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Background:  For several antiretroviral drugs the relationship between HIV genotype, phenotype, and drug activity in vivo is incompletely understood. To assess individual drug activity in the presence of resistance mutations, we implemented an in vivo phenotyping protocol based on a short-duration single-drug interruption strategy.

Methods:  Patients with HIV RNA > 500 copies/ml on a stable stavudine (d4T)-containing regimen were eligible. Following a 7-day baseline sampling period, patients interrupted d4T while continuing the remaining drugs. During the 14-day interruption period, frequent samplings were obtained. Shifts in the virus population were ruled out comparing standard genotypes obtained soon before and at the end of interruption.

Results:  In all, 11 patients completed the study. d4T activity was influenced by the presence of an increasing number of TAM (p < 0.0001, R² = 0.7), however, as many as 3 TAM, d4T mean antiviral activity was superior to 0.7 log₁₀ HIV RNA (see the figure). The effect of specific TAM was similar, ranging from a residual antiviral activity of  0.2 log₁₀ (K70R) to 0.39 log₁₀  (M41I). In all cases the effect of a specific TAM was statistically significant (p < 0.005). Genome sequencing revealed no evidence of change in the mutant virus population during the interruption period.

Conclusions:  d4T exerts a persistent anti-HIV activity despite the presence of multiple TAM as demonstrated by the increment in viremia during drug interruption. d4T may represent a valuable choice in resistant-virus bearing patients. The single drug interruption strategy may be useful in heavily pre-treated patients to identify drugs still effective on the resistant mutants.

Keywords: resistance; in-vivo; stavudine