Effect of 24 Week Intensification with a CCR5-Antagonist on the Decay of the HIV-1 Latent Reservoir

Transcription

1 Effect of 24 Week Intensification with a CCR5-Antagonist on the Decay of the HIV-1 Latent Reservoir Laura Díaz 1, Carolina Gutiérrez 2, Carmen Page 2, Raquel Lorente 1, Beatriz Hernández-Novoa 2, Alejandro Vallejo 2, Ester Domínguez 2, María Abad 2, Nadia Madrid 2, Ana Moreno 2, María Jesús Pérez-Elías 2, Rafael Rubio 3, María Ángeles Muñoz-Fernández 1 and Santiago Moreno 2. 1 Immunobiology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain, 2 Infectious Diseases Service, Hospital Universitario Ramón y Cajal, Madrid, 3 Infectious Diseases Service Hospital Universitario Doce de Octubre, Madrid, Spain

2 Background 1 Chun TW, et al. J Infect Dis 2007; 2 Dinoso JB et al. PNAs 2009, 3 Buzón n MJ et al. Nature Med 2010

3 Objectives To evaluate the influence of treatment intensification with a CCR5 coreceptor antagonist (maraviroc( 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

4 ART Study Design ART + Maraviroc Baseline Study Week 0 (3 months) Week 12 Week 24 Week 36 Week 48 Laboratory Determinations

5 Over 18 years of age Chronic HIV infection Methods Inclusion criteria 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/mm 3 Demonstration of R5 viral tropism by phenotyping plasma samples stored before antiretroviral therapy

6 Laboratory Determinations 1-Latent reservoir 450ml 4-Immune activation markers 2-Residual viremia 3-Episomal DNA with 2 LTRs

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

8 Methods Single Copy Assay (Dr. Sarah Palmer) Episomal DNA with 2 LTRs Immune activation markers: CD38 + and HLA-DR + on CD4 and CD8 cells

9 Baseline characteristics of the patients Patient Gender Age CD4 count (cells/mm 3 ) CD8 count (cells/mm 3 ) HIV Viral load (copies/ml ml) ART Duration of ART (months) 1 M <50 ddi+3tc+nvp M <50 FTC+TDF+ATV/r 75 3 M <50 3TC+ABC+ATV 78 4 F <50 FTC+TDF+LPV/r 57 5 M <50 AZT+3TC+ABC M <50 AZT+3TC+ABC M <50 FTC+TDF+ATV/r 50 8 M <50 FTC+TDF+LPV/r 42 9 M <50 FTC+TDF+EFV 38 Median [IQR] 46 [31-48] 711 [ ] 793] 784 [ ] <50-75 [38-144]

10 HIV-1 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 RNA copies/ml HIV-1 1 Residual Viremia (Single Copy Assay) Detection limit < 2 cop/ml Detection limit <0,6 and < 0,4 cop/ml Detection limit < 0,3 cop/ml Basal Week 12 * Week 24 * Failure of internal standard in 2 samples

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

14 CD38 + HLA-DR + (%) HIV-1 Negative CD4 cell activation p<0.001 Basal Baseline w4 w12 w24 w36 p=0.755 p=0.03 w4 Immune Activation Markers w12 p=0.115 p=0.05 Follow up (weeks) 3.2 [ ] 2.5 [ ] 0.8 [ ] 1.6 [ ] 1.8 [ ] w24 p=0.031 w36 CD38 + HLA-DR + (%) HIV-1 Negative CD8 cell activation p<0.001 Basal Baseline w4 w12 w24 w36 p=0.731 p=0.04 w4 w12 p=0.009 p=0.19 w24 Follow up (weeks) 5.4 [ ] 5.4 [ ] 2.3 [ ] 3.3 [ ] 3.5 [ ] p=0.28 w36

15 Cell/mm 3 CD4 cell count Baseline w12 w24 Baseline w4 Baseline W12 W24 Immunological Status 711 [ ] 686 [ ] 680 [ ] CD45RA + CD62L + (%) Baselin e W4 W12 W24 Naive CD4 cells w12 42 [22 53] 46 [35 51] p= [30 58] p= [18 55] p= w24

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.

17 Discussion The impact on residual replication and viremia is similar to previous reports: no impact/increase (Dinoso et al. PNAs 2009; Buzón n 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 avir (Buzón n et al. Nature Medicine, 2010) 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) - Activation of transcription by the mechanism of action of MVC - Evaluation of these mechanisms are currently in progress

19 Hospital University Ramón n 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 Marañó ñón Laboratory of Immunovirology Madrid, Spain María Angeles Muñoz-Fernández Laura Díaz Raquel Lorente D. Pedrero. Radiophysic University of Córdoba. C Spain Eduardo Muñoz 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 Spanish Medical Research Fund (FIS) PI08/0958& The Spanish AIDS Research Network (RIS) RD06/006 IAS HIV RESERVOIRS WORKSHOP, 16 & 17 JULY 2010, VIENNA