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The Body PRO Covers: The 10th Conference on Retroviruses and Opportunistic Infections

Resistance Profile of Tipranavir

February 11, 2003

  • Baseline Phenotypic Susceptibility to Tipranavir/Ritonavir (TPV/r) Is Retained in Isolates From Patients With Multiple Protease Inhibitor (PI) Experience (BI 1182.52) (Poster 596)
    Authored by D. Cooper, D. Hall, D. Jayaweera, S. Moreno, C. Katlama, S. Schneider, L. Minoli, P. Yeni, R. Steigbigel, S. McCallister, V. Kohlbrenner, E. Cuaresma, J. Sabo, D. Mayers
    View the original abstract


This industry-sponsored study (BI 1182.52) was performed to provide further information on the resistance profile of the anti-HIV protease inhibitor tipranavir (TPV) when given in concert with low doses of ritonavir (RTV, Norvir). The trial was a multicentered, blinded, randomized study of three combinations of these drugs (TPV/r 500 mg/100 mg, 500 mg/200 mg, or 750 mg/200 mg) in 216 patients who had previously received at least two protease inhibitors (PIs) and who had at least one primary mutation in the protease (PR) gene of their plasma virus from among 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, and 90M. After the addition of TPV/r to a background-failing regimen for 14 days -- which was performed to assess responsiveness to TPV/r -- therapy was optimized with effective drugs.

The patients studied had a median baseline viral load of 4.5 logs copies/ml and CD4 counts of 153 cells/mm3. Their viruses in 157 cases had near wild-type IC50 values for TPV but significantly increased IC50s in regard to each of the following: lopinavir (LPV+RTV, Kaletra), amprenavir (APV, Agenerase), saquinavir (SQV, Invirase or Fortovase), indinavir (IDV, Crixivan), nelfinavir (NFV, Viracept), and ritonavir (RTV, Norvir).

After two weeks of therapy, those patients whose viral baseline susceptibilities to TPV were either less than 1-fold wild-type (wt) (42 percent) or 1- to 2-fold wt (27 percent) had viral load reductions of ~1.23 logs, while patients whose viral baseline susceptibilities to TPV showed some degree of resistance (i.e. 2- to 4-fold wt (18 percent) or more than 4-fold wt (12 percent)), showed viral load reductions of only about 0.2 logs during this time.

These data point to the potency of TPV in PI-experienced patients whose viruses were moderately resistant to currently approved PIs and to a lesser degree of activity of TPV against viruses that demonstrated higher degrees of baseline resistance to the latter drug.

The number of primary protease-associated mutations needed to confer significant resistance to currently approved PIs was less (one or two) than the number needed to confer reduced susceptibility to TPV (three mutations), against a background of multiple PR secondary mutations. In addition, the breakthrough point for susceptibility to TPV was approximately two-fold, the IC50 for wt virus. These results demonstrate that TPV/r is likely to be effective therapy for highly treatment-experienced patients who have failed other PI-containing regimens.

It is important to note that responsiveness to TPV/r declined in this study if increasing numbers of primary PR mutations were present in patients' viral samples. No significant differences appeared to be present among the three different TPV/r regimens that were studied. Nor did prior experience with drugs in classes other than PIs appear to affect any of the outcomes that were studied. These studies now constitute a basis for further analysis on the combination of TPV/r in long-term follow-up of efficacy. These trials termed "Resist 1" and "Resist 2" will soon be underway and will be performed in individuals whose resistance profiles are likely to indicate responsiveness to TPV/r but not to currently approved PIs.


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This article was provided by TheBodyPRO.com. It is a part of the publication The 10th Conference on Retroviruses and Opportunistic Infections.
 



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