Development of resistance of human immunodeficiency virus (HIV) to anti-HIV agents: how to prevent the problem?
Of the multitude of reverse transcriptase inhibitors and protease inhibitors that have been pursued for the treatment of HIV infections, nine compounds (viz. zidovudine, didanosine, zalcitabine, stavudine, lamivudine, saquinavir, ritonavir, indinavir and nevirapine) have been approved and several others (i.e. adefovir dipivoxyl [bis(POM)-PMEA], PMPA, bis(POC)-PMPA, 1592U89, delavirdine, loviride, MKC-442, nelfinavir and VX-478) are under clinical development. All these compounds can select for mutations in the reverse transcriptase or protease that confer various degrees of resistance or diminished susceptibility to the compounds. Both the reverse transcriptase and protease are able to accumulate multiple mutations in their genome, thus engendering high-level resistance. To avoid drug resistance from emerging it is recommended to use from the beginning combinations of the different drugs at sufficiently high (that is maximal tolerated) doses. If installed as soon as possible after infection, when it has become evident that the virus is replicating, these drug combinations may achieve a pronounced and sustained virus suppression. This should be reflected by a dramatic reduction of viral load in both the plasma and lymphnodes. With the most effective drug combination regimens, the viral load may even fall under the threshold of detection, and this may clinically translate into an arrest or prevention of progression to AIDS.
De Clercq
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Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.