18th International HIV Drug Resistance Workshop Basic Principles & Clinical Implications June 9–13 2009, Fort Myers, Florida, USA

DIFFERENT EVOLUTION AND PATTERNS OF GENOTYPIC RESISTANCE PROFILES IN EMTRICITABINE PLUS TENOFOVIR AND LAMIVUDINE PLUS TENOFOVIR CONTAINING REGIMEN

Antivir Ther 2009; 14 Suppl 1:A25 (abstract no. 23)

V Svicher¹, C Alteri¹, F Forbici², MM Santoro¹, D Schols³, K Van Laethem³, E Boumis², P De Longis², P Narciso², A Antinori², F Ceccherini-Silberstein¹, J Balzarini³ and CF Perno^1,2
1University of Rome Tor Vergata, Rome, Italy; ²INMI L Spallanzani, Rome, Italy; ³Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium

BACKGROUND: We recently observed a prevalence of M184V in patients failing emtricitabine+tenofovir (FTC+TDF) lower than that in patients failing lamivudine (3TC) ±TDF. In vitro experiments were performed to investigate characteristics and developments of genotypic resistance profiles to FTC+TDF and 3TC+TDF in treated patients.

METHODS: A total of 1,337 HIV-1 B subtype pol sequences from 168 FTC+TDF-treated patients, 249 3TC+TDF-treated patients and 920 3TC-treated/TDF-naïve patients were analysed. Resistance to 3TC or FTC ±TDF in HIV-1 B subtype was investigated using in vitro selection experiments on CEM cells with various concentrations of 3TC (from 0.025 µM to 0.25 µM) and FTC (from 0.025 µM to 0.25 µM), ±TDF (from 1.25 µM to 10 µM). A total of 249 matched genotype/phenotype pairs collected from the Stanford Database were used as controls.

RESULTS: A lower prevalence of M184V in FTC+TDF-treated patients compared with 3TC+TDF-treated and 3TC-treated/TDF-naïve patients was observed both in pluri-experienced patients (38.7% versus 55.8% and 68.0%; P<0.01) and in patients failing their first-line HAART (11.4% versus 25.9% versus 51.0%; P<0.01). Multivariate analysis shows that factors favouring M184V emergence were prior 3TC use (OR 2.28 [95% CI 1.74–2.98]; P<0.001) and thymidine analogues use (OR 1.66 [95% CI 1.16–2.38]; P=0.004), while factors preventing M184V emergence were TDF use (OR 0.60 [95% CI 0.42–0.88]; P=0.008) and boosted-PIs use (OR 0.50 [95% CI 0.33–0.75]; P=0.0009). The protective role of TDF was further confirmed in in vitro selection experiments. Indeed, M184V emergence in vitro was not observed up to 10 passages (2 months) for all the 16 dual drug combinations of 3TC+TDF or FTC+TDF tested. Other RT mutations, beyond M184V, could be specifically selected in vitro under the selective pressure of 3TC+TDF or FTC+TDF. Among them, T69I, which was absent in drug-naïve patients and present in 0.4% 3TC+TDF-failed patients, emerged under in vitro selective pressure of 3TC+TDF (but not of FTC+TDF) and its presence (in the absence of M184V) was significantly associated with a 39.2-fold increase in 3TC fold change resistance (P=0.03). Additionally, in vitro selection experiments highlighted the ability of 3TC+TDF and FTC+TDF to select the mutations P345S and R461K, localized in the connection and RNAseH RT domain, respectively (prevalence was 0.8% and 19% in treated patients, respectively).

CONCLUSIONS: In vivo analysis, confirmed by in vitro experiments, showed lower rates of M184V development in FTC+TDF regimens versus 3TC+TDF and highlighted TDF as having a protective role in M184V emergence. RT mutational patterns, more complex than currently known, may contribute to resistance to NRTI, including FTC/3TC.

2009-06-09
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