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Aids 20072007 What Is New AIDSAIDS 20072007 WHAT IS NEW ROBERTO CAUDA Istituto di Clinica delle Malattie Infettive Università Cattolica Sacro Cuore Roma THE HISTORY OF AIDS • THE YEARS OF DESPERATION: 1984-1992 • THE HEROIC ERA: 1992-1996 • THE MIDDLE AGES: 1996-1999 • THE MODERN TIME: 1999-TODAY TherapyTherapy ofof PatientsPatients withwith HIVHIV InfectionInfection Therapy of Opportunistic Infection 1° and 2° Prevention OIs Antiretroviral Therapy 1980 1990 2000 Evolution of HIV infection: from lethality to long-term manageability Rapidly Manageable Incremental therapeutic advances lethal long-term HIV found Dual NRTI to be cause therapy of AIDS NNRTI-containing New HAART drug Antibody test classes? Entry RNA test Life inhibitors Life expectancy expectancy PI-containing <10 years Zidovudine HAART 20+ years QoL poor QoL good 1980 1985 1990 1995 2000 2005 2010 Novel Antiretrovirals in Development: Current Classes Mature virus Entry inhibitors TNX-355 CCR5 inhibitors CXCR4 inhibitors MK-0518 GS-9137 Protease Integrase inhibitors inhibitors Reverse transcriptase PA-457 inhibitors Timeline for New Antiretrovirals PIs NNRTI CXCR4 Entry inhibitors inhibitors (eg, anti-gp120, CCR5) MK-0518 GS-9137 Maturation inhibitors CCR5 Integrase inhibitors inhibitors PA-457 2005 2006 2007 2008 2009 Darunavir TMC278 Etravirine Brecanavir PROTEASE INHIBITOR OF SECOND GENERATION Tipranavir § Novel nonpeptidic protease inhibitor CH developed to provide a new treatment OH 3 option for PI-experienced patients Potent in vitro activity H C § 3 against WT HIV-1 and the majority of O O multiple PI-resistant HIV-1 NH § Requires co-administration with 200mg ritonavir SO2 § Available as a soft-gel capsule (250 N mg) F3C 11 POWER 1 and 2: VL < 50 copies/mL at Week 48 (ITT-TLOVR) o Ongoing 96-week randomized 100 DRV/RTV 600/100 mg BID trial of 3-class experienced CPI/RTV pts (%) 80 1 primary PI mutation c/mL 45%* n ≥ 60 46%* n VL > 1000 copies/mL 40 o DRV/RTV 600/100 BID chosen as optimal dose 12% 20 10% at Week 24 Pts With VL < 50 With VL < Pts 0 o Superior efficacy at Week 48 over comparator 0 8 16 24 32 40 48 boosted PIs Weeks *P < .001 vs CPI/RTV. Not all patients reached Week 48 at the time of analysis; patients who had not reached Week 48 were censored Lazzarin A, et al. IAC 2006. Abstract TUAB0104 at their last available visit. MAIN OBSTACLES not enough potent ARTs Sanctuaries HIV-1 drug resistance Insufficient immune responses HIV-1 infected cells need to be recognized by the immune system INDUCING HIV’s “COMING OUT” INDUCE GENE EXPRESSION -cytokines (IL-2, IL-6, IL-7) receptor -anti-CD3 antibodies CD3 -prostratin, DPP, DAG lactones DAG -valproic acid DNA histones acetate acetyl valproic acid histone deacetylases INDUCE GENE EXPRESSION -cytokines (IL-2, IL-6, IL-7) receptor -anti-CD3 antibodies CD3 -prostratin, DPP, DAG lactones DAG -valproic acid DNA IMPROVED ART Integrase inhibitors: a) O (18) coumarin-based 1995 OH OH inhibitor O O O O H O OH b) H (10) equisetin 1995 N O OH OH (25) L-731,988 1999 c) N O O OH F HN HN N d) N 1999 N (23) 5-CITEP O OH Cl O S N O F N e) H 2002 N (31) L-870,810 N O OH OH f) O N 2006 O Cl (34) JTK-303 / GS 9137 F O OH Savarino A. Expert Opin. Investig. Drugs 2006 hydrophobic portion Chloroquine: A)HIV-1 maturation inhibitor B)P-glycoprotein blocker Effects of chloroquine (CQ) on viral particle glycosylation Data #1 Data #1 [H3] glucosamine 200 150 cpm cpm 100 cpm cpm cpm 50 0 0 0.0001 0.001 0.01 0.1 1 CQ conc. [mM] [mM[mM CQ] CQ] [S35] cysteine / CQ conc.: 0mM 10-1mM 1 mM methionine 120 KDa Savarino et al. JAIDS 2004 Figure: Can chloroquine interact with sugar-modifying enzymes? This computer-assisted simulation of ligand/protein docking by use of the program GOLD12 indicates that chloroquine (red) fits to the active site of UDP N-acetylglucosamine 2 epimerase (grey). This evidence suggests that chloroquine could inhibit the enzyme that catalyses the rate-determining step in the sialic acid biosynthetic pathway. Savarino et al. Lancet Infect Dis 2006 Effects of quinoline X4 virus R5 virus antimalarials in combination with known antiretroviral AZT agents Nevirapine Lopinavir Structure and mechanism of action of an ATP- binding cassette transporter Reyes et al., Science 2005 Chloroquine acts as a chemosensitizer by increasing the intracellular concentrations of ABC substrates Savarino et al. Lancet Oncol. 2006. Sanctuaries of HIV-1 Replication during Therapy •Brain •Lymphoid tissue •Testis The P-glycoprotein is involved in drug efflux from these organs Effects of mefloquine and chloroquine on the intracellular concentrations of LPV Treatment quantity of LPV / 106 cells (ng) uptake efflux LPV 22.6 ± 4.2 2.6 ± 0.5 LPV + MQ 1mM 10.3 ± 6.1 3.2 ± 0.2 LPV + CQ 1mM 17.6 ± 3.2 12.3 ± 4.6 LPV + RTV 5mM n.d. 3.6 ± 0.6 Savarino A. et al. Drug Develop Res, 2007, in press. STEP-3: KILLING HIV-INFECTED CELLS Nature Medicine - 12, 1365 - 1371 (2006) NATURAL MECHANISMS OF HIV-1- INFECTED CELL KILLING •Antibody-mediated killing •CD8 cell responses •Natural killer (NK) cells ANTIBODY-MEDIATED CELL CELL KILLING IMMUNOTOXINS IMMUNOTOXINS IN ANTI-HIV-1 STRATEGIES •Anti-gp120 antibodies conjugated with different toxins (e.g. Cholera toxin) •Effective and selective killing of HIV-1-infected cells. •Cell killing enhanced in the presence of chloroquine CD8-cell mediated cytotoxicity Comparsa di malattie opportunistiche in relazione al numero di linfociti T CD4 Up to what CD4 count is the risk of AIDS reduced if ART is started ? 100 CD4 count (95% CI) 0-49 50 50-199 200-349 350-499 note log scale log note 500+ – 10 5 1 Rate % of AIDS (per year) (per year) of AIDS % Rate 0 .5 1 1.5 2 Years from start of ART ART-Cohort Collaboration 2004 Pre-therapy Median CD4 cell count in ART-naive patients initiating ART in Europe and North America 300 250 200 150 100 50 0 1995-6 1997 1998 1999 2000 2001 2002-3 Year of initiating ART # pts: 1232 4785 4583 3699 3203 2783 1932 ART Cohort Collaboration, Lancet, 2006 Impact of HAART on the Incidence of Opportunistic Infections HAART 350 Any OI 300 yrs yrs - - 250 200 150 Incidence per 100 pt Incidence per 100 pt 1992 1993 1994 1995 1996 1997 Year Impact of HAART on the Incidence of Opportunistic Infections HAART 140 120 yrs yrs - - PCP 100 MAC 80 60 CMV retinitis 40 Incidence per 100 pt Incidence per 100 pt Toxoplasmosis 20 1992 1993 1994 1995 1996 1997 1998 1999 Year IDSA 2001 Do Opportunistic Infections Occur in 2007? 8000 Opportunistic infections Therapy 4000 Pubblicazioni 0 1985/90 1991/96 1997/00 2001/06 Years Incidence of opportunistic infections for various CD4+ cell count strata: Traditionally believed thresholds value indicated by the red line CMV/MAC/TOXO PCP/OC PULMTB/EXPULMTB 100 10 1 0,1 Incidence per 1000 PYFU (95%CI) PYFU 1000 per Incidence 0,01 <100 <100 <100 >=500 >=500 >=500 100-199200-299300-399400-499 100-199200-299300-399400-499 100-199200-299300-399400-499 Latest CD4 count (cells/ ml) N OIs: 134 45 13 9 2 2 89 55 61 35 13 16 12 9 10 11 11 14 EuroSIDA: Podlekareva et al, JID 2006 Occurrence of OIs in ART-Naive Patients: The ALLRT Cohort • ART-naive patients in ACTG trials included in A5001 (N = 2154) • Most common OIs: PCP, MAC, esophageal candidiasis • Most OIs occurred during first 2 months on HAART • No data reported on OI prophylaxis *Multivariate model controlled for race. Smurzynski M, et al. CROI 2006. Abstract 782. Incidence of AIDS-Defining Events After Initiation of HAART Mycobacterium avium Disease Kaposi’s Sarcoma 25 25 20 20 15 15 10 10 Incidence Incidence 5 5 0 0 (per 1000 person years) (per 1000 person years) 0-3 4-5 7-12 13-24 25-36 0-3 4-5 7-12 13-24 25-36 Period After Starting HAART (mo) Period After Starting HAART (mo) Cytomegalovirus Disease Pneumocystis jiroveci Pneumonia 25 25 20 20 15 15 10 10 Incidence 5 Incidence 5 (per 1000 person years) 0 0 0-3 4-5 7-12 13-24 25-36 (per 1000 person years) 0-3 4-5 7-12 13-24 25-36 Period After Starting HAART (mo) Period After Starting HAART (mo) ART-CC: d’Arminio Monforte et al. Arch Intern Med. 2005 DEMOGRAPHIC CHARACTERISTICTS OF PATIENTS WITH THE FIRST AIDS RELATED EVENT UCSC (n=2.569) 1985/1994 1995/1996 1997/2000 2001/2006 (1294 pts) (476 pts) (407 pts) (392 pts) Age (years) (median, IQR) 33 (30-38) 35 (32-40) 38 (34-44) 42 (36-48) Male sex (%) 80 74 74 74 Median CD4 (IQR) 17 (1-72) 20 (0-83) 40 (8-141) 68 (20-160) Risk group (%) (sex/IDU) 43/46 38/51 62/26 64/23 Prior exposure to dual NRTI therapy (%) 5 13 10 12 Exposure to HAART (%) _ _ 14 24 Current HAART use (%) _ _ 12 24 Incidenza dei diversi tipi di primi eventi AIDS in relazione ad anno di calendario nella coorte UCSC PCP 50 PML TBC 10 Toxoplasmosi Linfomi cerebrali 40 Candidosi CMV ADC SK 30 Micobatteriosi 5 Polmoniti batteriche 20 ricorrenti N° casi-anno N° casi-anno 10 0 0 1985/90 1991/96 1997/00 2001/06 1985/90 1991/96 1997/00 2001/06 PI INHIBIT PNEUMOCYSTIS CARINII C. Atzori et al. JID, 2000 HIV unifected controls No HAART HAART CD4>200 CD4>200 HAART No HAART CD4>250 CD4<200 Prevalence of main neurological disorders (%).
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