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Failure Therapy

Failure Therapy. VIRAL RESITANCE ADHERENCE!!!!!!!!!!! DRUG INTERACTION. HBV Drugs. Anti HCV in the pipeline. HBV Resistance Pattern. Why Does HIV Resistance Occur?. Patient non-adherence to HAART Suboptimal dosing of drugs Spontaneous mutation of the HIV genome

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Failure Therapy

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  1. Failure Therapy • VIRAL RESITANCE • ADHERENCE!!!!!!!!!!! • DRUG INTERACTION

  2. HBV Drugs

  3. Anti HCV in the pipeline

  4. HBV Resistance Pattern

  5. Why Does HIV Resistance Occur? • Patient non-adherence to HAART • Suboptimal dosing of drugs • Spontaneous mutation of theHIV genome • Selection of Resistant viruses • Transmission of drug-resistant virus Hirsch. JAMA. 1998;279:1984.

  6. Selection of resistants virus

  7. Mechanism of Resistance

  8. Resistance Mechanism to PI • PI are small molecules that block the viral substrate by competition. • Mutation close to the active site inhibit the attachment of the drug. • Major mutations are usually closer to the active site.

  9. Mutations that confer resistance to PI 54 46 48 36 77 50 30 84 20 10 90 63

  10. RESISTANCE MECHANISM TO nRTI

  11. Advantage of M184V M184V

  12. Evaluation ofresistance phenotypictest • Phenotypic test isbasedon the concentration of active product needsto inhibit virale replication by 50% or 90% (IC50orIC90). • Fold resistance: Phenotypic resistance is mesuredby comparisonIC50 of viral isolates testedwith IC50of WT. • Cuttoff: measure from which we consider resistance.

  13. Genotypic Test • Based on RT and PR sequencing • Genotypic resistance reflects the presence of mutations that confer phenotypic or clinical resistance. • This test is less expensive than phenotypic test, rapid, and alert for resistance before phenotypic resistance. • Population of viruses should be >20% in regular tests.

  14. Mutation wt M codon 184 mut V

  15. ALGORYTHM

  16. Stanford Database

  17. Stanford Database

  18. Resistance and Cross-Resistance significantly limit Therapeutic Options Therapy Drugs NRTI AZT d4T 3TC ddI ABC TDF NNRTI EFV NVP PI IDV ATV SQV RTV APV LPV NLF + + 3TC IDV AZT 41L 67N 210W 215F 184V 82T 84V 46L 90M 82T 84V 46L 90M Selected Mutations

  19. Resistance and cross-resistance significantly limit therapeutic options Therapy Drugs NRTI AZT d4T 3TC ddI ABC TDF NNRTI EFV NVP PI IDV SQV RTV APV LPV NLF + + 3TC EFV AZT 41L 67N 210W 215F 184V 103N 82T 84V 46L 90M Selected Mutations

  20. Genetic Barrier

  21. EFV/NVP Low genetic barrier K103N

  22. 3TC Low genetic barrier M184V

  23. PI PI Low effect of one mutation V82A

  24. PI High genetic barrier M46L I50L V82A I84M L90M

  25. Boosted PI High genetic barrier M46L I50L V82A I84M L90M

  26. Fitness 3TC WT K103N EFV M184V

  27. Levels of viremia in the potential transmitter population harbouring NNMs, TAMs and M184V. Turner et al. JAIDS 2004; 37:1627-1631

  28. 3TC TI 3TC Alone vs Treatment Interruption in Patients Failing 3TC-Based HAART Mean VL Increase (ITT) Mean CD4+ Decrease (ITT) Weeks 2.0 3TC TI 4 12 24 36 48 P = .0015 0 1.5 -50 Mean Change in HIV-1 RNA (log10 copies/mL) 1.0 -100 Mean Change in CD4+ Cell Count (cells/mm3) -150 0.5 -200 -250 P = NS 0 4 12 24 36 48 -300 Weeks • In contrast to treatment interruption arm, 3TC alone resulted in: • Smaller recovery in replication capacity • No further selection of resistance mutations Castagna A, et al. AIDS. 2006 Apr 4;20(6):795-803

  29. Single Dose NVP in MTCT

  30. How Can Resistance Further Be Prevented? • Combination Therapy- HAART • Completely suppressing viral replication • in every cell-type • in all compartments (prevent sanctuary escape) • Shortening the time to undetectable levels (hypothetical) • Improve adherence (Dr, Pharmacist & patient) • Avoid drug interaction

  31. Special Problems • Transmission of drug resistance viruses • New drugs – new mutational patterns • Different pattern in different subtypes

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