Genotypic determinants of the virological response to tenofovir disoproxil fumarate in nucleoside reverse transcriptase inhibitor-experienced patients.
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 < or = 2 predicted the absence of resistance to TDF and > or = 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 > or = 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.


CONCLUSIONS
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.
Masquelier
Bernard
B
Laboratoire de Virologie, CHU de Bordeaux, France. bernard.masquelier@chu-bordeaux.fr
Tamalet
Catherine
C
Montès
Brigitte
B
Descamps
Diane
D
Peytavin
Gilles
G
Bocket
Laurence
L
Wirden
Marc
M
Izopet
Jacques
J
Schneider
Véronique
V
Ferré
Virginie
V
Ruffault
Annick
A
Palmer
Pierre
P
Trylesinski
Aldo
A
Miller
Michael
M
Brun-Vézinet
Françoise
F
Costagliola
Dominique
D
D000225:Adenine / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use*; D003062:Codon; D015331:Cohort Studies; D005602:France; D005838:Genotype; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D015999:Multivariate Analysis; D063065:Organophosphonates / Q000097:blood / Q000627:therapeutic use*; D017354:Point Mutation / Q000187:drug effects; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D000068698:Tenofovir
D003062:Codon; D063065:Organophosphonates; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D054303:HIV Reverse Transcriptase; D000225:Adenine