Im at the Third Intl Workshop on Drug Resistance and Treatment Strategies more commonly referred to as the Resistance Meeting. Todays opening session was called New Antiretrovirals and included new preliminary but promising data on several drugs for use in salvage situations. In particular promising salvage data was reported for tipranavir, ABT-378, DAPD and the second generation fusion inhibitor T-1249. As well, John Eriickson discussed his project to develop a PI (RS-344) designed to suppress virus with specific PI mutations. Following is the first report on tipranavir. I have to run to the poster session now but will follow with other reports later. Incidentally, in the ABT-378 study 77% (Intent-To-Treat analysis) were undetectable (<400 copies/ml) after 24 weeks; details will follow.
Tipranavir
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.
Previous reports have indicated tipranavir (TPV) has activity against HIV resistant to other PIs. Larder said they think this is because TPV has flexibility in the way it binds in the protease active site. But Dale Kempf of Abbott took issue with Larder saying he questioned the flexibility explanation.
The sample selection was from previously characterized PI resistant clinical isolates in Vircos repository, representing a broad spectrum of PI susceptibility:
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.
Results
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.
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.
Viruses resistant only to NFV (n=10) or RTV (n=13) were had no resistance to TPV, but the 5 saquinavir resistant viruses showed a 2.5 fold hypersenstivity to TPV. Larder reported 21 isolates with high-level resistance to the 4 PIs but had 3.3 fold hypersensity to TPV. The ritonavir-only resistant viruses displayed mtations at 10, 46, 54, 71, 77, 82A, 82T, 84, and 90. The nelfinavir-only resistant viruses showed predominantly the D30N, which is the hallmark nelfinavir mutation. Almost 100% of these viruses had a D30N and 88 mutation. Also observed were mutations at 10, 36, and 71. The saquinavir mutations observed were a predominance of 48 and 90 and also 10, 36, 46, 54, 71, and 77.
Larder suggested hypersensitivity to TPV was associated with the presence of 48V/82A in a background of other secondary mutations. So far they have not been able to characterize a mutation profile for TPV. When I asked about this Marty Markowitz said this occurred with indinavir but obviously eventually they characterized indinavirs mutation profile.