretroviral Therapy initiation strategies, changes in weight, obesity and trunk/limb were greater with dolutegravir/tenofovir alafenamide/Emtricitabine (+6 kg), than with dolutegravir/tenofovir disoproxil fumarate/emtricitabine (+3 kg) and even more than with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/efavirenz (EFV) (+1 kg) at W48.
Women, blacks and persons over 60 years experienced greater weight gain in the two years after versus before switch in the follow-up from 1997-2017 of AIDS-Clinical-Trials-Group (A5001 and A5322) participants who were switched to DTG, RAL or elvitegravir (EVG).
In the Women's Interagency HIV study (WIHS) from 2006-2017, women who switched to or added an INSTI (DTG/RAL/EVG) to Antiretroviral Therapy, experienced mean greater increase in body weight compared to women who did not. The increases in weight gain were limited or not reported in other retrospective studies that included mainly men and Caucasian individuals. However, most of these studies were retrospective and evaluated weight but not fat mass. Reasons for this weight gain are still unknown.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •HIV positive patient > 18 years
- •HIV RNA < 50 copies/ml in the last 6 months
- •on INSTI based regimen (dual or 3-DR) since at least 6 months
- •Creatinine clearance > 60 ml/min
- •With a body weight increase defined as:
- •10% from pre INSTI body weight whatever duration of INSTI duration OR
- •5% during the first year after INSTI regimen initiation
排除标准
- •Prior hypersensitivity to NNRTI
- •Resistance to doravirine in past resistance genotype(s) if available
- •Full resistance to tenofovir in past resistance genotype(s) if available
- •Diabetes, type 1 or type 2 assessed on by fasting glycemia over 7mmol/L, or non-fasting glycemia over 11 mmol/L or receiving anti-diabetic medications.
- •Pregnancy and breast feeding
- •Prior bariatric surgery
- •Hemostasis disorder or hemophilia
- •Oral or injectable anti-diabetics, thyroid hormones, growth hormone, insulin, and corticosteroid therapy lasting more than 5 days.
- •Body weight increase (in a context of recent tobacco cessation, introduction of psychotropic drugs, corticosteroids for at least one month, dysthyroidism, anabolic treatment or any hormonal therapy 6 months)
- •Current antineoplastic chemotherapy
- •Patient with instable housing
- •Any acute infection or tumor
- •Subjects under judicial protection due to temporarily and slightly diminished mental or physical faculties, or under legal guardianship
研究组 & 干预措施
Pathogenesis study
This pathogenesis study aimed to evaluate potential changes in adipose tissue after switching from an INSTI-based regimen (RAL or DTG or BIC) to TDF/FTC/DOR.
干预措施: Switch from an INSTI-based regimen to the non INSTI-based regimen combining TDF/3TC/Doravirine (Drug)
结局指标
主要结局
Measure the phenotype and alterations in adipose tissue to assess the impact of this weight gain
时间窗: 48 weeks
Measure the size of adipocytes assessed by Immunohistochemistry experiments Measure the presence of beige adipocytes within the white adipose tissue (Uncoupling protein 1) assessed by Immunohistochemistry experiments Measure the fibrosis (Red Sirius, collagens, fibronectin, Transforming Growth Factor-β, alpha smooth muscle actin) assessed by Immunohistochemistry experiments
Measure of markers of white adipose tissue, brown/beige adipose tissue, to assess changes in gene expression
时间窗: 48 weeks
Measure of markers leptin, adiponectin, transforming growth factor beta and fibroblast growth factor 21 assessed by ReverseTranscriptase-Polymerase Chain Reaction
Measure of markers of white adipocytes, brown adipocytes, differentiation lipogenesis, lipolysis enzymes and major players in insulin sensitivity to assess changes in gene expression
时间窗: 48 weeks
Measure of markers peroxisome proliferator-activated receptor, enhancer binding protein alpha, Cell death activator CIDE-A, Protein domain containing 16, Peroxisome proliferator-activated receptor gamma coactivator 1-alpha, Uncoupling Protein 1, sterol regulatory element binding protein 1C, hormone-sensitive lipase, ATGL and glucose transport protein 4 assessed by ReverseTranscriptase-Polymerase Chain Reaction
Measure of components of extra cellular matrix to assess changes in gene expression
时间窗: 48 weeks
Measure of markers alpha smooth muscle actin, fibronectin, transforming growth factor beta , collagens, connective tissue growth factor, lactate oxidase lipoxygenase assessed by ReverseTranscriptase-Polymerase Chain Reaction
次要结局
未报告次要终点