Clinical Significance of Drug Resistance in HIV-1 Infection

Treatment of HIV-1 infection with potent combination therapy (sometimes called highly active antiretroviral therapy, or HAART) dramatically slows progression to AIDS. In the developed world, the wide-spread use of HAART has resulted in a sharp decrease in the number of deaths due to AIDS over the last five years (1). Although transient improvements in survival have been demonstrated with nucleoside monotherapy and dual combination therapy, the clinical benefit of such regimens may be limited by the eventual development of drug resistance. The high error rate of reverse transcriptase (the viral enzyme responsible for reproducing the viral genome, or genetic material), coupled with high levels of HIV-1 replication result in the very rapid emergence of drug-resistant strains of HIV-1 in most settings where treatment fails to completely suppress virus replication.

Current triple therapy regimens are able to delay the development of drug resistance because they suppress virus replication to undetectable levels. However, problems with adherence to treatment, drug toxicities, differences in drug absorption or metabolism (i.e., pharmacokinetics), and other host factors can compromise the activity of a HAART regimen. Over time, these factors may allow the accumulation of mutations that confer drug resistance, leading eventually to treatment failure. Although individual drugs select for specific resistance mutations, the rate at which these mutations emerge is quite variable, and often difficult to predict. In particular, failure of a triple-drug regimen may be associated with resistance to only one or two drugs in the regimen (2). Therefore, knowledge of the specific pattern of drug resistance may be helpful in choosing the next treatment regimen. For this reason, considerable effort has been devoted to the development of assays for HIV-1 drug resistance. As a result, the tests have improved considerably over the last few years and are quickly becoming an essential tool in choosing therapy for patients experiencing treatment failure.

4/15/01

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