HIGH-LEVEL RESISTANCE TO ZIDOVUDINE BUT NOT TO ZALCITABINE OR DIDANOSINE IN HUMAN-IMMUNODEFICIENCY-VIRUS FROM CHILDREN RECEIVING ANTIRETROVIRAL THERAPY

Human immunodeficiency virus type 1 (HIV-1) isolates from children rec eiving long-term therapy with an alternating regimen of zidovudine and zalcitabine, or with didanosine monotherapy, were evaluated for resis tance to zidovudine, zalcitabine, and didanosine, and for mutations kn own to be associated with zidovudine or didanosine resistance. HIV-1 f rom four of six patients receiving zidovudine with zalcitabine develop ed high-level resistance to zidovudine. A mutation in the HIV-1 revers e transcriptase that is highly associated with zidovudine resistance w as identified in all four zidovudine-resistant posttherapy isolates. I n contrast, none of the HIV-1 isolates from the seven patients receivi ng didanosine developed high-level resistance to this agent, despite t he identification of a didanosine-associated mutation in six of these posttherapy isolates, although small decreases in sensitivity to didan osine were observed. These results indicate that nucleoside analog-ass ociated mutations in HIV-1 occur frequently in children receiving long -term antiretroviral therapy and that alternating combination therapy does not prevent the development of resistance to zidovudine. They als o suggest that there may be differences in the degree of resistance co nferred by mutations that result from therapy with different nucleosid e analogs. These findings underscore the need for studies to define th e clinical importance of these mutations, and for treatment strategies to overcome the emergence of viral resistance in vivo.