1. ACHI E V2 E, COHERE & EuroCoord Added value of collaborative studies Geneviève Chêne Inserm U897, Bordeaux Segalen University

2. IAS 2011, ANRS satellite symposium “HIV-2: A model of attenuated HIV Infection”, 19 July Main features of HIV2 Occur mainly in West Africa, though growing numbers in Europe, India and the US Low transmissibility HIV2 RNA undetectable even at late stages, slow CD4 decline, slow immuno-clinical progression Intrinsically resistant to some commonly used classes for antiretroviral treatment Poor CD4 recovery once treatment is started

3. IAS 2011, ANRS satellite symposium “HIV-2: A model of attenuated HIV Infection”, 19 July Main challenges for HIV2 Are natural history of HIV1 & HIV2 so different? How best to quantify the virus? How best to monitor treatment response? What endpoint should be used in clinical trials? When to start treatment? What to start with? Use of collaborative studies Power, representativeness Potential for standardisation Comparisons with HIV1

4. IAS 2011, ANRS satellite symposium “HIV-2: A model of attenuated HIV Infection”, 19 July Rationale of collaborative studies on HIV2: examples Need for standardisation Establish a standard to quantify HIV2 RNA What to start with? Compare different first-line regimens Comparisons with HIV1 Are HIV1 and HIV2 characterised by different CD4 cell decline at any HIV RNA levels?

5. IAS 2011, ANRS satellite symposium “HIV-2: A model of attenuated HIV Infection”, 19 July HIV2 RNA quantification, quality control: lessons learned Feasible: 12 labs participating in 3 continents (Europe, Africa, North America) Different situations for subtypes Use of a standard improved quantification of subtype A Remaining heterogeneity in the quantification of subtype B virus, even with the use of a standard, collaborations needed across countries where subtype B is circulating Comparisons difficult when subtype B involved Commercial kit warranted, control quality needed Damond et al. J Clin Microbiol 2008, 2011 (revised)

6. IAS 2011, ANRS satellite symposium “HIV-2: A model of attenuated HIV Infection”, 19 July 170 naive HIV2 patients started on either PI/r or 3 nucs, 7 European cohorts Standardisation of data collection through the HICDEP system commonly used for collaborations on HIV1 Potential of 1,000 HIV2 patients/250 treatment-naive Inform the design of clinical trials Benard et al. Clin Infect Dis 2011

7. IAS 2011, ANRS satellite symposium “HIV-2: A model of attenuated HIV Infection”, 19 July Virus typeNBaseline CD4/µl Baseline viral load CD4 decline (annual rate) 11204584.315.9% 2496181.34.1% Individuals seen on at least 3 occasions, during ≥ 1 year, baseline CD4+ T cell > 200/µl Mean follow-up ~3 years Plasma HIV RNA higher in HIV1 than HIV2 despite similar rates of DNA Similar rate of CD4 decline after adjustment for baseline HIV2 RNA Gottlieb et al. J Infect Dis 2002

8. IAS 2011, ANRS satellite symposium “HIV-2: A model of attenuated HIV Infection”, 19 July Virus typeNBaseline CD4/µl Baseline viral load CD4 decline (annual rate) Sero-incident 1983994.11-49 2495852.40-9 Seroprevalent* 13203244.39-49 21602602.62-11 After ARVBefore 2M/after 1592774.64+59/+46 2632672.92+29/-3 ANRS CO3 Aquitaine and CO5 HIV-2 *Difference remaining after adjustment for baseline HIV RNA or CD4 Drylewicz et al. AIDS 2008

9. IAS 2011, ANRS satellite symposium “HIV-2: A model of attenuated HIV Infection”, 19 July Collaboration with COHERE in EuroCoord EU-funded NoE established by several of the biggest HIV-1 cohorts and collaborations within Europe 35 cohorts, 30 countries ~250,000 adults, mothers, children

10. IAS 2011, ANRS satellite symposium “HIV-2: A model of attenuated HIV Infection”, 19 July Investigating the lower pathogenicity of HIV-2, COHERE in EuroCoord/ACHIEVE Project lead: S Matheron, Statistician: R Thiébaut Objective: to compare immunological outcome in HIV-1 and HIV-2 infected patients while controlling for plasma HIV RNA in three different populations –Natural history (absence of antiretroviral therapy) –seroincident patients (known/estimated date infection) –seroprevalent patients –Response to first line cART –Largest possible sample size, longitudinal design, comparison to matched HIV1 individuals, most recent and potent ARV Outcomes: CD4 slopes adjusted for plasma HIV RNA in HIV-1 and HIV-2 infected patients presenting similar characteristics at inclusion or cART initiation Timelines: data merger end July 2011, preliminary results March 2012

11. IAS 2011, ANRS satellite symposium “HIV-2: A model of attenuated HIV Infection”, 19 July Perspectives Results inform the design of clinical trials (standardised quantitative viral load, composite outcome, rate of progression) and ongoing collaborations Exploit the infrastructures of international consortium of longitudinal studies Census of available biobank (Achieve, EuroCoord) Drug resistance: comparison of preferred pathways between HIV1 & HIV2 (CHAIN) Models of clinical progression, when to start (ART- CC, IeDEA) Need to identify specific funding for this research

12. IAS 2011, ANRS satellite symposium “HIV-2: A model of attenuated HIV Infection”, 19 July Acknowledgments To the patients, to the funder of ACHIEVE: Agence Nationale de Recherches sur le Sida et les hépatites virales (ANRS) To the ACHI E V 2 E collaboration Clinical centres France: Sophie MATHERON 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 Coordinating centre, INSERM U897 France: Antoine BENARD Geneviève CHENE Audrey TAIEB COHERE (www.cohere.org) and EuroCoord (www.EuroCoord.net)