Different evolution of genotypic resistance profiles to emtricitabine versus lamivudine in tenofovir-containing regimens.
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.
Svicher
Valentina
V
Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy. valentina.svicher@uniroma2.it
Alteri
Claudia
C
Artese
Anna
A
Forbici
Federica
F
Santoro
Maria Mercedes
MM
Schols
Dominique
D
Van Laethem
Kristel
K
Alcaro
Stefano
S
Costa
Giosuè
G
Tommasi
Chiara
C
Zaccarelli
Mauro
M
Narciso
Pasquale
P
Antinori
Andrea
A
Ceccherini-Silberstein
Francesca
F
Balzarini
Jan
J
Perno
Carlo Federico
CF
D000220:Adaptation, Biological; D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D024882:Drug Resistance, Viral; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D063065:Organophosphonates / Q000627:therapeutic use*; D012367:RNA, Viral / Q000235:genetics; D000068698:Tenofovir; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics
D019380:Anti-HIV Agents; D063065:Organophosphonates; D012367:RNA, Viral; D054302:pol Gene Products, Human Immunodeficiency Virus; D003841:Deoxycytidine; D019259:Lamivudine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine