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IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA

Effect of 24 Week Intensification with a CCR5-Antagonist on the Decay of the HIV-1 Latent Reservoir. IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA. Laura Díaz 1 , Carolina Gutiérrez 2 , Carmen Page 2 , Raquel Lorente 1 ,

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IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA

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  1. Effect of 24 Week Intensification with a CCR5-Antagonist on the Decay of the HIV-1 Latent Reservoir IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA Laura Díaz1, Carolina Gutiérrez2, Carmen Page2, Raquel Lorente1, Beatriz Hernández-Novoa2, Alejandro Vallejo2, Ester Domínguez2, María Abad2, Nadia Madrid2, Ana Moreno2, María Jesús Pérez-Elías2, Rafael Rubio3, María Ángeles Muñoz-Fernández1 and Santiago Moreno2. 1Immunobiology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain, 2Infectious Diseases Service, Hospital Universitario Ramón y Cajal, Madrid, 3Infectious Diseases Service Hospital Universitario Doce de Octubre, Madrid, Spain

  2. Background • Intensification of successfulantiretroviraltherapy has beenproposed as a strategythatcould control residual replication, diminishthe HIV latentreservoirs, and so be usefulforeradication purposes1. • However, recentlyreportedstudieshavefailedtodemonstrateanysignificantimpact of treatmentintensificationon residual HIV-1 viremia in patientswithchronicinfectiontreatedwith HAART2,3 • As a consequence, intensificationisclosedtobeingdiscarded as usefulforeradicationpurposes. IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA 1Chun TW, et al. J Infect Dis 2007; 2Dinoso JB et al. PNAs 2009, 3Buzón MJ et al. Nature Med 2010

  3. Objectives • To evaluate the influence of treatment intensification with a CCR5 coreceptor antagonist (maraviroc) on: • Primary endpoint • - Latent HIV-1 reservoir • Secondary endpoints • - Residual viremia measured by ultrasensitive PCR (SCA, <1 copy HIV RNA/mL) • - Episomal DNA with 2 LTRs • - Immune activation markers IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA

  4. Study Design ART ART + Maraviroc IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA Baseline Study(3 months) Week 0 Week 12 Week 24 Week 36 Week 48 * * * * * * * Laboratory Determinations

  5. Methods • Inclusion criteria • Over 18 years of age • Chronic HIV infection • Successful antiretroviral therapy with at least 3 drugs with viral load below 50 copies HIV RNA/mL for at least 2 years • CD4+ T lymphocyte count above 350 cells/mm3 • Demonstration of R5 viral tropism by phenotyping plasma samples stored before antiretroviral therapy IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA

  6. Laboratory Determinations IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA 4-Immune activation markers 1-Latent reservoir 450ml 2-Residual viremia 3-Episomal DNA with 2 LTRs

  7. Methods: Latent reservoir 3 2 1 IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA 6 5 4 Every week Results: IUPM Day 15 and 21 CD8 T cells

  8. Methods Single Copy Assay (Dr. Sarah Palmer) Episomal DNA with 2 LTRs IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA Immune activation markers: CD38+ and HLA-DR+ on CD4 and CD8 cells

  9. Baseline characteristics of the patients IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA

  10. HIV-1 Latent Reservoir IUPM Open symbols represent measurements below the limit of detection

  11. UIPM UIPM UIPM UIPM UIPM Open symbols represent measurements below the limit of detection

  12. HIV-1 Residual Viremia (Single Copy Assay) IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA HIV-1 RNA copies/mL Week 12 * Week 24 Basal Detection limit < 2 cop/mL Detection limit <0,6 and < 0,4 cop/mL * Failure of internal standard in 2 samples Detection limit < 0,3 cop/mL

  13. Episomal DNA with 2 LTRs Number of patients IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA Follow up (weeks)

  14. Immune Activation Markers CD4 cell activation CD8 cell activation p<0.001 p=0.731 p=0.009 p=0.04 p=0.19 p=0.28 p<0.001 10 p=0.755 10 p=0.115 8 8 p=0.03 p=0.05 p=0.031 6 6 CD38+HLA-DR+ (%) IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA CD38+HLA-DR+ (%) 4 4 2 2 0 0 HIV-1 Negative Basal w4 w12 w24 w36 HIV-1 Negative Basal w4 w12 w24 w36 Follow up (weeks) Follow up (weeks)

  15. Immunological Status CD4 cell count Naive CD4 cells CD45RA+CD62L+ (%) Cell/mm3 IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA w24 w12 w24 w12 Baseline w4 Baseline

  16. Conclusions • After 48 weeks of intensification with MVC, a decrease in the size of the latent reservoir is observed in most patients evaluated. The quantification of the reduction is limited by the sensitivity of the method. • In an apparent paradox, an increase in the residual viremia (SCA) and the episomal DNA with 2 LTRs is found in some of the patients evaluated. • A reduction in the proportion of activated CD4 and CD8 cells was observed. • Overall, we feel that intensification with a CCR5 antagonist may have an impact on the reservoirs and deserves further evaluation. IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA

  17. Discussion The impact on residual replication and viremia is similar to previous reports: no impact/increase (Dinoso et al. PNAs 2009; Buzón et al. Nature Medicine, 2010) Only one previous study has measured episomal DNA with 2 LTRs: a transient increase was found during intensification with raltegravir (Buzón et al. Nature Medicine, 2010) IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA • No previous studies have evaluated the consequences of intensification on the latent reservoir in resting CD4 T cells in chronically infected patients • -Only one study has measured the effect of initial therapy with a 4 drug regimen, including enfuvirtide (Gandhi et al.JID 2009) • -One study evaluated the impact in patients treated during acute infection (Chun TW et al.JID 2007)

  18. Discussion - Inhibition of viral replication in extra plasma sites (e.g. Gut) IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA - Activation of transcription by the mechanism of action of MVC - Evaluation of these mechanisms are currently in progress

  19. Hospital University Ramón y Cajal Service of Infectious Diseases Madrid, Spain Santiago Moreno Guillén Carolina Gutiérrez Beatriz Hernández Alejandro Vallejo Carmen Page Nadia Madrid María Abad Ester Dominguez José Luis Casado Fernando Dronda Ana Moreno Enrique Navas María Jesús Pérez-Elías Paloma Martí-Belda Maria Pumares Javier Zamora. Statistician Belén Capuz. Radiophysic Hospital University Gregorio Marañón Laboratory of Immunovirology Madrid, Spain María Angeles Muñoz-Fernández Laura Díaz Raquel Lorente D. Pedrero. Radiophysic University of Córdoba. Spain Eduardo Muñoz IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA Karolinska Institute. Stockholm, Sweden Viktor Dahl Sarah Palmer Hospital 12 de Octubre. Madrid, Spain Rafael Rubio Thanks to all participating patients and their families

  20. IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA Spanish Medical Research Fund (FIS) PI08/0958& The Spanish AIDS Research Network (RIS) RD06/006

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