Phenotypic susceptibility to didanosine is associated with antiviral activity in treatment-experienced patients with HIV-1 infection.
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 < or =1.3, 50% (33/66) for patients with an FC of 1.3-2.2, and 29% (4/14) for patients with an FC > or =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.
Flandre
Philippe
P
Unité INSERM U720, BP 335-75625, Paris, France. pflandre@ccde.chups.jussieu.fr
Chappey
Colombe
C
Marcelin
Anne Genevieve
AG
Ryan
Kirk
K
Maa
Jen-Fue
JF
Bates
Mike
M
Seekins
Daniel
D
Bernard
Marie Charlotte
MC
Calvez
Vincent
V
Molina
Jean Michel
JM
D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016049:Didanosine / Q000494:pharmacology / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D023381:Endpoint Determination; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D012367:RNA, Viral / Q000097:blood; D013045:Species Specificity; D019562:Viral Load
D019380:Anti-HIV Agents; D012367:RNA, Viral; D016049:Didanosine