Antiretroviral drug summary: Lamivudine (3TC; Epivir)
Last updated on Sep 11, 2007
M184V causes high-level resistance to 3TC (>300-fold reduced susceptibility). In patients with viruses containing M184V, there is some benefit in continuing 3TC because viruses with M184V replicate less well than wild-type viruses and because this mutation increases susceptibility to ZDV, d4T, and TDF (Campbell et al. 2005; Larder et al. 1995; Nijhuis et al. 1997). However, the benefit of continued 3TC will be less than the benefit of 3TC in patients with wild-type virus.
K65R reduces 3TC susceptibility ~15-fold (Rhee et al. 2006). This level of resistance appears insufficient to completely interfere with 3TC activity in vivo because almost all virologic failures in patients receiving this drug occur with viruses containing M184V, even if K65R is also present. K65N is an rare mutation that has an effect on NRTI susceptibility similar to K65R (Margot et al. 2006; Ross et al. 2006).
Usually in combination with V75I, F77L, F116Y
Q151M has little effect on 3TC susceptibility. However, the combination of Q151M with V75I, F77L, and F116Y reduces 3TC susceptibility ~10-fold (Shafer et al. 1995).
The presence of four or more TAMs is usually associated with ~5-fold reduced susceptibility to 3TC. The clinical significance of this reduction is not known. M41L, L210W, and T215Y appear to have the greatest effect on 3TC susceptibility.
T69 insertion mutations
Insertions at position 69 occur in ~1% of treated patients, nearly always in combination with multiple TAMs. The combination leads to an intermediate level of 3TC resistance (>20-fold reduced susceptibility).
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. 3TC is usually administered as part of a fixed-dose combination with ZDV, ABC, or ZDV and ZBC.. The combination of 3TC 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 3TC. 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, 3TC or FTC are 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.
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- 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.
- 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.
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- Larder, B.A., S.D. Kemp, and P.R. Harrigan. 1995. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science 269: 696-699.
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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.
- Nijhuis, M., R. Schuurman, J.D. de, L.R. van, J. Lange, S. Danner, W. Keulen, G.T. de, and C.A. Boucher. 1997. Lamivudine-resistant human immunodeficiency virus type 1 variants (184V) require multiple amino acid changes to become co-resistant to zidovudine in vivo. J.Infect.Dis. 176: 398-405.
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- Ross, L.L., R. Dretler, P. Gerondelis, E.G. Rouse, M.L. Lim, and E.R. Lanier. 2006. A rare HIV reverse transcriptase mutation, K65N, confers reduced susceptibility to tenofovir, lamivudine and didanosine. Aids 20: 787-789.
- Shafer, R.W., A.K. Iversen, M.A. Winters, E. Aguiniga, D.A. Katzenstein, and T.C. Merigan. 1995. Drug resistance and heterogeneous long-term virologic responses of human immunodeficiency virus type 1-infected subjects to zidovudine and didanosine combination therapy. The AIDS Clinical Trials Group 143 Virology Team. J.Infect.Dis. 172: 70-78.