simposio 9: terapia antirretroviral. una mirada al futuro dr. luis enrique soto ramírez profesor de...

Simposio 9: Terapia Simposio 9: Terapia Antirretroviral. Una Antirretroviral. Una

mirada al futuromirada al futuro

Dr. Luis Enrique Soto RamírezDr. Luis Enrique Soto RamírezProfesor de Medicina Interna, Infectología y VIH/SIDAProfesor de Medicina Interna, Infectología y VIH/SIDA

Jefe Laboratorio de Virología MolecularJefe Laboratorio de Virología MolecularDepartamento InfectologíaDepartamento Infectología

Instituto Nacional de Ciencias Médicas y NutriciónInstituto Nacional de Ciencias Médicas y NutriciónCoordinadorCoordinador

Comité de Atención Integral CONASIDAComité de Atención Integral CONASIDA

Resistencia del VIH a los ARvs

Resistencia:Resistencia:

- Disminución de la Disminución de la susceptibilidad de un virus a susceptibilidad de un virus a un medicamentoun medicamento

- Resistencia fenotípica - Resistencia genotípica

- Resistencia primaria- Resistencia secundaria

- Resistencia cruzada

Resistencia a ARV: DefinicionesResistencia a ARV: Definiciones

Mecanismos de falla a ARV Mecanismos de falla a ARV

Resistencia Pre-existente

Alts. Farma-cocinèticas

Pobre Apego

Replicación Viral Persistente

Desarrollo de resistencia

Falla Virológica

POTENCIA LIMITADA

Consecuencias de la Terapia Consecuencias de la Terapia ARVARV

Corto plazo Largo Plazo

Resistencia

Reacciones de Hipersensibilidad: ABC,NVP

* Partially reversible

Diarrea/Nausea Hiperlipidemia

Efectos de SNC Lipodistrofia*

Reversible

Irreversible

Algunos ejemplos:

““La Resistencia es un continuo” La Resistencia es un continuo”

Susceptible Resistente

Mutaciones

Fold Change

Actividad del Medicamento

DHHS, IAS-USA, EACS

Infección primaria

PEP (Fuente Pt)

Crónica(< 2 años)

Falla al tratamiento

Embarazo

Niños

Recomendaciones para el usode pruebas de resistencia

Importancia del las pruebas de resistencia en Importancia del las pruebas de resistencia en el diagnóstico y abordaje del VIHel diagnóstico y abordaje del VIH

• Resistencia primaria- Determinar tratamiento de inicio

• Tipo• Respuesta

• Resistencia secundaria- Nucleósidos- No Nucleósidos- IPs- I. Integrasa- Falla múltiple

Resistencia Primaria Resistencia Primaria

1 1 XIII IHDRW, Tenerife, June 2004; XIII IHDRW, Tenerife, June 2004; 2 2 Wensing AMJ, XII IHDRW, June 2003, #117; Wensing AMJ, XII IHDRW, June 2003, #117; 3 3 Delfraissy JF,Delfraissy JF, Rapport 2004Rapport 2004

% de nuevas infecciones por VIH con resistencias primarias

USA: ~10%1

Canada~8.5%1

Europe:~112*

UK: ~181†

Mexico: ~7%1

Australia:~131

France: ~123‡

Spain: ~9.51

Argentina 7-15%

Brazil 0-30%

Efecto de la resistencia transmitida sobre el tiempo a supresión virológica

N/A, Not available; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PR, protease; RT, reverse transcriptase.aMDR, Multi-drug resistant, defined as the presence of drug-resistant mutations for more than one class of antiretroviral drug.

AIDS:Volume 18 Supplement 3June 2004pp S9-S13

Primary Antiretroviral Resistance in Brazil

Primary Antiretroviral Resistance in Brazil

Recently acquired infection (%)

Long-standing infection (%)

NRTIs T215Y/F M184V M41L

22.79.19.14.5

21.11.73.53.5

NNRTIs 0 15.7

PIs 13.6 8.1

Cumulative 32 29.2

M C A Sucupira. High Levels of Primary Antiretroviral Genotypic Resistance and B/F Recombinants in Santos SP, Brazil. 676, 11th CROI, San Francisco 2004.

Persistence of transmitted resistant virus

1. Little SJ, et al. XII Resistance Workshop, Los Cabos 2003, #115; 2. Ravaux I, et al. 2nd IAS, Paris 2003, #822; 3. Brenner B, et al. J Virology 2002; 766:1753; 4. Chan K, et al. AIDS 2003; 17:1256

n=101

NNRTI (n=9)NRTI (n=3)PI (n=3)

Primary HIVInfection

9-145 1 of 10

Reversions

n=1 PI2 156 None

n=4 MDR3 36-260 None

n=24

MDR (n=1)NNRTI (n=1)

26-156 None

Follow-up (Weeks)

• Reversion of DR is rare even after 1 year

Resistencia secundariaResistencia secundaria

Historia de TARV previo y secuenciación

Medicamentos con pasado

-ITRAN, ITRNN, IPs

-Necesitan de Genotipo a la falla para determinar su actividad

Medicamentos sin pasado

-Inh Integrasa, CCR5 yfusión

-Pueden ser usados sin Genotipo

AZT o d4T

Factores desconocidos

TAMs 141L210W215Y

TAMs 267N70R219Q

Mas alto nivel de resistencia a AZTMayor resistencia cruzada a ITRANs

Mayor decremento en resistencia con M184V

Patrones Dicotómicos de Resistencia


Menor nivel de resistencia a AZTMenor resistencia cruzada a ITRANs

Menor decremento en resistencia con M184V


TAMs 141L210W215Y


TAMs 267N70R219Q+ 215F


TAMs 141L210W215Y+ 67N


Efecto de TAMs, NAMs o ZAMs en la respuesta a Efecto de TAMs, NAMs o ZAMs en la respuesta a otros nucleósidosotros nucleósidos

NARVAL: Brazo de cuidado estándar

Respuesta subsecuente< 3TAMs 3TAMs pa ( log10 CV)

d4T -1.2343 -0.2632 0.036

ABC -1.7636 -0.5891 0.039

ddI -1.1249 -0.2534 0.023

ddI + 3TC -2.40 -0.5197 NS

Costagliola D. Abstract 7. 3rd European Symposium on the Clinical Implications of HIV Drug Resistance, Frankfurt 2001

All Patients

M184V

No TAMs

1-2 TAMs

3+ TAMS w/ 41 or 210

3+ TAMS w/o 41 or 210

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

Cha

nge

in H

IV R

NA

(Log

10 c

/ml)

Response to Tenofovir DF:Effect of TAMs (Gilead 902 & 907)

Miller M, et al. 9th CROI, 2002, Abstract 43

Pocos ITRANs activos en pacientes en falla a primer esquema en Malawi

Pocos ITRANs activos en pacientes en falla a primer esquema en Malawi

Resistencia a ITRANs en pacientes en falla a primer esquema

País Esquema usado/evaluado

% TAMs % M184V

México n=134 [1]

d4T/ZDV + 3TC + EFV

55 58

Vietnam n=136 [2]

d4T/ZDV + 3TC + NVP/EFV

72 75

India n=350 [3]

d4T/ZDV + 3TC + NVP/EFV

62 71

1. Rodríguez-Diaz R. et al. In Press AIDS 2. Truong Giang L, et al. IAC 2008. Abstract TUPDA201. 2. Vidya M, et al. IAC 2008. TUPDA205.

GS934: Resistance Development Through Week 144

1. p=0.037

TDF + FTCTDF + FTC(n = 244)(n = 244)

ZDV/3TCZDV/3TC(n = 243)(n = 243)

Patients genotyped, n (%)Patients genotyped, n (%) 19 (8)19 (8) 2929 (12)(12)

Wild type, nWild type, n 6 6 77

Any resistance, nAny resistance, n 1313 2222

• EFV resistance EFV resistance mutations, nmutations, n 1313 2121

• M184V/I, nM184V/I, n 22 1010**

• TAMs, nTAMs, n 00 22

• K65R, nK65R, n 00 00*P = .02

Arribas JR, et al. IAS 2007. Abstract WEPEB029.

No emergence of K65R during 3 years

Arribas JR, et al. IAS 2007. Abstract WEPEB029.

No emergence of K65R during 3 years

GS 903 (brazoTDF n=299)GS 903 (brazoTDF n=299)Desarrollo de K65R, M184V/I & mutaciones Desarrollo de K65R, M184V/I & mutaciones

relacionadas a EFV en 144 semanasrelacionadas a EFV en 144 semanas

7

10

4

2

12

46

16

0

2

4

6

8

10

12

14

16

18

0-48 Weeks 48-96 Weeks 96-144 Weeks

Nu

mb

er o

f Pat

ien

ts w

ith M

uta

tion

s

K65R

M184V/I

EFV-R

Patrones de Resistencia para ITRNN

K103N

L100I

P225H

Y181C

K101E

G190A

EFAVIRENZ NEVIRAPINA

RESISTENCIA CRUZADA A ETRAVIRINA

§§

Y181IY181IY181VY181VK101PK101PL100IL100IY181CY181CM230LM230LE138AE138AV106IV106IG190SG190SV179FV179FV90IV90I

V179DV179DK101EK101EK101HK101HA98GA98GV179TV179TG190AG190A

§V179F was never present as single INTELENCE RAM (always with Y181C)

Score for individual mutationsScore for individual mutations

Add togetherAdd together Total weighted score

Total weighted score

33

2.52.52.52.51.51.51.51.51111111

Determinación del score genotípico con peso relativo para Etravirina

• Weight for each mutation added together = total weighted score• No single mutation confers a reduced response (≥4)

Pat

ien

ts w

ith

co

nfi

rmed

VL

H

IV-1

RN

A <

50 c

op

ies/

mL

(%

)

Highest response

Intermediateresponse

Reduced response

Highest responses occurred with a weighted score of 2

Relación entre score genotípico basal y respuesta virológica (<50 copias/mL) a semana 24

Hatched bars indicate virologic response for the entire category

74.4%

52.0%

37.7%

4/13 1/33/914/2719/3611/156/1137/53115/148 32/59 2/7 1/5 4/9 2/11N

Response category

2008 weighted mutation score for ETR

TPV weighted score

Mutation Weight

L10V 1

L24I -2

M36I 2

K43T 2

M46L 1

I47V 6

I50L/V -4

I54A/M/V 3

I54L -7

Q58E 5

T74P 6

L76V -2

V82L/T 5

N83D 4

I84V 2

Score Response

≤3 Susceptible

>3 – ≤10 Partially susceptible

>10 Resistant

Scherer et al, EACS 2007

Response by total score

Minor mutation

Major mutation

Increased response

TMC114 (Darunavir) related mutations:

V11I, V32I, L33F, I47V, I50V, I54L/M, G73S (T74P), L76V, I84V, L89V

Different “weight” of these mutations:

FC>4 3-4 2-3 <2

50V(4.5) 54M(3.5)76V(3.5)84V(3.5)T74P(3.5)

32I(2.5) 33F(2.5)47V(2.5)89V(3)

11I(1.5) 54L(1.5) 73S(1.5)

Diminished response to Darunavir when 3 or more of these mutations where present at BL

Antiviral Therapy 2006; 11: S83

Score genotípico para Darunavir

Combined effect of ETR and DRV RAMs on virological response (<50 copies/mL)

Patients with VL <50 copies/mL, % (n)

ETR RAMs weighted score*

[0; 2] [2.5; 3.5] ≥4

DRV RAMs

0 71 (12/17) 83 (5/6) 60 (3/5)1 83 (53/64) 72 (21/29) 53 (8/15)

2 77 (41/53) 64 (14/22) 26 (5/19)

3 74 (40/54) 38 (9/24) 43 (9/21)

>3 59 (23/39) 19 (4/21) 24 (4/17)

Patients with VL<50 copies/mL (%)

Subgroup of patients treated with ETR; not de novo ENF (n=406)

0

20

40

60

80

100

ETR RAMs weighted score

Res

po

nse

at

Wee

k 24

(%

)

DRV RAMs >3

32

10

[0; 2] [2.5; 3.5] ≥4

59

74

77

8371 83

72

64

38

19 24

43

26

53

60

65%

<65%

*from the list of 17 ETR RAMs (Vingerhoets et al. IHDRW 2008) Haubrich et al. XVII WAC, Mexico 2008


Res

po

nse

at

Wee

k 24

(%

)

DRV RAMs >3

32

10

[0; 2] [2.5; 3.5] ≥4

59

74

77

8371 83

72

64

38

19 24

43

26

53

60


Res

po

nse

at

Wee

k 24

(%

)

DRV RAMs >3

32

10

[0; 2] [2.5; 3.5] ≥4

59

74

77

8371 83

72

64

38

19 24

43

26

53

60


Res

po

nse

at

Wee

k 24

(%

)

DRV RAMs >3

32

10

[0; 2] [2.5; 3.5] ≥4

59

74

77

8371 83

72

64

38

19 24

43

26

53

60


Res

po

nse

at

Wee

k 24

(%

)

DRV RAMs >3

32

10

[0; 2] [2.5; 3.5] ≥4

59

74

77

8371 83

72

64

38

19 24

43

26

53

60


Res

po

nse

at

Wee

k 24

(%

)

DRV RAMs >3

32

10

[0; 2] [2.5; 3.5] ≥4

59

74

77

8371 83

72

64

38

19 24

43

26

53

60


Res

po

nse

at

Wee

k 24

(%

)

DRV RAMs >3

32

10

[0; 2] [2.5; 3.5] ≥4

59

74

77

8371 83

72

64

38

19 24

43

26

53

60


Res

po

nse

at

Wee

k 24

(%

)

DRV RAMs >3

32

10

[0; 2] [2.5; 3.5] ≥4

59

74

77

8371 83

72

64

38

19 24

43

26

53

60


Res

po

nse

at

Wee

k 24

(%

)

DRV RAMs >3

32

10

[0; 2] [2.5; 3.5] ≥4

59

74

77

8371 83

72

64

38

19 24

43

26

53

60


Res

po

nse

at

Wee

k 24

(%

)

DRV RAMs >3

32

10

[0; 2] [2.5; 3.5] ≥4

59

74

77

8371 83

72

64

38

19 24

43

26

53

60


Res

po

nse

at

Wee

k 24

(%

)

DRV RAMs >3

32

10

[0; 2] [2.5; 3.5] ≥4

59

74

77

8371 83

72

64

38

19 24

43

26

53

60

Primary protease resistance in naPrimary protease resistance in naїїve ve patients failing boosted-PIspatients failing boosted-PIs

1 Murphy R. et al., 10th EACS, Dublin, Ireland, Nov. 2005; #P7.9/3; 2 Kempf D, et al. J Infect Dis 2004: 189: 51-60; 3 Feinberg J, et al. XIV IAC, Barcelona, July 2002, # B4445, 4Cahn P, et al. 1st IAS, Buenos Aires, Argentina, July 2001, #779, 5Molina JM. et al., 3rd IAS, Rio de Janeiro, Brazil, #WePe16.7B04; 6Malan N, et al., 13th CROI, Denver, #LB107; 7Gathe JC, et al. AIDS 2004, 18:1529-37.

Weeks

0/32 isolates 7

0/3 isolates 6

0/19 isolates 1

0/51 isolates 5

0/13 isolates 4 0/5 isolates 3 0/23 isolates 2

100 200 300 400

ATV/r BMS-089

fosAmp/r SOLO

Kaletra studies

SQV/r GEMINI 0/17 isolates 7

• Adherencia??Adherencia??

• Zona de Presión SelectivaZona de Presión Selectiva

• Alta Ptencia de los IPs/rAlta Ptencia de los IPs/r

• Alta barrera genéticaAlta barrera genética

• Mecanismos alternativos de resistenciaMecanismos alternativos de resistencia- Sitios ruptura de gagSitios ruptura de gag

Como explicar la NO resistencia a IPs/r?Como explicar la NO resistencia a IPs/r?

MONARK Study: LPV/RTV MONARK Study: LPV/RTV Monotherapy vs LPV/RTV + 2 NRTIsMonotherapy vs LPV/RTV + 2 NRTIs

• Primary endpointsPrimary endpoints- HIV-1 RNA < 400 copies/mL at Week 24HIV-1 RNA < 400 copies/mL at Week 24- HIV-1 RNA < 50 copies/mL at Week 48HIV-1 RNA < 50 copies/mL at Week 48

• Patients underwent genotyping when evidence of suboptimal Patients underwent genotyping when evidence of suboptimal response was present or at the treating physician’s requestresponse was present or at the treating physician’s request

Delaugerre C, et al. HIV Resistance Workshop 2007. Abstract 75.

Antiretroviral-naive, HIV-infected patients with

HIV-1 RNA < 105 copies/mL,CD4+ cell count > 100 cells/mm3, andno evidence of resistance at screening

(N = 278)

LPV/RTV SGC 400/100 mg BID (n = 83)

LPV/RTV SGC 400/100 mg +ZDV/3TC 300/150 mg BID

(n = 53)

Week 24 Week 48 Week 96

Ongoing

SGC, soft-gel capsule.

MONARK StudyMONARK Study

• 32 patients in LPV/RTV arm 32 patients in LPV/RTV arm vs 7 in LPV/RTV + ZDV/3TC vs 7 in LPV/RTV + ZDV/3TC arm qualified for genotypic arm qualified for genotypic resistance testingresistance testing- Suboptimal response in 7 vs Suboptimal response in 7 vs

4 subjects, respectively 4 subjects, respectively - 5 vs 2 discontinuations5 vs 2 discontinuations- 20 vs 1 requests for genotyping20 vs 1 requests for genotyping

• 5 patients with major 5 patients with major mutations in monotherapy mutations in monotherapy armarm- L76V mutation in 3 patientsL76V mutation in 3 patients

• All 3 with HIV viral subtype All 3 with HIV viral subtype CRF 02 CRF 02

• LPV/RTV should be LPV/RTV should be administered with an NRTI administered with an NRTI backbone to reduce selection backbone to reduce selection for resistancefor resistance

Delaugerre C, et al. HIV Resistance Workshop 2007. Abstract 75.

LPV/RTVLPV/RTV(n = 32)(n = 32)

LPV/RTV LPV/RTV ++

ZDV/3TCZDV/3TC(n = 7)(n = 7)

No change No change from from screeningscreening

1515 33

Any change Any change in protease in protease genegene

1717 44

IAS minor PI IAS minor PI resistance resistance mutationmutation

55 00

IAS major PI IAS major PI resistance resistance mutationmutation

55 00

Mutaciones Primarias y Secundarias que afectan la Susceptibilidad a RAL

Fo

ld C

han

ge

IC5

0100

200

300

400

500

600Q148HQ148H/G140SQ148KQ148K/E138AQ148K/G140AQ148K/E138A/G140AQ148RQ148R/G140S

Q148 Pathway

Q148 key mutation emerges, associated with secondary mutations

N155 Pathway

N155H key mutation emerges, associated with secondary mutations

Fo

ld C

han

ge

IC5

0

10

203040

50

70 N155HN155H/L74MN155H/T97AN155H/E92Q

60

Hazuda DJ, et al. HIV Resistance Workshop 2007. Abstract 8.

Q148H

Raltegravir Resistance Evolution

N155H + Q148H

N155H N155H + Q148H

Q148H + others

Q148H + others

Q148H + others

Fransen S, et al. Resist Wkshp 2008. Abstract 7.

Cambios en la Susceptibilidad FENOTÍPICA Cambios en la Susceptibilidad FENOTÍPICA a EVG y RAL de mutaciones sitio-dirigidasa EVG y RAL de mutaciones sitio-dirigidas

• Integrase sequenced in patients with virologic failureIntegrase sequenced in patients with virologic failure- Site-directed mutants constructed from those data and used to determine Site-directed mutants constructed from those data and used to determine

susceptibility to EVG, RAL, and 2 antiretroviral controls (TDF and LPV)susceptibility to EVG, RAL, and 2 antiretroviral controls (TDF and LPV)

Fold Change of Mutant Viruses: Single Integrase Mutations

Drug T66I E92Q E138K G140S S147G Q148H Q148K Q148R N155H

EVG 15 33 0.7 5.0 8.0 6.4 67 118 38

RAL 1.4 6.0 0.9 2.0 1.0 20 34 30 23

TDF 0.9 1.0 1.0 0.8 0.8 0.9 0.8 0.7 1.0

LPV 1.0 1.0 0.9 0.8 0.8 0.7 0.9 0.7 1.0

Fold Change of Mutant Viruses: Clinical EVG Mutation Patterns

Drug T66I/S147G

T66I/E92Q

E92Q/N155H

G140S/Q148H

E138K/S147G/Q148R

EVG 46 145 166 > 1000 175

RAL 2.5 33 135 > 1000 34

TDF 1.1 0.9 0.9 0.9 0.9

LPV 1.0 1.0 0.7 0.9 0.8

McColl DJ, et al. HIV Resistance Workshop 2007. Abstract 9.

ARvs recomendados en 212 casos analizados

HIV-1 drug resistance genotyping in treatment-naïve subjects using dried whole blood spots

Silvia Bertagnolio, Luis Soto-Ramirez, Richard Pilon, Richard Harrigan, Roberto Rodriguez, MonicaViveros, Luis Fuentes, Theresa Mo, Don Sutherland, Paul Sandstrom.

Antivir Ther. 2007; 12(1):107-13

Methods: We prospectively collected specimens from newly-diagnosed, treatment-naïve HIV+ subjects in Mexico. Whole blood was spotted onto filter cards, air dried at room temperature and stored with desiccant at 37°C & 85% humidity for 3 months. Genotypes obtained from DBS-extracted nucleic acids using an in-house nested RT-PCR method were compared to genotypes derived from matched plasma.

PDR Surveillance

Results of replicate amplifications of DBS extracts where drug resistance mutations

were detected in either specimen type.

Specimen IDPlasma DBS Mutations from

Replicate RT-PCR (n=11)Mutation Detected in DBS

A2-0229 M41LL210W

11-M41L11-L210W

100%100%

A2-0805 K103NY181CY

8-K103N, 2-K103KN, 1-K103K9-Y181C, 2-Y181CY

90.9%100%

A2-0916 L90MK70RT215FK219E

11-L90M11-K70R11-T215F11-K219E

100%100%100%100%

B5-0054 M41L 11-M41L 100%

B5-0042 M41L 11-M41ML 100%

B1-0015 K103KNV108I

9-K103KN, 2-K103K7-V108I, 4-V108IV

81.8%100%

B5-0119 V108IV 11-V108V 0%

A2-0535 M184M 10-M184M, 1-M184MV 9.1%

B4-0050 D67D 6-D67DN, 5-D67D 54.5%

DBS replicate genotypes were generated from 3 RT-PCR that served as template for 11 nested PCR, except in the case of B5-054 and B1-0015, where only 2 RT-PCR were used as template.All differences between specimen types were partial discordances (mixed bases). In 1 case, B5-0119, a mixed wild type/mutant was detected in plasma and no mutations were detected in matched DBS sequences. Two specimens, A2-0535 and B4-0050, were wild type in plasma and found as mixed wild type/ mutant in 9.1% and 54.5% of replicates in DBS, respectively.

Score del Evaluador 3

3.002.502.001.501.00


Fre

qu

en

cy

20

10

0

Std. Dev = .68

Mean = 2.47

N = 34.00


3.002.502.001.501.00.500.00


Fre

qu

en

cy

14

12

10

8

6

4

2

0

Std. Dev = .83

Mean = 2.26

N = 35.00

Sobreprescripción en base a genotipo

En 30 ocasiones se utilizaron fármacos más potentes de lo requerido según las mutaciones mostradas por el genotipo y la historia de esquemas antiretrovirales previos.

Evaluador 1(2.90): 5/35 (14.28%) Evaluador 2 (2.66): 7/35 (20%) Evaluador 3 (2.47): 17/35 (48.5%) Evaluador 4 (2.26): 1/35 (2.85%)

Los fármacos ARV más sobre prescritos:

Raltegravir 9/30 (30%).

Darunavir 8/30 (26.66%)

T20: 5/30 (16.66%)

Etravirina 5/30 (16.66%)

Tipranavir 3/30 (10%)

LALatin American HIV Resistance Network

Bogotá, ColombiaMayo 6, 2010

simposio 9: terapia antirretroviral. una mirada al futuro dr. luis enrique soto ramírez profesor de...

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