Phenotypic Susceptibility to Didanosine Is Associated with Antiviral Activity in Treatment-Experienced Patients with HIV-1 Infection

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Abstract

Objective.

We investigated the relationship between human immunodeficiency virus (HIV) phenotypic susceptibility to didanosine and the antiviral activity of didanosine (ddI) in the JAGUAR study.

Methods.

Baseline plasma HIV phenotypic susceptibility to ddI was assessed using a phenotype assay of patients randomized to receive ddI or placebo for 4 weeks in addition to their current regimen. Phenotypic susceptibility scores (PSSs) were then calculated for each sample. Associations between PSS and week 4 reductions in plasma HIV-1 RNA load or virologic response were assessed using linear regression and Jonckherre's test and the Wilcoxon and Cochran-Armitage tests, respectively.

Results.

In the ddI arm, a significant association between reduction in viral load and continuous PSS was observed (P<.0001). Using distinct categories, an increasing fold change (FC) in susceptibility to ddI was strongly associated with smaller reductions in plasma HIV-1 RNA load (P<.0001). The proportion of virologic responders was 83% (15/18) for patients with a ddI FC ≤1.3, 50% (33/66) for patients with an FC of 1.3-2.2, and 29% (4/14) for patients with an FC ≥2.2 (P=.0008). After we determined these findings, 3 ddI FC categories were defined using 1.3 and 2.2 as thresholds.

Conclusions.

The relationship between phenotypic susceptibility to ddI and reduction in plasma HIV-1 RNA load describes a continuum. The establishment of a lower clinical cutoff at 1.3 and an upper clinical cutoff at 2.2 are clinically relevant.

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