3TC and FTC

  • The key 3TC/FTC-associated mutation is M184V.1
  • M184V confers a high degree of resistance to 3TC and FTC, but to some extent protects against other mutations and makes the virus more susceptible to AZT and certain other drugs.
  • Even with the M184V mutation, therapy with 3TC and FTC has been found to be effective when taken with a boosted protease inhibitor and another NRTI.2

Resistance to 3TC is commonly seen amongst people who experience virological failure on a first-line antiretroviral regimen, typically due to emergence of the M184V mutation in the HIV reverse transcriptase enzyme. This mutation also confers cross-resistance to the related drug FTC (emtricitabine, Emtriva). 

Drug resistance generally increases the risk of treatment failure and disease progression, but the presence of the M184V mutation appears to decrease viral fitness by reducing its ability to replicate and increasing its susceptibility to AZT, stavudine, and tenofovir. Thymidine analogue mutations (TAMs) have been seen to develop more slowly in people who continue taking 3TC after treatment failure.3 Viral load may actually increase by a small amount when people with this mutation stop taking 3TC, indicating that the drug had an antiviral effect despite resistance.4 5 

To see if 3TC would be effective in a second-line regimen once the M184V mutation appeared, Canadian researchers looked retrospectively at treatment outcomes for persons with the M184V mutation who had either added a boosted protease inhibitor (PI) to a regimen of 3TC or FTC plus another NRTI; remained on the same combination while adding one or more other active drugs, or who switched to two other NRTIs (excluding 3TC and FTC) plus a boosted PI, with or without additional active drugs. Standard three-drug boosted PI-based regimens containing 3TC proved to be as effective as more intensive multi-drug combinations or 3TC-sparing regimens. Researchers suggested that early detection of virological failure before extensive NRTI resistance develops may enable subsequent virological suppression by adding a boosted PI to the 3TC backbone.2

The COLATE study group found no additional benefit to continuing 3TC after failing a 3TC-containing regimen with the M184V mutation, but it is not clear whether subsequent regimens included the use of a boosted protease inhibitor.6

Virus which is already resistant to other NRTIs will not lose these mutations if 3TC is added. Instead, other NRTI-associated mutations may lead to cross-resistance between 3TC and other NRTIs. Several research groups have reported that resistance to other NRTIs undermines the antiviral effect of 3TC, even in the absence of the M184V mutation. 7 8

FTC (emtricitabine, Emtriva) is an NRTI that is closely related to 3TC. A study of people taking d4T or FTC, plus ddI and efavirenz (Sustiva), found that M184V only occurred in people taking FTC. However, TAMs were much more common among people taking d4T. There was also a trend toward fewer ddI and NNRTI-associated mutations in the FTC group. Several of the drugs used in this older study – d4T and ddI – are no longer in common use.9

An Italian study found that, amongst patients experiencing a rebound in viral load, those taking 3TC and tenofovir were more likely than those taking FTC and tenofovir to develop a number of key NRTI resistance mutations, including K70R, M184V, and T215F. The Y181C mutation was also twice as common with 3TC and tenofovir as with FTC and tenofovir. Y181C confers resistance to NNRTIs, including etravirine (Intelence).10

A separate, international team of investigators also found a significantly lower prevalence of the M184V mutation in patients taking FTC and tenofovir than in those taking either 3TC and tenofovir or 3TC and another drug (14 vs 40 vs 56%). Subsequent statistical analysis showed that treatment with FTC reduced the risk of the M184V mutation by 68%.11

References

  1. Stanford HIV Drug Resistance Summaries. Stanford HIV Drug Resistance Summaries Online at http://hivdb.stanford.edu/pages/drugSummaries.html, accessed 2007
  2. Hull MA et al. A lamivudine (3TC)-based backbone in conjunction with a boosted protease inhibitor (PI) is sufficient to achieve virologic suppression in the presence of M184V mutations. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract H-916, 2009
  3. Goetz MB et al. Evolution of HIV resistance mutations in patients maintained on a stable treatment regimen after virologic failure. J Acquir Immune Defic Syndr. 43:541-549, 2006
  4. Eron JJ et al. Persistent antiretroviral activity of nucleoside analogues after prolonged zidovudine and lamivudine therapy as demonstrated by rapid loss of activity after discontinuation. J Acquir Immune Defic Syndr 37: 1581-1583, 2004
  5. Wainberg M et al. The M184V mutation in association with multidrug resistance. Antivir Ther 7: S68, 2002
  6. Fox Z et al. A randomized trial to evaluate continuation versus discontinuation of lamivudine in individuals failing a lamivudine-containing regimen: the COLATE trial. Antiviral Ther 11: 761–770, 2006
  7. Hertogs K et al. 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: 568-73, 2000
  8. Romano L et al. Broad nucleoside-analogue resistance implications for human immunodeficiency virus type 1 reverse transcriptase mutations at codons 44 and 118. Journal of Infectious Diseases 185(7): 898-904, 2002
  9. Cahn P et al. Virologic efficacy and patterns of resistance mutations in ART-naïve patients receiving combination therapy with once-daily emtricitabine compared to twice-daily stavudine in a randomized, double-blind, multi-center clinical trial. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract P606, 2003
  10. Maserati R et al. Emerging mutations at virological failure of HAART combinations containing tenofovir and lamivudine or emtricitabine. AIDS 24 (advance, online publication), 2010., 2010
  11. Svicher V et al. Different evolution of genotypic resistance profiles to emtricitabine versus lamivudine in tenofovir-containing regimens. J Acquir Immune Defic Syndr, advance online publication, August 24, 2010, 2010