DIDEOXYNUCLEOSIDE RESISTANCE EMERGES WITH PROLONGED ZIDOVUDINE MONOTHERAPY

Human immunodeficiency virus type 1 (HIV-1) isolates resistant to zido vudine (ZDV) have previously been demonstrated to exhibit in vitro cro ss-resistance to other similar dideoxynucleoside agents which contain a 3'-azido group; However, cross-resistance to didanosine (ddI) or did eoxycytidine (ddC) has been less well documented. ZDV, ddI, and ddC su sceptibility data have been collected from clinical HIV-1 isolates obt ained by five clinical centers and their respective retrovirology labo ratories. All subjects were treated only with ZDV. Clinical HIV-1 isol ates were isolated, amplified, and assayed for drug susceptibility in standardized cultures of phytohemagglutinin-stimulated donor periphera l blood mononuclear cells obtained from healthy seronegative donors. A ll five cohorts showed a correlation between decreased in vitro suscep tibility to ZDV and decreased susceptibility to ddI and ddC. For each 10-fold decrease in ZDV susceptibility, an average corresponding decre ase of 2.2-fold in ddI susceptibility was observed (129 isolates studi ed; P < 0.001, Fisher's test of combined significance). Similarly, sus ceptibility to ddC decreased 2.0 fold for each 10-fold decrease in ZDV susceptibility (82 isolates studied; P < 0.001, Fisher's test of comb ined significance). These data indicate that a correlation exists betw een HIV-1 susceptibilities to ZDV and ddI or ddC for clinical HIV-1 is olates.