Resistance

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

References

  1. Colonno RJ et al. Identification of amino acid substitutions correlated with reduced atazanavir susceptibility in patients treated with atazanavir-containing regimens. Antivir Ther 7: S4, 2002
  2. Schnell T et al. Distinct cross-resistance profiles of the new protease inhibitors amprenavir, lopinavir and atazanavir in a panel of clinical samples. AIDS 17: 1258-1260, 2003
  3. Barrios A et al. Atazanavir plasma levels associated with efficacy and safety in protease inhibitor-experienced HIV-infected patients. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 606, 2004
  4. Zala C et al. Virologic determinants of 24 week efficacy of atazanavir with or without ritonavir in patients with prior failure on a protease inhibitor. Ninth European AIDS Conference, Warsaw, abstract F7/2, 2003
  5. Vora S et al. Clinical validation of atazanavir / ritonavir genotypic resistance score in protease inhibitor-experienced patients. AIDS 20: 35-40, 2006
  6. Naeger LK et al. Effect of baseline protease genotype and phenotype on HIV response to atazanavir / ritonavir in treatment-experienced patients. AIDS 20: 847-853, 2006
  7. Pellegrin I et al. Virological responses to atazanavir-ritonavir-based regimens: resistance-substitutions score amd pharmacokinetic parameters (Reyaphar study). Antivir Ther 11: 421-429, 2006
  8. Colonno R et al. Activities of atazanavir (BMS-232632) against a large panel of human immunodeficiency virus type 1 clinical isolates resistant to one or more approved protease inhibitors. Antimicrob Agents Chemother 47: 1324-1333, 2003
  9. Colonno R et al. Pathways to atazanavir resistance in treatment-experienced patients and impact of residue 50 substitutions. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 656, 2004
  10. Weinheimer S et al. Recombinant HIV gag-pol proteins display unique I50L phenotype of selective atazanavir resistance and increased susceptibility to other PI. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 625, 2004
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