AZT Resistance Predicts Poor Outcome

Several studies presented at the 4th National Conference on Retroviruses and Opportunistic Infections evaluated the effect of AZT resistance codon mutations on outcome. One of the most important studies presented by David Katzenstein and other members of the ACTG 175 protocol team analyzed the genetic sequences of HIV isolates from 85 patients who participated in ACTG 175 (a large NIH-sponsored clinical trial which showed that AZT + ddI, AZT + ddC or ddI monotherapy were superior to AZT monotherapy in both AZT naive and experienced persons with CD4 counts between 200- and 500). Twenty seven patients (32%) had the codon 215 mutation which confers high level AZT resistance; these patients had a faster decline in CD4 cells and increasing HIV RNA viral load during 56 weeks of AZT monotherapy as compared to the 56 patients with wild-type virus. Of 42 patients with wild-type virus at entry, 31% developed codon 215 over the ensuing 56 weeks of follow-up. The concern about AZT resistance was magnified by the results of another study conducted in rural Iowa by Kozal and others who retrospectively sequenced the pol gene from HIV isolates of 99 patients presenting for evaluation from 1993-96. Although all were protease inhibitor naive, 29% had reverse transcriptase mutations. Of 65 newly diagnosed patients 5 had resistance codon mutations, of which 4 of 5 conferred AZT resistance. Of 32 patients with a history of reverse transcriptase inhibitor therapy, 72% had RTI mutations (75% AZT, 11% ddN, 7% 3TC and 7% NNRTI). In addition 26% of patients had codon mutations which confer resistance to protease inhibitors, and 23% harbored virus with multiple protease resistance mutations (mostly at codon 63). Most of the patients had been placed on antiretroviral regimens for which the their virus already had developed resistance. The high frequency with which drug resistance mutations occurred in this study suggests that treatment regimens based on blind algorithms of drug switching may lead to patients being switched or started on regimens for which their HIV-1 isolates are already resistant.