RESISTANCE OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1) TO NONNUCLEOSIDE HIV-1-SPECIFIC REVERSE-TRANSCRIPTASE INHIBITORS

Various non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been reported to specifically inhibit HIV-1: viz. tetrahydroimidazobenzodiazepinone (TIBO), hydroxyethoxymethylphenylthiothymine (HEPT), dipyridodiazepinone (i.e. nevirapine), pyridinone, bis(heteroaryl)piperazine (BHAP), tert-butyidimethyisiiyispiroaminooxathiole-dioxide (TSAO), alpha-anilinophenylacetamide (alpha-APA) and quin oxaline derivatives. The most potent among the TIBO, HEPT and (alpha-APA derivatives have been found to inhibit HIV-1 replication at nanomolar concentrations that are 100,000-fold lower than the cytotoxic concentrations. These compounds therefore offer great potential for the treatment of HIV-1 infections. Yet, the virus may rapidly develop resistance to these drugs. The mutations conferring resistance have been, mapped at the reverse transcriptase positions 100 (Leu --> lie), 103 (Lys --> Asn), 106 (Val --> Aia), 108 (Val --> IIe), 138 (Glu --> Lys), 179 (Val --> Asp), 181 (Tyr --> Cys --> IIe), 188 (Tyr --> Cys/His), 190 (Gly --> Glu), 230 (Met --> IIe) and 236 (Pro --> Leu). However, these mutations do not necessarily lead to cross-resistance among the various NNRTls and, in some cases, they have proved to be mutually suppressive. Several strategies can be envisaged to circumvent or prevent the resistance problem. (i) switching from one NNRTI (to which the virus has developed resistance) to another (to which it has not developed resistance); (iii combination of different NNRTIs that do not confer cross-resistance, or even counteract development of resistance to one another; (iii) using from the start sufficiently high (''knocking out'') concentrations so as to completely shut off virus replication and prevent resistance from emerging; and (iv) by combining strategies (ii) and (iii), using from the start combinations of different drugs so as to achieve virus ''knock out'' at even lower concentrations.