HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 DRUG SUSCEPTIBILITY DURING ZIDOVUDINE (AZT) MONOTHERAPY COMPARED WITH AZT PLUS 2',3'-DIDEOXYINOSINE OR AZT PLUS 2',3'-DIDEOXYCYTIDINE COMBINATION THERAPY

Human immunodeficiency virus type I (HIV-1) isolates obtained prior to and during a combination therapy trial comparing zidovudine (AZT; 3'- azidothymidine) monotherapy with AZT plus 2',3'-dideoxyinosine (ddI) o r AZT plus 2',3'-dideoxycytidine (ddC) were assessed for the developme nt of drug resistance. Drug susceptibility was measured by using two d ifferent phenotypic assays, one that requires infection of peripheral blood mononuclear cells with HIV-1 isolated from cocultures and a seco nd based on infection of HeLa CD4(+) cells with recombinant virus cont aining the reverse transcriptase (RT) of the clinical isolate. In addi tion, genotypic assessment of resistance was obtained by DNA sequencin g of the RT coding region. No difference in the development of AZT res istance was noted in isolates from individuals receiving AZT monothera py or combination therapy. However, a low frequency of ddI or ddC resi stance was seen in isolates from the combination arms, which may at le ast partially explain the enhanced efficacy observed with these drug c ombinations compared with monotherapy. It was noted from DNA sequencin g that a relatively high frequency of the nonnucleoside RT inhibitor r esistance mutation, codon 181 changed from encoding Tyr to encoding Cy s, was present in some isolates both before and during nucleoside anal og combination therapy. Since these patients were unlikely to have acc ess to nonnucleoside RT inhibitors, it is probable that this mutation preexisted at a reasonable level in the wild-type virus population. Co mparisons of the AZT susceptibility assays indicated a good correlatio n between the phenotypic and genotypic determinations. However, direct numerical comparisons between the phenotypic assays were not reliable , suggesting that valid comparisons of different resistance data sets will require the use of the same assay procedure.