HIV pharmacogenetics and pharmacogenomics: From bench to bedside

Abstract

Abstract Thirty five years after the identification of the human immunodeficiency virus (HIV) as the etiologic agent for AIDS, there are still no effective vaccines and no sterilizing cures. Fortunately, combination antiretroviral therapy (ART) has turned a deadly disease into a manageable, chronic condition. Effective and lifelong antiretroviral therapy is the foundation of the fight to reduce HIV-associated morbidity and mortality, and to improve the quality of life for the estimated 36.9 million persons living with HIV. Increasingly, antiretroviral medications also are being used to protect HIV-negative individuals from HIV infection. Antiretroviral treatment, however, is associated with numerous toxicities that range from mild to life-threatening and that affect nearly all organ systems. As the number of people on ART increases and the population ages, genetic predictors of toxicities and age-related morbidities due to ART become increasingly critical. HIV/AIDS has been subjected to intensive genetic investigation in an effort to explain the variability in HIV/AIDS, to identify potential targets for therapeutic intervention, and to reveal the genetic basis for interpersonal and inter-population variation in efficacy and toxicities associated with antiretroviral therapies An and Winkler [1]; Aouizerat et al. [145]; Tozzi [31]. These studies have identified a number of genetic variants that are important correlates of HIV pathogenesis and antiretroviral therapy. Whole-genome association studies in the general population have revealed genetic factors associated with metabolic disorders (i.e., type 2 Diabetes mellitus and lipodystrophy); genetic profiling might have utility in the choice of ART regimens to avoid drugs associated with metabolic toxicities. Pharmacogenetics is just beginning to be incorporated into clinical practice, most notably screening for HLA-B*5701, which is associated with abacavir hypersensitivity reaction. Pharmacogenetics is also being applied to drug selection at the population level particularly in resource-limited settings, based in part on the population prevalence of fast and slow metabolizing variants in a given geographic region or among specific human populations. Here we review the role of pharmacogenetics and pharmacogenomics in HIV therapy and drug-related toxicities, the utility of genetic screening for personalized HIV care, and what is needed to bring personalized, genetics-informed care to the clinic.