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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:  We applied this strategy for the study of tenofovir (TDF) activity. Patients with HIV RNA > 500 copies/mL on a stable TDF-containing regimen were eligible. Following a 7 days baseline sampling period, patients interrupted TDF 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:  We report the results of the first 5 patients completing the study. TDF activity was highly influenced by the presence of an increasing number of TAM. In the first patient presenting 41L+215T mutations the residual TDF activity was 0.382 log₁₀. In the 2 patients with 3 TAM 41L+210W+215Y and 41L+67N+210W the residual activity  was null:  0.013 log₁₀ and –0.04 log₁₀, respectively. In the patient with 5 TAM (41L+67N+70R+210W+215Y) the interruption of TDF induced a reduction of  plasma HIV RNA of –0.15 log₁₀. Surprisingly, a similar and more marked result was observed in the final patient not presenting TAM and treated with AZT+3TC+TDF. The withdrawal of TDF induced a HIV RNA reduction of 1.11 log₁₀. Genome sequencing revealed no evidence of change in the mutant virus population of any patient during the interruption period.

Conclusions:  The single drug interruption strategy may be useful in heavily pre-treated patients to identify drugs still effective on the resistant mutants. TDF anti-HIV activity in the presence of multiple TAM is negligible. The negative interaction we observed in the patient treated with three NRTI may explain virologic failures of such combinations in the absence of resistance-conferring mutations.

Keywords: TAM; Tenofovir; in-vivo