Transcript Response at Week 24 - International AIDS Society

Simposio 9: Terapia
Antirretroviral. Una
mirada al futuro
Resistencia del VIH a los ARvs
Dr. Luis Enrique Soto Ramírez
Profesor de Medicina Interna, Infectología y VIH/SIDA
Jefe Laboratorio de Virología Molecular
Departamento Infectología
Instituto Nacional de Ciencias Médicas y Nutrición
Coordinador
Comité de Atención Integral CONASIDA
Resistencia a ARV: Definiciones
Resistencia:
- Disminución
de la susceptibilidad
de un virus a un medicamento
-
Resistencia fenotípica
Resistencia genotípica
-
Resistencia primaria
Resistencia secundaria
-
Resistencia cruzada
Mecanismos de falla a ARV
POTENCIA LIMITADA
Resistencia
Pre-existente
Alts. Farmacocinèticas
Replicación Viral Persistente
Desarrollo de resistencia
Falla Virológica
Pobre
Apego
Consecuencias de la Terapia
ARV
Algunos ejemplos:
Corto plazo
Largo Plazo
Reversible
Diarrea/Nausea
Hiperlipidemia
Efectos de SNC
Lipodistrofia*
* Partially reversible
Irreversible
Reacciones de
Hipersensibilidad: ABC,NVP
Resistencia
“La Resistencia es un continuo”
Mutaciones
Fold Change
Susceptible
Actividad del Medicamento
Resistente
Recomendaciones para el uso
de pruebas de resistencia
DHHS, IAS-USA, EACS
Infección primaria
PEP (Fuente Pt)
Crónica(< 2 años)
Falla al tratamiento
Embarazo
Niños
Importancia del las pruebas de resistencia en
el 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
% de nuevas infecciones por VIH con resistencias primarias
Canada
~8.5%1
USA: ~10%1
UK: ~181†
France: ~123‡
Europe:~112* Spain: ~9.51
Mexico:
~7%1
Brazil 0-30%
Argentina 7-15%
1 XIII
IHDRW, Tenerife, June 2004; 2 Wensing AMJ, XII IHDRW, June 2003, #117;
3 Delfraissy JF, Rapport 2004
Australia:
~131
Efecto de la resistencia transmitida sobre
el tiempo a supresión virológica
Primary Antiretroviral Resistance in
Brazil
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
NRTIs
T215Y/F
M184V
M41L
NNRTIs
PIs
Cumulative
Recently acquired
infection (%)
Long-standing
infection (%)
22.7
21.1
0
15.7
13.6
8.1
32
29.2
9.1
9.1
4.5
1.7
3.5
3.5
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
• Reversion of DR is rare even after 1 year
Primary HIV
Infection
n=101
NNRTI
NRTI
PI
(n=9)
(n=3)
(n=3)
Follow-up (Weeks)
9-145
Reversions
1 of 10
n=1 PI2
156
None
n=4 MDR3
36-260
None
26-156
None
n=24
MDR
NNRTI
(n=1)
(n=1)
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
Resistencia secundaria
Historia de TARV previo y secuenciación
Medicamentos con pasado
Medicamentos sin
pasado
-ITRAN, ITRNN, IPs
-Necesitan de Genotipo a la
falla para determinar su
actividad
-Inh Integrasa, CCR5 y
fusión
-Pueden ser usados sin
Genotipo
Patrones Dicotómicos de Resistencia
AZT o d4T
Factores
desconocidos
TAMs 1
41L
210W
215Y
+ 67N
Mas alto nivel de resistencia a AZT
Mayor resistencia cruzada a ITRANs
Mayor decremento en
resistencia con M184V
Factores
desconocidos
TAMs 2
67N
70R
219Q
+ 215F
Menor nivel de resistencia a AZT
Menor resistencia cruzada a ITRANs
Menor decremento en
resistencia con M184V
Efecto de TAMs, NAMs o ZAMs en la respuesta a
otros nucleósidos
NARVAL: Brazo de cuidado estándar
Respuesta subsecuente
a (  log10 CV)
< 3TAMs
 3TAMs
p
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
Response to Tenofovir DF:
Effect of TAMs (Gilead 902 & 907)
0
Change in HIV RNA (Log10 c/ml)
-0.1
-0.2
3+ TAMS w/ 41 or
210
-0.3
-0.4
-0.5
-0.6
All Patients
1-2 TAMs
-0.7
M184V
-0.8
No TAMs
-0.9
Miller M, et al. 9th CROI, 2002, Abstract 43
3+ TAMS w/o 41
or 210
Pocos
Resistencia
ITRANs
a ITRANs
activos en
en pacientes
pacientes en
en
falla afalla
primer
a primer
esquema
esquema
en Malawi
País
Esquema
% TAMs
usado/evaluado
%
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
TDF + FTC
(n = 244)
ZDV/3TC
(n = 243)
19 (8)
29 (12)
Wild type, n
6
7
Any resistance, n
13
22
13
21
2
10*
0
2
0
0
Patients genotyped, n (%)
• EFV resistance
mutations, n
• M184V/I, n
• TAMs, n
• K65R, n
*P = .02
1.
p=0.037

No emergence of K65R during 3 years
Arribas JR,
JR, et
et al.
al. IAS
IAS 2007.
2007. Abstract
Abstract WEPEB029.
WEPEB029.
Arribas
Number of Patients with Mutations
GS 903 (brazoTDF n=299)
Desarrollo de K65R, M184V/I & mutaciones
relacionadas a EFV en 144 semanas
18
16
14
12
10
8
6
4
2
0
16
12
7
K65R
M184V/I
EFV-R
6
4
1
0-48 Weeks
4
2
48-96 Weeks
0
96-144 Weeks
Patrones de Resistencia para ITRNN
EFAVIRENZ
NEVIRAPINA
K103N
Y181C
L100I
K101E
P225H
G190A
RESISTENCIA CRUZADA
A ETRAVIRINA
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)
Score for individual mutations
Y181I
Y181V
K101P
L100I
Y181C
M230L
E138A
V106I
G190S
V179F §
V90I
V179D
K101E
K101H
A98G
V179T
G190A
3
3
2.5
2.5
2.5
2.5
1.5
1.5
1.5
1.5
1
1
1
1
1
1
1
Add together
§V179F
Total weighted
score
was never present as single INTELENCE RAM (always with Y181C)
Patients with confirmed VL
HIV-1 RNA <50 copies/mL (%)
Relación entre score genotípico basal y respuesta
virológica (<50 copias/mL) a semana 24
100
Highest
response
80
74.4%
Reduced
response
Intermediate
response
Response category
60
52.0%
37.7%
40
20
0
N
0.0 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5  7.0
115/148 37/53
6/11
11/15
32/59
2/7
19/36
1/5
14/27
3/9
4/9
4/13
1/3
2008 weighted mutation score for ETR

Highest responses occurred with a weighted score of  2
Hatched bars indicate virologic response for the entire category
2/11
TPV weighted score
Mutation
Weight
L10V
L24I
M36I
K43T
M46L
I47V
I50L/V
I54A/M/V
I54L
Q58E
T74P
L76V
V82L/T
N83D
I84V
1
-2
2
2
1
6
-4
3
-7
5
6
-2
5
4
2
Response by total score
Score
Response
≤3
Susceptible
>3 – ≤10
Partially susceptible
>10
Resistant
Increased response
Minor mutation
Major mutation
Scherer et al, EACS 2007
Score genotípico para Darunavir
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
Combined effect of ETR and DRV RAMs on
virological response (<50 copies/mL)
Response at Week 24 (%)

100
83
71
83
77
80
60
72
74
60
Patients with VL<50 copies/mL (%)
64
53
65%
59
40
43
38
20
Subgroup of patients treated with
ETR; not de novo ENF (n=406)
26
<65%
1
24
19
3
2
0
DRV RAMs
>3
0
[0; 2]
[2.5; 3.5]
≥4
ETR RAMs weighted score
Patients with VL
<50 copies/mL, % (n)
0
1
2
DRV RAMs
3
>3
[0; 2]
71 (12/17)
83 (53/64)
77 (41/53)
74 (40/54)
59 (23/39)
ETR RAMs weighted score*
[2.5; 3.5]
83 (5/6)
72 (21/29)
64 (14/22)
38 (9/24)
19 (4/21)
*from the list of 17 ETR RAMs (Vingerhoets et al. IHDRW 2008)
≥4
60 (3/5)
53 (8/15)
26 (5/19)
43 (9/21)
24 (4/17)
Haubrich et al. XVII WAC, Mexico 2008
Primary protease resistance in naїve
patients failing boosted-PIs
0/19 isolates 1
0/23 isolates 2
0/5 isolates 3
0/13 isolates 4
Kaletra studies
0/51 isolates 5
ATV/r BMS-089
0/3 isolates 6
fosAmp/r SOLO
0/32 isolates 7
SQV/r GEMINI
0/17 isolates 7
100
200
Weeks
300
400
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.
Como explicar la NO resistencia a
IPs/r?
•
Adherencia??
•
Zona de Presión Selectiva
•
Alta Ptencia de los IPs/r
•
Alta barrera genética
•
Mecanismos alternativos de resistencia
-
Sitios ruptura de gag
MONARK Study: LPV/RTV
Monotherapy vs LPV/RTV + 2 NRTIs
Week 24
Antiretroviral-naive,
HIV-infected patients with
HIV-1 RNA < 105 copies/mL,
CD4+ cell count > 100 cells/mm3, and
no evidence of resistance at screening
(N = 278)
Week 48
Week 96
LPV/RTV SGC 400/100 mg BID
(n = 83)
LPV/RTV SGC 400/100 mg +
ZDV/3TC 300/150 mg BID
(n = 53)
Ongoing
• Primary endpoints
•
- HIV-1 RNA < 400 copies/mL at Week 24
- HIV-1 RNA < 50 copies/mL at Week 48
Patients underwent genotyping when evidence of suboptimal
response was present or at the treating physician’s request
SGC, soft-gel capsule.
Delaugerre C, et al. HIV Resistance Workshop 2007. Abstract 75.
MONARK Study
• 32 patients in LPV/RTV arm
vs 7 in LPV/RTV + ZDV/3TC
arm qualified for genotypic
resistance testing
- Suboptimal response in 7 vs
•
4 subjects, respectively
5 vs 2 discontinuations
20 vs 1 requests for genotyping
5 patients with major
mutations in monotherapy
arm
- L76V mutation in 3 patients
• All 3 with HIV viral subtype
CRF 02
• LPV/RTV should be
administered with an NRTI
backbone to reduce selection
for resistance
LPV/RTV
(n = 32)
LPV/RTV
+
ZDV/3TC
(n = 7)
No change
from
screening
15
3
Any change
in protease
gene
17
4
IAS minor PI
resistance
mutation
5
0
IAS major PI
resistance
mutation
5
0
Delaugerre C, et al. HIV Resistance Workshop 2007. Abstract 75.
Mutaciones Primarias y Secundarias
que afectan la Susceptibilidad a RAL
Q148 key mutation
emerges, associated with
secondary mutations
Fold Change IC50
Q148 Pathway
N155H key mutation
emerges, associated with
secondary mutations
Fold Change IC50
N155 Pathway
600
500
400
300
200
Q148H
Q148H/G140S
Q148K
Q148K/E138A
Q148K/G140A
Q148K/E138A/G140A
Q148R
Q148R/G140S
100
70
60
50
40
30
20
10
Hazuda DJ, et al. HIV Resistance Workshop 2007. Abstract 8.
N155H
N155H/L74M
N155H/T97A
N155H/E92Q
Raltegravir Resistance Evolution
N155H
N155H + Q148H
Q148H + others
N155H + Q148H
Q148H + others
Q148H
Q148H + others
Fransen S, et al. Resist Wkshp 2008. Abstract 7.
Cambios en la Susceptibilidad FENOTÍPICA
a EVG y RAL de mutaciones sitio-dirigidas
• Integrase sequenced in patients with virologic failure
-
Site-directed mutants constructed from those data and used to determine
susceptibility to EVG, RAL, and 2 antiretroviral controls (TDF and LPV)
Fold Change of Mutant Viruses: Single Integrase Mutations
Drug
T66I
E92Q
E138
K
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
PDR Surveillance
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.
Results of replicate amplifications of DBS extracts
where drug resistance mutations were detected in
either specimen type.
Plasma
DBS Mutations from
Replicate RT-PCR (n=11)
Mutation Detected in DBS
A2-0229
M41L
L210W
11-M41L
11-L210W
100%
100%
A2-0805
K103N
Y181CY
8-K103N, 2-K103KN, 1-K103K
9-Y181C, 2-Y181CY
90.9%
100%
A2-0916
L90M
K70R
T215F
K219E
11-L90M
11-K70R
11-T215F
11-K219E
100%
100%
100%
100%
B5-0054
M41L
11-M41L
100%
B5-0042
M41L
11-M41ML
100%
B1-0015
K103KN
V108I
9-K103KN, 2-K103K
7-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%
Specimen ID
DBS replicate genotypes were generated from 3 RT-PCR that served as template for 11 nested PCR, except in the case of B5054 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 2
Score del Evaluador 1
20
30
20
10
Frequency
Frequency
10
Std. Dev = .59
Std. Dev = .42
Mean = 2.66
Mean = 2.90
N = 35.00
0
1.50
2.00
2.50
3.00
N = 35.00
0
1.00
3.50
1.50
2.00
2.50
Score del Evaluador 1
Score del Evaluador 2
Score del Evaluador 3
Score del Evaluador 4
20
3.00
3.50
14
12
10
8
10
6
Frequency
Frequency
4
Std. Dev = .68
Std. Dev = .83
2
Mean = 2.47
N = 34.00
0
1.00
1.50
2.00
Score del Evaluador 3
2.50
3.00
Mean = 2.26
N = 35.00
0
0.00
.50
1.00
1.50
Score del Evaluador 4
2.00
2.50
3.00
 En
Sobreprescripción en base a
genotipo
30
ocasiones
se  Los fármacos ARV
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%)
más sobre
prescritos:
 Raltegravir
9/30
 Darunavir
8/30
 T20:
5/30
 Etravirina
5/30
 Tipranavir
3/30
(30%).
(26.66%)
(16.66%)
(16.66%)
(10%)
LA
Latin American HIV
Resistance Network
Bogotá, Colombia
Mayo 6, 2010