• Resistance to Tipranavir is Uncommon in a Randomized Trial of Tipranavir/Ritonavir (TPV/RTV) in Multiple PI-Failure Patients (BI 1182.2)
  Abstract 562-T
  Authored by R. Schwartz¹, P. Kazanjian², L. Slater³, B. Hathaway⁴, M. Markowitz⁵, D. Wheeler⁶, M. Goldman⁷, M. Drulak⁸, S. McCallister⁸, and D. Mayers⁸ (¹Associates in Res., Fort Myers, FL; ²Univ. of Michigan Hlth. System, Ann Arbor; ³Univ. of Oklahoma Health Sci. Ctr., Oklahoma City; ⁴Eastern Carolina Univ. Sch. Med. Greenville, NC; ⁵Aaron Diamond AIDS Res. Ctr., Rockefeller Univ., New York, NY; ⁶Infectious Disease Physicians Res. Ctr., Annandale, VA; ⁷Indiana Univ. Sch. Med., Indianapolis; and ⁸Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT)
  View the original abstract

Tipranavir is the first non-peptidomimetic protease inhibitor. Clinical development has been eagerly awaited. Tipranavir's activity against a wide variety of highly protease-resistant virus was first presented more than two years ago. However, at least two important questions remain about the resistance pattern. First, will the clinical response in patients with resistant virus be as impressive as the test tube response? Second, will resistance to tipranavir emerge rapidly and what will it look like?

This study provides very encouraging preliminary answers to these questions. The clinical results of this phase 2 trial were presented at the IAS conference in Buenos Aires. It compared two doses of tipranavir with ritonavir in highly treatment-experienced patients. The patients were highly protease inhibitor-experienced and they were resistant to multiple agents. At baseline, only one of 41 patients had reduced sensitivity to tipranavir. The antiviral response was similar in patients who had major protease inhibitor mutations at baseline. These included mutations at 46, 82, 84 and 90, commonly seen with other protease inhibitors. There was no significant difference in response between those with less than 5 versus more than 5 mutations.

Over the course of the study, 35/41 (85%) of the isolates remained susceptible to tipranavir (defined as less than a 4-fold change by the Virco assay). Five patients developed modest changes (4-10 fold change in susceptibility) and one developed resistance (>10 fold change). The mutations most commonly seen in the six patients with change in tipranavir resistance were V82T and L33I, F or V. Interestingly, there was no major change in resistance to other protease inhibitors after tipranavir exposure.

This is a small study and was complicated by a change in formulation during the study. The final dosing of tipranavir with ritonavir is being worked out in ongoing studies. The tolerability is not fully known and may depend on the final dose and formulation. However, the resistance data is very encouraging. It suggests that tipranavir remains active against very resistant virus, that resistance does not emerge rapidly, even with less than optimized dosing, and that there is not an obvious selection of cross-resistant virus.

As is always the case with early data, larger studies are needed. Surprises are the rule with new agents. However, we clearly need good news about agents for patients with resistant virus.