Current Pharmaceutical Design, 2010, 16, 3379-3389 3379 1381-6128/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd. Pharmacogenetics of the Metabolic Disturbances and Atherosclerosis Associated with Antiretroviral Therapy in HIV-Infected Patients Sergi Veloso 1 , Joaquim Peraire 1 , Consuelo Viladés 1 , Miguel López-Dupla 1 , Xavier Escoté 1,2 , Montserrat Olona 1 , Graciano Garcia-Pardo 1 , Frederic Gómez-Bertomeu 1 , Antoni Soriano 1 , Joan-Josep Sirvent 1 and Francesc Vidal 1, * 1 Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Tarragona, Spain; 2 CIBER Diabetes y Enfer- medades Metabólicas Asociadas (CIBERdem). Instituto de Salud Carlos III, Spain Abstract: The availability of highly active antiretroviral therapy has markedly improved the survival rate and quality of life in patients infected with HIV. At present, however, there is still no cure for HIV and those undergoing treatment have to do so for life. The use of antiretroviral drugs has been associated with several toxicities that limit their success. Some acute and chronic toxicities associated with these drugs include hypersensitivity reactions, neurotoxicity, nephropathy, liver damage, the appearance of body fat redistribution syn- drome and the different metabolic alterations that accompany it. Some of these toxicities are family- or even drug-specific. Since not all patients that take a particular antiretroviral medication develop the adverse effect that has been attributed to that drug, it has therefore been postulated that there must be a genetically-conditioned individual predisposition to developing the adverse effect. Pharmacogenetics is the science that studies interindividual variations in the response to and toxicity of drugs due to variations in the ge- netic composition of individuals. Sufficient advances have been made in this discipline to allow this fertile field of research to move out of the basic science laboratory and into clinical applications. The present article reviews the investigations that have been published re- garding the association between the genetic determinants of persons infected with HIV and the metabolic toxicity and chronic vascular consequences resulting from antiretroviral drugs. The influence of host genetic variants on dyslipidemia, hyperglycemia and insulin resis- tance, lipodystrophy and atherosclerosis are presented and discussed. Keywords: HIV, HAART, adverse effects, pharmacogenetics, dyslipidemia, insulin resistance, lipodystrophy, atherosclerosis. INTRODUCTION The impact of highly active antiretroviral treatments (HAART) on improving the survival rate and quality of life in patients in- fected with HIV is of such a magnitude that it has led some to claim that “medical miracles” do indeed exist [1]. This is due to the pow- erful suppressor effect that current antiretroviral drugs have on the viral load which is observed in a significant number of patients who take these medications appropriately. As a result, a substantial qualitative and quantitative improvement to the immune system occurs, which translates into an increase in the absolute CD4+ T- lymphocyte count and the recovery of lost functions. This im- provement often permits the prophylaxis of opportunistic infections to be suppressed [2,3]. At present, however, there is still no cure for HIV and those undergoing treatment for it have to do so for life. The use of antiret- roviral drugs has been associated with several toxicities that limit their efficacy. Some acute and chronic toxicities associated with these drugs include hypersensitivity reactions (HSR) [4], nephropa- thy [5], liver damage [6] and the appearance of body fat redistribu- tion syndrome and the different metabolic alterations that accom- pany it [7,8]. Some of these toxicities are family- or even drug- specific. An intriguing fact is that not all patients who take a par- ticular antiretroviral medication develop the adverse effect that has been attributed to that drug. It has therefore been postulated that there must be a genetically-conditioned individual predisposition to developing the adverse effect [9,10]. Pharmacogenetics is the science that studies interindividual variations in the response to and toxicity of drugs due to variations in the genetic composition of individuals, in other words, how a person’s genetic make-up influences the favorable or adverse *Address correspondence to this author at the Infectious Diseases and HIV/AIDS Section, Department of Internal Medicine, Hospital Universitari de Tarragona Joan XXIII, Mallafré Guasch, 4. 43007 Tarragona; Tel: 977295833; Fax: 977224011; E-mail: fvidalmarsal.hj23.ics@gencat.cat effects of a certain treatment. Sufficient advances have been made in this discipline to allow this fertile field of research to move out of the basic science laboratory and into the realm of potential clinical applications. The analysis of the human genome indicates that the most common genetic variation is constituted by single-nucleotide poly- morphisms (SNPs), which are alterations in the sequence of nucleo- tides that occur every 100-300 base pairs (bp) in the 3 billion bp of the human genome [11]. These changes in the DNA sequence do not always affect the genetic expression (phenotype). The combina- tion of multiple SNPs inherited together is called a haplotype. Haplotypes provide a more accurate prediction of genetic activity because they reflect the sum of the effects of the different SNPs. Most of the data on genetic susceptibility to a specific antiretrovi- ral-related toxicity are based on gene association studies in which researchers attempt to determine the relationship between candidate SNPs and their consequences by means of statistical analyses [12]. Some of these studies are also based on prior evidence of gene- toxicity associations for the general population, as is the case, for example, with the studies of SNPs associated with dyslipidemia [13]. But in many cases the hypothetical association is not actually confirmed in the end, which has led to the recent publication of preliminary guides for conducting such studies in order to prevent the diffusion of false positive results [14,15]. With the rapidly decreasing cost of genotype testing and the forecasted increase in its use as a toxicogenetic predictive tool in clinical practice related to HIV infection, some aspects of associa- tions between genetic markers and a specific event must be consid- ered. These include their reproducibility with high positive predic- tive values of the associations of SNPs with well-defined clinically relevant adverse events as well as the preference for studies that evaluate the contribution of SNPs in the context of the analysis of multiple SNPs and haplotypes, and finally, the validation of the genetic markers in large independent cohorts [10].