Download - Failure Therapy
![Page 1: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/1.jpg)
Failure TherapyFailure Therapy
• VIRAL RESITANCE
• ADHERENCE!!!!!!!!!!!
• DRUG INTERACTION
![Page 2: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/2.jpg)
Category Agents
L-nucleosides Lamivudine
Emtricitabine
Telbivudine
Clevudine
Acyclic phosphonates Adefovir
Tenofovir
Cyclopentane/pentene ring Entecavir
Abacavir
HBV Drugs
![Page 3: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/3.jpg)
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
![Page 4: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/4.jpg)
AntiviralResistanceGroup Number Reverse Transcriptase Mutations
Lamivudine 1 L180M + M204V/I/S
2 M204I
3 L80V/I + M204I [non-A genotype]
4 V173L + L180M + M204V
5 I169 T + V173L + L180M + M204V
6 A181T
7 T184S+ L180M+ M204V
8 Q215S + L180M + M204V
Adefovir 1 N236T
2 A181V/T
3 V84M / S85A / L80V/I
4 V214A / Q215S
Entecavir [3TC backbone*] 1 I169T + V173L + L180M + T184G + S202I + M204V
2 I169T + V173L + L180M + M204V + M250V
3 Various combinations of mutations at codons 184, 202, and 250
Tenofovir 1 L180M + A194T + M204V
2 V214A, Q215S
3 A181IV + M204I
HBV Resistance Pattern
![Page 5: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/5.jpg)
Why Does HIV Why Does HIV Resistance Occur?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.
![Page 6: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/6.jpg)
Selection of resistants virusSelection of resistants virus
![Page 7: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/7.jpg)
Mechanism of ResistanceMechanism of Resistance
![Page 8: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/8.jpg)
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.
![Page 9: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/9.jpg)
54
46 48
50 77 36
30
84
10 90
20
63
Mutations that confer resistance to PI
![Page 10: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/10.jpg)
RESISTANCE RESISTANCE MECHANISM TO nRTIMECHANISM TO nRTI
![Page 11: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/11.jpg)
P PP P
PP
P
P
PA
B
OHHC A U
AUGC
Nucleotide Incorporation
P PP P
PPPOH
C A U
UG AC
NTP-dependent Excision
P
P
P PP P
PA
B
PPOH
C A U
UG AC
POH
P
P
P PP P
PPOH
A U
UG AC
POH
HC
P
ACTIVE SITE
ACTIVE SITE
TAMs may facilitate reverse binding of ATP, which can act as pyrophosphate donor
K65R, L74V, M184V discriminate between chain-terminators and natural dNTPs at the active site
![Page 12: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/12.jpg)
P PP P
PP
P
P
PA
B
OHHC A U
AUGC
Nucleotide Incorporation
P PP P
PPPOH
C A U
UG AC
NTP-dependent Excision
P
P
P PP P
PA
B
PPOH
C A U
UG AC
POH
P
P
P PP P
PPOH
A U
UG AC
POH
HC
P
ACTIVE SITE
ACTIVE SITE
TAMs may facilitate reverse binding of ATP, which can act as pyrophosphate donor
K65R, L74V, M184V discriminate between chain-terminators and natural dNTPs at the active site
M184V
Advantage of M184V
![Page 13: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/13.jpg)
EEvaluation valuation ofof reresistancesistancephpheenotypinotypicc ttestest
• Phenotypic test is based on the concentration of active product needs to inhibit virale replication by 50% or 90% (IC50 or IC90).
• Fold resistance: Phenotypic resistance is mesured by comparison IC50 of viral isolates tested with IC50 of WT.
• Cuttoff: measure from which we consider resistance.
![Page 14: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/14.jpg)
Genotypic TestGenotypic 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.
![Page 15: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/15.jpg)
wtM
codon184
mutV
Mutation
![Page 16: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/16.jpg)
![Page 17: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/17.jpg)
![Page 18: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/18.jpg)
![Page 19: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/19.jpg)
![Page 20: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/20.jpg)
ALGORYTHMALGORYTHM
![Page 21: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/21.jpg)
Stanford Database
![Page 22: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/22.jpg)
Stanford Database
![Page 23: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/23.jpg)
Therapy
Selected Mutations
Resistance and Cross-Resistance significantly limit Resistance and Cross-Resistance significantly limit Therapeutic OptionsTherapeutic Options
Drugs
NRTI
AZT
d4T
3TC
ddI
ABC
TDF
NNRTI
EFV
NVP
PI
IDV ATV
SQV
RTV
APV
LPV
NLF
AZT
3TC+
41L 67N
210W
215F
184V
82T 84V
46L 90M
+ IDV
82T 84V 46L 90M
![Page 24: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/24.jpg)
Therapy
Selected Mutations
Drugs
NRTI
AZT
d4T
3TC
ddI
ABC
TDF
NNRTI
EFV
NVP
PI
IDV
SQV
RTV
APV
LPV
NLF
AZT
3TC EFV+ +
41L 67N
210W
215F
103N184V
82T 84V
46L 90M
Resistance and cross-resistance Resistance and cross-resistance significantly limit therapeutic optionssignificantly limit therapeutic options
![Page 25: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/25.jpg)
Genetic BarrierGenetic Barrier
![Page 26: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/26.jpg)
K103NK103N
EFV/NVPEFV/NVP
Low genetic barrierLow genetic barrier
![Page 27: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/27.jpg)
M184VM184V3TC3TCLow genetic barrierLow genetic barrier
![Page 28: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/28.jpg)
PI PI
V82AV82A
Low effect of one mutationLow effect of one mutation
![Page 29: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/29.jpg)
PI
High genetic barrierHigh genetic barrier
V82AV82A I84MI84M L90ML90MM46LM46LI50LI50L
![Page 30: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/30.jpg)
Boosted PI
High genetic barrierHigh genetic barrier
V82AV82A I84MI84M L90ML90MM46LM46LI50LI50L
![Page 31: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/31.jpg)
FitnessFitnessWTWT
K103NK103N
M184VM184V
3TC
EFV
![Page 32: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/32.jpg)
0
10000
20000
30000
40000
50000
178 17 27 64 43 35 81 107
Mea
n V
iral
Lo
ad (
cop
ies/
ml) Levels of viremia in the potential transmitter population
harbouring NNMs, TAMs and M184V.
Turner et al. JAIDS 2004; 37:1627-1631
![Page 33: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/33.jpg)
3TC Alone vs Treatment Interruption in Patients Failing 3TC-Based HAART
Castagna A, et al. AIDS. 2006 Apr 4;20(6):795-803
-300
4 12 24 36 48
Mea
n C
ha
ng
e in
HIV
-1
RN
A (
log
10 c
op
ies/
mL
) Weeks
Mea
n C
ha
ng
e in
CD
4+
Cel
l C
ou
nt
(cel
ls/m
m3)
Weeks
04 12 24 36 48
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 3TC TI
In contrast to treatment interruption arm, 3TC alone resulted in:– Smaller recovery in replication capacity– No further selection of resistance mutations
3TC TI
![Page 34: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/34.jpg)
clinicaloptions.com/hiv
HIV Journal Options
Eshleman S, et al. J Infect Dis. 2005;192:30-36.
Main Findings
Higher frequency of NVP resistance mutations in women with subtype Cvs subtype A or D at6- 8weeks post-SD-
NVP administration
Detection rates for K103N, Y181C, and Y188 C) significantly higher for subtype C womenP = . 03 in all
;cases P <. 001in many cases(
3)3.1( 2)1.4( 11)16.9(Y188C
16)16.5( 8)5.6( 21)32.3(Y181C
28)28.9( 25)17.4( 38)58.5(K103N
16)16.5(
35)36.1(
HIVNET 012 Subtype D
) n =97(
12)8.3( 28)43.1(= 2mutations
HIVNET 012Subtype A
) n =144(
NVAZSubtype C
) n =65((%) NVP Resistance Mutation, n
28)19.4( 45)69.2(= 1mutation
Single Dose NVP in MTCT
![Page 35: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/35.jpg)
How Can Resistance Further How Can Resistance Further Be Prevented?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
![Page 36: Failure Therapy](https://reader035.vdocuments.mx/reader035/viewer/2022062520/5681587a550346895dc5dc69/html5/thumbnails/36.jpg)
Special Problems
• Transmission of drug resistance viruses
• New drugs – new mutational patterns
• Different pattern in different subtypes