Perspectivas del Maraviroc en el Tratamiento del VIH

Hernán Valdez, MD

Director Médico Global, Virología

Pfizer, Inc.

Perspectivas del Maraviroc en el Tratamiento del VIH

Tópicos

● Tropismo

● Efectos extra-antivirales de Maraviroc, alguna evidencia?

● Se puede usar el Maraviroc una vez al dia?

Tropismo

Trofile Patient Population

1216 Randomized

Patients (47%)

Screening Population 1434 R5 patients

(56%)

and

1126 DM or X4 patients (44%)

Virologic benefit with MVC

R5MOTIVATE

1 and 2

N = 1049

NON-R5A4001029

n = 167

No net virologic benefit with MVC

Harrigan, IAS 2009

Genotype Patient Population

1216 Randomized

Patients

R5MOTIVATE

1 and 2

N = 999

NON-R5A4001029

n = 165

96% of clinical validation set

Harrigan, IAS 2009

Methods

● Triplicate PCR with fully automated sequence analysis

● Tropism prediction using “Geno2pheno” algorithm (g2P - 5% FPR) without knowledge of clinical outcome

● Initial endpoint of 8 week change in viral load; 24 weeks endpoint also analyzed

Harrigan, IAS 2009

Median Viral Load Reduction in the MVC BID Arm is Predicted by Trofile

Weeks From Start of Treatment

Trofile R5 (n = 406)

Trofile X4 (n = 57)

Lo

g10

Ch

ang

e in

Vir

al L

oad

(co

pie

s/m

L)

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

P < 0.001

0 4 8 12

X

X

X

X

X Harrigan, IAS 2009

X

Median Viral Load Reduction in the MVC BID Arm is Predicted by Trofile and Genotype

Weeks From Start of Treatment

Trofile R5 (n = 406)

Trofile X4 (n = 57)

g2p R5 (n = 394)

g2p X4 (n = 69)

Lo

g10

Ch

ang

e in

Vir

al L

oad

(co

pie

s/m

L)

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

P < 0.001

P = 0.002

0 4 8 12

X X

X XX

X X

X

Harrigan, IAS 2009

Trofile and Genotype Have Similar Sensitivity and Specificity to Predict Antiviral Activity to MVC at Week 8: MVC BID

* A response at week 8 was defined as a viral load < 50 or a viral load reduction of 2 log.

Assay Tropism VL response*, n+ - R5 Success Sens. Spec.

TrofileR5 272 108

72% 92% 20%X4 25 27

g2PR5 263 103

72% 89% 24%X4 34 32

Harrigan, IAS 2009

Concordant and Discordant Results in Combined MVC Arms: Similar Virologic Responses Regardless of the Direction of Discordance

Concordant Results Discordant Results

Concordant R5 n = 735

Concordant X4 n = 80

Trofile X4/g2p R5 n = 31

Trofile R5/g2p X4 n = 60

Weeks From Start of Treatment

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0 4 8 12

Lo

g10

Ch

ang

e in

Vir

al L

oad

(co

pie

s/m

L)

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0 4 8 12

Harrigan, IAS 2009

Genotype is Comparable to Trofile in Predicting the Percent of R5 Patients Viral

Load <50 copies (Week 24; MVC BID)

Pat

ien

ts A

chie

vin

g H

IV R

NA

< 5

0 c/

mL

(%

)46.4%

95%CI 41.6- 51.3

0

20

40

60

80

100

Trofile g2P

n = 188/405 181/393

46.1%

95%CI 41.2, 51.0

MOTIVATE+1029 studies enrolled triple class experienced and/or resistant patients.

The use of raltegravir, darunavir, or etravirine was not allowed

Harrigan, IAS 2009

Conclusiones

● El genotipo es un método viable para identificar pacientes con experiencia previa que responderán al Maraviroc

● Las características del genotipo son muy similares a las de la prueba de Trofile original

● La genotipificación ofrece un método más viable para identificar a candidatos para el maraviroc

Efectos extra-antivirales del Maraviroc, hay alguna evidencia?

Greater CD4 Cell Increases on MVC in Non-responders (> 50 c/mL) at Week 48 Were Related to a Lower Incidence of Category C Events

21

2

9

0

2

4

6

8

10

12

14

16

Viral Load at Week 48

Pat

ien

ts (

%)

N= 256 285 104 75

< 50 copies/mL > 50 copies m/L

Lazzarin, ICAAC 2008

Med

ian

CD

4+ c

han

ge

fro

m b

asel

ine

to w

eek

48

Non-responders (> 50 c/mL) at Week 48

-200

-100

0

100

200

300

400

500

131

77

MaravirocN=96

EfavirenzN=63

Maraviroc

Efavirenz

15

Background and Objectives• Untreated HIV-infection is associated with chronic immune activation (IA) and evidence of

inflammation

• Decreases in immune activation and inflammation during HAART have been associated with decreased expression of adhesion molecules and a redistribution of CD4+ cells from lymphoid tissues to blood1 – This redistribution may account for the rise in peripheral blood CD4+ cells that occurs early after HAART

initiation

• MVC treatment has been associated with larger increases in CD4+ cell counts than is attributable to its antiviral activity2-5

– Differences in CD4+ rises between MVC and control occur early in therapy2,4

• It is unknown whether these CD4+ cell rises are related to MVC’s potential effect on markers of immune activation or inflammation

• We analyzed a subset of patients from the MERIT study to explore whether MVC for HIV‑infected treatment-naive patients has different effects than EFV on clinically relevant markers of immune activation and inflammation

• Secondary objectives included:– Explaining differences in clinical or laboratory outcomes in the MERIT study

– Exploring whether MVC has early immunologic effects beyond those expected after antiviral activity

– Identifying potential clinical markers to be studied prospectively

Change in plasma HIV-1 RNA levels: ACTG 315

100

1000

10000

100000

0 2 4 6 8 10 12 14

Weeks

Cop

ies/

mL

• After treatment with HAART there is a 99.9% decrease in HIV-RNA in the first 3 months

• Most of that decrease (99%) occurs in the first 4 weeks

Lederman, JID 1998

ACTG 315: Effects of HAART on co-expression of activation antigens - CD38, HLA-DR

0

20

40

60

0 10 20 30 40 50 60 70 80 90

Day

Per

cen

tag

e o

f cel

ls c

o-e

xpre

ssin

g

CD

38/H

LA

-DR

*

*

59

29

25

13

CD8+

CD4+

• Whereas decrease in activation occurs more slowly

• Less than half of the decrease in activated CD8 occurs in the first month of HAART

• Similar kinetics are observed in decreases in TNF-alpha

Lederman, JID 1998

18

Randomization 1:1

MERIT Study: Phase 3 Trial Design

Maraviroc (MVC 300 mg BID) + Combivir (ZDV+3TC)*

Efavirenz (EFV 600 mg QD) + Combivir (ZDV+3TC)*

Primary analysis

0 48 wk 96 wkScreening(6 weeks)

Patients stratified by:• HIV-1 RNA < and ≥100,000 copies/mL at screening• Geographic location: Northern Hemisphere and Southern Hemisphere

Patient eligibility criteria: • ≥ 16 years of age• Treatment naive• R5 HIV-1 infection

First patient visit

Nov 2004

• HIV-1 RNA ≥ 2,000 copies/mL• No evidence of resistance to EFV, ZDV, or 3TC

MVC QD arm discontinued at end of Phase 2b (Week 16) for failure to meet protocol-defined criteria to continue (205 patients completed 16 weeks)

* Patients experiencing toxicity to zidovudine (ZDV) or lamivudine (3TC) were permitted to substitute an alternative NRTI

19

Marker Sample Rationale

CD38 expression on CD4+ cells PBMC Marker of immune activation, associated with early rises in CD4+ cells after HAART

CD38 expression on CD8+ cells PBMC Marker of immune activation; better prognostic indicator than viral load; remains elevated despite HAART

High sensitivity C-reactive protein (hsCRP) Plasma Elevated despite HAART in some patients. High levels

associated with increased cardiovascular disease

D-dimer Plasma Elevated despite HAART in some patients. High levels associated with increased mortality and cardiovascular disease

Interleukin-6 (IL-6) Plasma Elevated despite HAART in some patients. High levels associated with increased mortality and cardiovascular disease

Tumor necrosis factor receptor I Plasma Elevated despite HAART; marker of activation

Tumor necrosis factor receptor II Plasma Elevated despite HAART; marker of activation

Neopterin Plasma Elevated despite HAART; marker of activation. Lower decrease after HAART associated with worse prognosis

Markers of Activation and Inflammation

Funderburg, ICAAC 2009

20

Med

ian

perc

ent c

hang

e in

C

D38

ant

ibod

ies/

CD

4+ c

ell

Vertical lines represent interquartile ranges (IQR; 25th–75th percentile)

24 48

Weeks

0

Earlier Decreases in CD38 Expression on CD4+ T cells on MVC

–23.3

+ 0.29

–26.8

–20.1

-60

-50

-40

-30

-20

-10

0

10

20 EFV

MVC

Funderburg, ICAAC 2009

21

Weeks

Earlier Decrease in D-Dimer Concentration on MVC

Vertical lines represent interquartile ranges (IQR; 25th–75th percentile)

Med

ian

per

cen

t ch

ang

e in

D

-dim

er c

on

cen

trat

ion

-70

-50

-30

-10

10

30

0 4 8 12 16 20 24 28 32 36 40 44 48

EFVMVC

Funderburg, ICAAC 2009

EFV + CBV MVC + CBV

Although a Smaller Percentage of Patients had HsCRP > 2 on MVC at Baseline, by Week 48 Twice as many EFV Patients had hsCRP > 2

Patie

nts

with

hsC

RP

> 2

(%)

45

66

36 36

0

10

20

30

40

50

60

70

80

90

100

Baseline Week 48

Funderburg, ICAAC 2009

23

Week 96(all patients)

35 cells/mm3 (95% CI 13, 58)

0

50

100

150

200

250

171*

207*

Mea

n C

D4+

Cel

l Cha

nges

Fr

om B

asel

ine

(per

mm

3 )

< 105 copies/mL ≥ 105 copies/mL

N= 205 199 143 153

Screening HIV-1 RNA

Mea

n C

D4+

Cel

l Cha

nges

Fr

om B

asel

ine

(per

mm

3 )

0

50

100

150

200

250

167190

178

227

Week 96

MVC + CBV

EFV + CBV

MVC-Treated Patients Showed Significantly Greater Increases in Mean CD4+ Cell Count with the Difference Accentuated in those with a Higher Screening Viral Load4,5

* Mean value adjusted for randomization strataLast observation carried forward; blinded therapy values only. Includes all patients who received at least one dose of study medication

Funderburg, ICAAC 2009

24

Larger Increases in CD4+ cells are Associated with Larger Decreases in Cell-associated Immune Activation Markers

Immune marker Correlation coefficient p-value

CD4+ cell activation (CD38 antibodies/cell) -0.3 0.01

CD4+ cell activation (percent of CD38+ CD4+ cells) -0.3 0.06

CD8+ cell activation (CD38 antibodies/cell) -0.3 0.02

CD8+ cell activation (percent of CD38+ CD8+ cells) -0.3 0.03

Interleukin-6 -0.06 0.68

D-dimer -0.08 0.55

hsCRP 0.16 0.22

Funderburg, ICAAC 2009

Immune activation and HIV Replication

Untreated HIV

HIV replication

Immune activation

+

+

Treated HIV

HIV replication

HAART

Viral load decrease

Decrease in immune activation

Direct drug effect:

rapidIndirect drug effect:

Slow and variable

Early changes on activation markers would suggest direct drug effect

Other factors: CMV, HBV, HCV, microbial translocation

26

Conclusiones

• En comparación con EFV, los pacientes que reciben MVC tienen una reducción modesta y más temprana en ciertos marcadores de activación inmunológica e inflamación

• Este efecto parece ser independiente y aditivo al efecto que resulta de la actividad antiviral del MVC

• La disminución de la activación en células CD4 y CD8 está asociada a un aumento mayor en las células CD4

¿Se puede usar el Maraviroc una vez al día en pacientes con experiencia previa?

¿Maraviroc una vez al día en pacientes experimentados?

● Razones para escoger la dosis de dos veces al día

● Dosis respuesta del Maraviroc y farmacología del Maraviroc con IP potenciados

● Experiencia clínica de Maraviroc una vez al día

MOTIVATE 1 and 2: Percentage of Patients with HIV-1 RNA < 50 copies/mL by Number of Active Drugs in OBT*

0

10

20

30

40

50

60

70

80

90

100

35 51

56 44

130

134

59

88

104

64 132 121

3

18

29

9

43 43

19

52 53 5561 58

0 1 2 ≥ 3Number of active drugs in OBT*

* Based on overall susceptibility score LOCF

Patie

nts

(%)

N=

MOTIVATE 1 & 2-Week 24 CROI 2007

MVC QD + OBTMVC BID + OBT

Placebo + OBTIncludes all patients who received at least one dose of study medication

Correlation of Phase 2a Monotherapy and Phase 2b/3 Clinical Data

• Phase 2a Monotherapy Dose/exposure response studies (A4001007 and 1015) • Unboosted MVC 300 mg BID achieved a reproductive ratio <1 in all subjects

• Based on exposure-response analysis from MOTIVATE, Cave required for therapeutic effect of MVC is 100 ng/mL

• Pop PK analyses in MOTIVATE:Median Cave of MVC when dosed 150 mg QD concomitantly with

•ATV/r: 109 ng/mL •LPV/r: 149 ng/mL

• This is consistent with achieving a Cave in the region of 100 ng/mL that correlates with near maximal virologic efficacy

Data on File

A4001052 - Effect of Darunavir/r on the Pharmacokinetics of Maraviroc in Healthy Subjects

Time post dose (hours)

0 2 4 6 8 10 12

Ma

ravi

roc

pla

sma

co

nce

ntr

atio

n (n

g/m

l)

0

100

200

300

400

500

600

700

maraviroc 150mg BID + darunavir/ritonavir maraviroc 150mg BID + placebo

MVC AUC increased 405% in the presence of DRV/r 600/100 mg BID

Abel S, et al. 8th Int Wkshp Clin Pharm HIV Ther 2007. Abstract 55

Mean Maraviroc Plasma Concentration vs Time

Simulated Patient with mean BL VL of 4.6 log10 c/mL with Different DRV-containing Regimens

Non-Virological Dropouts

0%

20%

40%

60%

80%

100%

0 12 24 36 48

Weeks on Treatment

Pro

po

rtio

n w

ith <

50

Co

pie

s/m

L (

ITT

) 

Max. Possible Simulated ResponseDRV/r+MVC 150 mg BIDDRV/r+MVC 150 mg QDDRV/r+NRTIsDRV/r MonotherapyNRTIs Alone

Data on File

Patients with HIV-1 RNA < 50 Copies/mL by Screening Viral Loads and Baseline CD4+ Cell Count (Week 48)

n/N (%) by subgroupPlacebo +

OBTN=209

MVC QD + OBTN=414

MVC BID + OBTN=426

Screening HIV-1 RNA, copies/mL

<100,000 32/123 (26) 140/238 (59) 142/243 (58)

≥100,000 8/84 (10) 55/170 (32) 61/176 (35)

Baseline CD4+ cell count, cells/mm3

<50 1/38 (3) 13/84 (15) 14/85 (16)

50–100 3/25 (12) 19/51 (37) 20/55 (36)

101–200 12/55 (22) 39/95 (41) 59/104 (57)

201–350 13/62 (21) 79/115 (69) 67/116 (58)

>350 10/26 (38) 44/62 (71) 43/59 (73)* Patients were stratified at time of randomization by screening HIV-1 RNA (< or ≥100,000 copies/mL)

† Baseline CD4+ cell count calculated as the average of all pre-dose measurementsIncludes all treated patients with valid baseline and on-treatment measurements;

Missing values imputed using last observation carried forward

MOTIVATE 1 & 2 – Week 48, HARDY CROI 2008

Includes all patients who received at least one dose of study medication

0102030405060708090

100

41 76 81 41 87 113 35 77 78

0

33 33

17

56 51 51

70 72

<1 1–<2 ≥2

N =

MVC QD + OBTMVC BID + OBT

Placebo + OBT All Subjects

<50

copi

es/m

L at

wk

48 (%

)

0102030405060708090

100

31 60 61 35 67 94 32 63 64

3743

20

66 5953

81 78

<1 1–<2 ≥2

N =

0

Subjects ≥50 CD4+ cells/mm3 at baseline

<50

copi

es/m

L at

wk

48 (%

)

Week 48 Virologic Responses by wOBTSS

Valdez ICAAC 2008

En Resumen

● La determinación de tropismo por genotipo es tan buena como el Trofile original en predecir respuestas clínicas al Maraviroc

● Maraviroc parece tener efectos anti-inflamatorios y anti-activación independientes de su actividad antiviral

– Numerosos estudios están investigando la relevancia clínica de estos hallazgos

● En pacientes con terapia antiviral previa que reciben algunos IP potenciados (atazanavir, lopinavir, saquinavir, darunavir), Maraviroc a una dosis de 150 mg una vez al día parece ser adecuado

– Tres estudios clínicos están analizando la actividad antiviral de estas combinaciones con Maraviroc una vez al día