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2014 “Towards an HIV Cure” symposium Melbourne

2014 “Towards an HIV Cure” symposium Melbourne. Impact of HAART on HIV Reservoirs. Pr Christine ROUZIOUX Virologie – Université Paris Descartes.

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2014 “Towards an HIV Cure” symposium Melbourne

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  1. 2014 “Towards an HIV Cure” symposiumMelbourne Impact of HAART on HIV Reservoirs Pr Christine ROUZIOUX Virologie – Université Paris Descartes

  2. The objective of this presentation is to understand the extent of which ART can reduce and limit the establishment and the persistence of the HIV reservoirs, as an important step towards HIV cure. • There is no consensus on the definition of HIV reservoirs • There is no consensus on HIV reservoir markers • However, there are many recent results which bring information that could help to design studies, to select patients as good candidates to receive the best combinations aiming at reducing HIV reservoirs and to achieve HIV drug free remission.

  3. Definition of HIV reservoirs Culture assay : IUPM Lewin & Rouzioux, AIDS 2011 Rouzioux & Richman, 2012

  4. Lewin & Rouzioux, AIDS 2011

  5. Comparative analysis of measures of viral reservoirs in HIV eradication studies: Erickson et al , Plos Path, 2013 r=0.70 p=0,008 r=0.65 p=0.016 r=0.58 p=0.015 r= 0.63 p=0.0042

  6. Kinetics of HIV reservoir decrease Treatment Interruption Viral Rebound - Naïves Palmer S et al. J Internal Medicine 2011

  7. Impact of Early HAART on HIV Reservoirs 272 Chronic Infections ADN-VIH (Log / M PBMC) 35 Primary- infections Better HIV-DNA decrease Better immune restoration Time with HIV-RNA <50 copies/ml (Years) Hocqueloux et al , JAC 2013

  8. Impact of ART on Gut reservoirs • Yukl S et al, AIDS 2010 • The Distribution of HIV DNA and HIV RNA in Cell Subsets differs in Gut and Blood in patients on HAART. Intensification with raltegravir produced no consistent decrease in HIV-RNA and HIV-DNA in blood, duodenum, colon or rectum. Moreover, ileum support ongoing productive infection, even in patients with plasma HIV-RNA undetectable. • Chege D et al AIDS 2012 • In long term virologically suppressed patients on HAART, intensification with raltegravir did not result in further decay of HIV-DNA in either the blood or GUT after 48 and 96 weeks of therapy. • Ananvoranitch J et al, Plos one 2012: • Gut T cell depletion and HIV reservoir seeding increases with progression . HAART induced immune restoration and reduced reservoir size • Kök A et al, Mucosal Immunology, 2014: • Early initiation of HAART helps to preserve and /or restore mucosal gut homeostasis, and reduce the gut reservoirs HIV-DNA level.

  9. ANRS 147 OPTIPRIM : Study design Arm 1 (N=45): Arm 2 (N=45): Primary end-point : HIV-DNA level at M24 Darunavir/R: 800/100 mg QD + Tenofovir/emtricitabine: 245/200 mg QD + Raltegravir: 400 mg BID + Maraviroc: 150 mg BID Darunavir/R: 800/100 mg QD + Tenofovir/emtricitabine: 245/200 mg QD Co-enrollment:-Cohort CO6 PRIMO - VISCONTI ? Treatment interruption Inclusion criteria: Patients with Acute HIV-1 infection < 10weeks 0 M24 M30 Chéret et al , CROI 2014

  10. ANRS 147 : OPTIPRIM trial : impact on reservoirs HIV-DNA kinetic from baseline to month 24 A B • HIV-DNA log copies/ per 106 PBMC • strongdecrease and continiousslope B. HIV-DNA log copies per ml of blood Could we do better? Chéret et al , CROI 2014

  11. Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues Fletcher et al PNAS 2014

  12. Probability to maintain HIV RNA <400 copies/ml after treatment interruption. : Immunovirological parameter evolution of the two post treatment controller patients A C D (PTC 1 and 2).

  13. Impact of 2 years of HAART in acute patients: OPTIPRIM ANRS147 Chéret et al CROI 2014

  14. HIV bloodreservoirs in T CD4+ subsets HAART at the Chronic PhaseHAART in Primary infection Chomont et al, Nat. Med 2009 Chéret et al, 2014 : OPTIPRIM ANRS 147 Elite controllers - VISCONTI Patients

  15. Interactions between Activation/ Inflammationand HIV reservoir levels Jain et al JID, 2013

  16. Interactions between Activation/ Inflammationand HIV reservoir levels Murray et al J Virol, 2014

  17. Impact of early HAART Murray et al J Virol, 2014

  18. 2013

  19. The VISCONTI study OR1 KPV OCP CXK 9 9 9 9 10 10 10 10 2000 2000 2000 2000 8 8 8 8 10 10 10 10 14 patients with Remission 7 7 7 7 10 10 10 10 1500 1500 1500 1500 6 6 6 6 10 10 10 10 5 5 5 5 10 10 10 10 CD4+ T cells/mm3 CD4+ T cells/mm3 RNA copies/ml CD4+ T cells/mm3 1000 1000 1000 1000 4 RNA copies/ml 4 RNA copies/ml 4 RNA copies/ml 4 CD4+ T cells/mm3 10 10 10 10 3 3 3 3 10 10 10 10 2 500 2 500 2 500 500 2 10 10 10 10 1 1 1 1 10 10 10 10 0 0 0 0 0 0 0 0 10 10 10 10 01 02 03 04 05 06 07 08 09 10 11 99 00 01 02 03 04 05 06 07 08 09 02 03 04 05 06 07 08 09 10 96 98 00 02 04 06 08 10 Year Year Year Year OR8 LY1 MWP OR2 9 9 9 10 10 10 9 10 2000 2000 2000 8 8 8 10 10 10 2000 8 7 10 7 7 10 10 10 1500 1500 1500 6 6 7 6 10 10 10 10 1500 5 5 5 10 6 10 10 10 CD4+ T cells/mm3 CD4+ T cells/mm3 CD4+ T cells/mm3 4 RNA copies/ml 1000 1000 4 1000 RNA copies/ml 4 RNA copies/ml 10 10 10 5 10 CD4+ T cells/mm3 RNA copies/ml 1000 3 3 3 10 10 10 4 10 2 2 2 500 500 500 10 10 10 3 10 500 1 1 1 10 10 10 2 0 10 0 0 0 0 0 10 10 10 98 99 00 01 02 03 04 05 06 07 08 09 10 11 99 00 01 02 03 04 05 06 07 08 09 10 01 02 03 04 05 06 07 08 09 10 0 1 10 Year Year Year 01 02 03 04 05 06 07 08 09 10 11 Year GXR OR3 LY2 JOGA 9 9 9 10 10 10 2000 2000 2000 8 8 8 10 10 10 9 9 10 10 7 7 7 10 10 10 8 8 2000 2000 10 10 6 1500 1500 1500 6 6 10 10 10 7 7 10 10 5 5 5 10 10 10 CD4+ T cells/mm3 6 6 1500 1500 10 10 CD4+ T cells/mm3 4 RNA copies/ml 4 RNA copies/ml 4 RNA copies/ml 1000 1000 1000 CD4+ T cells/mm3 10 10 10 5 5 10 10 3 3 3 10 10 10 4 4 1000 1000 10 10 2 2 2 500 500 500 10 10 10 3 3 10 10 1 1 1 10 10 10 2 2 500 500 10 10 0 0 0 0 0 0 10 10 10 1 1 10 10 98 99 00 01 02 03 04 05 06 07 08 09 10 02 03 04 05 06 07 08 09 10 00 01 02 03 04 05 06 07 08 09 10 11 0 0 0 0 10 10 Year Year Year SL2 MO1 9 10 2000 8 10 RNA copies/ml 7 CD4+ T cells/mm3 RNA copies/ml CD4+ T cells/mm3 10 1500 6 10 CD4+ T cells/mm3 RNA copies/ml 5 10 1000 4 10 3 10 500 99 00 01 02 03 04 05 06 07 08 09 10 11 12 99 00 01 02 03 04 05 06 07 08 09 10 11 12 2 Year Year 10 10 0 1 96 98 00 02 04 06 08 10 12 Year Saez-Cirion et al Plos Pathogens 2013

  20. Post-treatment controllers have an extremelyweak HIV-1 reservoir 6 5 4 HIV-DNA (log10 copies/106 PBMC) 3 2 1 PHI Chronic cART ALT HIC PTC Lewin and Rouzioux AIDS, 2011

  21. Post-treatment controllers have low levels of HIV-1 DNA in PBMC, which further decreased after treatment interruption in some cases 4 3 2 Cell associated HIV-1 DNA (Log copies/106 PBMC) 1 0 0 30 60 90 120 Time after treatment interruption (months) Saez-Cirion et al Plos Pathogens 2013

  22. The VISCONTI patients, now ! (n=20) Post-treatment interruption • Median Follow-up = 9.3 years(IQR: 8.4-10 – range: 4.5-12.5) • Median age = 48 (IQR: 43-53) • No AIDS event • Treatment resumption in 1/20 patient • Cancer ORL • VL <40 cp/mL before cART resumption • In remission after 2 years • No treatment resumption linked to viral replication • 338 Viral loads measured after treatment interruption • 287/338 (85%) were <50 cp/mL • 45/338 (13%) were >50 et <400 cp/mL • 6/338 (2%) were >400 cp/mL

  23. CONCLUSIONS • The study of HIV reservoirs in treated patients bring many new arguments in favor of early treatment initiation: • Protecting long-life memory T cells • Reducing the damage of activation/inflammation • Inducing VISCONTI cases with long-term control after treatment interruption • Pharmacological studies indicate that better combinations with better concentrations in lymphoïd tissues, including lymph nodes, might have a better impact on HIV reservoirs. • Lastly, the impact of new drugs, new combinations should be systematically evaluated on HIV reservoirs, to prepare patients to the next objective to achieve long-term HIV drug free remission.

  24. Acknowledgements Patients and clinicians who participate in the study Institut Pasteur Régulation des Infections Rétrovirales Asier Saez-Cirion Gianfranco Pancino Daniel Scott-Algara Françoise Barré-Sinoussi Pierre Versmisse CHU Necker Enfants Malades Laboratoire de Virologie Christine Rouzioux Véronique Avettand-Fenoel Adeline Mélard CHU Pitié-Salpetriere INSERM UMR-S 945 Brigitte Autran Charline Bacchus Benjamin Descours Assia Samri Ioannis Theodorou Julien Guergnon Faculté de Médecine Paris Sud INSERM U1012 Alain Venet Olivier Lambotte Cécile Goujard Isabelle Girault Camille Lecuroux INSERM U1018 Laurence Meyer Faroudy Boufassa CHR Orléans La Source Service Maladies Infectieuses Thierry Prazuck Laurent Hocqueloux INSERM UPMC U943 Dominique Costagliola Valérie Portard CHU Hôtel-Dieu Unité Immuno-Infectiologie Jean-Paul Viard FHDH “French Hospital Database on HIV” ANRS CO18 “HIV controllers” ANRS CO6 “PRIMO” ANRS CO15 “ALT”

  25. Merci

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