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

Early resistance data suggested that atazanavir would usually be active against HIV in people who have failed another protease inhibitor. For example, only 5% of virus isolates with reduced sensitivity to one protease inhibitor showed a similar reduction in sensitivity to atazanavir. In contrast, only 30% of 63 virus isolates with reduced sensitivity to three protease inhibitors and 67% with reduced sensitivity to four or more protease inhibitors also showed reduced sensitivity to atazanavir. Unsurprisingly, a greater number of mutations was associated with reduced sensitivity to atazanavir^[1].

More recent studies have suggested that atazanavir may not be as active against protease inhibitor-resistant virus as previously thought. In one study, 40% of people who had taken one protease inhibitor had reduced sensitivity to atazanavir. Furthermore, resistance testing showed that 3.5-fold resistance to other protease inhibitors reduced sensitivity to atazanavir in approximately 80% of viral isolates^[2]. In addition, patients with more protease inhibitor resistance mutations had a worse outcome^[3][4].

Mutations in the protease gene that have been linked to atazanavir resistance include:

• L10I/V/F/R.
• 16E.
• K20I/M/R.
• L24I.
• L33I/F/V.
• M46I/L.
• I54L/M/T/V.
• Q58E.
• 60E.
• L64P.
• A71I/L/V/T.
• G73A/C/F/T.
• V77I.
• V821/F/S/T.
• I84V.
• 85V.
• L90M^[5].

The presence of more than five of these mutations reduces susceptibility to atazanavir by threefold^[6][7]. A study of viral isolates found that viruses resistant only to nelfinavir and ritonavir were more likely to be susceptible to atazanavir than viruses resistant to three or more protease inhibitors, suggesting that atazanavir may be used in people who have experienced failure of nelfinavir (Viracept) with a good chance of success.

On a positive note, the I50L mutation, which confers resistance to atazanavir, may increase susceptibility to other protease inhibitors. This unique mutation commonly emerges in people who develop resistance to atazanavir taken as first-line therapy. I50L significantly improves susceptibility to indinavir (Crixivan), saquinavir (Invirase), lopinavir and ritonavir, and possibly nelfinavir^[8][9][10].