Genetic barrier to resistance

Luber AD (2005) Genetic barriers to resistance and impact on chnical response. MedGenMed 7 69... 

The field is now poised to move into a new phase that will address opportunities for improvement on the profiles of RAL and EVG. These "next generation" drugs will need to deliver notable advantages in resistance profile along with having a high genetic barrier to resistance [51,52]. 

Etravirine has in vitro activity against a wide variety of wild-type and NNRTT-resistant HIV-1, and it was approved in the USA for use in treatment-experienced patients with HIV infection in early 2008. Etravirine may be effective against strains of HIV that have developed resistance to first-generation NNRTTs, depending on the number of mutations present. Although etravirine has a higher genetic barrier to resistance than the other NNRTTs, mutations selected by etravirine usually are associated with resistance to efavirenz, nevirapine, and delavirdine. 

Although virologic failures have been uncommon in clinical trials of raltegravir to date, in vitro resistance requires only a single point mutation (eg, at codons 148 or 155). The low genetic barrier to resistance emphasizes the importance of combination therapies and of adherence. Integrase mutations are not expected to affect sensitivity to other classes of antiretroviral agents. 

Two classes of entry inhibitors have been developed. The first entry inhibitor approved as HIV therapy was enfuvirtide, a fusion inhibitor. In contrast with aU other antiretrovirals, this drug must be administered subcutaneously and twice a day, which represent important disadvantages to the patient. It is very potent and generally reserved for heavily antiretroviral-experienced patients with virologic failure. Unfortunately enfuvirtide shows a low genetic barrier for resistance (Fig. 2) and should be administered in combination with at least one other active drug. 

F%. 2 Potency and genetic barrier for resistance according to different antiretroviral drug families... 

The risk of passing resistance genes from a crop to a wild related species is not inconceivable. A number of crops, (e.g., rice, millets, sorghum, oats, rapeseed, sugar beets, sunflower, alfalfa, peas, and potatoes) could be involved in introgression. Therefore, as herbicide resistant crops are engineered, a genetic barrier between crops and weeds must be devised. 

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