The Genetic Barrier to Resistance
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1 The Genetic Barrier to Resistance Jonathan M Schapiro, MD National Hemophilia Center, Israel Stanford University School of Medicine, USA Beijing, May 2013
2 The Genetic Barrier to Resistance The genetic barrier to resistance is an important concept in antiretroviral therapy Understanding and accurately assessing it for each drug and combination regimen is a key component in our decision process as HIV clinicians We will attempt to improve our ability to determine the genetic barrier to resistance and its implications in routine clinical care
3 Protease Inhibitors
4 Protease Inhibitors A key feature of boosted protease inhibitors is their high genetic barrier to resistance
5 Genetic Barrier to Resistance: Virology and Pharmacology
6 Genetic Barrier to Resistance: Virology and Pharmacology Plasma concentration of Drug Drug level Time (hours)
7 Genetic Barrier to Resistance: Virology and Pharmacology Plasma concentration of Drug Drug level Time (hours)
8 Drug level
9 Drug level
10 Estimating the Barrier to Resistance
11 Estimating the Barrier to Resistance
12 Estimating the Barrier to Resistance Is this the clinically relevant Genetic Barrier to Resistance?
13 Correcting for Protein Binding of Drug in Plasma
14 Correcting for Protein Binding of Drug in Plasma corrected for protein binding
15 Estimating the Barrier to Resistance What is Missing? corrected for protein binding
16 How Much Resistance from a Single Mutation to the Drug Drug level to inhibit most potent single mutation to the drug corrected for protein binding
17 How Much Resistance from a Single Mutation to the Drug Fold Change Resistance of Single Mutant Drug level to inhibit most potent single mutation to the drug corrected for protein binding
18 Example Drug level to inhibit single mutation =? Fold Change Resistance of Single Mutant = 4 corrected = 2
19 Example Drug level to inhibit single mutation = 8 Fold Change Resistance of Single Mutant = 4 corrected = 2
20 Estimating the Barrier to Resistance Drug level to inhibit most potent single mutation to the drug corrected for protein binding
21 Estimating the Barrier to Resistance Drug with potentially high genetic barrier to resistance Drug level to inhibit most potent single mutation to the drug corrected for protein binding
22 Estimating the Barrier to Resistance Drug level to inhibit most potent single mutation to the drug corrected for protein binding
23 Estimating the Barrier to Resistance Drug level to inhibit most potent single mutation to the drug Drug with potentially Low genetic barrier to resistance corrected for protein binding
24 Factors Contributing to a High Genetic Barrier to Resistance Potentially High Genetic Barrier Fold Change Resistance of Single Mutant = 3 Drug level to inhibit most potent single mutation to the drug corrected for protein binding
25 Factors Contributing to a High Genetic Barrier to Resistance Fold Change Resistance of Single Mutant = 30 Drug level to inhibit most potent single mutation to the drug Potentially Low Genetic Barrier corrected for protein binding
26 Summary A general assessment of each drug s genetic barrier to resistance can be made from publically available data This can be useful to the practicing clinician to: Critically evaluate data presented on the compound Consider utility of suggested clinical trials Guide treatment decisions not only of when to use drug but at what dosing schedule
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