Failure Therapy VIRAL RESITANCE ADHERENCE DRUG INTERACTION HBV
Failure Therapy • VIRAL RESITANCE • ADHERENCE!!!!!! • DRUG INTERACTION
HBV Drugs Category Agents L-nucleosides Lamivudine Emtricitabin e Telbivudine Clevudine Acyclic phosphonates Adefovir Tenofovir Cyclopentane/pentene ring Entecavir Abacavir
Anti HCV in the pipeline Modified Nucleosi Interferon de s analogs Nonnucleo side analogs • Albuferon • NM-283 • Consens • R 126 us • MK-0608 interferon • HCV-796 • BI-2071 • A-848837 Protease Inhibitors • VX-950 • SCH 3034 • BMS 5339 • GS-9132 • BI-1335 • BI-1230
HBV Resistance Pattern Antiviral Lamivudine Adefovir Entecavir [3 TC backbone*] Tenofovir Resistance Group Number Reverse Transcriptase Mutations 1 L 180 M + M 204 V/I/S 2 M 204 I 3 L 80 V/I + M 204 I [non-A genotype] 4 V 173 L + L 180 M + M 204 V 5 I 169 T + V 173 L + L 180 M + M 204 V 6 A 181 T 7 T 184 S+ L 180 M+ M 204 V 8 Q 215 S + L 180 M + M 204 V 1 N 236 T 2 A 181 V/T 3 V 84 M / S 85 A / L 80 V/I 4 V 214 A / Q 215 S 1 I 169 T + V 173 L + L 180 M + T 184 G + S 202 I + M 204 V 2 I 169 T + V 173 L + L 180 M + M 204 V + M 250 V 3 Various combinations of mutations at codons 184, 202, and 250 1 L 180 M + A 194 T + M 204 V 2 V 214 A, Q 215 S 3 A 181 IV + M 204 I
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.
Selection of resistants virus
Mechanism of Resistance
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.
Mutations that confer resistance to PI 54 46 48 36 77 50 30 20 84 90 63 10
RESISTANCE MECHANISM TO n. RTI
Advantage of M 184 V
Evaluation of resistance 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.
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.
Mutation wt M codon 184 mut V
ALGORYTHM
Stanford Database
Stanford Database
Resistance and Cross-Resistance significantly limit Therapeutic Options Therapy Drugs NRTI AZT + 3 TC + IDV AZT d 4 T 3 TC dd. I ABC TDF NNRTI EFV NVP 41 L 67 N 210 W 215 F 82 T 84 V 46 L 90 M 184 V 82 T 84 V 46 L 90 M PI IDV SQV RTV APV Selected Mutations LPV NLF ATV
Resistance and cross-resistance significantly limit therapeutic options Therapy Drugs NRTI AZT + 3 TC + EFV AZT d 4 T 3 TC dd. I ABC TDF NNRTI EFV NVP 41 L 67 N 210 W 215 F 82 T 84 V 46 L 90 M 184 V 103 N PI IDV SQV RTV APV Selected Mutations LPV NLF
Genetic Barrier
Low genetic barrier K 103 N EFV/NVP
3 TC Low genetic barrier M 184 V
Low effect of one mutation V 82 A PI PI
High genetic barrier M 46 L I 50 L PI V 82 A I 84 M L 90 M
Boosted PI High genetic barrier M 46 L I 50 L V 82 A I 84 M L 90 M
Fitness 3 TC WT K 103 N EFV M 184 V
Levels of viremia in the potential transmitter population harbouring NNMs, TAMs and M 184 V. Turner et al. JAIDS 2004; 37: 1627 -1631
3 TC Alone vs Treatment Interruption in Patients Failing 3 TC-Based HAART 2. 0 3 TC Weeks TI P =. 0015 1. 0 0. 5 0 4 12 Mean CD 4+ Decrease (ITT) 24 36 Weeks 48 Mean Change in CD 4+ Cell Count (cells/mm 3) Mean Change in HIV-1 RNA (log 10 copies/m. L) Mean VL Increase (ITT) 0 -50 -100 -150 -200 -250 -300 4 12 3 TC 24 TI 36 48 P = NS In contrast to treatment interruption arm, 3 TC 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
Single Dose NVP in MTCT
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
Special Problems • Transmission of drug resistance viruses • New drugs – new mutational patterns • Different pattern in different subtypes
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