Different evolution of genotypic resistance profiles to emtricitabine versus lamivudine in tenofovir-containing regimens

Valentina Svicher, Claudia Alteri, Anna Artese, Federica Forbici, Maria Mercedes Santoro, Dominique Schols, Kristel Van Laethem, Stefano Alcaro, Giosuè Costa, Chiara Tommasi, Mauro Zaccarelli, Pasquale Narciso, Andrea Antinori, Francesca Ceccherini-Silberstein, Jan Balzarini, Carlo Federico Perno

Research output: Contribution to journalArticlepeer-review

Abstract

Background: To investigate genotypic resistance profiles to emtricitabine + tenofovir (FTC + TDF) in-vivo and in-vitro, and compare them with lamivudine + tenofovir (3TC + TDF). Methods: Three hundred fifty-two HIV-1 B-subtype pol sequences from 42 FTC + TDF-treated patients, 40 3TC + TDF-treated patients, and 270 patients treated with 3TC plus another nucleoside reverse transcriptase inhibitor (but not TDF). All patients never received FTC, 3TC, and TDF in their previous therapeutic regimen. 3TC/FTC ± TDF resistance was investigated using in vitro selection experiments and docking simulations. Results: The M184V mutation is less prevalent in FTC + TDF-treated patients than in 3TC + TDF-treated, and 3TC-treated/TDF-naive patients (14.3% versus 40.0%, P = 0.01 and 55.6%, P <0.001). Multivariable analysis shows that factors correlated with a lower probability of M184V emergence at failure were the use of FTC compared with 3TC [odds ratio (OR): 0.32 (95% confidence interval (CI): 0.10 to 0.99), P = 0.04], the use of boosted protease inhibitor, and the use of TDF [OR: 0.20 (95% CI: 0.11 to 0.37), P <0.001, and OR: 0.47 (95%CI: 0.22 to 1.01), P = 0.05, respectively]. In vitro selection experiments and docking analysis show that other reverse transcriptase (RT) mutations, even localized in RT connection domain, can be selected by 3TC + TDF or FTC + TDF in M184V absence and can affect RT affinity for 3TC/FTC and/or TDF. Conclusions: Our study shows lower rates of M184V development in FTC + TDF regimens versus 3TC + TDF and suggests a potential role of boosted protease inhibitors and TDF in delaying the M184V emergence. Novel RT mutational patterns, more complex than currently known, can contribute to 3TC, FTC, and TDF resistance.

Original languageEnglish
Pages (from-to)336-344
Number of pages9
JournalJournal of Acquired Immune Deficiency Syndromes
Volume55
Issue number3
DOIs
Publication statusPublished - Nov 1 2010

Keywords

  • docking analysis
  • drug resistance
  • emtricitabine
  • HIV-1
  • in-vitro selection experiment
  • lamivudine
  • RT
  • structural analysis
  • tenofovir

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)
  • Medicine(all)

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