15th International HIV Drug Resistance Workshop 13-17 June 2006, Sitges, Spain

IMPACT OF ENFUVIRTIDE RESISTANCE GENOTYPE ON CD4 INCREASES IN PATIENTS WITH ONGOING VIRAL REPLICATION WHILE RECEIVING ENFUVIRTIDE

Antivir Ther. 2006, 11:S43 (abstract no. 35)

T Melby¹, M DeSpirito¹, R DeMasi¹, G HeilekSnyder², J Thommes³, ML Greenberg¹ and N Graham^1
1Trimeris, Inc., Morrisville, NC; ²Roche Palo Alto, CA; ³Roche Nutley, NJ, USA

BACKGROUND: In enfuvirtide phase 3 studies patients receiving enfuvirtide + optimized background (OB) showed significantly higher CD4 responses through 48 weeks than OB alone (91 versus 48 cells/mm³). Aquaro et al. (CROI 2006) reported that patients failing enfuvirtide with the V38A/E mutation had a CD4 increase at 24 weeks of 94 cells/mm³ versus. a decline in CD4 count for patients with Q40H+L45M. We compared changes in CD4 cell counts from study baseline and post-virological failure (VF) based on enfuvirtide resistance genotypes from the TORO database.

METHODS: This analysis included patients who had met VF criteria through 48 weeks and had available CD4 cell count data at 8, 24 and 48 weeks post-VF (n=134). Patients were classified by the mutually exclusive presence of a substitution in viral gp41 at position V38 (group 1; n=58, 43%), Q40 and/or N43 (group 2; n=31, 23%) or for any other genotype (n=45, 34%). Analysis of Covariance (ANCOVA) adjusting for baseline factors and change in viral RNA was used to calculate CD4 count changes and to compare for significant differences between groups.

RESULTS: LSmean CD4 count increases from study baseline through 48 weeks were 91, 49, and 69 cells/mm³ for the 3 groups, respectively. Post-VF LSmean CD4⁺ cell count changes at 8, 24 and 48 weeks were +2, +21 and +33 cells/mm³, respectively, for group 1; -21 cells/mm³, -28 and -32 cells/mm³, respectively, for group 2; and -18, -13 and -6 cells/mm³, respectively, for group 3. The differences between groups in CD4 changes post-VF were statistically significant at 24 weeks (group 1 versus groups 2 or 3; each P<0.05) and at 48 weeks (group 1 versus group 2; P<0.01).

CONCLUSIONS: Substitutions at the V38 position were associated with continued CD4 increases in patients failing ongoing enfuvirtide-based therapy independent of residual virological activity. Other substitutions in gp41 were associated with varying degrees of sustained CD4 increases from baseline and deserve further study. These data are consistent not only with a viral fitness cost but also suggest a reduced pathogenicity in viruses developing resistance to enfuvirtide.

2006-06-13
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