NUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS AND RESISTANCE OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1

Drug-resistant isolates of human immunodeficiency virus type 1 (HIV-1) emerge during longterm treatment with nucleoside reverse transcriptase inhibitors, such as zidovudine. The clinical significance of in vitro drug resistance to zidovudine has been difficult to determine. However, in a virologic analysis of baseline specimens from the AIDS Clinical Trials Group (ACTG) 116B/117 study, high-level zidovudine resistance, defined as an IC50 of greater than or equal to 1 mu M at study entry, was significantly associated with clinical disease progression. High-level zidovudine resistance also was an independent predictor of death as an end point, although this finding does not imply a direct causal effect. Duration and cumulative dose of prior zidovudine therapy did not predict clinical disease progression. More potent antiretroviral agents are needed that can be used in combination to achieve more complete virus suppression and to reduce the selection of drug-resistant HIV-1 mutants.