Strategie per ottimizzare il risultato clinico

della HAART

Prof. Adriano LazzarinUniversità Vita-Salute San Raffaele

Milano

Break-study (FTC weekly)

Soria A. et al, in press

Is VL < 50 Achievable in Treatment-Experienced Patients With MDR HIV?

1. Cahn P, et al. ICAAC. 2007. Abstract H-717. 2. Kumar P, et al. EACS 2007. Abstract P7.2/06. 3. Lalezari J, et al. ICAAC 2007. Abstract H-718a.

34%

63%*

Weeks

Pati

en

ts (

%)

*P < .001 vs PL

0 2 4 8 12 16 240

20

40

60

80

100 BENCHMRK-1 and -2[2]

RAL + OBRPL + OBR

MVC BID + OBRPL + OBR

47%*

16%

Weeks0 4 8 16 24 32 40 48

0

20

40

60

80

100MOTIVATE 1[3]

25%

49%* *P < .0001 vs PL

Pati

en

ts (

%)

Weeks

Pati

en

ts (

%)

0 2 4 8 12 16 240

20

40

60

80

100

*P < .0001 vs PL

DUET 1 and 2[1]

ETR + OBR PL + OBR

59%*

41%

MOTIVATE 1 and 2: Virologic Suppression by LPV/RTV Use, Wk 24

van der Ryst E, et al. IAS 2007. Abstract WEPEB115LB.

0

60

100

Pat

ien

ts (

%)

20

40

80

HIV-1 RNA < 400 copies/mL HIV-1 RNA < 50 copies/mL

0

60

100

Pat

ien

ts (

%)

20

40

80

60.0

87.096.3

LPV/RTV First Use

26.0

59.860.6

LPV/RTV Exp/Resistant

n = 10 2327 50 12794

50.0

69.674.1

LPV/RTV First Use

22.0

41.747.9

LPV/RTV Exp/Resistant

10 2327 50 12794

Placebo + OBR MVC QD + OBR MVC BID + OBR

DUET Week 96: response (VL <50 copies/mL TLOVR) by PSS*

*DRV considered sensitive if FC 10; ENF counted as sensitive if used de novo; etravirine not included in the PSS calculation; analysis excludes patients who discontinued except for VF

Trottier B et al. CAHR 2009. Abstract P148

Patients in the etravirine + BR group achieved consistently higher response rates than patients in the placebo + BR group, irrespective of number of active background agents; the difference was most apparent in patients with no active background agents

Pat

ient

s w

ith V

L <

50 c

opie

s/m

L a

t W

eek

96

(%

)Placebo + BR (n=477)etravirine + BR (n=497)

Number of active background ARVs (PSS)0 1 2

46%

6%

61%

29%

76%

59%

39/84 5/81 117/191 52/181 168/222 126/215

p<0.0001

p<0.0001

p<0.0001

100

90

80

70

60

50

40

30

20

10

0

Figure 1 – Trend of the virological and immunological parameters

Bars represent first and third quartiles.

0 10 20 30 40 500

50

100

150

200

250

300

350

400

0.00

0.05

0.10

0.15

0.20

0.25

CD4+ (cells/uL) CD4+/CD8+ ratio

follow-up (weeks)

Me

dia

n c

ha

ng

e C

D4

+(c

ells

/uL

)

Me

dia

n c

ha

ng

e C

D4

+/C

D8

+ra

tio

0 8 16 24 32 40 480

20

40

60

80

100

HIV-1 RNA<400 copies/mL

HIV-1 RNA<50 copies/mL

follow-up (weeks)

Pro

po

rtio

n o

f p

ati

en

ts (

%)

ICI - TRIAL

New scenario in rescue therapy: new naive patients

Main safety haematological findings in 28 HIV-1 infected failing pts receiving raltegravir, maraviroc and etravirine alone as salvage therapy.

Baseline Week 48 Change W48 p-value

Haemoglobin (g/dL)

13.6 (12.3-15.1)

15.1 (14.5-15.9)

1.1 (0.6-2.5)

<0.0001

Platelet count (109/mm3)

178 (149-207)

203 (163-243)

7.5 (-17/+61)

0.047

White blood cells (106/mm3)

5150 (4100-5900)

6700 (5300-8300)

1400 (0-2900)

0.0007

Lymphocytes (106/mm3)

1800 (1400-200)

2300 (2000-2900)

600 (100-950)

0.0002

Neutrophils (106/mm3)

2450 (2000-3700)

3800 (2600-4700)

500 (-200/+1300)

0.061

Increase of RBC, WBC and PTL N° after the NUCS step

BL W4 W12 W24 W36 W48 p-value

Creatinine (mg/dl)

0.99 0.98 0.97 0.91 0.94 0.88 0.0011

ICI - TRIAL

Nozza S et al, submitted

0 10 20 30 40 500

100

200

300

400

0

5

10

15

20

25

30

CKcreatininaacido urico

LDH

follow-up (weeks)

Med

ian

val

ue

Med

ian v

alue

ICI - TRIAL

Nozza S et al, submitted

The Next line of drugs for cART in failing MEXP

Elvitegravir ViiV 572 Rilpivirine Bevirimat Elvucitabine New NNRTI, and NRTI Therapeutic vaxins

…but mainly recycling of hold drugs active against revertant virus (NA,PI/r, entry inhibitors)

Naive: 2 - Reduce the treatment discontinuation due to SAE

Early decrease in CD38 expression on CD4+ cells on MVC

The kinetics of change in the proportion of CD38+ on CD4+T cells and in the density of of CD38+ on CD4+T cells were similar

IRIS Zone

To prevent the disease progression in HIV controlled patients

that enough a simplified maintenance Rx?

SEMPLIFICATION:a long-term treatment strategy in HIV controller

Time

VL

Induction Maintenance strategy

3 drugs required

Which antiviral strength Do we need to maintain full viral suppression • PI/r ? • 2 drugs ? • Others ?

4–5 log drop

Which markers do we use ?- HIV RNA < 50 copies- Viral DNA ?- GSS in DNA ?

Schematic representation; Katlama C, personal communication

Boosting PIs alone: for potency and genetic barrier could be an option for

monotherapy in maintenance ART

0

10

20

30

40

50

60

70

80

90

100

DRV/r + 2NRTI (PP) DRV/r mono (PP) DRV/r + 2NRTI (ITT) DRV/r mono (ITT)

MONET: Primary Efficacy Analysis:MONET: Primary Efficacy Analysis:HIV RNA <50 copies/mL at Week 48, TLOVR, S = F HIV RNA <50 copies/mL at Week 48, TLOVR, S = F

Table EFF 4-5

HIV RNA<50 byWeek 48(%)

Per Protocol analysis (PP) Intent to Treat analysis (ITT)Primary analysis

N=123 N=123 N=129 N=127

87.8% 86.2% 85.3% 84.3%

-1.6%; lower limit 95%CI: -10.1% -1%; lower limit 95%CI: -9.9%

J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB

Elite controller: a selected core of LTNP

FINDINGS HIV RNA (ultrasensitive method) is found

in all controller (except one). High levels of proviral DNA and cell based

RNA is proven.

HIV negativeBefore ART Under ART

Ln

Brenchley JM, et alJ Exp Med. 2004 Sep 20;200(6):749-59.

Primary HIV Infection of Gut-Associated Lymphoid Tissue (GALT) is the First Pathogenic Event Leading to Substantial CD4+ T cell

Destruction and the main source of persistant activation

HIV-HIV- HIV+HIV+

G. Pantaleo et al., Nature 1994

Lymph Nodes GALT

Response to long-term antiretroviral treatment in 47 HIV+ with HIV-RNA < 1 copies/mL and >500 CD4/mcl

HIV-1 RNA Log copies/ml

Median (IQR)

CD4+ T-cells (cells/mcl)Median (IQR)

CD8+ T-cells (cells/mcl)Median (IQR)

Pre-therapy

4.68 (4.37-5.02)

243 (130-354) 675 (537-918)

After 4 years

<1.69 (NA)* 485 (405-696)* 738 (530-983)

After 7 years

<1.69 (NA)* 648 (564-737)* 647 (468-877)

F. Cossarini et al, ongoing study

CD8+ CD38+ T cells decay over time

Pretherapy Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 After Year 70

20

40

60

80

CD

8+

CD

38+

cells

(% C

D8+

T c

ells/

L)

CD8+ HLA-DR+ T Cells decay over time

Pretherapy Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 After Year 70

20

40

60

CD

8+

HL

A-D

R+

cells

(% C

D8+

T c

ells/

L)

CD38+ cells in HIV-Uninfected and infected subjects after 7 years on treatment

CD4+38+ HIV+ CD4+38+ HIV- CD8+38+ HIV+ CD8+38+ HIV-0

20

40

60

80

100

CD

38+

T c

ells

(%

CD

4+

or

CD

8+

cells

)

HLA-DR+ cells in HIV uninfected and infected subjects after 7 years on treatment

CD4+HLA-DR+ HIV+ CD4+HLA-DR+ HIV- CD8+HLA-DR+ HV+ CD8+HLA-DR HIV--0

20

40

60

80

HL

A-D

R+

T c

ells (

% C

D4+

or

CD

8+

ce

lls)

CD38+ HLA-DR+ Cells in HIV- uninfected and infected ubjects after 7 years on treatment

CD4+CD38+DR HIV+ CD4+CD38+DR HIV- CD8+CD38+DR HIV+ CD8+CD38+DR HIV-0

20

40

60

CD

38+

HL

A-D

R+

T c

ells (

% C

D4+

or C

D8+

cells)

Conclusions

The study doesn’t show a linear correlation between HIV-1 RNA on treatment and CD38+HLA+ T cells subsets.

HIV-RNA on antiretroviral treatment is therefore not a sufficient stimulus to mantain levels of T cell activation, which does not support the possibility of ongoing rounds of viral replication in the plasma compartment.

Most of the virus is in central memory and transitional memory CD4+ T cells

Courtesy of Brigitte Autran

Not HIV but ……..