Antiretroviral drug summary: Emtricitabine (FTC; Emtriva)
Last updated on Sep 11, 2007
M184V causes high-level resistance to FTC (>300-fold reduced susceptibility). However, in patients with viruses containing M184V, there is often benefit in continuing FTC because viruses with M184V replicate less well than wild-type viruses and because M184V increases susceptibility to ZDV, d4T, and TDF. However, the benefit of continued FTC in the presence of M184V is less than the benefit of FTC in the presence of wildtype virus.
K65R reduces FTC susceptibility ~15-fold. This level of resistance is insufficient to completely interfere with FTC activity in vivo because 3TC-escape mutants with K65R nearly always also contain M184V (Gallant et al. 2006). K65N is an rare mutation that has an effect on NRTI susceptibility similar to K65R (Margot et al. 2006; Ross et al. 2006a).
K70E decreases 3TC - and therefore probably also FTC - susceptibility by about 5-10 fold (Delaugerre et al. 2005; Ross et al. 2005; Van Houtte et al. 2006).
Usually in combination with V75I, F77L, F116Y
Q151M has little effect on 3TC or FTC susceptibility. However, the combination of Q151M with V75I, F77L, and F116Y reduces 3TC and FTC susceptibility ~10-fold.
The presence of four or more TAMs is usually associated with ~5-fold reduced susceptibility to FTC. The clinical significance of this reduction is not known. M41L, L210W, and T215Y appear to have the greatest effect on FTC susceptibility. The effect of the TAMs on FTC is similar to their effect on 3TC (Ross et al. 2006b).
T69 insertion mutations
Insertions at position 69 occur in ~1% of treated patients, nearly always in combination with multiple TAMs. The combination leads to intermediate / high-level FTC resistance
E44D +/- V118I
E44D and V118I are accessory mutations that usually occur with multiple TAMs. They contribute some degree of resistance to each of the NRTIs including 3TC and FTC (Delaugerre et al. 2001; Gianotti et al. 2006; Girouard et al. 2003; Hertogs et al. 2000; Lin et al. 1999; Montes and Segondy 2002; Romano et al. 2002).
Each of the preferred dual NRTI backbones in the US DHHS Guidelines includes either 3TC or FTC. The efficacy of these NRTIs is due to their potency and their synergism with ZDV, d4T, and TDF. FTC is usually administered as part of a fixed-dose combination with TDF. The combination of FTC with ddI is also highly effective and is categorized as an "alternative" dual NRTI backbone by the US DHHS Guidelines.
M184V will be present in a large proportion of patients failing a regimen containing FTC. Therefore the role of FTC for early virologic failure is less prominent than the role of other NRTIs that maintain activity against viruses with M184V. However, FTC is often continued despite the presence of M184V, especially in patients taking ZDV, d4T, or TDF, because of the increased activity of these NRTIs against viruses with M184V.
- Delaugerre, C., M. Mouroux, A. Yvon-Groussin, A. Simon, F. Angleraud, J.M. Huraux, H. Agut, C. Katlama, and V. Calvez. 2001. Prevalence and conditions of selection of E44D/A and V118I human immunodeficiency virus type 1 reverse transcriptase mutations in clinical practice. Antimicrob Agents Chemother 45: 946-948.
- Delaugerre, C., L. Roudiere, G. Peytavin, C. Rouzioux, J.P. Viard, and M.L. Chaix. 2005. Selection of a rare resistance profile in an HIV-1-infected patient exhibiting a failure to an antiretroviral regimen including tenofovir DF. J Clin Virol 32: 241-244.
- Gallant, J.E., E. DeJesus, J.R. Arribas, A.L. Pozniak, B. Gazzard, R.E. Campo, B. Lu, D. McColl, S. Chuck, J. Enejosa, J.J. Toole, and A.K. Cheng. 2006. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 354: 251-260.
- Gianotti, N., L. Galli, E. Boeri, A. De Bona, M. Guffanti, A. Danise, S. Salpietro, A. Lazzarin, and A. Castagna. 2006. The 118I reverse transcriptase mutation is the only independent genotypic predictor of virologic failure to a stavudine-containing salvage therapy in HIV-1-infected patients. J Acquir Immune Defic Syndr 41: 447-452.
- Girouard, M., K. Diallo, B. Marchand, S. McCormick, and M. Gotte. 2003. Mutations E44D and V118I in the reverse transcriptase of HIV-1 play distinct mechanistic roles in dual resistance to AZT and 3TC. J Biol Chem 278: 34403-34410.
- Hertogs, K., S. Bloor, V. De Vroey, C. van Den Eynde, P. Dehertogh, A. van Cauwenberge, M. Sturmer, T. Alcorn, S. Wegner, M. van Houtte, V. Miller, and B.A. Larder. 2000. A novel human immunodeficiency virus type 1 reverse transcriptase mutational pattern confers phenotypic lamivudine resistance in the absence of mutation 184V. Antimicrob Agents Chemother 44: 568-573.
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- Margot, N.A., J.M. Waters, and M.D. Miller. 2006. In Vitro HIV-1 Resistance Selections with Combinations of Tenofovir and Emtricitabine or Abacavir and Lamivudine. Antimicrob Agents Chemother 50: 4087-4095.
- Montes, B. and M. Segondy. 2002. Prevalence of the mutational pattern E44D/A and/or V118I in the reverse transcriptase (RT) gene of HIV-1 in relation to treatment with nucleoside analogue RT inhibitors. J Med Virol 66: 299-303.
- Romano, L., G. Venturi, S. Bloor, R. Harrigan, B.A. Larder, J.C. Major, and M. Zazzi. 2002. Broad nucleoside-analogue resistance implications for human immunodeficiency virus type 1 reverse-transcriptase mutations at codons 44 and 118. J Infect Dis 185: 898-904.
- Ross, L., P. Gerondelis, Q. Liao, B. Wine, M.L. Lim, M. Shaefer, A.E. Rodriguez, K. Limoli, W. Huang, N. Parkin, J. Gallant, and R. Lanier. 2005. Selection of the HIV-1 reverse transcriptase mutation K70E in antiretroviral-naive subjects treated with tenofovir/abacavir/lamivudine therapy [abstract 92]. HIVDRW2005: S102.
- Ross, L.L., R. Dretler, P. Gerondelis, E.G. Rouse, M.L. Lim, and E.R. Lanier. 2006a. A rare HIV reverse transcriptase mutation, K65N, confers reduced susceptibility to tenofovir, lamivudine and didanosine. Aids 20: 787-789.
- Ross, L.L., N. Parkin, P. Gerondelis, C. Chappey, M.R. Underwood, M.H. St Clair, and E.R. Lanier. 2006b. Differential Impact of Thymidine Analogue Mutations on Emtricitabine and Lamivudine Susceptibility. J Acquir Immune Defic Syndr.
- Van Houtte, M., M. Staes, A. Geretti, T. Patterry, and L. Bacheler. 2006. NRTI resistance associated with the RT mutation K70E in HIV-1. HIVDRW2006.