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 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]. However, many people can continue to benefit from combinations that include 3TC, even after development of this mutation^[5]. This is probably due to the mutant virus being less able to replicate than wild-type or unmutated virus^[6]. 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 nucleoside reverse transcriptase inhibitors (NRTIs), meaning that once a patient develops resistance to one NRTI, the effectiveness of the other NRTIs will be diminished. HIV that has developed resistance to 3TC may be cross-resistant to ddI (didanosine, Videx / VidexEC), although in practice this cross-resistance appears to be rare^[7]. Virus with the M184V/I mutation is also cross-resistant to FTC (emtricitabine, Emtriva) and abacavir (Ziagen). Furthermore, moderate resistance to 3TC may develop in the absence of the 184 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. Thus, a patient is likely to get some benefit from 3TC even after exposure to AZT or d4T (stavudine, Zerit). Conversely, patients resistant to 3TC may benefit from other NRTIs, including AZT and d4T^[9][10].

Some studies have also found that HIV that has developed resistance to 3TC may also be resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs)^[11][12].