Die Toronto Konferenz. K. Arasteh Auguste-Viktoria-Klinikum

Transcription

1 Die Toronto Konferenz K. Arasteh Auguste-Viktoria-Klinikum

2 Subjektive Schwerpunkte Medizinische Prävention Monotherapie CD4 guided treatment interuption (CD4-TI)

3 HIV Prävention (Gita Ramjee)

4 Rationale

5 Herausforderungen und Möglichkeiten

6 Was wird wo gemacht?

7 Studien mit Microbiciden

8 Einfachere Anwendung?

9 Es geht den Männern an den Kragen

10 Jetzt schlucken alle

11 Für Menschen die mehr als bis 3 zählen können

12 LPV/r Monotherapie Studien LPV/r Monotherapy MONARK (n=138, LPV/r vs LPV/r+ZDV/3TC) LPV/r Induction/Maintenance M (n=155, LPV/r+ZDV/3TC LPV/r vs EFV+ZDV/3TC) LPV/r Simplification OK-2004 (n=198, LPV/r simplification vs maintain LPV/r + 2 NRTIs regimen)

13 MONARK Study Design and Baseline Characteristics Entry criteria Antiretroviral naïve, HIV-1 RNA <100,000 c/ml, CD4 > 100 cells/mm3 Baseline characteristics: Mean (range) HIV-1 RNA (log10 c/ml): 4.39 ( ; mono) vs 4.34 ( ; Triple) CD4 (cell/µl): 257 ( ; mono) vs 234 ( ; Triple) Primary efficacy analysis Proportion of subjects with HIV-1 RNA < 400 copies/ml at Week 24 AND < 50 copies/ml at Week 48 Delfraissy JF. et al., XVI IAC, Toronto, 2006, #THLB0202

14 MONARK Study Design and Baseline Characteristics Screening LPV/r SGC 400/100 mg BID, n=83 96 weeks LPV/r SGC 400/100 mg + AZT/3TC 300/150 mg) BID, n=53 Wk 24 Wk 48 Delfraissy JF. et al., XVI IAC, Toronto, 2006, #THLB0202

15 Virologic Response HIV-1 RNA < 50 copies/ml (ITT, M=F) % Patients < 50 c/ml (ITT, 95% CI) AZT/3TC/LPVr, ITT, missing = failure LPVr, ITT, missing = failure 75% 71% 0 Sample Size LPV/r Arm Triple Arm Week Delfraissy JF. et al., XVI IAC, Toronto, 2006, #THLB0202

16 Virologic Response HIV-1 RNA < 50 copies/ml (OT) Delfraissy JF. et al., XVI IAC, Toronto, 2006, #THLB0202

17 Resistance Testing Genotypic testing performed: at time of virologic failure (HIV-1 RNA > 500 c/ml after nadir < 400 c/ml, or HIV-1 RNA > 500 c/ml at time of discontinuation after nadir < 400 c/ml) at investigator request for subject safety Subjects qualifying for resistance testing Genotypic results available Subjects w/ PI resistance mutations Subjects w/ AZT resistance mutations Subjects w/ 3TC resistance mutations LPV/r (n=83) 21 (25%) 21 2*/21 0/21 0/21 LPV/r + AZT/3TC (n=53) 3 (6%) 3 0/3 0/3 1/3 * No phenotypic resistance Norton M. et al., XV IHDRW, Sitges, 2006, #74

18 100% 80% 60% MONARK: Summary of Disposition and Virologic Response LPV/r Discontinued On study, HIV RNA > 400 c/ml LPV/r + AZT/3TC 40% 20% 0% Week On study, HIV RNA c/ml On study, HIV RNA < 50 c/ml Week Delfraissy JF. et al., XVI IAC, Toronto, 2006, #THLB0202

19 M03-613: Study Design and Baseline Characteristics Inclusion criteria Antiretroviral naïve, HIV-1 RNA >1000 c/ml, Any CD4 count No resistance to study drugs Baseline characteristics: Mean (range) HIV-1 RNA (log10 c/ml): 5.0 ( ) in LPV arm vs 4.8 ( ) in EFV arm CD4 count (cell/µl): 227 (6-773) in LPV arm vs 250 (3-756) in EFV arm Open label, 2:1 randomization, Primary outcome: HIV-1 viral load < 50 c/ml at week 96 (24 months) Primary analysis: intention-to-treat, prior failure (> 50 c/ml x 2) = failure Cameron DW et al., XVI IAC, Toronto, 2006, #THLB0201 M03-613

20 M03-613: Study Design and Baseline Characteristics Screening LPV/r SGC 400/100 mg BID + ZDV/3TC (n=104) EFV 600 mg QD + ZDV/3TC (n=51) LPV/r 400/100 mg BID LPV/r 400/100 mg BID + ZDV/3TC 96 weeks Cameron DW et al., XVI IAC, Toronto, 2006, #THLB0201

21 100% 80% 60% 40% M03-613: Summary of Disposition and Virologic Response LPV/r Discontinued On study, HIV RNA >500 c/ml On study, HIV RNA c/ml EFV 20% 0% Week On study, HIV RNA <50 c/ml Week Cameron DW et al., XVI IAC, Toronto, 2006, #THLB0201

22 OK04 Study Design and Baseline Characteristics Entry criteria HIV-1 RNA <50 copies/ml for > 6 months, on LPV/r + 2 NRTIs for > 1 month, no virological failure to PI Baseline characteristics Median time <50 copies/ml: Mono 19 (11-31) vs Triple 17 (11-28) Mean CD4 count (range, cell/µl): Mono 474 ( ) vs Triple 473 ( ) Primary study endpoint: Therapeutic failure by Week 48 2 viral loads > 500 c/ml 2 weeks apart OR Change of randomized therapy for reasons different from re-induction OR Treatment discontinuation OR Lost to follow-up Arribas JR. et al., XVI IAC, Toronto, 2006, # THLB0203

23 OK04 Study Design and Baseline Characteristics Screening after 6m <50c/ml LPV/r 400/100 mg BID No NRTIs Mono (n=100) Maintain current regimen 2 NRTIs Triple (n=98) 96 weeks Arribas JR. et al., XVI IAC, Toronto, 2006, # THLB0203

24 100% 80% OK04: Summary of Disposition and Virologic Response OK Triple Discontinued 60% On study, HIV RNA >500 40% On study, HIV RNA % 0% Week Arribas JR. et al., XVI IAC, Toronto, 2006, # THLB0203 On study, HIV RNA < Week

25 CD4+ Cell Count Guided Treatment Interruption (CD4-TI): Rationale HAART hat das große Sterben in den Industrienationen beendet, aber: Behandlungsmüdigkeit Entwicklung von Resistenzen Kardiovaskuläre und metabolische Komplikationen Hohe Kosten CD4+ cell count guided TIs könnten theoretisch Vorteile und Nachteile dieser Therapie ausgleichen

26 CD4+ Cell Count Guided TIs: Studiendesign Parameter Staccato [3] (N = 326) SMART [4] (N = 5472) Arms Randomized 1:2 CT, TI Randomized 1:1 CT, TI CD4+ count at entry (cells/mm³) Inclusion VL (copies/ml) > 350 < 500 > 350 None specified Study design Resume therapy if CD4+ count < 350 Resume therapy if CD4+ count < 250 Endpoints CD4+ count < 350; progression; death; development of resistance; complications HIV disease progression or death *Conducted in developing nations 1. Skiest D, et al. CROI Abstract Danel C, et al. CROI Abstract 105 LB. 3. Ananworanich J, et al. CROI Abstract El-Sadr W, et al. CROI Abstract 106 LB.

27 CD4+ Cell Count Guided TIs: Baseline Data and Outcomes Parameter Staccato [3] (N = 326) SMART [4] (N = 5472) Median time on ARV before study, mos Median age, yrs Median CD4+ count, cells/mm³ at entry (TI arm) Median nadir CD4+ count PYFU in TI arm AIDS or death/100 years TI arm CT arm Endpoint events Progression Death (non-aids) Trial stopped

28 CD4+ Cell Count Guided TIs: Staccato and SMART Staccato [1] 80% on SQV/r-based regimens 2% resistance rate, similar in each arm No difference in resistance profiles between groups Parameter Median CD4+ count, cells/mm³ CD4+ > 350 cells/mm³, % Baseline After HAART retreatment TI Arm Virologic failure, n 9 Resuppressed, % 91 CT Arm Time on HAART, % SMART [2] Treatment experienced cohort Parameter Median time on HAART at baseline, yrs TI Arm Treatment naive, % 4.5 Prior clinical AIDS 24.7 Percent of time on tx below CD4+ thresholds < 200 < 250 < 350 Clinical AIDS or death/100 PY CT Arm Ananworanich J, et al. CROI Abstract El-Sadr W, et al. CROI Abstract 106 LB, Lundgren J. et al Toronto, Abstract

29 Studieneinschluss Smart Studie

30 Primäre Endpunkte

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36 CD4+ Cell Count Guided TIs: Summary Bei Behandlungsunterbrechungen sollte ab 350 CD4 Zellen/mm 3 mit der HAART wieder begonnen werden Patienten mit Viruskontrolle < 50c/ml sollten besonders engmaschig kontrolliert werden (Allgemeininternistisch, Kardiologisch) Nach Möglichkeit nur in Studien um weitere Erkenntnisse bezüglich der Indikation zu erhalten

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