Current knowledge of HIV-1 reverse transcriptase mutations selected during nucleoside analogue therapy: the potential to use resistance data to guide clinical decisions

Massive viral turnover and the high error rate of reverse transcriptase create the potential for drug-resistant viral variants to appear rapidly under the selective pressure of antiretroviral therapy. Loss of antiviral effect in treatment compliant persons is most commonly coincident with the appearance of viral mutants with reduced drug sensitivity. Thus, detection of viral resistance may represent an early marker of therapy failure. Similarly, substantial reduction in viral replication in the plasma compartment, to below quantification of a viral load assay, is associated with a sustained therapeutic response and delayed development of viral resistance. Information on patterns of resistance to and cross-resistance between antiretroviral agents are increasingly well characterized and represents an important consideration when deciding how to combine and/or sequence antiretrovirals to achieve optimal antiviral effects. When switching therapy, the change of several agents in the treatment regimen is currently recommended. The use of novel means of evaluating resistance, such as a genotypic probe, may guide clinicians in choosing an agent to which the patient's dominant viral quasispecies remains sensitive, potentially increasing the chances of achieving a therapeutic response. However, no studies using resistance to guide clinical decision making have yet been reported and available sequencing studies have focused largely on switching or adding therapies to patients who have received zidovudine monotherapy. Thus, no resistance driven treatment algorithm is currently available.