1. ANRS C05 HIV-2 Cohort Clinical case management S Matheron Hopital Bichat – Claude Bernard Université Denis Diderot Paris 7

2. 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, 19 th July 60% women 50% > 40 years 75% from subsaharan Africa (WA) 24% previously given cART Year of HIV-2 diagnosis

3. ANRS CO5: Patients’ characteristics CD4 counts (median) At inclusion CDC stage (n=719) A B C N 600 31 88 87 345 132 264 (%) 83.3% 4.4% 12.3% 37% 47% 18% 35% 18% 30% 51% 516 302 138 27% 26% 95% 70% IAS 2011, ANRS satellite, HIV-2, 19 th July A B C (Tuberculosis 44 %)

4. 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/mm 3 [300-500]/mm 3 <300/mm 3 Follow-up (n=702) Lost of follow-up cART initiation (n=488) Survival at 5 years Non progression to AIDS at 5 years N 600 31 88 87 345 132 264 (%) 83.3% 4.4% 12.3% 37% 47% 18% 35% 18% 30% 51% 516 302 138 27% 26% 95% 70% IAS 2011, ANRS satellite, HIV-2, 19 th July

5. 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/mm 3 [300-500]/mm 3 <300/mm 3 Follow-up (n=702) Lost of follow-up cART initiation (n=488) Survival at 5 years Non progression to AIDS at 5 years N 600 31 88 87 345 132 264 (%) 84% 4% 12% 38% 47% 18% 35% 18% 30% 51% 516 302 138 27% 26% 95% 90%

6. 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/mm 3 [300-500]/mm 3 <300/mm 3 Follow-up (n=702) Lost of follow-up cART initiation (n=488) Survival at 5 years Non progression to AIDS at 5 years N 600 31 88 87 345 132 264 (%) 84% 4% 12% 38% 47% 18% 35% 18% 30% 51% 516 302 138 27% 26% 95% 90%  Natural history  Response to cART

7. Drylewicz J et al, AIDS, 2008 7 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, 19 th July

8. 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, 2008 IAS 2011, ANRS satellite, HIV-2, 19 th July

9. Non progressor and HIV controllers patients ANRS CO5 HIV-2 HIV-2 patients with at least one follow-up available since 2009 with known date of HIV diagnosis n=357 HIV-2 infection ≥ 8 years n=221 At least 3 plasma viral loads and CD4 in the last five years n=176 Asymptomatic patients n=119 Antiretroviral naïve patients n=60 CD4 nadir ≥ 500 cells/µl n=36 « LTNP* » CD4 nadir ≥ 600 cells/µl n=26 « LTNP** » CD4 slope ≥ 0 over the last 5 years n=8 « Elite-LTNP » 1,5% Among which 5 HIV controlers and 5 Elite controlers HIV infection ≥ 10 years n=44 90% of pVL ≤ 500 copies/ml n=40 « HIV controlers » 9% Last pVL ≤ 100 copies/ml n=37 « Elite-controlers » 8;8% Among which 23 LTNP and 5 Elite LTNP 6%

10. 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

11. 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 slope W0-W12 : +23 CD4/mm3/mth W13-W96: +8 CD4/mm3/mth IAS 2011, ANRS satellite, HIV-2, 19 th July

12. 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, 19 th July match according to VL at D0 (>3.5 versus 3.5 log10 cp/ml)

13. M0-M3 +12/mm 3 /month + 6/mm 3 /month p=0.24 M4-M12 +76/mm 3 /year - 60/mm 3 /year p=0.002 Estimated CD4 cell count changes (n=158) IAS 2011, ANRS satellite, HIV-2, 19 th July ACHIeV2e : 3 INTI vs 2 INTI+PI/r as 1 st line N=44N=126 Bénard, CID, 2011

14. M0-M3 -0.2 log 10 cp/month -0.4 log 10 cp/month p=0.02 M4-M12 +1.2 log 10 cp/ml/year -0.12 log 10 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, 19 th July ACHIeV2e : 3 INTI vs 2 INTI+PI/r as 1 st line Bénard, CID, 2011

15. Case reports –Experienced patients (several cART failures) ANRS CO5 raltegravir including cART

16. Recommendations – First line 2 INTI + PI/r : LPV, or DRV/r or SQV/r – 2 nd line ? Same strategy as for HIV-1 –Tolerance, observance, PK, and genotype Integrase inhibitors Anti CCR5 Clinical case management

17. Questions : Start earlier ? Start stronger ?  impact on tolerance, observance ?  which options for 2 nd line ? Clinical research –Evaluation of new treatment strategies International network –Randomized trial Clinical case management

18. Investigateur coordonnateur Sophie Matheron SMIT, Bichat-Claude Bernard Coordination virologique Francoise Brun-Vézinet, Laboratoire de Virologie, Bichat-Claude Bernard Florence Damond Coordination immunologique Brigitte Autran, Laboratoire d’immunologie cellulaire, Pitié-Salpétrière Coordination méthodologique Genevieve Chêne, NSERM U593, Bordeaux Antoine Bénard Monitorage Dien Le, SMIT, Bichatt Statistique et informatique Audrey Taïeb, INSERM U593 HIV-2 cohort Clinical centres Germany: 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 Laboratories Belgium: 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 cohort Acknowledgments Patients Investigators