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

There has been a large number of publications describing patients with prior protease inhibitors experience who have failed lopinavir treatment. However, Kaletra has a high genetic barrier to lopinavir resistance and is very effective in protease inhibitor-experienced patients, making it difficult to ascertain the combination of mutations necessary for Kaletra therapy to fail.

To date, reduced sensitivity to Kaletra has been mainly associated with mutations 46I, 54V, 71V, 82A and 84V^[1][2][3]. Other mutations which have been associated with resistance to Kaletra include L10F/I/R/V and L90M, as well as mutations at codons 20, 24, 32, 33, 46, 47, 50, 53, 63 and 90^[4][5][6][7]. One study reported that having five or more mutations at these positions or positions 33, 36, or 48 is associated with complete resistance to Kaletra, while having three or four of these mutations is linked to mild resistance^[8]. V47A also causes resistance to Kaletra in patients infected with HIV-2^[9].

All of the protease inhibitors are, to some extent, cross-resistant. This means that resistance mutations that emerge in the presence of one protease inhibitor reduce the effectiveness of other protease inhibitors. There is evidence that HIV with reduced susceptibility to Kaletra shows high-level resistance to indinavir (Crixivan) and ritonavir, intermediate resistance to amprenavir (Agenerase) and susceptibility to saquinavir (Invirase)^[10].