Mutations conferring resistance to zidovudine diminish the antiviral effect of stavudine plus didanosine

This study evaluated the influence of zidovudine (ZDV) resistance mutations on the antiviral effect of the combination of stavudine (D4T) plus didanos ine (ddC) in patients treated previously with ZDV plus zalcitabine (ddC). T wenty patients who had been treated with ZDV plus ddC for a median duration of 11 months (range, 7-42 months) were switched to D4T (40 mg twice a day [BIDI]) + ddl (200 mg BID) in an open pilot study lasting 6 months. The CDC classes were A (n = 10) and B (n = 10). The median baseline CD4 count was 285/mm(3) and the median baseline plasma virus RNA (Amplicor HIV Monitor RT -PCR assay) was 4.6 log copies/ml. Population-based sequence analysis detec ted mutations associated with resistance to reverse transcriptase (RT) inhi bitors in the RT domain of virus RNA from baseline plasma samples in 13/20 (65%) patients. Twelve patients had mutations associated with zidovudine re sistance (3 T215Y - M41L - L210W; 3 T215Y - M41L; 2 T215Y - L210W; 3 T215Y; 1 K70R) and 1 patient had a multi-dideoxynucleoside resistance mutation (Q 151M). Patients with a resistance mutation had a significantly lower RNA su ppression after 3 and 6 months (median RNA reduction -0.5 log and -0.1 log) than the remaining patients (-1.6 log and -2 log). Fifty percent of patien ts with wildtype viruses had undetectable plasma RNA after 24 weeks of D4T plus ddC therapy, whereas all those with mutated viruses had HIV RNA concen tration > 3 log copies/ml at week 24 (P<.05). Our finding may have implicat ions when deciding on a second line therapy with three or four drugs that i ncludes two new nucleoside analogues. Cross-resistance between nucleoside a nalogues deserves maximal attention to ensure optimal antiretroviral therap y and design algorithms for antiretroviral management based on genotypic an tiretroviral resistance testing. (C) 1999 Wiley-Liss, Inc.