CONVERGENT COMBINATION THERAPY CAN SELECT VIABLE MULTIDRUG-RESISTANT HIV-1 IN-VITRO

THE reverse transcriptase enzyme of human immunodeficiency virus type 1 (HIV-1) is the target for many inhibitors1. Amino-acid substitutions in functional regions of the enzyme that abolish reverse transcriptase activity also prevent HIV-1 replication2,3. But selection pressure by drugs such as AZT (3'-azido-3'-deoxythymidine, zidovudine)4-6, ddI(2',3'-dideoxyinosine)7,8 and non-nucleoside reverse transcriptase inhibitors (NNRTIs)9-14 causes outgrowth of resistant variants due to non-lethal mutations in the enzyme7,9-16. Reports of synergy17-19 and lack of cross-resistance between reverse transcriptase inhibitors (refs 7, 9, 10, 12-14, 17, 18, 20, 21), plus the reversal of AZT resistance by mutations induced by ddI7 and NNRTIs14, have indicated that specific drug combinations directed at reverse transcriptase might curtail resistance. Chow et al.22 extended this concept in a report that specific multiple combinations of resistance mutations in the reverse transcriptase can significantly impair HIV-1 replication. They concluded that evolutionary limitations may exist to prevent the emergence of multidrug resistance to inhibitors of reverse transcriptase22. We report here that HIV-1 co-resistant to AZT, ddI and the NNRTI nevirapine23 can be readily selected in cell culture starting with dual AZT- and ddI-resistant virus. We found no evidence for 'replication incompatible' combinations of resistance mutations, although a mutation (M184-->V) conferring oxathiolane-cytosine nucleoside resistance in reverse transcriptase24,25 completely suppressed AZT resistance in a triple-resistant background. These in vitro observations suggest that triple drug combination therapy might ultimately result in co-resistant HIV-1, although they do not preclude assessment of such combinations for treatment of HIV-1 disease.