Human Immunodeficiency Virus Type 1 Pharmacogenomics in Clinical Practice: Relevance of HIV-1 Drug Resistance Testing (Part 2)

Abstract

Throughout most of the past century, physicians could offer patients no treatments for infections caused by viruses. The experience with treatment of infection by human immunodeficiency virus (HIV) has changed the way healthcare workers deal with viral infections and has triggered a growing rate of discovery and use of antiviral agents, the first fruits of the expanding genomics revolution. HIV treatment also provides an informative paradigm for pharmacogenomics because control of infection and its consequences is limited by the development of viral drug resistance and by host factors. This report summarizes studies published to date on the significance of testing of HIV-1 resistance to antiretroviral drugs. The only Food and Drug Administration-approved kit is commercially available through Visible Genetics, Inc., for HIV drug resistance testing by genotypic sequencing. Genotyping sequencing alone is most likely an adequate test to assist in the therapeutic decision-making process in cases of previous regimen failure, treatment-naïve patients in areas of high prevalence of transmitted resistant virus, and pregnant women. However, in exceptional cases of highly complex mutation patterns and extensive cross-resistance, it may be useful to obtain a phenotype test, because that result may more easily identify drugs to which the virus is least resistant. There are no published clinical trial results on the usefulness of the so-called virtual phenotype over genotypic sequencing alone. The paradigm of viral pharmacogenomics in the form of HIV genotypic sequencing has been not only useful to the treatment of other viral diseases but also important to the real-life implementation of the growing discipline of genomics or molecular medicine. The application of this paradigm to the thousands of potential therapeutic targets that have become available through the various human genome projects will certainly gradually change the landscape of diagnosis and management of many diseases, including cancer.

From Traditional Biomarkers to Transcriptome Analysis in Drug Development

“…Furthermore, it can serve as an intermediate surrogate indicative of the effectiveness of treatments in chemopreventive trials [70], which would otherwise take much longer and cost much more to complete. Examples of other such surrogate biomarkers that have been used successfully to expedite clinical trials in their respective disease areas include bone mineral density or bone turnover markers in osteoporosis [71][72][73][74][75], blood glucose or glycosylated hemoglobin levels in diabetes [76][77][78][79][80][81], cholesterol levels in cardiovascular diseases [51,52,[82][83][84][85], CD4 counts in HIV infections [54,55,86,87].…”

“…A series of subsequent measurements of the cholesterol levels will allow doctors to monitor the effectiveness of the prescribed drug and, if necessary, change the course of treatment. In the case of HIV patients undergoing cocktail therapy, the viral load test and viral mutation test will allow physicians to monitor potential drug resistance to therapy and adjust the "cocktail" accordingly [87].…”

Immunological and molecular assessment of HIV-1 mutations for antiretroviral drug resistance in Saudi Arabia

“…Resistance to ARV, which is caused by viral mutations that diminish drug sensitivity, is the primary cause of HIV treatment failure [ 10 , 11 ]. Molecular tests detect HIV drug-resistance mutations [ 12 ]. Antiretroviral therapy (ART) inhibits viral replication and restores immune function in immunocompromised individuals [ 13 ].…”