Failure TherapyFailure Therapy

• VIRAL RESITANCE

• ADHERENCE!!!!!!!!!!!

• DRUG INTERACTION

Category Agents

L-nucleosides Lamivudine

Emtricitabine

Telbivudine

Clevudine

Acyclic phosphonates Adefovir

Tenofovir

Cyclopentane/pentene ring Entecavir

Abacavir

HBV Drugs

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

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

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.

Selection of resistants virusSelection of resistants virus

Mechanism of ResistanceMechanism 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.

54

46 48

50 77 36

30

84

10 90

20

63

Mutations that confer resistance to PI

RESISTANCE RESISTANCE MECHANISM TO nRTIMECHANISM TO nRTI

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

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

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.

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.

wtM

codon184

mutV

Mutation

ALGORYTHMALGORYTHM

Stanford Database

Stanford Database

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

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

Genetic BarrierGenetic Barrier

K103NK103N

EFV/NVPEFV/NVP

Low genetic barrierLow genetic barrier

M184VM184V3TC3TCLow genetic barrierLow genetic barrier

PI PI

V82AV82A

Low effect of one mutationLow effect of one mutation

PI

High genetic barrierHigh genetic barrier

V82AV82A I84MI84M L90ML90MM46LM46LI50LI50L

Boosted PI

High genetic barrierHigh genetic barrier

V82AV82A I84MI84M L90ML90MM46LM46LI50LI50L

FitnessFitnessWTWT

K103NK103N

M184VM184V

3TC

EFV

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

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

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

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

Special Problems

• Transmission of drug resistance viruses

• New drugs – new mutational patterns

• Different pattern in different subtypes