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

2. CategoryAgents L-nucleosidesLamivudine Emtricitabine Telbivudine Clevudine Acyclic phosphonatesAdefovir Tenofovir Cyclopentane/pentene ringEntecavir Abacavir HBV Drugs

3. Modified Interferons Protease Inhibitors Nucleoside analogs Nonnucleoside analogs Albuferon Consensus interferon NM-283 R126 MK-0608 HCV-796 BI-2071 A-848837 VX-950 SCH-3034 BMS-5339 GS-9132 BI-1335 BI-1230 Anti HCV in the pipeline

4. Antiviral Resistance Group NumberReverse Transcriptase Mutations Lamivudine1L180M + M204V/I/S 2M204I 3L80V/I + M204I [non-A genotype] 4V173L + L180M + M204V 5I169 T + V173L + L180M + M204V 6A181T 7T184S+ L180M+ M204V 8Q215S + L180M + M204V Adefovir1N236T 2A181V/T 3V84M / S85A / L80V/I 4V214A / Q215S Entecavir [3TC backbone*]1I169T + V173L + L180M + T184G + S202I + M204V 2I169T + V173L + L180M + M204V + M250V 3Various combinations of mutations at codons 184, 202, and 250 Tenofovir1L180M + A194T + M204V 2V214A, Q215S 3A181IV + M204I HBV Resistance Pattern

5. Why Does HIV Resistance Occur? Patient non-adherence to HAART Suboptimal dosing of drugs Spontaneous mutation of the HIV 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. 54 4648 50 77 36 30 84 10 90 20 63 Mutations that confer resistance to PI

10. RESISTANCE MECHANISM TO nRTI

12. M184V Advantage of M184V

13. Evaluation of resistance phenotypictest phenotypic test Phenotypic test is based on the concentration of active product needs to inhibit virale replication by 50% or 90% (IC 50 or IC 90 ). Fold resistance: Phenotypic resistance is mesured by comparison IC 50 of viral isolates tested with IC 50 of WT. Cuttoff: measure from which we consider resistance.

14. 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.

15. wt M codon 184 mut V Mutation

20. ALGORYTHM

21. Stanford Database

23. Therapy Selected Mutations Resistance and Cross-Resistance significantly limit Therapeutic Options Drugs NRTI AZT d4T 3TC ddI ABC TDF NNRTI EFV NVP PI IDVATV SQV RTV APV LPV NLF AZT 3TC + 41L67N210W215F184V 82T84V46L90M + IDV 82T84V46L90M

24. Therapy Selected Mutations Drugs NRTI AZT d4T 3TC ddI ABC TDF NNRTI EFV NVP PI IDV SQV RTV APV LPV NLF AZT 3TCEFV ++ 41L67N210W215F103N184V 82T84V46L90M Resistance and cross-resistance significantly limit therapeutic options

25. Genetic Barrier

26. K103NEFV/NVP Low genetic barrier

27. M184V3TC

28. PI V82A Low effect of one mutation

29. PI High genetic barrier V82AI84M L90M M46LI50L

30. Boosted PI High genetic barrier V82AI84M L90M M46LI50L

31. FitnessWT K103N M184V 3TC EFV

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

33. 3TC Alone vs Treatment Interruption in Patients Failing 3TC-Based HAART Castagna A, et al. AIDS. 2006 Apr 4;20(6):795-803 -300 412243648 Mean Change in HIV-1 RNA (log 10 copies/mL) Weeks Mean Change in CD4+ Cell Count (cells/mm 3 ) Weeks 0 412243648 P = NS -250 -200 -150 -100 -50 0 Mean CD4+ Decrease (ITT)Mean VL Increase (ITT) P =.0015 0.5 1.0 1.5 2.0 3TCTI  In contrast to treatment interruption arm, 3TC alone resulted in: –Smaller recovery in replication capacity –No further selection of resistance mutations 3TCTI

34. Single Dose NVP in MTCT

35. 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

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