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)

点击翻译按钮获取中文摘要

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.