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Didanosine Resistance in HIV-infected Patients Switched from Zidovudine to Didanosine Monotherapy

Michael J. Kozal, MD; Kenda Kroodsma, BS; Mark A. Winters, MS; Robert W. Shafer, MD; Brad Efron, PhD; David A. Katzenstein, MD; and Thomas C. Merigan, MD
[+] Article and Author Information

From Stanford University Medical Center, Stanford, California. Requests for Reprints: Michael J. Kozal, MD, Division of Infectious Diseases, Stanford University Medical Center, Room S-156, Stanford, CA 94305. Grant Support: In part by the National Institute of Health grants AI-27762 and AI-27666.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1994;121(4):263-268. doi:10.7326/0003-4819-121-4-199408150-00005
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Objective: To determine the frequency and pattern of development of specific drug resistance mutations for human immunodeficiency virus (HIV) reverse transcriptase in patients switched from zidovudine to didanosine 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 were switched from zidovudine to didanosine monotherapy.

Setting: A university hospital.

Patients: 64 patients infected with HIV who were switched from zidovudine to didanosine monotherapy. Patients had the acquired immunodeficiency syndrome (AIDS), AIDS-related complex, or were asymptomatic (mean [±SD] starting CD4+ T-cell count of 129 ±88 cells/mm3).

Measurements: Serial serum specimens were tested for the didanosine resistance mutation at codon 74 of the HIV reverse-transcriptase 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 codon 74 increased from 0% to 56% (36 of 64). In contrast, the proportion of patients with the zidovudine resistance mutation at codon 215 decreased from 84% at the start to 59% after 24 weeks of didanosine therapy (a 25% decrease, 95% lower CI, 15%; P < 0.0001). Patients who developed the codon 74 mutation had a greater decrease in CD4+ T cells after the development of the mutation than did patients without the mutation (P < 0.001). In addition, after 24 weeks of didanosine, patients who developed the codon 74 mutation had a greater serum HIV RNA burden than patients who remained wild type (did not have the mutation) at codon 74 (225 000 compared with 82 400 HIV RNA copies/mL serum; P = 0.01).

Conclusions: Among patients infected with HIV who had advanced disease 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 mutation had a greater decline in CD4+ T cells after the development of the mutation and had a greater serum virus burden than did patients without the codon 74 mutation.

Figures

Grahic Jump Location
Figure 1.
Mean CD4+ T-cell changes before the appearance of the HIV reverse-transcriptase mutation at codon 74 and CD4+ T-cell changes after the appearance of the mutation in 38 patients switched from zidovudine to didanosine.

The point of the codon 74 mutation (measured in the serum HIV RNA of the patients) is at time 0 and is the reference point for all other CD4+ T-cell counts to be compared; x-axis, −24 to 0 represents the time receiving didanosine before the codon 74 mutation and 0 to 24 represents the time receiving didanosine after the mutation. The y-axis represents the mean CD4+ T-cell change in relation to the CD4+ T-cell level at the time of the mutation. The number of patients evaluable are above each time point.

Grahic Jump Location

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