Mechanisms of resistance to antiretroviral drugs--clinical implications

HIV resistance to antiretroviral agents involves the selection of mutations within the reverse transcriptase (RT) and protease (PRO) genes, that result in structural changes causing in most instances a loss of affinity of RT and PRO inhibitors for their respective targets. Then, the inhibitory competition caused by these molecules in respect to the physiologic substrates of the RT and PRO enzymes is lost. For nucleoside analogs, a second mechanism of resistance involves the removal of the chain terminators (pyrophosphorolisis) and is caused by the classical AZT-resistance mutations. Complex interactions between drug resistance mutations make difficult how to interpret and predict the benefit of antiretroviral agents in the clinical arena. However, for most antiretroviral agents, resistance is not a dichotomic situation but rather a relatively continuous phenomenon, in which some partial activity of compounds is found even in the face of drug resistance mutations. Based in this fact, resistance to PRO inhibitors may be overcome when plasma levels of PRO inhibitors are boosted using low doses of ritonavir.