ANRS C05 HIV-2 CohortClinical case management

S MatheronHopital Bichat – Claude BernardUniversité Denis Diderot Paris 7

• Open, multi-centric national cohort - since 1994 - 121 investigating centers

- 847 patients included (June, 2011)- + 155 since 2007

ANRS HIV-2 cohort

• Clinical, epidemiological, biological and therapeutic follow-up

– / 6 months*• Virological follow-up

– untreated patients– / 6 months *– / 3 months if plasma VL>100copies/ml

– treated patients – M1, / 3 months

* + in case of intermediate event

Inclusion criteria • HIV-2 Infection only• ≥ 18 years old, • > 1 year in France

IAS 2011, ANRS satellite, HIV-2, 19th July

• 60% women• 50% > 40 years • 75% from subsaharan Africa (WA)

• 24% previously given cART

Year of HIV-2 diagnosis

ANRS CO5: Patients’ characteristics

CD4 counts (median)

At inclusion• CDC stage (n=719)

A B C

N

6003188

87

345132264

(%)

83.3% 4.4%12.3%

37%

47%18%35%

18%30%51%

516302138

27%26%

95%70%

IAS 2011, ANRS satellite, HIV-2, 19th July

A

B

83,3%

4,4%

12,3%

C (Tuberculosis 44 %)

ANRS CO5: Patients’ characteristics

Detectable plasma RNA

CD4 counts (median)

Median : 2.8 log

At inclusion• CDC stage (n=719)

A B C

• Plasma RNA >100 copies/ml (n=235)

• CD4+ T lymphocytes >500/mm3

[300-500]/mm3

<300/mm3

Follow-up (n=702)• Lost of follow-up• cART initiation (n=488)

• Survival at 5 years• Non progression to AIDS at 5 years

N

6003188

87

345132264

(%)

83.3% 4.4%12.3%

37%

47%18%35%

18%30%51%

516302138

27%26%

95%70%

IAS 2011, ANRS satellite, HIV-2, 19th July

ANRS CO5: Patients’ characteristics

Detectable plasma RNA

CD4 counts (median)

Median : 2.8 log

At inclusion• CDC stage (n=719)

A B C

• Plasma RNA >100 copies/ml (n=235)

• CD4+ T lymphocytes >500/mm3

[300-500]/mm3

<300/mm3

Follow-up (n=702)• Lost of follow-up

• cART initiation (n=488)

• Survival at 5 years• Non progression to AIDS at 5 years

N

6003188

87

345132264

(%)

84% 4%12%

38%

47%18%35%

18%30%51%

516302138

27%

26%

95%90%

ANRS CO5: Patients’ characteristics

Detectable plasma RNA

CD4 counts (median)

Median : 2.8 log

At inclusion• CDC stage (n=719)

A B C

• Plasma RNA >100 copies/ml (n=235)

• CD4+ T lymphocytes >500/mm3

[300-500]/mm3

<300/mm3

Follow-up (n=702)• Lost of follow-up

• cART initiation (n=488)

• Survival at 5 years• Non progression to AIDS at 5 years

N

6003188

87

345132264

(%)

84% 4%12%

38%

47%18%35%

18%30%51%

516302138

27%

26%

95%90%

Natural history

Response to cART

Drylewicz J et al, AIDS, 20087

HIV-1

HIV-2

_49 cells/ml PY_1.01%/year

_9 cells/ml PY_0.04%/year

Comparison of viro-immunological marker changes between HIV-1 and HIV-2-infected patients (n= 6707/ 592)

IAS 2011, ANRS satellite, HIV-2, 19th July

Comparison of viro-immunological marker changes between HIV-1 and HIV-2-infected patients

8

HIV-2

HIV-1 _49 cells/ml PY

_11 cells/ml PY

Drylewicz J et al, AIDS, 2008IAS 2011, ANRS satellite, HIV-2, 19th July

Non progressor and HIV controllers patients

ANRS CO5 HIV-2HIV-2 patients with at least one follow-up available

since 2009 with known date of HIV diagnosisn=357

HIV-2 infection ≥ 8 yearsn=221

At least 3 plasma viral loads and CD4 in the last five years

n=176

Asymptomatic patientsn=119

Antiretroviral naïve patientsn=60

CD4 nadir ≥ 500 cells/µln=36 « LTNP* »

CD4 nadir ≥ 600 cells/µln=26 « LTNP** »

CD4 slope ≥ 0 over the last 5 yearsn=8 « Elite-LTNP » 1,5%Among which 5 HIV controlers

and 5 Elite controlers

HIV infection ≥ 10 yearsn=44

90% of pVL ≤ 500 copies/mln=40 « HIV controlers » 9%

Last pVL ≤ 100 copies/mln=37 « Elite-controlers » 8;8%

Among which 23 LTNPand 5 Elite LTNP

6%

Treatment• Clinical case management in the setting of cohort study

features and specificities of HIV-2 infection– Fewer patients– Slower infection

» Fewer clinical events » Slower CD4 decrease

– Lower viral replication – Viral load quantification

» Threshold 100 cp/ml– Fewer potent drugs – Resistance pathway

data through retrospective studies• currently higher evidence-based level of knowledge on treatment

Viral load can’t be used as primary endpoint

Limited options for second and further lines

• lopinavir/r - containing cART (29 naïve patients, 2002-2007)

– Response at W24 : + ≥ 50 CD4 at M6, and VL < 100 cp/ml= 59%

– Median CD4 gain • W24 +71 (28)• W48 +122 (19)• W96 +132 (13)

A Benard , AIDS, 2008

ANRS CO5: Response to cART

Estimated CD4 slopeW0-W12 : +23 CD4/mm3/mthW13-W96: +8 CD4/mm3/mth

IAS 2011, ANRS satellite, HIV-2, 19th July

Drylewicz, AIDS, 2008

+59/mth

+24/mth

- 1.56 log/m - 0,62 log/m

+ 46/y

- 2,88/y

Comparison of viro-immunological marker changes between HIV-1 and HIV-2-infected patients

IAS 2011, ANRS satellite, HIV-2, 19th July

match according to VL at D0(>3.5 versus 3.5 log10 cp/ml)

M0-M3

+12/mm3/month

+ 6/mm3/monthp=0.24

M4-M12

+76/mm3/year

- 60/mm3/yearp=0.002

Estimated CD4 cell count changes (n=158)

IAS 2011, ANRS satellite, HIV-2, 19th July

ACHIeV2e : 3 INTI vs 2 INTI+PI/r as 1st line

N=44 N=126

Bénard, CID, 2011

M0-M3

-0.2 log10 cp/month

-0.4 log10 cp/month

p=0.02

M4-M12

+1.2 log10 cp/ml/year

-0.12 log10 cp/ml/year

p=0.19

Estimated HIV-2 RNA changes in patients with detectable values at treatment initiation (n=67)

IAS 2011, ANRS satellite, HIV-2, 19th July

ACHIeV2e : 3 INTI vs 2 INTI+PI/r as 1st line

Bénard, CID, 2011

• Case reports– Experienced patients (several cART failures)

ANRS CO5 raltegravir including cART

Recommendations

– First line• 2 INTI + PI/r : LPV, or DRV/r or SQV/r

– 2nd line ?• Same strategy as for HIV-1

– Tolerance, observance, PK, and genotype• Integrase inhibitors• Anti CCR5

Clinical case management

Questions :• Start earlier ?• Start stronger ?

impact on tolerance, observance ? which options for 2nd line ?

• Clinical research– Evaluation of new treatment strategies

• International network– Randomized trial

Clinical case management

• Investigateur coordonnateurSophie Matheron SMIT, Bichat-Claude Bernard

• Coordination virologiqueFrancoise Brun-Vézinet , Laboratoire de Virologie, Bichat-Claude BernardFlorence Damond

• Coordination immunologiqueBrigitte Autran, Laboratoire d’immunologie cellulaire, Pitié-Salpétrière

• Coordination méthodologiqueGenevieve Chêne ,NSERM U593, BordeauxAntoine Bénard

• MonitorageDien Le, SMIT, Bichatt

• Statistique et informatiqueAudrey Taïeb, INSERM U593

HIV-2 cohort

Clinical centresGermany: Jürgen ROCKSTROH,

Carolynne SCHWARZE-ZANDER

Netherlands: Frank DE WOLF *,

Ard van SIGHEM *, Peter REISS

Maarten SCHIM VAN DER LOEFF

Portugal: Francisco ANTUNES*

Emilia VALADAS *

Kamal MANSINHO *

Spain: Vicente SORIANO* Ana TREVINO *

Carlos TORO *

Berta RODES *

Switzerland: Jürg BÖNI *

Martin RICKENBACH *

Alexandra CALMY *

UK: Jane ANDERSON

Jennifer TOSSWILL

LaboratoriesBelgium: Patrick GOUBAU *,

Jean RUELLE

Canada: Marc WAINBERG France: Brigitte AUTRAN

Françoise BRUN-VEZINET *

Florence DAMOND*, Diane DESCAMPS *

François SIMON *

Gambia: Akum AVEIKA, Matthew COTTEN

Sarah ROWLAND-JONES

Germany: Bernd KUPFER

Italy: Claudia BALOTTA *

Carlo TORTI

Netherlands: Martin SCHUTTEN

Portugal: Vitor DUQUE, Joao VAZ

Ricardo CAMACHO *, Perpetua GOMES *

Sweden: Jan ALBERT

USA: Geoffrey GOTTLIEB

UK: Deenan PILLAY, Bridget FERNS, Jeremy GARSON

19 19

ANRS CO5 HIV-2 cohortAcknowledgments• Patients• Investigators