579-T.
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T69D/N pol Mutation, HIV-1 RNA Levels and Syncytium-Inducing (SI) Phenotype were Associated with CD4 Cell Depletion during Didanosine Therapy
W. E. Naugler*1, F. H. Yong2, V. J. Carey2, J. Dragavon1, R. W. Coombs1, and L. M. Frenkel1
1Univ. of Washington, Seattle and 2Harvard Univ., Boston, MA
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Background: The contribution of virologic and host factors to CD4 cell depletion associated with Human Immunodeficiency Virus-1 (HIV-1) was evaluated in children, drawn from a larger efficacy trial of 2 doses of didanosine (ddI) monotherapy (PACTG 144).
Methods: 30 children, half with stable CD4+ cell counts (non-progressors) and half with a marked decline in CD4+ cell counts (progressors), were studied during 60-72 weeks of ddI. The children were matched for age and CD4 cell counts at study entry. Parameters were compared using Wilcoxon 2-sample test, Fisher's Exact Test, and exact logistic regression.
Results: Differences were not evident in weight for age Z-scores from study entry to week 48 between the 15 progressors and 15 nonprogressors (p=0.32), and the CCR5/32DELTAccr5 genotype was not different between the groups.3 viral parameters, syncytium-inducing (SI) phenotype (p=0.003), a higher viral load (P=0.003) and the mutation in HIV-1 pol encoding T69D/N (P=0.01), were associated with disease progression. In addtition, the prevalence of D67N and L210W tended to be greater in the progressors, (p=0.20) and (p=0.10), respectively. Disease progression was not associated with mutations in the RT gene previously associated with resistance to ddI (L74V, p= 1.00; K65R or M184V, not observed in either group).
Conclusions: The selection of T69D/N mutation in children with HIV-1 disease progression during ddI therapy suggests that this mutation confers a fitness advantage to the virus that may include resistance to ddI.
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