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NUEVOS ENFOQUES TERAPEUTICOS Daniel Podzamczer Unidad VIH. S Enf. Infecciosas Hospital Universitari de Bellvitge L’Hospitalet. Barcelona.

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Presentation on theme: "NUEVOS ENFOQUES TERAPEUTICOS Daniel Podzamczer Unidad VIH. S Enf. Infecciosas Hospital Universitari de Bellvitge L’Hospitalet. Barcelona."— Presentation transcript:

1 NUEVOS ENFOQUES TERAPEUTICOS Daniel Podzamczer Unidad VIH. S Enf. Infecciosas Hospital Universitari de Bellvitge L’Hospitalet. Barcelona

2 Agenda - Intensificación (reducir reservorio; mejorar aterosclerosis) - Cambios de TAR (marcadores inflamatorios) - Tto intensivo para reducir RCV - Monoterapia (y SNC) - SNC - LRA (latency-reversing agents)

3 Effect of Maraviroc Intensification on the Decay of HIV-1 DNA in PBMC and residual viremia of Recently Infected Patients Initiating Treatment with Raltegravir plus Tenofovir/Emtricitabine> a 48-week Randomized Study Maria C Puertas 1, Josep M Llibre 2, Mònica Ballestero 1, Marta Massanella 1, Maria J Buzon 1, Anna Esteve 3, Josep M Miró 4, Julià Blanco 1, Bonaventura Clotet 1,2, Javier Martinez-Picado 1,5 * and the Maraviboost Study group 1 IrsiCaixa – AIDS Research Institute, Institut de Recerca en Ciències de la Salut Germans Trias i Pujol (IGTP), Badalona, Spain; 2 Lluita Contra la SIDA Foundation, Hospital Universitari Germans Trias i Pujol, Badalona, Spain 3 Center for Epidemiological Studies on STI and HIV/AIDS of Catalonia, Badalona, Spain; 4 Hospital Clinic - IDIBAPS, University of Barcelona, Barcelona, Spain; 5 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain #351

4 Recruitment and follow-up HIV infection < 24 weeks CCR5 +

5 Results 1: Standard clinical parameters (cont)

6 Results 2: Residual viremia Viral load rapidly decays during the first 4 weeks, reaching a final 4 log decay at week 48 (1.04 vs 1.12 log RNA HIV-1 copies/ml respectively, in the intensified and the control arm). Fitting the kinetics of residual viremia to a two-phase decay model shows a slightly higher fast decay rate in the control arm (0.77 vs 0.60 log per week) during the first phase decay, followed by a second linear phase decay similar in both arms.

7 Results 3: Total HIV-1 DNA in PBMC Total HIV-1 DNA in PBMC is progressively reduced, from baseline to week 48, in both treatment groups. On the whole, we observed an 8 fold decrease in the total HIV-1 DNA reservoir in the cells.

8 Results 5: Episomal HIV-1 DNA forms A transient increase in 2-LTR circles, a surrogate marker of recent infection events, was observed in both groups early after treatment initiation. Of note, in the intensified group the amount of 2-LTR circles in PBMC significantly decayed below the BL as early as week 12, while in the control group these episomal forms only reached a significant decrease after week 24.

9 Conclusions Early HAART initiation in recently HIV-1 infected patients rapidly decreases the plasma viremia and total HIV-1 DNA in PBMC, and +MVC reduces viral replication faster, but… No major differences in latent reservoir size between groups were observed after 48 weeks.

10 Buzon M, et al. #151

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13 Aim: to determine the effect of MVC intensification on vascular function Primary outcome: change in FMD from baseline to week 24

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18 Changes in Cardiovascular Biomarkers in Subjects Switching from Ritonavir-Boosted Protease Inhibitors to Raltegravir: The SPIRAL Study. E Martinez 1, P Monteiro 1, JM Llibre 2, F Gutierrez 3, D Podzamczer 4, A Antela 5, J Berenguer 6, I Perez 1, J Pich 1, JM Gatell 1, and the SPIRAL Study Group. 1 Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona; 2 Germans Trias i Pujol University Hospital and Lluita contra la SIDA Foundation, Badalona; 3 Hospital General Universitario de Elche, Elche; 4 Hospital Universitari de Bellvitge, L`Hospitalet de Llobregat; 5 Complexo Hospitalario Universitario de Santiago, Santiago de Compostela; and 6 Hospital General Universitario Gregorio Marañón, Madrid, all in Spain. #834

19 InitiationProgressionComplication hsCRP, MCP-1 OPG, IL-6 TNF-alpha, IL-10 ICAM-1, VCAM-1 E-Selectin, P-Selectin Insulin, Adiponectin D-dimer Inflammation Endothelial dysfunction Insulin resistance Hypercoagulability Triglycerides, Total cholesterol, LDL cholesterol, HDL cholesterol Lipids (fasting) Biomarkers and lipids measured at baseline and 48 weeks

20 Biomarkers: Median difference of percent change RAL minus PI/r (95% CI)

21 Correlations between ∆ biomarkers and ∆ lipids ∆Triglycerides∆Total cholesterol∆LDL cholesterol∆HDL cholesterol ∆hsCRP--Spearman's rho (P=0.0016) - ∆MCP-1-Spearman's rho (P=0.0320) -Spearman's rho (P=0.0202) ∆OPG---- ∆IL ∆IL ∆TNF-alpha---- ∆ICAM ∆VCAM ∆E-selectin---- ∆P-selectin---- ∆Adiponectin---- ∆InsulinSpearman's rho (P=0.0001) Spearman's rho (P=0.0040) -- ∆D-dimer---- Only correlations showing a P value <0.005 are shown

22 Conclusions Switching from PI/r to RAL led to significant changes in several cardiovascular biomarkers associated with inflammation, insulin resistance and hypercoagulability, although not in those assoc. with endothelial dysfunction. There were few and weak significant correlations between changes in lipids and changes in biomarkers suggesting that decreases in inflammation, insulin resistance, and hypercoagulability biomarkers were rather independent of lipid changes.

23 Carotid Intima-media thickness assessment moderate/high cardiovascular risk HIV- infected patients randomized to an intensive intervention on lifestyle versus routine controls: 96-week results Maria Saumoy* 1, Antonio Navarro 1, Montserrat Olmo 1, Elena Ferrer 1, Ramon Vila 2 Josep Maria Ramón 3, Antonia Vila 1, D. Podzamczer 1 HIV Unit. Infectious Disease 1, Vascular Surgery 2 and Preventive Medicine 3 Services. Bellvitge University Hospital. Bellvitge Biomedical Research Institute (IDIBELL). L’Hospitalet de Llobregat. Barcelona. Spain #827

24 Fig. 6 Percentage of patients who quitted tobacco at week 96 Control group Intervention group Fig. 5 Median changes in lipid parameters between baseline and 96 weeks Fig. 7 Mean change (Week 96 - baseline) in cardiovascular risk estimation by Framingham equation Results

25 Common carotid Carotid bulb P=0.197*P=0.016* Median change (IQR), mm (week 96- baseline) Control group Intervention group P value between groups COMMON CAROTID0.025 (-0.05;0.215)0.125 (0;0.30)0.207 BULB0.4 (0.0375;0.70)0.550 (0.150;0.680)0.428 P=0.001*P<0.001* *Wilcoxon test to analyze within-arm change Carotid-IMT at baseline and week 96 in control and intervention groups

26 In our pts with moderate/high CVR, an intensive and multidisciplinary intervention on lifestyle was associated with an increase in cIMT, specially in carotid bulb region, despite and improvement in lipid profile and quitting smoking. Probably a more intensive reduction in LDL-c is crucial to decrease cIMT progression in addition to a better control of other CVR factors such as tobacco. Conclusions

27 Long-Term Monotherapy With Lopinavir/ritonavir (>2 years) is not Associated with Greater HIV-Associated Neurocognitive JR Santos 1, JA Muñoz-Moreno 1, J Moltó 1, I Bravo 1, A Prats 1, DR McClernon 2, A Curran 3, P Domingo 4, JM Llibre 1, B Clotet 1, 5 1 Lluita contra la Sida Foundation, HIV Clinic, Hospital Universitari Germans Trias i Pujol, Badalona, Spain, 2 bioMONTR, Research Triangle Park, North Carolina, USA, 3 Infectious Diseases Department, Hospital Vall d'Hebron, Barcelona, Spain, 4 Infectious Diseases Unit, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain, 5 IrsiCaixa Foundation, HIV Clinic, Hospital Universitari Germans Trias i Pujol, Badalona, Spain #483

28 * LPV/r-MT > median prior ART and > time on virological suppression Methods *

29 Figure 3. Percentages of subjects with neurocognitive impairment Neurocognitive outcomes Confounding comorbidities included: depression or anxiety disorders, drug use, presence of a psychiatric diagnosis, psychopharmacologic treatment, or current or past opportunistic infection involving CNS. In the LPV/r-MT group 7 (41%) patients showed NCI while in LPV/r-HAART group this occurred in 10 (59%); p=0.48. When patients with possible confounding comorbidities were excluded, the results were similar: 6/13 (46%) patients showed NCI in LPV/r-MT group (46%) and 8/13 (61%) in LPV/r-HAART group (p=0.43). Considering neurocognitive functioning, values were mildly better in MT group. In total sample, GDS was 0.23 in MT group and 0.46 in HAART group (p=0.025), and in non-comorbities sample 0.25 and 0.5 (p=0.04), respectively.

30 Figure 2. Patients with complete CSF-virological suppression (RNA HIV <1 copy/mL). Virological outcomes The proportion of patients with HIV-1 RNA <1 copy/mL in CSF in the LPV/r-MT group was similar to LPV/r-HAART group Three patients on LPV/r-MT had determinations of CSF HIV-1 RNA of 1, 75 and 120 copies/mL. One patient on LPV/r + ABC + 3TC ( LPV/r-HAART group) had a CSF HIV RNA of 2 copies/mL.

31 Neurocognitive Impairments in Patients Using Lopinavir/ritonavir Monotherapy vs. Lopinavir/ritonavir-based HAART Torsak Bunupuradah 1, Ploenchan Chetchotisakd 2, Supunnee Jirajariyavej 3, Victor Valcour 4, Chureeratana Bowonwattanuwong 5, Warangkana Munsakul 6, Virat Klinbuayaem 7, Wisit Prasithsirikul 8, Jiratchaya Sophonphan 1, Jintanat Ananworanich 1,9,10 on behalf of HIV STAR study 1 HIV-NAT, the Thai Red Cross AIDS Research Centre, Bangkok, Thailand; 2 Khon Kaen University, Khon Kaen, Thailand; 3 Taksin Hospital, Bangkok, Thailand; 4 Memory and Aging Center, University of Califonia, San Francisco, USA; 5 Chonburi Hospital, Chonburi, Thailand; 6 Faculty of Medicine, University of Bangkok Metropolitan Administration, Bangkok, Thailand; 7 Sanpatong Hospital, Chiang Mai, Thailand; 8 Bamrasnaradura Institute, Nonthaburi, Thailand; 9 Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; 10 SEARCH, the Thai Red Cross AIDS Research Centre Bangkok, Thailand #479

32 Results Multivariate analysis: NCI at 48 wks: NCI at BL (OR 3.8) and lower education (OR 3.1)

33 Rapid Increase of Astrocytic and Inflammatory Markers in the cerebrospinal Fluid of HIV+ Patients on LPV/r-Monotherapy Renaud du Pasquier 1, Malela Kalubi 1, Samantha Jilek 1, Sabine Yerly 2, Christoph Fux 3, Christine Gutmann 4, Alexia Cusini 5, Milos Opravil 5, Matthias Cavassini 1, Pietro Vernazza 4, and the Swiss HIV Cohort Study 1 University Hospital of Lausanne; 2 University Hospital of Geneva; 3 University Hospital of Berne; 4 Hospital of St-Gall; 5 University Hospital of Zurich, Switzerland #480

34 Results Table 1. Results of the five biomarkers in the CSF of all three categories of study subjects, including patients HIV viral failure in blood and/or CSF Results are expressed as median +/- interquartile range (IQR). Statistical analyses were performed with GraphPad Prism software (San Diego, CA, USA). The difference between two groups was tested using the non-parametric Mann-Whitney ranked test. n=52 pts. HIV+ (MOST study) and 37 pts HIV- with AD. Mean duration MT 47wks

35 Results Table 2. Results of the five biomarkers in the CSF of all three categories of study subjects, after removal of all HIV viral failure in blood and/or CSF

36 Conclusions In the CNS, HIV seems to affect the astrocytes before the microglia/macrophages ( S100-β may be an early marker of sub-optimal anti-retroviral therapy in the CNS) Neuronal damage does not seem to be an early feature of HIV infection of the CNS

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42 * ** * PAOFI and ADL ** MMT-r and VALPAR

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45 Major barriers to cure in HIV infection - Latently infected cells - Low-level persistent viral replication - Anatomical reservoirs Treatment intensification Very early ART To reverse latent infections

46 Epigenetic Silencing of HIV Expression Leads to Latency From J. Karn

47 Agents Which Induce Latent HIV Expression in vitro Histone deacetylase (HDAC) inhibitors –Class I-selective: Vorinostat (Vor, SAHA) –Non-selective: Trichostatin A (TSA), valproic acid (VPA) NF-kB activators –Prostratin –PMA –TNF  Akt/HEXIM-1 modulators –Hexamethylbisacetamide (HMBA) Histone/DNA methyltransferase inhibitors –BIX1294 : targets G9a HMT – Imai et al, 2010 –azaCdR: targets DNA MT – Kauder et al, 2009 Jak/Stat pathway –IL-7

48 Session 33: Pathways towards a cure: viral latency and reservoirs Session 42: HIV persistency, latency and eradication - Early treatment reduces viral reservoir (#151) - More data on zinc finger nucleases (SB-728-T) (#155) - SAHA!!! (latency-reversing agent)

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51 (HDAC= histone deacetylases)

52 “Open” Histones Acetylated Histone tails Reduced Higher Order Structure Access to Transcription Factors Transcription Enabled “Closed”Nucleosome Hypo-Acetylated Histone tails Stable, Compact Chromatin Less accessible to Transcription Factors Transcription Repressed deacetylated acetylated HIV Lives within Chromatin Latency restriction at transcription initiation

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