RESISTANCE, DRUG FAILURE, AND DISEASE PROGRESSION

The clinical significance of the reduced in vitro susceptibility of HIV to antiretroviral agents has been difficult to elucidate for nucleoside analogs such as zidovudine. However, the virological significance of resistance to nevirapine and other HIV-1-specific reverse transcriptase inhibitors has been established. With antiretroviral therapy, disease progression is not equivalent to drug failure, which is not equivalent to drug resistance. Clinical disease progression is only indirectly linked to HIV replication. Drug resistance is complex, and combining drugs does not appear to delay emergence of resistant strains of HIV although it may affect the specific amino acid substitutions. Drug resistance does appear to contribute to drug failure. The clinical trial ACTG 116B/117 found that the duration of prior zidovudine therapy was not related to the relative benefit of switching to didanosine. Preliminary results of analysis of resistant strains of HIV isolated from ACTG 116B/117 patients revealed that the relative hazard of progression was about threefold higher for patients with high-level resistance to zidovudine, syncytium-inducing biological phenotype, and an AIDS diagnosis at baseline. This study showed clearly that acquisition of an HIV strain with high-level resistance to zidovudine was a poor prognostic factor. Although nevirapine resistance emerges rapidly, preliminary data suggest that high dosages may be active against HIV even in the presence of resistant HIV strains. At the present time, viral resistance and biological phenotype are not useful in the management of individual patients.