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  9th Conference on Retroviruses and Opportunistic Infections
Seattle, Washington, February, 2002
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Tipranavir (new PI) Resistance Report
Written by Jules Levin
  Tipranavir is a new protease inhibitor that shows promise to be uniquely important for patients with resistance to the current protease inhibitors & other available drugs. Tipranavir appears to have a novel design allowing it to bind to the protease enzyme despite the presence of PI resistance mutations. Tipranavir will have to be boosted by small ritonavir dosing to reach adequate blood levels.
It is important to bear in mind that several hurdles remain to be addressed. The ultimate test for this drug, as for any HIV drug, is the planned but not yet implemented testing of safety and antiviral effectiveness in patients with extensive PI resistance in phase 2 and large phase 3 studies. Drug-drug interactions have to be researched, and hopefully there will not be any troublesome interactions. Adequate production facilities will have to be planned. And if the drug proves to be effective, an expanded access program will have to be made available.
New promising resistance data on tipranavir was reported at the recent Retrovirus Conference. Patients with resistance to current protease inhibitors and other HIV drugs are the most in need of quick access to this drug. The most pressing need in HIV today is new therapies for these patients. They have been through the currently available drugs and have advanced HIV with low CD4s and/or high viral load. The Retrovirus Conference was promising in that several pharmacuetical companies presented information that they have a commitment to developing new classes of drugs. In particular, there are 2 integrase inhibitors in early development that show early promise. As well, there are 2 entry inhibitor programs with several drug candidate ideas in development. But, it will take a while before these programs bring actual drugs to patients, if in fact they do succeed. A more immediate need are drugs effective for patients who need new drugs more quickly. They have extensive resistance to currently available drugs and advanced HIV. Also at Retrovirus there was new information presented on NNRTIs in early development but are in studies of HIV+ patients. These drugs appear promising and are closer to reaching patients than the integrase and entry inhibitor programs.
Here are additional key drugs for patients with drug resistance. T-20 is a fusion inhibitor, a type of entry inhibitor, and is currently in large phase 3 studies. This is the last step before FDA approval. This is a new class of drugs and should be effective for patients with resistance to NRTIs, NNRTIs, and protease inhibitors. Unfortunately, T-20 is administered by subcutaneous self-injection, not the most convenient. In addition, Tenofovir (Viread) was recently approved by the FDA and is an important new potent drug. It is effective for most patients with extensive NRTI resistance. And is convenient, one 300mg pill per day. A new once a day PI in large phase 3 studies called atazanavir has effectiveness against HIV with limited PI resistance and so far looks as though it does not raise cholesterol and triglycerides, as other protease inhibitors can do. It does not appear as though atazanavir will be very effective against HIV with extensive PI resistance.
The development of tipranavir has been torturous and repeatedly delayed for several years. It was sold last year from Pharmacia & Upjohn to Boerhinger Ingelheim. Boerhinger has the TPV development program in progress as studies to clearly identify the right dose and to test the drug in patients with extensive drug resistance are planned for this year.
TPV appears to be a promising protease inhibitor for patients with resistance because it has good antiviral activity; the safety profile appears so far to be adequate, and it appears potent against PI resistant viruses in vitro and in vivo. The subject of this report is new tipranavir (TPV) resistance information from patient clinical isolates (blood samples) reported by R Schwartz and Boehringer Ingelheim.
At the ICAAC Conference in December 2001, findings were reported from a pilot study comparing TPV/RTV + saquinavir to ritonavir+saquinavir in patients with PI experience. The study authors said the problem with study was that although TPV showed promising antiviral activity, 40%-50% of the study patients did not have PI resistance nor did the study report the PI resistance profile for the patients with PI resistance. This prevents the proper analysis needed to see how effective TPV is against viruses with extensive PI resistance. The HIV viral load reductions seen in this study were reduced by 1.40 log for all the regimens in the study. About 50% of the study patients achieved at least a 1-log reduction in viral load. The discontinuation rate was higher in the RTV/SQV patients so TPV appeared relatively tolerable. GI side effects appear to be the most commonly associated with TPV, although it was reported that the GI side effects may resolve after being on therapy for a brief period. Triglyceride elevations occurred in 10%-14% of the patients receiving TPV.
To read the more detailed report here is link:
At Retrovirus, R Schwartz and Boerhinger Ingelheim reported on TPV resistance from a phase 2 trial consisting of 2 TPV/RTV doses (low dose: 500mg/100mg RTV; high dose: 1000mg/RTv 100 mg). Patients had never taken NNRTIs, they were failing their second PI regimen, and had viral load >5000 copies/ml. They analyzed blood samples from 41 patients. Genotypic resistance was determined by the VGI Trugene system and phenotypic resistance testing was performed by the Virco Antivirogram test.
Resistance to TPV and Other Protease Inhibitors at Baseline
At baseline, most patients had extensive phenotypic resistance to protease inhibitors, but not to TPV. Resistance to TPV (greater than 10-fold) was detected for one patient. After 80 weeks of therapy 35/41 patients maintained on average a 2-log reduction in viral load.
But, on the whole, most patients had extensive resistance at baseline to other protease inhibitors. The average phenotypic fold resistance was 0.80 to TPV, 1.70 to amprenavir, 8.3 to indinavir, 24 to NFV, 18 to RTV, ad 7-fold to saquinavir. At baseline, 33/41 patients had >6 fold nelfinavir resistance; 8 patients had <2 fold NFV resistance. 24/41 patients had >6 fold indinavir resistance; 16 patients had <5 fold IDV resistance. 20/33 patients had >7 fold ritonavir resistance; 13 patients had <5 fold RTV resistance. 20/40 patients had >7 fold saquinavir resistance; 16 patients had <4 fold SQV resistance. Interestingly, only 6/39 patients >6 fold amprenavir resistance; 27 patients had <4 fold APV resistance, showing potential utility for APV when patients have PI resistance. Kaletra was not examined. Perhaps, patients failing Kaletra will be sensitive to TPV.
Response to TPV
Patients demonstrated good viral load reductions whether they had few or many PI mutations at baseline, and whether or not they had any or all major PI mutations. In other words, patients (n=5) with no major PI mutations had an average reduction in viral load of 2.64, and patients (n=17) with any or all major PI mutations (46, 82, 84, 90) had an average log reduction of 2.43, after 80 weeks of therapy. As well patients (n=12-14) with <5 PI mutations had average viral load reductions of 1.88 to 2-log. Patients with >5 mutations had average viral load reductions of 1.35 to 1.52 log reductions, after 80 weeks.
During the study 6/41 patients developed decreased susceptibility to TPV but itıs not clear if it was due to non-adherence or not. Researchers reported that high level TPV resistance (>10-fold) was seen in only 1 patient.
Certain mutations emerged for patients developing decreased sensitivity to TPV. 5/6 patients with decreased TPV sensitivity newly developed the V82T mutation, and 4 of these 6 had one of several L33 type mutations. There does not yet appear to be a distinct resistance profile emerging for TPV.
More research is needed on TPV before it might be ready for patients including getting a clear picture of safety, tolerability, resistance, and antiviral effectiveness.