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Predicting Response to d4T
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"d4T virtual phenotype can predict virological response to d4Tmonotherapy after AZT treatment, but not at the current cutoff"
ABSTRACT 118
Antiviral Therapy 2004; 9:S132.
NS Shulman1, M Hughes2, MA Winters1, J Delgado1, TC Merigan1, DA Katzenstein1
1 Stanford University, Stanford, Calif.; and 2 SDAC, Harvard
University, Boston, Mass., USA
BACKGROUND: Virtual phenotypes (VPT, Virco) are used in clinical practice to interpret resistance genotypes, however clinical outcome data supporting specific reported cutoffs are lacking for many of the drugs. The current VPT reports d4T as suscetible for anything less than 1.8-fold change. This data is based on the biological cutoff and not on clinical outcome data.
OBJECTIVE: To determine if VPT can predict the antiviral activity of d4T monotherapy in AZT experienced subjects and if so to determine the appropriate clinical cutoff.
METHODS: Genotyping (ABI) was performed previously on baseline HIV isolates obtained from 29 patients in ACTG 302 who received >3 years of AZT monotherapy and received d4T monotherapy. Baseline and follow-up (8 weeks) plasma HIV-1 RNA levels were measured and patients who had a decrease >0.3 log were classified as responders. VPTs were determinedfor these sequences. The exact Wicoxon test was used to detect VPT differences in the responders and non-responders.
RESULTS: Seven of the 29 (24%) patients responded. All seven responders (100%) had D4T VPT of 0.9 whereas only 7/22 (32%) of non-responders had a D4T VPT of 0.9 (and none had less than 0.9). The remaining 15/22 (68%) of non-responders had a D4T VPT of 1.0 or higher.
Only 1/22 non-responders had a predicted d4T fold change of 1.8 or greater. D4T VPT was more predictive of response than counting TAMS at positions 41, 67, 70, 210, 215, 219; responders d4T VPT--median 0.9, range 0.9--0.9 vs non-responders--median 1.1, range 0.9--2.5 (P=0.005); number of TAMS-- median 1, range 1--1 vs median 2, range 0--4, respectively (P=0.11). Defining d4T resistance as 1.0 fold-change or greater had a 100% sensitivity and 74% specificity, while a 1.1 reduced the specificity to 68% at 1.8, the specificity was a mere 5%.
CONCLUSION: d4T VPT can predict response to d4T monotherapy in AZT experienced patients, but the current cutoff of 1.8 is too high. A cutoff of 1.0 or greater was the most predictive in this cohort.
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