actualités des traitements arv: du sud au nord pierre-marie girard imea & hôpital st antoine...

Actualités des traitements ARV: du Sud au Nord

Pierre-Marie Girard

IMEA&

Hôpital ST Antoine

DU IMEA FOURNIER PARIS VII Novembre 2009Partie I

Les Cohortes au SUD

Castelnuovo B et al, CID, 2009

Second Line ARV in adults and children

96% 99%

4% 1%0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Adults Pediatric

% p

ati

en

ts

Renaud-Théry F, AIDS 2007

Cumulative proportion of patients needing 2nd Line ARV

Switch to 2d Line: mean 3% per year

5%6%

9%

12%

16%

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

2006 2007 2008 2009 2010

Renaud-Théry F, AIDS 2007

AIDS, 2009

Low performance of WHO criteria for the diagnosis of virological failure

CID, 2009

Smith AD et al, Lancet, 2009

Essais au SUD

Essai DART « Big-Dart »

REYADAK à Dakar « Small is beautiful »

Essais PTME et Pédiatrie « Hit hard, hit early »

IAS July 2009

MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda

TASO, Uganda

University of Zimbabwe, Harare, Zimbabwe

Joint Clinical Research Centre, Kampala, Uganda

Infectious Diseases Institute, Makerere University, Uganda

MRC Clinical Trials Unit, UK

Imperial College, UK

DFID, UK

GlaxoSmithKlineGilead SciencesBoehringer-IngelheimAbbott

RockefellerFoundation

MRC, UK

DART partnersDART partners

Support:

IAS July 2009

SurvivalSurvival

0.90

0.87

0.08

0.92

0.90

0.18

0.95

0.94

0.55

0 1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

1.0

Pro

port

ion

aliv

e

Years from enrolment

Entebbe Cohort(Uganda):pre-ART 1996-2000, median CD4 75 at enrolment:57.7/100 PY

DARTLCM: 2.2/100 PYCDM: 2.9/100 PY

IAS July 2009

Resource allocationResource allocation

• 6.7 million adults and children in Sub-Saharan Africa were estimated to need ART in December 2007

– only 2.2 million were receiving ART

• Global economic crisis is threatening programme funding

• Using DART to help resource allocation

– what could be achieved in an ART programme with $1,000,000 over 5 years...

IAS July 2009

21

271

35

366

0

100

200

300

400

Number of patients

LCM: TREAT 292 CDM: TREAT 401 (extra 109)

treated, alive treated, died

For $1,000,000 over 5 yearsFor $1,000,000 over 5 years

Mean cost/patient: LCM $3,425, CDM $2,493

Assuming cost of patients not treated is $0. Based on difference in life-years from CEA.

IAS July 2009

36

73

21

271

35

366

0

100

200

300

400

Number of patients



not treated, died not treated, alive

For $1,000,000 over 5 yearsFor $1,000,000 over 5 years


Totaldeaths

94

from Entebbe Cohort data

Totaldeaths

35


IAS July 2009

112326

341

35

366

0

100

200

300

400

Number of patients


Excluding routine toxicity tests in LCM

Excluding routine toxicity tests in LCM


Totaldeaths

49


not treated, died not treated, alive from Entebbe Cohort data

Totaldeaths

35


Impact of « not-switching » on survival

Risk of death Switching pts vs no Switching = 3.3 [1.6-6.8] Ive P et al, CROI, 2009

Evaluation of didanosine/lamivudine and atazanavir QD first line regimen in HIV-1 infected adults in Senegal IMEA 031 trial

0

20

40

60

80

100

BL 4 12 24 36 48

Weeks

% VL < 400 c/ml

% VL < 50 c/ml%

0

20

40

60

80

100

BL 4 12 24 36 48

Weeks

% VL < 400 c/ml

% VL < 50 c/ml%

Les Cohortes au Nord

Nature 2009

Hunt, JID 2009

Les Essais au Nord

Stratégies abandonnées

Traitement tardif (< 200/mm3) Combinaisons initiales:

En quadrithérapie IN+INN+IP En épargne de nucléosidiques par IP+INN ??

Traitements intermittents à cycles longs Interruptions programmées chez patients avec

CD4 < 500/mm3 Initiation par nucléosidiques seuls Intensification simple (« Add on ») Immunothérapie non spécifique par IL2 Vaccinothérapie avec candidats-vaccins actuels

Première ligne: IP vs NNRTI

clinicaloptions.com/hiv

Weighing the Options: Choosing the Initial Antiretroviral Regimen

ACTG 5142: First-line EFV + NRTIs vsLPV/RTV + NRTIs Multicenter, prospective, open-label, randomized, phase III clinical trial

Primary endpoints: time to virologic failure and time to regimen completion

Riddler SA, et al. N Engl J Med. 2008;358:2095-2106.

Antiretroviral-naive HIV-infected pts with

HIV-1 RNA = 2000 copies/mL

(N = 753)

EFV 600 mg QD + 2 NRTIs*(n = 250)

LPV/RTV SGC 400/100 mg BID + 2 NRTIs*(n = 253)

EFV 600 mg QD + LPV/RTV SGC 533/133 mg BID

(n = 250)

Wk 96Stratified by HIV-1 RNA < or = 100,000 copies/mL, presence or absence of chronic hepatitis infection (B, C, or both), and NRTI selection

*NRTIs = 3TC 150 mg BID or 300 mg QD + either ZDV 300 mg BID, d4T extended release 100 mg QD (participants < 60 kg received 75 mg QD), or TDF 300 mg QD.



ACTG 5142: HIV-1 RNA < 50 copies/mLand CD4+ Cell Count Increases at Wk 96 Multicenter, randomized, prospective, open-label phase III

clinical trial

89

7783

0

20

40

60

80

100

EFV + 2 NRTIs (n = 250)LPV/RTV + 2 NRTIs (n = 253)EFV + LPV/RTV (n = 250)

HIV

-1 R

NA

< 5

0 c/

mL

(%)*

P = .003

Riddler SA, et al. N Engl J Med. 2008;358:2095-2106.

0

50

100

150

200

250

300 Median C

D4+ C

ell Count

Increase (cells/mm

3)

230

287 273

P = .01

P = .01

*ITT analysis including all pts on who remained on protocol; missing values were censored.

EFV vs LPV/r chez les patients naïfs à CD4+ < 200 : HIV-1 RNA <50 copies/mL à S48

0

20

80

100

0 16 32 48

Week8 24 40

Efavirenz (n = 95)

LPV/RTV (n = 94)

Nombre de Pts avec ARN VIH < 50 copies/mL

EFV 29 70 68 67LPV 8 53 56 50

70.5%

53.2%

0

20

40

60

80

100

HIV

-1 R

NA

< 5

0 co

pie

s/m

L (%

)

79%

49%

64%57%

P = 0.012 P = 0.15

EFVLPV/RTV

n = 42 45 53 49

≤ 50 cell/mm3 > 50 cell/mm3

EFV supérieur à LPV/RTV: Δ 17% (CI 95%: 3.5% to 31.0%; P = .017)

HIV

-1 R

NA

< 5

0 co

pie

s/m

L (%

)

Selon les CD4 à BL

60

40

Madero JS, et al. IAC 2008. Abstract TUAB0104.



Boosted PIs in ARV-Naive Pts: VirologicSuppression at Wk 48

0

10

20

30

40

50

60

70

80

90

100

This slide is an illustration only and not meant to be a cross-study comparison.*P < .05 between LPV/RTV QD and DRV/RTV QD; no other significant differences in any comparisons above. †Use of LPV/RTV BID or QD was not randomized and was dependent on site and pt preference. ‡SGC or tablet until Wk 8; tablet after Wk 8.

Pts

Wit

h H

IV-1

RN

A

< 5

0 c

op

ies

/mL

(%)

1. Eron J Jr, et al. Lancet. 2006;368:476-482. 2. Walmsley SL, et al. J. Infect Dis. 2009;50:367-374. 3. Ortiz R, et al. AIDS. 2008;22:1389-1397. 4. Molina JM, et al. Lancet. 2008;372:646-655. 5. Gathe J, et al. CROI 2008. Abstract 775.

440443

CASTLE[4]

(ITT) NRTIs: TDF/FTC

ATV/RTV300/100

QD

LPV/RTV400/100

BID

76 7878*

KLEAN[1]

(ITT-E, TLOVR) NRTIs: ABC/3TC

GEMINI[2]


ARTEMIS[3]


65

FPV/RTV700/100

BID

LPV/RTV400/100

BID

66

LPV/RTV†

400/100 BID or

800/200 QD

DRV/RTV 800/100

QD

84*

434444 343

65

SQV/RTV1000/100

BID

LPV/RTV400/100

BID

170 167

64

346n = 333331

M05-730[5]

(ITT, NC = F) NRTIs: TDF/FTC

LPV/RTV800/200

QD‡

LPV/RTV400/100

BID‡

75 76

Patients naïfs: Etudes en cours ou prochaines avec molécules disponibles

MERIT: CBV+EFV vs CBV+MVC COL11429: ABC/3TC + RAL APILOT-1: TDF/FTC+rATV vs rATV+MVC NEAT: TDF/FTC+rDRV vs RAL+rDRV CCTG589: rLPV+RAL vs Atripla ACTG A5262: rDRV+RAL Inv08: rLPV+RAL Merck072 RADAR: rDRV+RAL vs TDF/FTC+rDRV ANRS Optimal: Haart vs Haart + MVC chez pts CD4<200 A009: TDF/FTC + rLPV vs TDF/FTC+RAL M10-336 PROGRESS: TDF/FTC+ rLPV vs TDF/FTC+RAL GS001: TDF/FTC + rLPV vs TDF/FTC+RAL RAN: TDF/FTC + RAL vs TDF/FTC+rATV AI 424-376: TDF/FTC+rATV vs RAL+ATV bid ADARC 07-01: TDF/FTC+rATV ±RAL/MVC lors PI ANRS Optiprim: TDF/FTC+rDRV+RAL+MVC vs TDF/FTC+rDRV lors PI

ClinicalTrials.gov

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