Josep Mallolas Hospital Clínic Barcelona

Size: px

Start display at page:

Download "Josep Mallolas Hospital Clínic Barcelona"

Catherine Charles
6 years ago
Views:

1 Nuevos paradigmas en la infección VIH Josep Mallolas Hospital Clínic Barcelona

2 1. Do you believe, I have to start ARV therapy?

3 Incidence and Mortality of AIDS in Spain

4 HIV and NON-AIDS complications

5 HIV and NON-AIDS complications

6 HIV and NON-AIDS complications

7 HIV and NON-AIDS complications

8 2.- What is my life expectancy?

9 Improve Survival in HIV Patients CD4 count 500mm 3 is associated with standard mortality ratio (SMR) similar to general population 1 8 CD4: 350 to 499/mm 3 CD4 500/mm SMR (CI) Time of truncation after initiation of cart (years) Lewden C, et al. J Acquir Immune Defic Syndr 2007;46(1):72 77

10 3.- Can I cure my HIV infection?

13 When start ARV Therapy? Hit hard and hit early David Ho, 1996

15 Slow decay of latently infected CD4 + T cells t ½ = 44.2 months Frequ uency (per 10 6 cells s) Time to eradication > 73.4 years Time on HAART (years) Finzi et al., Science, 1997 Wong et al. Science, 1997 Finzi et al., Nature Med., 1999 Chun et al., Nature Med., 1995 Chun et al., PNAS, 1997 Siliciano et al., Nature Med., 2003 Chun et al., Nature, 1997

17 ARV Armentarium 2009 ZDV ddi ddc d4t NVP 3TC DLV ABC EFV TDF FTC RAL ETR NRTI SQV NFV LPV/r NNRTI PI Entry inhibitor Integrase inhibitor RTV IDV APV ATV FPV ENF TPV DRV MVC 25 unique ARV agents approved, 6 different classes

19 HIV Lifecycle Phases: binding and entry, reverse transcription, replication, budding, and maturation Reverse Transcriptions Act Here 6. Release Protein Inhibitors Act Here 1. Attachment 3. Transcription 2. Entry 4. Integration 7. Maturation 5. Polyprotein Production

20 4.- So, what treatment do you suggest?

21 HAART: Studies in Naïve patients With > 65% Response (VL < 50 at Wk 48) COMBINE (NVP + ZDV/3TC) 2NN (NVP BID + d4t + 3TC) ZODIAC (EFV + ABC QD + 3TC) M (LPV/RTV + d4t + 3TC) ZODIAC (EFV + ABC + 3TC) CNA30024 (EFV + ZDV + 3TC) 2NN (NVP QD + d4t + 3TC) 2NN (EFV + d4t + 3TC) CNA30024 (EFV + ABC + 3TC) M (LPV/RTV + FTC + TDF QD) FTC301 (EFV + FTC + ddi QD) DMP (EFV + D4T + 3TC) CLASS (EFV + ABC + 3TC) ANRS (EFV + ddi + 3TC) M (LPV/RTV + d4t + 3TC) Dart 1 (EFV + ddi EC + 3TC) GS903 (EFV + d4t + 3TC) GS903 (EFV + TDF + 3TC) ANRS 091 (EFV + ddi + FTC) 30 NNRTI Boosted PI Percentage With HIV-1 RNA < 50 copies/ml at Week 48 Bartlett JA, et al. AIDS. 2006;20:

22 HAART is effective! Recent Randomized ARV Trials Proportion with VL <50 copies/ml Week 48 (ITT) Naïve Trials Experienced Trials Gemini 64-65% Benchmrk 64% KLEAN 65-66% 66% Victor E1 (Wk 24) 64% ACTG 5142 (Wk 96) 77-89% Motivate 42-47% Artemis 78-84% Power 46% Merit 65-69% Duet 60-61% MK % TITAN 61-70% Castle 76-78% HEAT 67-68% Walmsley EACS, 2007, Eron, Lancet, 2007; Ridler, WAC, 2006; Clumeck, EACS, 2007; Saag, IAS, 2007; Markowitz, 8,JAIDS, 2007; y,,,, ;,, ;,, ; g,, ;,,, ; Molina, CROI, 2008; Smith CROI, 2008, Cooper, CROI 2008, Steigbigel, CROI 2008, Zingman, CROI 2008; Lalezari ICAAC 2007, Falkenheuer, EACS, 2007; Lazzarin, Lancet, 2007; Haubrich, CROI, 2008; Johnson CROI 2008; Madruga Lancet, 2007

23 Safety and Tolerability of Many Current Regimens Are Excellent Study Drug regimen Discontinuations Due to AEs,* % AI [1] GS934 [2] ATV + d4t + 3TC ATV/RTV + d4t + 3TC EFV + TDF + FTC EFV + ZDV/3TC KLEAN [3] FPV/RTV + ABC/3TC 12 LPV/RTV + ABC/3TC 10 ARTEMIS [4] CASTLE [5] DRV/RTV + TDF/FTC LPV/RTV + TDF/FTC ATV/RTV + TDF/FTC LPV/RTV + TDF/FTC HEAT [6] ABC/3TC + LPV/RTV 4 TDF/FTC + LPV/RTV 6 GEMINI [7] SQV/RTV + TDF/FTC LPV/RTV + TDF/FTC Malan N, et al. IAS Abstract WEPEB Arribas JR, et al. IAS Abstract WEPEB Eron J Jr, et al. Lancet. 2006;368: DeJesus E, et al. ICAAC Abstract 718-b. 5. Molina JM, et al. CROI Abstract Smith K, et al. CROI Abstract Walmsley SL, et al. EACS Abstract PS1.4.

24 We have better and more tolerable therapy It appears we have: - Less short term toxicity-diarrhoea, dyslipidemia - Less long term toxicities such as lipodystrophy - Better formulations - easier to take - lower pill burdens-one pill once a day - no refrigeration

25 When to start ARV Therapy? Late clinical i l stage Initial clinical stage < 200 High HIV viral load 20 0 CD4 > Low HIV viral load

26 ACTG 5202: ABC/3TC vs TDF/FTC + EFV or ATV/RTV Randomized, double-blind, open-label phase IIIb study Stratified by HIV 1 RNA Week 96 Stratified by HIV-1 RNA < or 100,000 copies/ml primary endpoint TDF/FTC* 300/200 mg QD + EFV 600 mg QD *Double blind. Open label. HIV-infected patients with HIV-1 RNA > 1000 copies/ml (N = 1858) ABC/3TC* 600/300 mg QD + EFV 600 mg QD TDF/FTC* 300/200 QD + ATV/RTV 300/100 mg QD ABC/3TC* 600/300 mg QD + ATV/RTV 300/100 mg QD Sax PE, et al. IAC Abstract THAB0303.

27 Boosted PIs in ARV-Naive Patients: Which to use? *P <.05 HIV-1 es/ml ients With A < 50 copie (%) Pati RNA ARTEMIS [3] (ITT) 48-Wk Noninferiority 84* 78* CASTLE [4] (ITT) 48-Wk Noninferiority i it n = LPV/RTV DRV/RT LPV/RTV 400/100 BID 400/100 BID or 800/200 QD V 800/100 QD 440 ATV/RTV 300/100 QD Ortiz R, et al. AIDS. 2008;22: Molina JM, et al. Lancet. 2008;372:

28 Eficacia de los ARV en pacientes naïve KLEAN 1 (ITT-E, TLOVR) 48 wk ALERT 2 GEMINI 3 ARTEMIS 4 (ITT, MD=F) (ITT) (ITT) 48 wk 48 wk 96 wk CASTLE 5 (ITT-CVR) 96 wk HIV RN NA <50 copie es ml (%) Non-inferiority Not powered* Interim analysis Superiority Non-inferiority , n=434 n=444 n=53 n=53 n=166 n=171 n=346 n=343 n=440 n=443 FPV/r LPV/r 700/ /100 BID BID FPV/r 1400/100 QD ATV/r 300/100 QD 0 SQV/r 1000/100 BID LPV/r 400/100 BID Neither FPV/r nor LPV/r QD are licensed in the EU. The EU licensed dose of DRV/r is 600/100 mg BID. *ALERT study was not powered for non-inferiority. Data in figures are from different studies and cannot be compared directly LPV/r DRV/r 800/ /100 BID /QD QD ATV/r 300/100 QD LPV/r 400/100 BID 1. Eron J, et al. Lancet. 2006;368: ; 2. Smith K, et al. IAS 2007, Abstract WEPEB023; 3. Raffi F, et al. IAS 2007, Abstract WEPEB027; 4. De Jesus E, et al. ICAAC 2007, Abstract LBA H-718b; 5. Molina J-M, et al. Lancet. 2008;DOI: /S (08)

29 5.-.and what about if I have side effects or virological failure?

30 Rescue Therapy in HIV infected patients Clinical Trials Clinical Trial Drug TORO Enfuvirtide RESIST. Tipranavir POWER. Darunavir DUET. Etravirine+Darunavir BENCHMRK. Raltegravir MOTIVATE Maraviroc

31 Patients with viral load <50 copies/ml (ITT-TLOVR): TLOVR): pooled 96-week analysis ETR + BR (n=599) Placebo + BR (n=604) 80 Patients with viral loa ad <50 cop ies/ml (%) % 41% 60% 39% p<0.0001* 57% 36% 0 Baseline Time (weeks) Mean change in CD4 cell count was 128 cells/mm 3 in the ETR + BR arm versus 86 cells/mm 3 in the placebo + BR arm (p<0.0001) 0001) *Logistic regression model controlling for baseline viral load, ENF use and study number ITT = intent-to-treat; TLOVR = time-to-loss of virological response algorithm

32 Week 48 Virologic Efficacy of New Drugs Defined as HIV-1 RNA < 50 c/ml Study Drug Regimen HIV-1 RNA TORO [1] RESIST [2] Enfuvirtide + OBR OBR alone Tipranavir + OBR Comparator PI + OBR < 50 copies/ml, % POWER Darunavir/ritonavir + OBR 45.0 [3] Comparator PI + OBR DUET [4,5] MOTIVATE [6] Etravirine + darunavir/ritonavir-containing OBR Placebo + darunavir/ritonavir-containing OBR Maraviroc QD + OBR 41.8 Maraviroc BID + OBR 46.8 Placebo + OBR 16.1 BENCHMRK Raltegravir + OBR 63.0 [7,8] Placebo + OBR Nelson M, et al. J Acquir Immune Defic Syndr. 2005;40: Hicks CB, et al. Lancet. 2006;368: Clotet B, et al. Lancet. 2007;369: Haubrich R, et al. CROI Abstract Johnson M, et al. CROI Abstract Lalezari J, et al. ICAAC Abstract H-718a. 7. Cooper DA, et al. N Engl J Med In press. 8. Steigbigel R, et al. N Engl J Med In press.

33 Is there a possibility to speed up this process? cy ) Frequenc (IUPM) t 1/2 = 44.2 months Time to eradication > 73 y Siliciano R, et al Time on HAART (years) Time needed for eradication estimated as 73.4 years!, however it might take only up to 7,7 years of continuous therapy in individuals who initiate HAART early in HIV infection ( months after the initiation of symptoms of primary HIV infection) Chun T-W et al. JID 2007;195:1762-4

34 6.- What about the future? What about the challenges?

35 ARV Therapy 2010,... and THE FUTURE. - More convenience-well tolerated regimens - New drugs available: - PI: Darunavir - NNRTI: Etravirine - Integrase inhibitors: Raltegravir - CCR5 antagonists: Maraviroc - New concept: Detectable is unacceptable - Revisiting the concept of eradication

36 ARV Therapy: Challenges-2010 Avoid new cases: Prevention Cure (eradication) Active vaccine Epidemic trends in developing countries

37 Public Health issues and HIV treatment If an HIV infected person has an undetectable VL can they transmit HIV to their partner? Can we treat our way out of the epidemic? Would expanding HAART to everyone diagnosed with HIV with a CD4 count below 350 cells/mm 3 together with prevention strategies, have a pronounced effect on transmission, by reducing viral load at a population p level. HIV Transmission under ART. XVII International AIDS Conference, Mexico City, SUSAT41, Wasserfallen FM Swiss statement for PLWHA on effective ARV treatment. XVII International AIDS Conference, Mexico City, abstract MOPE0212, 2008,Lima VD et al.j Infect Dis 198 (online edition), 2008.

38 COSTE MENSUAL EN EUROS DE LOS TARV DISPONIBLES (PVL + 4% IVA). Hospital Clínic. Año 2010 T mg c/12h MVC 1 comp c/12h RAL 400 mg c/12h TPV/r 500/200 c/12h DRV/r 600/100 mg c/12h DRV/r 800/100 mg c/24h ATV/r 300/100 mg c/24h ATV 400 mg c/24h LPV/r 2 comp c/12h FPV/r 700/100 mg c/12h SQV/r 1000/100 mg c/12h SQV/r 1500/100 mg c/24h RTV 100 mg c/12h ETR 200 mg c/12h EFV 600 mg c/24h NVP 200 mg c/12h Atripla 1 comp c/24h Trizivir 1 comp c/12h Truvada 1 comp c/24h Kivexa 1 comp c/24h Combivir 1 comp c/12h TDF 245 mg c/24h ABC 300 mg c/12h ddi 400 mg c/24h FTC 200 mg c/24h 3TC 300 mg c/24h d4t 40 mg c/12h d4t 30 mg c/12h AZT 300 mg c/12h ddi 250 mg c/24h

Management of Treatment-Experienced Patients: New Agents and Rescue Strategies. Joel E. Gallant, MD, MPH Johns Hopkins University School of Medicine

Management of Treatment-Experienced Patients: New Agents and Rescue Strategies Joel E. Gallant, MD, MPH Johns Hopkins University School of Medicine When to Modify Therapy! Studies to date show better responses