Intermittent selection pressure with zidovudine plus zalcitabine treatmentreduces the emergence in vivo of zidovudine resistance HIV mutations

The development of mutations conferring drug resistance was investigated in 49 antiretroviral-naive asymptomatic HIV-1 subjects with CD4(+) cell count s of 250-500/mm(3) given intermittent (6-week courses, 6 weeks apart) or co ntinuous treatment with zidovudine (AZT) plus zalcitabine (ddC) over 54 wee ks. The concentration of human immunodeficiency virus type 1 RNA in the pla sma and the CD4 cell counts were measured every 6 weeks. The rate of decrea se of HIV-1 RNA concentration in plasma after a 6-week course of AZT + ddC was similar for each treatment cycle (approximately 1-log reduction). The p lasma HIV-1 RNA concentration returned to its initial level at each treatme nt interruption. The mean CD4 cell counts after 54 weeks in the two treatme nt groups were similar. Genotype analysis by sequencing the reverse transcr iptase coding region from plasma viral RNA on treatment showed a lower freq uency of AZT resistance mutations after 54 weeks in patients given intermit tent treatment (18%) than in those treated continuously (79%, P < 0.001). N o mutations conferring ddC resistance or multidideoxy-nucleoside resistance were observed in either group. These findings may have clinical implicatio ns for long-term treatment strategies. (C) 1999 Wiley-Liss, Inc.