Effect of resistance on combination chemotherapy for human immunodeficiency virus infection

The effect of 3 drug combinations (AZT/FLT, AZT/ddI and FLT/ddI) upon the replication of AZT-sensitive and -resistant human immunodeficiency virus (HIV) was studied. The 3 combinations synergistically inhibited drug sensitive virus. However, AZT resistant virus showed an altered response to the combinations containing AZT: synergy was replaced by addition or antagonism. Thus, the susceptibility to a drug may affect the synergistic effect of combinations containing that drug. Other drug combinations may not be affected, since the AZT resistant virus retained a synergistic response to the combination of FLT/ddI. The synergistic effect could be regained upon reversion of resistance; a viral isolate taken after cessation of therapy, which had reverted to sensitivity to AZT, regained the synergistic response to drug combinations containing AZT. These results have implications for the use of combination chemotherapy to treat infection with HIV. Drug combinations will be most useful if the virus is sensitive to all components in the combination. It might be preferable to avoid the inclusion in combinations of drugs to which there is resistance, since we saw an antagonistic effect for combinations containing AZT in AZT resistant virus. Other combinations not containing the drug to which resistance has arisen may maintain their synergistic effect and remain good choices. Thus, a strategy of monitoring drug sensitivity and altering the combination therapy accordingly would appear to offer promise for the treatment of HIV infection.