TAILoR (TelmisArtan and InsuLin Resistance in Human Immunodeficiency Virus [HIV]): An Adaptive-design, Dose-ranging Phase IIb Randomized Trial of Telmisartan for the Reduction of Insulin Resistance in HIV-positive Individuals on Combination Antiretroviral Therapy

Author:

Pushpakom Sudeep1,Kolamunnage-Dona Ruwanthi2,Taylor Claire3,Foster Terry1,Spowart Cath3,García-Fiñana Marta2,Kemp Graham J4,Jaki Thomas5,Khoo Saye1,Williamson Paula2,Pirmohamed Munir1, ,Ainsworth Jonathan,Chadwick David,Chaponda Mas,Chauhan Mayur,Churchill Duncan,Das Satyajit,Gompels Mark,Hereika Elbushra,Johnson Margaret,Leen Clifford,Loay David,Martin Fabiola,Minton Jane,Peters Barry,Post Frank,Schembri Gabriel,Vora Jiten,Whitehead John

Affiliation:

1. Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom

2. Department of Biostatistics, University of Liverpool, United Kingdom

3. Clinical Trials Research Centre, University of Liverpool, United Kingdom

4. Liverpool Magnetic Resonance Imaging Centre, University of Liverpool, United Kingdom

5. Department of Mathematics and Statistics, Lancaster University, United Kingdom

Abstract

Abstract Background Combination antiretroviral therapy results in metabolic abnormalities which increase cardiovascular disease risk. We evaluated whether telmisartan reduces insulin resistance in human immunodeficiency virus (HIV)–positive individuals on antiretrovirals. Methods We conducted a multicenter, randomized, open-label, dose-ranging controlled trial of telmisartan. Participants with HIV infection receiving combination antiretroviral therapy were randomized equally to either no intervention (control) or 20, 40, or 80 mg telmisartan once daily. The adaptive design allowed testing of all dose(s) of telmisartan in stage I, with the promising dose(s) being taken into stage II. The primary outcome measure was reduction in homeostasis model assessment of insulin resistance (HOMA-IR) at 24 weeks. Results A total of 377 patients were recruited. In stage I, 48, 49, 47, and 45 patients were randomized to control and 20, 40, and 80 mg telmisartan, respectively (total n = 189). At the interim analysis, 80 mg telmisartan was taken forward into stage II. At the end of stage II (n = 105, control; 106, 80-mg arm), there were no differences in HOMA-IR (estimated effect, 0.007; SE, 0.106) at 24 weeks between the telmisartan (80 mg) and nonintervention arms. Longitudinal analysis over 48 weeks showed no change in HOMA-IR, lipid or adipokine levels. There were significant (P ≤ .05), but marginal, improvements in revised Quantitative Insulin Sensitivity Check Index (QUICKI) (0.004) and plasma hs-CRP (−0.222 mg/L) and reduction in liver fat content (1.714 mean reduction; P = .005). Conclusions No significant effect of telmisartan was demonstrated on the primary outcome (HOMA-IR), but there were marginal improvements with some secondary outcome measures. Further studies in this population are warranted to identify novel strategies for preventing cardiovascular morbidity and mortality. Clinical Trial Registration ISRCTN registry (51069819).

Funder

MRC NIHR Efficacy and Mechanism Evaluation

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Microbiology (medical)

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