Antonio Liras, Profesor de Fisiología. Universidad Complutense de Madrid. SPAIN, aliras@hotmail.com

Genomic medicine helps understand the causes of disease from a molecular etiopathogenetic viewpoint (genomics, transcriptomics, proteomics, metabolomics). It is also helpful for differentiating environmental from genetic causes, for anticipating the course of disease and, of course, for effective management (pharmacogenetics, pharmacogenomics, gene therapy). The resulting balance or imbalance between the genome and environment leads to a state of health or disease respectively. Environmental factors having the greatest influence on this balance include nutrition, the air we breathe, the fluids we drink, and the drugs used. Such environmental factors have to act as preventive elements to avoid disease, and pharmacogenomic and pharmacogenetic intervention represents here the tool for disease control, prevention, and treatment using therapeutic optimization criteria. With regard to HIV infection, an analysis of the genetic profile of patients allows for understanding the adverse reactions to antiretroviral drugs, because one of the characteristics of infection with this virus is that it follows a very different course in each individual. Incorporation of analysis of the genetic profile of patients into clinical practice could allow for an increasingly individualized, effective, and safe antiretroviral prescription.

One of the main problems when diagnosing diseases if the lack of the so-called presymptomatic or predicting markers, that may allow for detecting the risk of experiencing a disease before this becomes evident. Such markers allow for identifying risks in advance and for implementing effective preventive programs. In early disease stages, conventional medicine characterizes the underlying pathological process using medical criteria, biochemical parameters, and genetic markers. At this symptomatic stage, genomic medicine uses genomic and proteomic analyses based on proven molecular markers having a high diagnostic reliability, which allows for implementing early intervention programs for early therapeutic management of the disease. Finally, in the late disease stages, conventional medicine is based on the use of symptomatic and palliative treatments, while genomic medicine needs to be able to design effective approaches for preventing disease progression using the so-called pharmacogenetics and pharmacogenomics (Meyer, 2004).

Genomic medicine helps understand the causes of disease from a molecular etiopathogenetic viewpoint (genomics, transcriptomics, proteomics, metabolomics). It is also helpful for differentiating environmental from genetic causes, for anticipating the course of disease and, of course, for effective management (pharmacogenetics, pharmacogenomics, gene therapy). The natural course of genomic medicine includes understanding the individual genes associated to the disease and the interaction of those defective genes with other genomic networks responsible for organization of enzymatic pathways (metabolomics), and identification of genes whose different polymorphic variables influence drug metabolism from both the safety and efficacy viewpoints.

It is well known that the structure of our genome is the result of evolution, positive and negative natural selection factors, random distribution of polymorphic variants inducing predisposition or resistance, beneficial or harmful genetic mutations, and so on. On the other hand, genome has a dynamic nature because of its constant relationship to our environment (Hunter, 2005). The resulting balance or imbalance between the genome and environment leads to a state of health or disease respectively. Environmental factors having the greatest influence on this balance include nutrition, the air we breathe, the fluids we drink, and the drugs used. Such environmental factors have to act as preventive elements to avoid disease, and pharmacogenomic and pharmacogenetic intervention represents here the tool for disease control, prevention, and treatment using therapeutic optimization criteria.

Pharmacogenomics are defined as the study of factors that determine the effectiveness of a drug as related to its regulatory effect on expression of genes causing a disease or related to its pathogenesis, while pharmacogenetics are defined as the study of factors that determine the safety of a drug in terms of its hepatic metabolism associated to a set of genes responsible for drug biotransformation and pharmacokinetics. Pharmacogenomics would rather address those genetic factors related to the efficacy of a drug, while pharmacogenetics would address genes responsible for drug safety.

Considering that approximately 1,500 genes in the genome are specifically related to drug metabolism and that some 3,000-5,000 genes are associated to specific diseases, it may be stated that the genetic network resulting from functional integration of all these genes would be able to discriminate from 4 to 10 million xenobiotic agents attacking the body every day.

It has been objectively documented that a drug works differently, sometimes better and sometimes worse, in some patients as compared to others (Eichelbaum et al, 2006). In other words, there is a pharmacological variability, 50% of which also depends on given genes. Other factors also include the side effects of drugs, intolerance, metabolic and pharmacokinetic factors, or nutritional problems.

In addition to the design of new drugs adapted to the needs of the diseased genome for regulating expression of abnormal genes using pharmacogenomic strategies, the other great challenge in genomic medicine is to standardize the pharmacogenetic protocols to administer to a patient the most suitable drug at its optimum dosage. This is the role of pharmacogenetics.

This applies to almost every disease, from hypertension and heart diseases to cancer or even, strikingly, certain infections such as that caused by the human immunodeficiency virus (HIV). Irremediably, therapeutic optimization will come in the future from implementation of these new pharmacogenetic and pharmacogenomic intervention strategies.

With regard to HIV infection, an analysis of the genetic profile of patients allows for understanding the adverse reactions to antiretroviral drugs, because one of the characteristics of infection with this virus is that it follows a very different course in each individual. An example of this is the widely changing time elapsed from HIV infection to AIDS progression, ranging from less than 5 to 20 years depending on the subject. This is due to both viral factors and genetic differences between individuals. By the same token, genes condition patient response to the different antiretroviral drugs.

Incorporation of analysis of the genetic profile of patients into clinical practice could allow for an increasingly individualized, effective, and safe antiretroviral prescription. The study of the genetic bases for variability in drug response and the consequences of the existing variables in a single gene (pharmacogenetics) or multiple genes (pharmacogenomics) is already being effectively applied for the treatment of HIV infection/AIDS. In this regard, very effective treatments are currently available for HIV infection/AIDS, and progress is being made to improve tolerability and increase treatment convenience and simplicity. However, there is still a high proportion of patients, ranging from 20% and 30%, who fail due to virus resistance or to high drug toxicity.

Pharmacogenomics may contribute to a more personalized selection of the antiretroviral therapy (Evans and McLeod, 2003). This particularly requires an analysis of the genetic factors related to an increased risk of virological and therapeutic failure (patients with a poorer absorption capacity and low drug levels in blood), an increased risk of toxicity (excess uptake or a low metabolic rate of the drug), an increased predisposition to metabolic disorders (dyslipidemia or lipoatrophy), or the development of drug allergy. In addition to viral load tests and CD4+ cell counts, new tools are currently available, including resistance and pharmacogenetic tests. It is now known that genetic predisposition may have a significant effect on treatment outcome, so that understanding the host pharmacogenomics will allow for predicting the toxicity and efficacy of treatments.

Significant advances have already been made in the understanding of some genetic factors associated to a high risk of toxicity from or a beneficial response to antiretroviral drugs. The ability to identify patients with a high risk of toxicity from an antiretroviral drug or who may particularly benefit from a treatment is an important goal for the different pharmacogenetic tests. Thus, for instance, abacavir -a nucleoside analogue reverse transcriptase inhibitor- is associated to an uncommon but potentially serious hypersensitivity reaction that is related to the presence of the HLA-B*5701 allele. Determination of the presence of this allele using a pharmacogenetic test may allow for a safer prescription of the drug.

Since the start of the HIV pandemic, multiple advances have been made in disease treatment, so that AIDS may be considered a chronic condition in most cases. The challenge now lies in achieving a long-term treatment that ensures patients, in addition to control of HIV infection, the highest possible quality of life, taking into account that all antiretroviral drugs have side effects that vary markedly from one patient to another.

Availability of tests that may allow us for predicting whether a drug may eventually fail or cause a greater than usual toxicity in a given patient will greatly contribute to taking more adequate therapeutic decisions and to optimize treatment for HIV/AIDS.

References

Eichelbaum M, Ingelman-Sundberg M, Evans WE. Pharmacogenomics and individualized drug therapy. Ann Rev Med 2006; 57: 119-37.

Evans WE, McLeod HL. Pharmacogenomics: Drug disposition, drug targets, and side effects. N Engl J Med 2003; 348: 538-49.

Hunter DJ. Gene-environment interactions in human diseases. Nat Rev Genet 2005; 6: 287-98.

Meyer UA. Pharmacogenetics: Five decades of therapeutic lessons from genetic diversity. Nat Rev Genet 2004; 5: 669-76.