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Five Mutations Tied to Better Tipranavir Response at 48 Weeks
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XVII International HIV Drug Resistance Workshop
June 10-14, 2008, Sitges, Spain
Mark Mascolini
Certain protease inhibitor (PI)-related mutations that enhance viral susceptibility to tipranavir/ritonavir and correlated with a better 48-week response to tipranavir regimens [1]. But 48-week response rates in people with these mutations before starting tipranavir were substantially lower than 8-week responses.
Resistance schemes from Monogram Biosciences and Virco and the tipranavir-weighted mutation score [2] all agree that five mutations appearing in virus before a person starts tipranavir/ritonavir make HIV more susceptible to these PIs: L24I, I50L, I50V, I54L, and L76V. With academic colleagues in three countries, Boehringer Ingelheim investigators measured the impact of these pre-tipranavir mutations on 8-week, 24-week, and 48-week response to tipranavir/ritonavir in completed phase 3 trials of this PI, adjusting response findings for activity of the background regimen. They also measured susceptibility of virus bearing these mutations to tipranavir/ritonavir in trial participants.
Looking at viral samples from 2116 people enrolled in phase 2 or 3 trials of tipranavir/ritonavir, the researchers found L24I in 15.5%, L76V in 8.4%, I54L in 7.1%, I50V in 6.9%, and I50L in 0.2%. Among 810 phase 3 RESIST trial participants with susceptibility to tipranavir measured before beginning the drug, mutated virus without one of these five these mutations had 1.8-fold lower susceptibility to tipranavir (measured as fold change in 50% inhibitory concentration, or IC50) compared with nonmutant virus. In contrast, fold change in IC50 with virus bearing one of these five mutations was consistently lower:
· L24I: 1.3-fold (interquartile range [IQR] 0.7 to 2.6)
· L76V: 1.0-fold (IQR 0.5 to 2.1)
· I50L: 1.0-fold (IQR 0.6 to 2.5)
· I50V: 0.7-fold (IQR 0.3 to 1.1)
· I54L: Not done
Evaluating only RESIST trial participants and defining response as at least a 1.5-log drop in viral load by week 8 or under 400 copies at week 48, the investigators recorded the following response rates in people with one of these mutations before starting tipranavir/ritonavir:
· L24I: Week 8, 59.4% with, 48.4% without; week 48, 34.2% with, 33.4% without
· L76V: Week 8, 59.1% with, 49.8% without; week 48, 43.3% with, 32.6% without
· I54L: Week 8, 68.0% with, 50.0% without; week 48, 57.1% with, 32.6% without
· I50L: Week 8, 100% with (only 2 patients), 50.5% without; week 48, 100% with (only 2 patients), 33.4% without
· I50V: Week 8, 69.8% with, 49.4% without; week 48, 37.2% with, 33.3% without
Among people with none of the five key mutations before starting tipranavir, response rates averaged 44.6% at week 8 and 31.6% at week 48. In a statistical analysis that factored in activity of other drugs in the tipranavir regimen and mutations that make HIV more resistant to tipranavir, at least two of these five mutations correlated with significantly better 8-, 24-, and 48-week responses to tipranavir/ritonavir (P = 0.045).
People taking a failing amprenavir regimen before tipranavir had the highest prevalence of mutations that boosted susceptibility to tipranavir. The investigators saw I50L most consistently with atazanavir failure, I54L with amprenavir failure, and L76V with amprenavir or lopinavir failure. Because these trials began before darunavir became available, this analysis could not determine the effect of that PI on emergence of mutations favoring tipranavir.
References
1. Hall DB, Baxter J, Schapiro J, et al. Mutations selected by other protease inhibitors predict durable response to tipranavir in treatment-experienced patients. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 124.
2. Scherer J, Boucher C, Baxter J, et al. Improving the prediction of virologic response to tipranavir: the development of a tipranavir weighted mutation score. 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 94.
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