Pharmacogenetics of antiretrovirals.
The introduction of highly active antiretroviral therapy (HAART) as standard of care has changed the natural history of HIV infection into a manageable chronic disease requiring long-term antiretroviral (ARV) treatment. However, response to HAART is often limited by the occurrence of toxicity or by the emergence of drug resistance. Antiretroviral treatment is characterized by differing rates of adverse events and responses. Genetic variations between human beings account for a relevant proportion of this variability. A relevant number of associations between human genetic variants and predisposition to adverse events have been described and for some antiretroviral drugs a clear and casual genotype-phenotype correlation has already been established. The strong association between abacavir hypersensitivity reaction and HLA-B*5701 has been demonstrated in both observational and blinded randomized clinical trials in racially diverse populations and represents the best example of the clinical utility of pharmacogenetic screening in HIV medicine. Genotyping for HLA-B*5701 before prescribing an abacavir containing regimen has been introduced into routine clinical practice as the standard of care for all patients. Other well-established associations include CYP2B6 alleles and efavirenz central nervous system side effects, UGT1A1 alleles and atazanavir-associated hyperbilirubinemia and HLA class II allele HLA-DRB*0101 and nevirapine-associated hypersensitivity. Despite genetic associations having been described for peripheral neuropathy, lipodystrophy, hyperlipidaemia, pancreatitis and renal proximal tubulopathy, numerous barriers exist to the successful introduction of widespread genetic testing to the clinic. Future prospects point in the direction of individualization of antiretroviral therapy through insights from host genetics. The present paper is aimed to provide a comprehensive review of the published literature and to summarize the state of research in this area. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.
Tozzi
Valerio
V
National Institute for Infectious Diseases Lazzaro Spallanzani, Via Portuense 292, 00149 Rome, Italy. tozzi@inmi.it
D000480:Alkynes; D019380:Anti-HIV Agents / Q000009:adverse effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D000069446:Atazanavir Sulfate; D048588:Benzoxazines / Q000009:adverse effects; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D015224:Dideoxynucleosides / Q000009:adverse effects; D014453:Glucuronosyltransferase / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy*; D015234:HLA-A Antigens / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D019829:Nevirapine / Q000009:adverse effects; D009842:Oligopeptides / Q000009:adverse effects; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D010597:Pharmacogenetics; D011725:Pyridines / Q000009:adverse effects; D000099227:Abacavir; D000099148:UGT1A1 Enzyme
D000480:Alkynes; D019380:Anti-HIV Agents; D001189:Aryl Hydrocarbon Hydroxylases; D000069446:Atazanavir Sulfate; D048588:Benzoxazines; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D015224:Dideoxynucleosides; D014453:Glucuronosyltransferase; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D059811:HLA-DRB1 Chains; D019829:Nevirapine; D009842:Oligopeptides; D010089:Oxidoreductases, N-Demethylating; D011725:Pyridines; D000099227:Abacavir; D000099148:UGT1A1 Enzyme; C484830:HLA-B*57:01 antigen; C487961:HLA-DRB1*01:01 antigen; C585599:CYP2B6 protein, human; C098320:efavirenz