TAILoR (TelmisArtan and InsuLin Resistance in HIV): A Dose-Ranging Phase II Randomised Open-Labelled Trial of Telmisartan as a Strategy for the Reduction of Insulin Resistance in HIV-Positive Individuals on Combination Antiretroviral Therapy (cART)

艾滋病毒现在是一种慢性病，可以通过联合抗逆转录病毒疗法(CART)进行治疗。这导致了艾滋病毒相关死亡率的下降，但也导致了艾滋病毒脂营养不良(HIVLD)等严重不良影响的出现。这种情况的特点是脂肪减少(面部和四肢)和脂肪积累(腹部和颈部)，高胆固醇水平，对胰岛素的反应降低(胰岛素抵抗)，有时还会患糖尿病，重要的是，缺血性心脏病的风险增加。一个关键的异常现象似乎是胰岛素抵抗，这种情况也可能发生在未经治疗的艾滋病毒患者中。尽管已经推出了更多“对脂质友好的”抗艾滋病毒药物，因为(A)药物必须联合使用，(B)由于其他副作用或病毒突变的发生而频繁更换药物，以及(C)我们正在治疗日益老龄化的艾滋病毒阳性人群，几乎所有患者都会出现胰岛素抵抗。需要找到新的策略来降低接受CART治疗的HIV阳性患者的胰岛素抵抗，这最终将降低相关的心血管风险。我们将使用替米沙坦，这是一种广泛用于治疗高血压的药物。在高血压患者中，它已被证明可以降低胰岛素抵抗，并改善心血管健康的各种指标(生物标记物)。在HIVLD中，脂肪细胞(脂肪细胞)是胰岛素抵抗发展的关键。抗HIV药物与脂肪细胞相互作用，在某些情况下使它们失去储存脂肪的能力，并增加被称为细胞因子的活性分子的分泌，这会导致炎症和胰岛素抵抗。我们已经证明，替米沙坦可以防止HIV药物诱导的脂肪细胞脂肪减少，脂联素(心脏健康的标志)和脂蛋白1(脂肪细胞形成的标志)的减少。这项拟议试验的目的是调查替米沙坦是否可以减少服用CART的HIV阳性患者的胰岛素抵抗。我们将比较3种不同剂量的替米沙坦与对照组(那些没有服用替米沙坦的人)，以确定在48周内对胰岛素抵抗的影响。我们在这项研究中使用了一种新的适应性试验设计--这是与西北MRC试验方法中心共同开发的。我们的团队由艾滋病毒药物、药理学和糖尿病方面的专家、科学家和试验统计师组成，以确保这项试验的成功进行，该试验将通过一个经认可的临床试验单位进行。我们已经为所要求的费用提供了充分的理由。如果替米沙坦对胰岛素抵抗有显著的有益效果，下一步将进行一项更大的III期研究，以评估其对接受CART治疗的HIV阳性患者心血管发病率的影响。

HIV is now a chronic disease treatable by combination antiretroviral therapy (cART). This has resulted in a reduction in HIV-related mortality, but has also led to the emergence of serious adverse effects such as HIV lipodystrophy (HIVLD). This condition is characterised by fat loss (from face and limbs) and fat accumulation (abdomen and back of neck), high cholesterol levels, reduced response to insulin (insulin resistance) and sometimes diabetes, and importantly, an increase in the risk of ischaemic heart disease. A key abnormality seems to be insulin resistance, which can also occur in untreated HIV patients. Although more “lipid-friendly” anti-HIV drugs have been introduced, because (a) drugs have to be used in combinations, (b) there is frequent switching of drugs because of other side effects or the occurrence of viral mutations, and (c) we are treating an increasingly older HIV-positive population, almost all patients will develop insulin resistance. There is a need to find new strategies to reduce insulin resistance in HIV-positive individuals treated with cART, which ultimately will reduce the associated cardiovascular risk. We will use telmisartan, a drug that is widely used for the treatment of hypertension. In hypertensive patients, it has been shown to reduce insulin resistance and improve various indicators (biomarkers) of cardiovascular health. In HIVLD, the fat cell (adipocyte) is key to the development of insulin resistance. Anti-HIV drugs interact with fat cells, making them lose their ability to store fat in some instances, and increase the secretion of active molecules called cytokines, which lead to inflammation and insulin resistance. We have shown that telmisartan can prevent HIV drug-induced fat loss in adipocytes, reduction in adiponectin (a marker of cardiac health) and lipin1 (a marker of fat cell formation). The aim of the proposed trial is to investigate whether telmisartan can reduce the insulin resistance observed in HIV-positive individuals on cART. We will compare 3 different doses of telmisartan with the control group (those who do not take telmisartan) to determine the effect on insulin resistance over a period of 48 weeks. We are using a novel adaptive trial design for this study – this has been developed in conjunction with the North West MRC trials methodology hub. Our team consists of experts in HIV medicine, pharmacology and diabetes, scientists and trial statisticians to ensure the successful conduct of this trial, which will be run via an accredited clinical trials unit. We have provided full justification for costs requested. If telmisartan shows a significant beneficial effect on insulin resistance, the next step would be to conduct a larger phase III study to assess its effect on cardiovascular morbidity in HIV-positive individuals treated with cART.