MECANISMOS DE RESISTENCIA A

ANTIRRETROVIRALES

1

Dr. Luis Enrique Soto Ramírez

Instituto Nacional de Ciencias Médicas y Nutrición

Salvador Zubirán

Current arsenal from the clinican‘s point of view

NNRTI

NRTI

FI

Ziagen

Combivir

Videx Retrovir Zerit

Hivid Epivir

Trizivir

Norvir

Crixivan

Viread

PI Fuzeon

Emtriva

Telzir

Kivexa

Truvada

1987 1991 1992 1994 1995 1996 1997 1998 1999 2000 1988 1989 1990 2001 2002 2003 2004 2005 2006 2007 2008

Sustiva

Viramune

Rescriptor

EI INI

Prezista

Agenerase

Kaletra Reyataz

Celsentri

Intelence

Isentress Fortovase

Invirase

Viracept

Aptivus

1987 1991 1992 1994 1995 1996 1997 1998 1999 2000 1988 1989 1990 2001 2002 2003 2004 2005 2006 2007 2008

65R, 74V

41L, 67N, 70R, 210W, 215Y, 219Q

75AMST

184V 184V 103N

103N, 190A 65R

74V+184V

65R+184V

41L, 67N, 70R, 210W, 215Y, 219Q

+184V

41L, 67N, 70R, 210W, 215Y, 219Q +74V+184V

103N, 181C

74V, 115F 184V

184V

181IV

X4-Tropismus

NNRTI

NRTI

FI

PI

EI INI

46I, 54V, 82A, 84V

48V, 90M

47V, 50V,54LM, 76V, 84V

46IL, 82AFT, 84V

48V, 90M

32I, 47VA, 76V, 82A

30N, 90M

50L, 90M

36S, 38A

50V, 84V

33F, 82LT, 84V

148RHK, 155H, 143RC

50V, 54ML, 76V, 84V

Current arsenal from the virologist‘s point of view

EARLY TREATMENT OF PTS WITH ACUTE HIV

INFECTION RESTRICTS SEEDING OF

RESERVOIRS

RV254/SEARCH 010: ongoing, prospective, open-label study of subjects seeking voluntary HIV testing (n = 75 with Fiebig stage I-III acute infection)

Before ART, HIV reservoir seeding limited

Integrated HIV-1 DNA undetectable in PBMCs (92%) and sigmoid colon (88%) of most Fiebig I pts

Lower infection frequencies of central memory CD4+ T cells vs other memory cells

After ART, decline in HIV reservoir size

Integrated HIV-1 DNA undetectable in PBMCs in 90% of pts at 1 yr

Reservoir primarily in transitional and effector memory CD4+ T cells

Suggests very early ART may prevent seeding of reservoirs

Fiebig Stages

Fiebig I: RNA+, p24 ̶ neg, 3rd-gen ELISA neg

Would not be detected by 4th-gen ELISA

Fiebig II: RNA+, p24+, 3rd-gen ELISA neg

Fiebig III: 3rd-gen ELISA+, WB neg

Ananworanich J, et al. CROI 2013. Abstract 47.

5

Mecanismos de falla a ARV

Resistencia Pre-existente

Alts. Farma- cocinèticas

Pobre Apego

Replicación Viral Persistente

Desarrollo de resistencia

Falla Virológica

POTENCIA LIMITADA

Generación de Resistencia: el virus

• Elevada tasa de error de la TR • Plasticidad de las proteínas virales • Elevada cinética de replicación

SELECCIÓN DE CEPAS RESISTENTES DURANTE TARV

Sin tratamiento Con tratamiento no supresor

Cepas susceptibles

Alta capacidad replicativa

Cepas Baja resistencia

Baja capacidad replicativa

Cepas Alta Resistencia

Alta capacidad replicativa

9

10

11

12

13

14

15

16

17

18

19

20

21

RESISTENCIA A ITRAN

22

23

Clavel, F. et al. N Engl J Med 2004;350:1023-1035

Mecanismos de Resistencia a los NRTIs

184V (3TC), 74V (ddI), 65R, 151M

TAMs

24

Clavel, F. et al. N Engl J Med 2004;350:1023-1035

Mecanismos de Resistencia a los NRTIs

TAMs

M184V

X

25

Resistencia a los NRTIs de acuerdo a NAMs

Efecto de TAMs en la respuesta a otros nucleósidos

NARVAL: Brazo de cuidado estándar

Respuesta subsecuente < 3TAMs 3TAMs p a ( 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

Mutation Patterns N of Seq

AZT foldn

D4T foldn

TDF foldn

ABC foldn

DDI foldn

DDC foldn

3TC foldn

41L,210W,215Y (44) 433 1546 2.56 3.63 3.26 1.66 1.64 2.96

41L,184V,210W,215Y (36) 561 7.519 2.020 1.28 6.621 1.619 2.215 20019

41L,67N,210W,215Y (49) 434 9099 6.49 5.56 6.69 2.29 1.84 7.29

41L,67N,184V,210W,215Y (41) 455 3624 2.724 1.616 6.522 2.024 2.219 20024

41L,67N,70R,215F (35) 82 7074 2.64 4.94 3.94 1.84 1.01 4.24

41L,67N,70R,184V,215F (27) 128 408 2.28 1.33 5.98 1.98 2.55 2008

Resistencia a TDF de acuerdo a patrones complejos de TAMs y efecto de M184V

MENOR INCIDENCIA DE M184V/I EN PACIENTES

TRATADOS CON FTC VS 3TC (ANÁLISIS CONJUNTO DE 3 ENSAYOS CLÍNICOS DE FASE III)

0.6%

0.96%

3.2%

2.4%

0

0.5

1

1.5

2

2.5

3

3.5

4

FTC (n = 522)

3TC (n = 841)

Estudios Analizados:

FTC: Estudio 934 (FTC/TDF/EFV) y Estudio FTC-301A (FTC/ddI/EFV)

3TC: Estudio 903 (3TC/TDF/EFV y 3TC/d4T/EFV) y 934 (3TC/ZDV/EFV)

FV (Análisis TLOVR) FV (Análisis VC)

p = 0,015

p = 0,009

(%)

M1

84

V

McColl DJ, et al. 10th European AIDS Conference, Poster #7.3/17.

Reduced viral fitness (lower replication rate)

Increased fidelity of RT (lower error rate during replication)

Inhibition of nucleotide excision (delay and reversal of ZDV resistance)

Increased susceptibility to other ARVs (ZDV, d4T, TDF)

Diminished initiation of HIV transcription

Diminished template switching

M184V MUTATION—CONSEQUENCES

FOR HIV REPLICATION?

NRTI SUSCEPTIBILITY WITH TAMS +/- M184V

0 1 2 3 4 5 6

10,000

1000

100

10

1

-1

ZDV

0 1 2 3 4 5 6

100

10

1

-1

TDF

0 1 2 3 4 5 6

100

10

1

-1

d4T

Number of TAMs

Fo

ld c

han

ge in

NR

TI

0 1 2 3 4 5 6

100

10

1

-1

3TC

0 1 2 3 4 5 6

10

1

-1

ddI

0 1 2 3 4 5 6

100

10

1

-1

ABC

Fo

ld c

ha

ng

e in

NR

TI

M184wt

M184V

Whitcomb J, CROI 2002

GS 903 (BRAZOTDF N=299)

DESARROLLO DE K65R, M184V/I Y MUTACIONES RELS A EFV EN 144

SEMANAS

7

10

4

2

12

4

6

16

0

2

4

6

8

10

12

14

16

18

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

Nu

mb

er

of

Pa

tie

nts

wit

h M

uta

tio

ns

K65R

M184V/I

EFV-R

DEVELOPMENT OF K65R BY

BASELINE RESISTANCE GENOTYPE

Baseline Genotype Number Developing K65R (%)

TAMs/no L74V 0/277*

TAMs + L74V 0/34*

No TAMs/no L74V 10/116 (8.6%)

p = 0.014 No TAMs + L74V 4/10 (40%)

*Presence of baseline TAMs negatively predicts K65R development (p < 0.001).

AS Bae1, JM Waters1, NA Margot2, K Borroto-Esoda1 and MD Miller2

XIII International HIV Drug Resistance Workshop, Tenerife, Spain, 2004

TIME COURSE OF K65R DEVELOPMENT

AND L74V LOSS IN PATIENT #8

* Estimates based on population sequencing

Detection limit of

population sequencing

Patient #8 (ddI + EFV + SQV/r, added TDF)

46%

76% >80%

75%

54%

24% <20%

2.6% 0

20

40

60

80

100

Baseline Week 4 Week 8 Week 12*

% o

f S

GS

Clo

ne

s

K65R

L74V

34

Pat 1 BU: Female, aged 45, ART-naive, presented 02/02

CDC class B3

Initial therapy: ABC, 3TC, ddI - started 10/02

Virologic rebound occurred at week 8

Genotype resistance test results:

Therapy TAMS Non-TAMS NNRTI PI

ART-Naive WT WT WT 20R, 63P, 77I

ABC, 3TC, ddI WT 65R, 74V, 115F,184V WT 63P, 77I

Resistencia a los NRTIs. Antagonismo ?

1

10

100

1000

10000

100000

1000000

10/02 11/02 12/02 1/03 3/03 11/03 4/04 6/04 7/04 8/04 9/04 11/04 1/05

Copies/ml

0

50

100

150

200

250

300

350

Cells/mm³

Viral load

CD4

Start

ABC,

3TC,

ddI

AZT

added

PT 1 BU: VIRAL LOAD AND CD4 COURSES

Resistencia a los NRTIs. Antagonismo ?

MECANISMOS DE

RESISTENCIA A ITRNN

37

Clavel, F. et al. N Engl J Med 2004;350:1023-1035

Mecanismos de Resistencia a los NNRTIs

DUET-1 AND -2: BL ETR MUTATIONS AND

VIROLOGIC RESPONSE AT WEEK 24

0 1

2 3

Pa

tie

nts

Wit

h H

IV-1

R

NA

< 5

0 c

op

ies

/mL

(%

)

0

10

20

30

40

50

60

70

80

90

100

4 5

No. of BL ETR Mutations

Patients (%) 40 30 16 8 5 1

13 mutations associated with ETR resistance

V90I A98G

L100I K101E/P

V106I V179D/F

Y181C/I/V G190A/S

Presence of ≥ 3 ETR mutations associated with response similar to placebo + OBR

– 70% of patients had 0 or 1 ETR resistance mutations at BL

– 14% of patients had ≥ 3 ETR

resistance mutations at BL

Katlama C, et al. IAS 2007. Abstract WESS204.2.

§

Y181I

Y181V

K101P

L100I

Y181C

M230L

E138A

V106I

G190S

V179F

V90I

V179D

K101E

K101H

A98G

V179T

G190A

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

Score for individual mutations

Add together

Total weighted

score

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

PUNTUACIÓN GENOTÍPICA SOPESADA PARA

ETRAVIRINA

• Weight for each mutation added together = total weighted score

• No single mutation confers a reduced response (≥4)

108I, 103N, 90I, 190A = 2

0

20

40

60

80

100

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

Pa

tie

nts

wit

h c

on

firm

ed

VL

HIV

-1 R

NA

<50 c

op

ies/m

L (

%)

Highest

response

Intermediate

response

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 1/3 3/9 14/27 19/36 11/15 6/11 37/53 115/148 32/59 2/7 1/5 4/9 2/11 N

Response category

2008 weighted mutation score for ETR

DESAPARICIÓN DE MUTACIONES DE

RESISTENCIA A NO NUCLEOSIDOS

1er

Esquema

AZT-3TC-

NVP

2001-2004

GENOTIPO

NO

REALIZADO

2do

Esquema

ABC-ddI-

SQV/r

2004-2007

GENOTIPO

NO

REALIZADO

3er

Esquema

AZT-ABC-

LPV/r

2007-2009

GENOTIPO

Proteasa Transcriptasa Reversa

32I 33F 47V 71T 84V

67N 70E 184V 219E

RESISTENCIA A INHIBIDORES

DE PROTEASA

45

46

Clavel, F. et al. N Engl J Med 2004;350:1023-1035

Inhibidor de la PR unido al homodimero de la PR (Panel A) Inhibidor de la proteasa unido a una Protesa WT (verde) y a una Preoteasa resistente (rojo) (Panel B)

Mecanismos de Resistencia a los IPs

47

Resistencia a IPs.

Mutaciones mas frecuentemente asociadas a Resistencia a IPs

Efecto de resistencia a DRV en la

configuración de la proteasa

Sugiura, Abstract 7, Int Workshop on HIV and Hepatitis Virus, Sitges, 2012

49

Mecanismos de Resistencia a IPs

PRIMARY PROTEASE RESISTANCE IN NAЇVE

PATIENTS 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 1/17 isolates 7

POSIBLES EXPLICACIONES A LA AUSENCIA DE MUTACIONES A IP/R EN PRIMERA LÍNEA

Adherencia??

Zona de Presiòn Selectiva: Aclaramiento del medicamento en episodios de no adherencia

Elevada Potencia de los IP reforzados

Alta Barrera Genética

Mecanismos alternos de resistencia fuera de la proteasa Sitios de ruptura proteolítica en gag Procesamiento incrementado de Proteasas mutadas

Efecto de mutaciones en gag y

resistencia a inhibidores de proteasa

SuTherland, Abstract 9, Int Workshop on HIV and Hepatitis Virus, Sitges, 2012

RESISTENCIA A INHBIDORES

DE INTEGRASA

INTEGRACIÓN DEL VIH EN LAS CÉLULAS

Síntesis del ADN viral

Ensamblado del ADN viral

en un complejo de

nucleoproteína

2

Procesado de los

extremos 3’

dependiente de la

integrasa

Ingreso en

el núcleo

3b

Corte del

ADN y unión

concertada

al mismo

3a

Unión al

ADN

(objetivo)

Reparación de la brecha

Provirus

maduro

MECANISMO DE ACCIÓN DE ISENTRESS®

56

MECHANISMO DE ACCIÓN DE LOS INHIBIDORES DE

TRANSFERENCIA DE CADENAS DE LA INTEGRASA

Dos componentes

estructurales:

1) Farmacóforo

Sitio activo metalo-

dependiente

La mutaciones de resistencia

a este nivel ocasionan:

- Resistencia cruzada

- Replicación viral

- “Fitness” de la enzima

2) Grupos R

Bolsa “hidrofóbica”

R

MUTACIONES DE RESISTENCIA EN

RALTEGRAVIR

Mutaciones observadas durante el tratamiento

Cercanas al sitio activo

Similar a las mutaciones seleccionadas in vitro

Tres vias genéticas parecen conferir resistencia a raltegravir

N155H+ (E92Q,V151I, T97A, G163R, L74M)

(Q148K/R//HG140S/A, E138K)

Y143R + (L74A/I, E92Q, T97A,

I203M, S230R)

Resistencia primaria

N155H presente en menos de 1.5%

No efecto clínico significativo

RALTEGRAVIR RESISTANCE AT VF IN

BENCHMRK 1 & 2: WEEK 48 RESULTS

Cooper DA, et al. N Engl J Med. 2008;359:355-365.

0

20

40

60

80

100

Ralt

eg

ravir

Resis

tan

ce a

t F

ailu

re (

%) Nonresponse (n = 13)

Viral rebound (n = 81)

62 67

23 23

43

30

10 15

155, 148, or 143 155 148 143

Integrase Codons

MUTACIONES PRIMARIAS Y SECUNDARIAS QUE

AFECTAN LA SUSCEPTIBILIDAD A RAL

Fo

ld C

ha

nge

IC

50

100

200

300

400

500

600 Q148H

Q148H/G140S

Q148K

Q148K/E138A

Q148K/G140A

Q148K/E138A/G140A

Q148R

Q148R/G140S

Q148 Pathway

Q148 key mutation emerges, associated with secondary mutations

N155 Pathway

N155H key mutation emerges, associated with secondary mutations

Fo

ld C

ha

nge

IC

50

10

20

30

40

50

70 N155H

N155H/L74M

N155H/T97A

N155H/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.

Clotet B., et al. Resistance Workshop 2010. Abstract 50.

COMPARACIÓN DE RESISTENCIA A RAL

EN PACIENTES EN PRIMERA FALLA Y

CASOS MULTI-EXPERIMENTADOS

(BENCHMRK1 VS STARTMRK2)

Patients BENCHMRK

(N = 462)

STARTMRK

(N = 281)

Virologic failure, n (%) 105 (22.7) 27 (9.6)

Available baseline and follow-up

samples, n

94 12

Known integrase resistance

mutations, n/N (%)

64/94 (68) 4/12 (33)*

*No resistance mutations in 5 patients; integrase gene could not be amplified in 3 patients.

1.- Clinical Infectious Diseases 2010;50:605-612. 2.- J. K. Rockstroh, 18th CROI, Boston MA, 2011

63

SUSCEPTIBILITY OF RALTEGRAVIR-RESISTANT

HIV-1 ISOLATES TO S/GSK1349572

Genotype S/GSK1349572 Raltegravir

N Median FC Range FC Median FC Range FC

N155H 1.37 1.22-1.45 19.0 14.0-36.0 5

G140S, Q148H 3.75 2.05-15.0 > 87 58 - > 87 7

G140S, Q148R 13.3 7.57-19.0 > 87 > 87 - > 87 2

T97A, Y143R 1.05 1.04-1.06 > 81 > 81 - > 81 2

Underwood M, et al. IAS 2009. Abstract WEPEA098. Reproduced with permission.

66

EVG, RAL AND DOLUTEGRAVIR (DTG)

SUSCEPTIBILITIES OF SITE-DIRECTED MUTANT

VIRUSES

Fold Change of Mutant Viruses versus Wild-type

Drug T66I E92Q T97A G140S S147G Q148H Q148R N155H G140S

Q148H

EVG 15 33 2.1* 5.0 6.0 6.0 118 38 > 1000

RAL 1.4 6.0 2.4 2.0 1.0 20 30 38 > 1000

DTG 0.3 1.6 ND 0.9 ND 0.9 1.4 1.0 2.6

Green: FC ≤ 2.5; Yellow: FC > 2.5 ≤ 10; Orange: FC > 10

RESISTENCIA A INHIBIDORES

DE CCR5

67

MECANISMOS DE RESISTENCIA A ESQUEMAS CON

MARAVIROC

Emergencia de virus X4 – No detectado previamente

Resistencia de virus R5

Falla debida a resistencia a otros medicamentos de la combinación usada

-100 0 100 200 300

0

100

200

300

400

500

POBLACIONES VIRALES EN FALLA A MARAVIROC.

ANÁLISIS FENOTÍPICO Y CLONAL DE TROPISMO

Time Since First Administration (Day)

R5 R5 DM DM DM DM DM DM R5 R5

1

2

3

4

5

6

HIV

-1 R

NA

(lo

g1

0 c

op

ies/m

L)

CD

4 C

ou

nt

(ce

lls/m

cL)

Patient T6

Lewis M et al. XVI International HIV Drug Resistance Workshop, June 2007, Abstract 56

VARIANTES VIRALES DE VIH DE ACUERDO A TROPISMO

Y RESPUESTA A INHIBIDORES DE CCR5 Y ENSAYO DE

TROPISMO

R5 X4

DM/R5 DM/X4

Actividad de InhCCR5

CD4+ CELL COUNT INCREASES WITH MVC AT FAILURE

DESPITE CXCR4 VIRUS

Mean CD4+ Change, cells/mm3

Placebo + OBR (n = 58)

MVC QD + OBR (n = 57)

MVC BID + OBR (n = 52)

A4001029 (N = 186)[1,2]

All patients +36 +60 +62

X4 virus only -104 (n = 2) +48 (n = 12) +33 (n = 12)

MOTIVATE 1/2[3]

All patients +24 +64 +74

R5 virus only NR +133 +57

X4 virus only NR +77 +47

1. Van der Ryst E, et al. Glasgow 2006. Abstract P393. 2. Mayer H, et al. IAC 2006. Abstract THLB0215. 3. Fätkenheuer G, et al. EACS 2007. Abstract PS3.5. 4. Saag M, et al. IAS 2007. Abstract WESS104.

In MERIT study of MVC in treatment-naive patients, CD4+ cell count increases greater in MVC arm vs EFV arm[4]

– 170 cells/mm3 vs 144 cells/mm3, respectively

MOTIVATE 1 Y 2: FALLAS DE ACUERDO A TROPISMO

Tropism result, Baseline → Treatment Failure

Placebo + OBT

N = 209

MVC QD + OBT

N = 414

MVC BID + OBT

N = 426

All treatment failures n = 97 n = 68 n = 77

R5 → R5 n = 80 n = 18 n = 17

R5 → D/M or X4 n = 4 n = 31 n = 32

Approximately 8% of patients had a change in tropism result between screening and

baseline, demonstrating the change in background tropism over a 4–6 week period in this

population

– Response to maraviroc treatment in these patients was

consistent with the results of study A4001029 in patients with

D/M-tropic virus (XVI IAC 2006, Abs THLB0215) Data excludes patients who had no tropism result at time

of failure and patients with non-R5 virus at baseline MOTIVATE 1 & 2-Week 24

MVCsens virus

gp120

binding site

on CCR5

Mutated gp120

recognizes CCR5

differently

Free

receptor

MVCres virus

wt gp120 MVCres

gp120

MVC (•)

bound

to CCR5

Binding site

disrupted

by MVC

Binding site

NOT disrupted

by MVC

VIRUS R5 RESISTENTES A MARAVIROC

No Entry Entry

MVC (•)

bound

to CCR5

Free

receptor

Mori J et al. XVI International HIV Drug Resistance Workshop, June 2007, Abstract 10

AMINO ACID SUBSTITUTIONS/DELETIONS

WERE SELECTED IN THE GP120 V3 LOOP

V

A/S

MVCres

CC1/85

(clade B)

T

MVCres

RU570

(clade G)

D*

* Also selected in drug-free control culture

Reviews in Antiviral Therapy 2009;1:58

ABSCENCE OF GENOTYPE-

PHENOTYPE CORRELATIONS TO

PREDICT PRIMARY RESISTANCE OF

CCR5-TROPIC HIV-1 TO

MARAVIROC.

Abstract 587, 20th CROI, 2013

RESULTADOS.

Abscence of genotype-phenotype correlations to predict primary resistance of CCR5-tropic HIV-1 to maraviroc. 587.

RESULTADOS.

Abscence of genotype-phenotype correlations to predict primary resistance of CCR5-tropic HIV-1 to maraviroc. 587.

CONCLUSIONES.

• La resistencia primaria de CCR5 en VIH-1 subtipo B a

Maraviroc es poco frecuente

• El genotipo V3 por si solo no puede predecir la

resistencia.

• Para un análisis adecuado se requiere de un fenotipo

viral con la expresion de la glucoproteina en toda la

envoltura.

• Al parecer los determinantes genotipicos localizados

por fuera de V3, juegan un rol importante en la

resistencia de CCR5 a MVC.

RESISTENCIA A INHIBIDORES

DE FUSION

79

MUTATIONS ASSOCIATED WITH RESISTANCE TO ENFUVIRTIDE

Johnson V, et al. Topics in HIV Medicine 2003. 11; 215-221.

Localizadas en gp41

No en ensayos de resistencia comerciales

Desarrolladas en 3 semanas en monoterapia

CHARACTERIZATION OF NEW MUTATIONAL PATTERN IN HIV-1 GP41 ASSOCIATED WITH T-20 TREATMENT

Aquaro* S, Svicher V, D’Arrigo R, Santoro M, Di Perri G, Lo Caputo S, Visco-Comandini U, Narcisco P, Antinori A, and

Perno C Poster 621, HDRW 2006

N140I MUTATION REINFORCES THE CD4 GAIN SEEN IN PATIENTS WITH V38A MUTATION

Median CD4 cells/ul (IQR)

Median Viremia (IQR)

0.05 104 (47-175) 64 (26-135)

0.94 0.9 4.3 (3.5-4.3)

4.8 (4.4-5.2)

15 (20) 38A

Week 48 Baseline Week 48 Baseline

23 (19-26) 71 (36-174) 4.8 (4.2-5.3)

4.9 (4.3-5.1) 53 (70.6) 38V

At Week 24

0.01 249 (196-260) 40 (10-64) 0.97 1.0 4.8 (4.2-5.3)

5.1 (5.0-5.2) 7 (9.3) 38A + 140I

P valuec Ratiob P valuec Ratiob Frequencya N (%)

Pattern of mutations

At Week 48

0.02 210 (200-342) 40 (10-64) 0.96 0.9 4.5 (4.3-4.8)

5.1 (5.0-5.2) 7 (9.3) 38A + 140I

0.06 151 (98-249) 64 (26-135)

0.95 0.9 3.8 (3.3-5.3)

4.8 (4.4-5.2)

15 (20) 38A

46 (28-197) 71 (36-174) 4.4 (4.0-4.9)

4.9 (4.3-5.1) 53 (70.6) 38V

Week 24 Baseline Week 24 Baseline

P valuec Ratiob Median CD4 cells/ul (IQR)

P valuec Ratiob Median Viremia (IQR)

Frequencya N (%)

Pattern of mutations

↑4

↑8.7

↑5.3

↑20.6

Aquaro. CROI 2007. Poster 621.

lesoto@hotmail.com