Metabolic consequences and therapeutic options in highly active antiretroviral therapy in human immunodeficiency virus-1 infection

Journal of Antimicrobial Chemotherapy (2008) 61, 238– 245 doi:10.1093/jac/dkm475 Advance Access publication 10 December 2007 Metabolic consequences and therapeutic options in highly active antiretroviral therapy in human immunodeficiency virus-1 infection Katherine Samaras* Diabetes Program, Garvan Institute of Medical Research, Department of Endocrinology, St Vincent’s Hospital, 384 Victoria St, Darlinghurst, NSW 2010, Australia The use of highly active antiretroviral therapy (HAART) in HIV-1 infection confers immunological and survival advantages, at the cost of induction of significant metabolic disturbances. These include insulin resistance, disturbances in lipid metabolism, glucose homeostasis, adipocyte physiology and body fat partitioning with peripheral lipoatrophy and visceral obesity. These metabolic disturbances produce clinical manifestations which impact on the future health of the HIV-infected patient, including hyperlipidaemia, lipodystrophy, metabolic syndrome, cardiovascular disease and type 2 diabetes. These conditions are evident in the relative short term as HAART (and possibly HIV infection) appears to accelerate their pathogenesis. The current understanding of the mechanisms and time courses for developing metabolic complications on HAART is reviewed in this paper. The efficacy of therapeutic interventions for insulin resistance, hyperlipidaemia, body fat partitioning disorders and metabolic syndrome is summarized. Keywords: metabolic syndrome, lipids, glucose, insulin resistance, HIV, diabetes, obesity, lipodystrophy Introduction The treatment of HIV infection with highly active antiretroviral therapy (HAART) confers significant morbidity and survival benefits. The advent of effective drugs, which restore immune system function and suppress viral replication, has transformed a once-fatal disease to significantly improved life expectancy. The cost of improved immune function and longevity may include metabolic complications however, which have become apparent with increasingly widespread and longer term use of HAART. These include hyperlipidaemia, insulin resistance, diabetes mellitus and disturbances in body fat partitioning. This leading article will describe the metabolic complications of HAART, specifically disturbances in glucose metabolism, lipids and body fat partitioning, with reference to emerging evidence of adverse long-term sequelae, specifically premature cardiovascular disease and type 2 diabetes, and review the current knowledge of efficacy of therapeutic interventions. HAART can currently be divided into five drug classes: protease inhibitors (indinavir, ritonavir, nelfinavir, fosamprenavir, saquinavir, atazanavir, tipranavir and darunavir), nucleoside reverse transcriptase inhibitors (NTRIs) (stavudine, zidovudine, lamivudine, abacavir, didanosine, tenofovir and emtricitabine), non-nucleoside reverse transcriptase inhibitors (NNTRIs) (efaviranz and nevirapine) and the newer classes, entry inhibitors (fusion inhibitors: enfuvirtide; and CCR5 inhibitors: maraviroc) and integrase inhibitors (raltegravir). At the time of writing, no metabolic data have been reported from Phase 3 clinical trials: (enfuvirtide, TORO; maraviroc, MOTIVATE 1 and MOTIVATE 2; and raltegravir, BENCHMRK-1 and BENCHMRK-2). Defining the metabolic complications Insulin resistance Insulin resistance refers to the reduced action of circulating insulin to induce uptake of glucose into cells, where glucose then serves as a major substrate for cellular function. Insulin stimulates its cell surface receptor, which sets up a phosphorylation cascade, firstly of insulin receptor substrate-1 which in turn initiates a number of further phosphorylation reactions. These eventually result in translocation of one form of glucose transporters, glucose transporter 4 (GLUT4), from the cytosol to the cell surface where it facilitates glucose entry into the cell. There are many points in this complex pathway where reduced insulin action may be induced. For example, it is known that high circulating fatty acids, through a mechanism termed lipotoxicity, interfere with post-insulin receptor signalling pathways.1 This is one of the mechanisms postulated to occur in the common form of obesity-induced insulin resistance and type 2 diabetes. Insulin resistance underlies many metabolic conditions. It is a core feature of type 2 diabetes and accompanies abdominal obesity. It is present in atherothrombotic cardiovascular disease. ..................................................................................................................................................................................................................................................................................................................................................................................................................................... *Corresponding author. Tel: þ61-2-9295-8312; Fax: þ61-2-9295-8201; E-mail: ..................................................................................................................................................................................................................................................................................................................................................................................................................................... 238 # The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. Downloaded from Forhttps://academic.oup.com/jac/article-abstract/61/2/238/766138 Permissions, please e-mail: by guest on 17 June 2018 Leading article It underlies the dyslipidaemia characterized by hypertriglyceridaemia and low HDL cholesterol. Insulin resistance is also recognized as the core component of the metabolic syndrome (discussed below), having been described by Reaven2 as the ‘common soil’ from which all metabolic diseases develop. Insulin resistance is considered to be the link between the clustering of metabolic disturbances within ‘metabolic syndrome’, including abdominal obesity, diabetes, heart disease, hypertension and dyslipidaemia. Insulin resistance is a pathophysiological state, which can be inferred from historical, clinical and laboratory data. Historically these include family history of type 2 diabetes or cardiovascular disease; clinically, abdominal obesity and hypertension; and biochemically, the presence of disturbed glucose metabolism and dyslipidaemia. Insulin resistance is, however, difficult to quantify and there are no valid measures available for clinical practice.3,4 The gold standard measure is the hyperinsulinaemic euglycaemic clamp, an invasive technique that is resource and time intensive, and suitable for research alone. Surrogate estimates such as fasting insulin and the homeostasis model assessment5 are again only suitable for research and epidemiological settings. Prio (...truncated)