Resistance

As with all other anti-HIV drugs, strains of HIV that are resistant to 3TC (lamivudine, Epivir) may emerge after a period of treatment. The emergence of drug-resistant strains coincides with a fall in the effectiveness of the drug.

HIV can rapidly develop resistance to 3TC if viral load is not suppressed below the limit of detection. This is likely to occur due to poor adherence, or if a patient takes a treatment interruption, due to the slow rate of decline of 3TC levels within cells.1 2 Resistance to 3TC seems to develop at the same rate in patients taking the drug once or twice a day.3

The primary mutation associated with 3TC resistance occurs at codon 184 of the reverse transcriptase enzyme, called M184V or M184I.4 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 susceptibility to other NRTIs.

This is demonstrated by the fact that viral load may increase by a small amount when people with this mutation stop taking 3TC, indicating that the drug had an antiviral effect despite resistance.5 6 The presence of M184V also seems to prevent or delay emergence of thymidine-associated mutations.7 Other mutations that cause low-level resistance to 3TC include K65R and amino acid insertions at codon 69.

There is considerable cross-resistance amongst the NRTIs, meaning that once a patient develops resistance to one NRTI, the effectiveness of the other NRTIs will be diminished. Virus with the M184V/I mutation is also cross-resistant to FTC (emtricitabine, Emtriva) and abacavir (Ziagen). Additionally, moderate resistance to 3TC may develop even in the absence of the M184 mutation if AZT (zidovudine, Retrovir)-associated mutations are present.8

However, resistance to some of the other NRTIs is unlikely to cause high-level resistance to 3TC, and vice versa. A patient is likely to get some benefit from 3TC even after exposure to AZT or d4T (stavudine, Zerit). Conversely, individuals with virus resistant to 3TC may experience greater susceptibility to other NRTIs, including AZT and d4T.9 10

A recent study found that, even with the M184V mutation in individuals using 3TC in an NNRTI-based regimen, switching to a regimen containing a boosted protease inhibitor and an NRTI backbone of 3TC or FTC with another NRTI was as effective in lowering viral load as were changes to either 3TC-sparing regimens or those with more intensive multi-drug combinations.11

 

References

  1. Morales-Lopetegi K et al. Selection of M184V mutation during repetitive cycles of structured antiretroviral treatment interruptions. Antivir Ther 6: S28, 2001
  2. Tremblay C et al. HIV evolution during repeated supervised treatment interruptions following early antiretroviral treatment of acute infection. Antiviral Therapy 6: 17, 2001
  3. Vavro C et al. Genotypic analysis of HIV-1 from subjects experiencing virologic breakthrough while taking 3TC QD vs 3TC BID, EFV and ZDV. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, abstract H-2052, 2002
  4. Boucher CA et al. High-level resistance to (-) enantiomeric 2'-deoxy-3'-thiacytidine in vitro is due to one amino acid substitution in the catalytic site of human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 37: 2231-2234, 1993
  5. Campbell TB et al. Antiviral activity of lamivudine in salvage therapy for multidrug-resistant HIV-1 infection. Clin Infect Dis 41: 236-242, 2005
  6. Wei X et al. The M184V mutation in HIV-1 reverse transcriptase reduces the restoration of wild-type replication by attenuated viruses. AIDS 16: 2391-2398, 2002
  7. Kuritzkes DR et al. Drug resistance and virologic response in NUCA 3001, a randomised trial of lamivudine (3TC) versus zidovudine (ZDV) versus ZDV plus 3TC in previously untreated patients. AIDS 10: 975-981, 1996
  8. 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
  9. Larder BA et al. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science 269: 696-699, 1995
  10. Wainberg MA et al. Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. Science 271: 1282-1284, 1996
  11. 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
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