Genotypic Determinants of the Virological Response to Tenofovir Disoproxil Fumarate in Nucleoside Reverse Transcriptase Inhibitor-Experienced Patients

Abstract

Objective

To assess the genotypic determinants of the virological response to tenofovir disoproxil fumarate (TDF) in a multicentre cohort of antiretroviral (ARV)-experienced patients receiving TDF as a part of a salvage therapy.

Methods

HIV-1 genotype was assessed at baseline in a subgroup of 161 patients of the French expanded access program receiving a stable TDF-including regimen for 3 months or more. Reverse transcriptase mutations associated with the viral load decrease at month 3 with a P-value <0.15 were retained for the construction of a mutation score. The score was then validated using a multivariate analysis and bootstrap resampling method.

Results

The strongest association with decrease in viral load was observed with a set of seven mutations (TDF mutation score) that consisted of M41L, E44D, D67N, T69D/N/S, L74V, L210W and T215Y/F RT mutations. The RT K65R mutation and the insertions at codon 69 were not included in the analysis due to low prevalences. A TDF mutation score of ≤2 predicted the absence of resistance to TDF and ≥6 mutations predicted resistance to TDF with corresponding reductions in viral load of –1.3 ±1.1, and +0.1 ±0.7 log₁₀ copies/ml, respectively. In patients with a TDF mutation score of 3–5, the decrease in viral load was –0.8 ±1.0 log₁₀ copies/ml and was considered possibly resistant. In the multivariate analysis, a TDF mutation score ≥6, previous use of amprenavir, indinavir and lopinavir, and co-prescription of didanosine were associated with a worse virological response. The bootstrap analysis showed the robustness of the TDF mutation score.

Conclusion

In ARV-experienced patients receiving TDF-containing regimens, a score derived from seven reverse transcriptase mutations was shown to be independently predictive of the virological response.