DIDANOSINE RESISTANCE IN HIV-INFECTED PATIENTS SWITCHED FROM ZIDOVUDINE TO DIDANOSINE MONOTHERAPY

Objective: To determine the frequency and pattern of development of sp ecific drug resistance mutations for human immunodeficiency virus (HIV ) reverse transcriptase in patients switched from zidovudine to didano sine therapy and to examine the relation of the didanosine resistance mutation at codon 74 of the HIV reverse-transcriptase gene to CD4(+) T -cell changes and virus burden. Design: Retrospective analysis of all patients enrolled at Stanford University in protocols where patients w ere switched from zidovudine to didanosine monotherapy. Setting: A uni versity hospital. Patients: 64 patients infected with HIV who were swi tched from zidovudine to didanosine monotherapy. Patients had the acqu ired immunodeficiency syndrome (AIDS), AIDS-related complex, or were a symptomatic (mean [+/-SD] starting CD4(+) T-cell count of 129 +/- 88 c ells/mm(3)). Measurements: Serial serum specimens were tested for the didanosine resistance mutation at codon 74 of the HIV reverse-transcri ptase gene and for a zidovudine resistance mutation at codon 215 using selective polymerase chain reactions (PCR). Serum HIV RNA levels were determined by quantitative PCR. CD4(+) T-cell counts were determined at serial time points. Results: By 24 weeks of didanosine therapy, the proportion of patients with the didanosine resistance mutation at cod on 74 increased from 0% to 56% (36 of 64). In contrast, the proportion of patients with the zidovudine resistance mutation at codon 215 decr eased from 84% at the start to 59% after 24 weeks of didanosine therap y (a 25% decrease, 95% lower CI, 15%; P < 0.0001). Patients who develo ped the codon 74 mutation had a greater decrease in CD4(+) T cells aft er the development of the mutation than did patients without the mutat ion (P < 0.001). In addition, after 24 weeks of didanosine, patients w ho developed the codon 74 mutation had a greater serum HIV RNA burden than patients who remained wild type (did not have the mutation) at co don 74 (225 000 compared with 82 400 HIV RNA copies/mL serum; P = 0.01 ). Conclusions: Among patients infected with HIV who had advanced dise ase and were switched from zidovudine to didanosine therapy, more than one half developed the didanosine resistance mutation at codon 74 by 24 weeks of didanosine therapy. Patients who developed the codon 74 mu tation had a greater decline in CD4(+) T cells after the development o f the mutation and had a greater serum virus burden than did patients without the codon 74 mutation.