Resistance

Tipranavir (Aptivus) was developed as an alternative to existing protease inhibitors, which display a high level of cross-resistance. Test tube studies report that resistance to tipranavir is slow to develop, and that there is no clear pattern of cross-resistance to currently available protease inhibitors.1 2

One study reported that 90% of HIV isolates taken from people with high level resistance to indinavir (Crixivan), ritonavir (Norvir), nelfinavir (Viracept) or saquinavir (Invirase) were completely sensitive to tipranavir, while 8% were moderately resistant to tipranavir and 2% were highly resistant. While encouraging, this study indicates that there is some level of cross-resistance between tipranavir and the other protease inhibitors.3

In general, the clinical studies of tipranavir have found that the more protease inhibitor mutations a patient has, the less likely they are to experience a benefit of tipranavir treatment. However, patients with numerous protease inhibitor resistance mutations tend to have a better chance of virological suppression with tipranavir than with other protease inhibitors.4

Study BI 1182.52 found that having three or more protease inhibitor-associated mutations was associated with a poorer response to ritonavir-boosted tipranavir.5 6 7 Two other studies have looked at susceptibility to tipranavir in treatment-experienced people, finding that one or two universal protease inhibitor-associated mutations (at positions 33, 82, 84 or 90) decreased susceptibility to currently available protease inhibitors, but more than two of these mutations were required for reduced susceptibility to tipranavir.8

Tipranavir requires the accumulation of multiple protease mutations for decreased susceptibility to the drug. Over 17 separate resistance mutations have been identified, including I13L/V, E35D, N37D, D60E and A71T, a number of which have not been associated with resistance to any other protease inhibitors.9

References

  1. Kemp S et al. Site-directed mutagenesis and in vitro drug selection studies have failed to reveal a consistent genotypic resistance pattern for tipranavir. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, abstract 2113, 2000
  2. Rusconi S et al. Susceptibility to PNU-140690 (tipranavir) of human immunodeficiency virus type 1 isolates derived from patients with multidrug resistance to other protease inhibitors. Antimicrob Agents Chemother 44: 1328-1332, 2000
  3. Larder B et al. Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples. AIDS 14: 1943-1948, 2000
  4. Mayers DL et al. Impact of three or four protease mutations at codons 33, 82, 84 and 90 on 2 week virological responses to tipranavir, lopinavir, amprenavir and saquinavir all boosted by ritonavir in phase 2B trial BI 1182.51. 13th International HIV Drug Resistance Workshop, Costa Adeje, abstract 147, 2004
  5. Yeni P et al. Correlation of viral load reduction and plasma levels in multiple protease inhibitor experienced patients taking tipranavir / ritonavir in a phase IIb trial. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 528, 2003
  6. Gathe J et al. Tipranavir / ritonavir demonstrates potent efficacy in multiple protease inhibitor experienced patients: BI 1182.52. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 179, 2003
  7. Squires K et al. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial. Ann Intern Med 139: 313-320, 2003
  8. Hall D et al. Characterisation of treatment-emergent resistance mutations in two Phase II studies of tipravanir. Antivir Ther 8: S16, 2003
  9. Kohlbrenner VM et al. Development of a tipranavir mutation score: analysis of protease mutations associated with phenotypic drug susceptibility and antiviral response in phase II clinical trials. Thirteenth International HIV Drug Resistance Workshop, Costa Adeje, abstract 129, 2004
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap
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