RESISTANCE, DRUG FAILURE, AND DISEASE PROGRESSION

The clinical significance of the reduced in vitro susceptibility of HI V to antiretroviral agents has been difficult to elucidate for nucleos ide analogs such as zidovudine. However, the virological significance of resistance to nevirapine and other HIV-1-specific reverse transcrip tase inhibitors has been established. With antiretroviral therapy, dis ease progression is not equivalent to drug failure, which is not equiv alent to drug resistance. Clinical disease progression is only indirec tly linked to HIV replication. Drug resistance is complex, and combini ng drugs does not appear to delay emergence of resistance strains of H IV although it may affect the specific amino acid substitutions. Drug resistance does appear to contribute to drug failure. The clinical tri al ACTG 116B/117 found that the duration of prior zidovudine therapy w as not related to the relative benefit of switching to didanosine. Pre liminary results of analysis of resistant strains of HIV isolated from ACTG 116B/117 patients revealed that the relative hazard of progressi on was about threefold higher for patients with high-level resistance to zidovudine, syncytium-inducing biological phenotype, and an AIDS di agnosis at baseline. This study showed clearly that acquisition of an HIV strain with high-level resistance to zidovudine was a poor prognos tic factor. Although nevirapine resistance emerges rapidly, preliminar y data suggest that high dosages may be active against HIV even in the presence of resistant HIV strains. At the present time, viral resista nce and biological phenotype are not useful in the management of indiv idual patients.