Tipranavir is being developed as a salvage PI for people with PI experience and resistance. This is excerpted from NATAP's report on tipranavir from the Resistance Workshop last Summer. The full report is available on the NATAP web site in the Conference Reports section. At the Resistance Workshop, Brendan Larder reported data from a test of over 125 clinical isolates with varying degrees of cross-resistance to indinavir, ritonavir, nelfinavir, and saquinavir in a recombinant phenotypic assay. These isolates ranged from having resistance to a single PI with a limited number of PI mutations to those highly co-resistant and containing 6 to 8 protease mutations.

Larder said they think this is because TPV has flexibility in the way it binds in the protease active site.

The sample selection was from previously characterized PI resistant clinical isolates in Vircoís repository, representing a broad spectrum of PI susceptibility:

* Highly PI cross-resistant (to 3 or 4 PIs) n=107

* Single resistance to ritonavir, nelfinavir or saquinavir. They could not find single resistance to indinavir.

All viruses were sequenced to confirm mutation pattern before phenotypic analysis. They used the VircoGen method which uses ABI genotypic sequencing and the Virco Antivirogram phenotypic assay.

TPV. Three of 107 (3%) showed resistance with changes in the IC50 >10-fold.

Of the 107 viruses cross-resistant to PIs the resistance to the other PIs ranged from 40 to 90 fold. TPV resistance was 2-fold. At least 85 isolates had >10-fold resistance to all four PIs. Among the highly cross-resistant isolates the more prevalent mutations were at 90, 71, 10, 48, 54, 82A, 84.

Larder reported all of the samples resistant to single PIs (RTV, NFV, or SQV) remained fully TPV susceptible or were hypersensitive.

Larder reported that 96/107 (90%) isolates showed susceptibilty to TPV. Eight (7.5%) showed intermediate levels of resistance to TPV. Three of 107 (3%) showed resistance with changes in the IC50 >10-fold.

Based on this in vitro data people are hopeful that tipranavir can be effective as a cornerstone of a salvage regimen. Of course, ultimately efficacy is evaluated in large human studies of people with multiple PI resistance. This trial is ongoing or about to start.

At Retrovirus, they presented an early 14-day study intended to look at the safety, tolerability and antiviral efficacy of the new protease inhibitor tipranavir with or without low dose ritonavir. Tipranavir exposure or blood levels is markedly enhanced in the presence of low-dose tipranavir. Tipranavir reduces RTV exposure 5 fold.

31 treatment naÔve people with HIV >5000 copies/ml and CD4s >50 were enrolled using the SEDDS 300 mg soft elastic capsule formulation. This new formulation is intended to reduce the pill burden. This was a 14-day, randomized, open-label study exploring various doses.

Treatment Groups-

TPV 1200 mg bid (n=10); median baseline CD4 445; VL 5.05 log (112,000 copies/ml)

TPV 300 mg bid + RTV 200 mg bid (n=10); CD4s 158; VL 5.19 log (155,000 copies/ml)

TPV 1200 mg bid + RTV 200 mg bid (n=11); CD4s 208; VL 4.91 log (81,000 copies/ml)

PK Parameters-

TPV 1200 TPV 300+200 RTV TPV 1200

AUC (0-12) 88 (41-122) 443 (275-915) 1253 (731-2667)

Cmin 0.76 (0.26-1.8) 21 (15-48) 67 ( 23-200)

Cmax 22.4 (9.6-34) 62.3 (41-112) 154 (94-269)

Tmax 4.0 (1.5-6.0) 4.0 (2.0-12) 4.0 (2.0-6.0)

T1/2 2.2 (1.5-3.8) 5.6 (3.8-8.4) 7.3 (3.0-16)

Treatment Adverse Events

15 patients had diarrhea or loose stools; 14 of them were grade 1. It started in first 5 days on therapy . In 14 patients the diarrhea stopped spontaneously before 14 day trial ended. There was 1 grade 3 diarrhea.

TPV 1200 -- 5-diarrhea, 1 each -nausea, vomiting, fatigue

TPV 300+RTV 200 -- 3- diarrhea, 3 fatigue, 1 -vomiting

TPV 1200+RTV 200 -- 7-diarrhea, 6- nausea, 2 vomiting

They reported no discontinuations due to TPV related adverse events. There was 1 grade 3 ALT (group 3) and one grade 3 thrombocytopenia (group 2, prior history).

All 3 arms had similar HIV RNA reductions in first 5 days but by day 14 the 1200 mg TPV arm leveled off to a total reduction of 0.8 log. The other two arms had about a 1.7 log reduction. At day 15, 9/10 patients in 1200 TPV+200 RTV arm had >1.5 log reduction from baseline.

In a separate abstract (81) Phillips and colleagues looked at TPV interactions with NRTIs and reported-- TPV decreases the steady-state plasma concentrations of ddI, d4T, 3TC, and ZDV. The observed differences (15% to 46% decrease) in NRTI concentrations are not of clinical importance, and therefore, TPV can be combined with these agents.