1/ 2 Mega-/Giga-HAART Interruption Lopinavir/r simple salvage - - PowerPoint PPT Presentation

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H.-J. Stellbrink, Hamburg

always undetectable Accept replication Mega-/Giga-HAART Lopinavir/r Doppel-PI Enfuvirtide Tipranavir Darunavir Etravirine Interruption „simple salvage“ Fitness disadvantage 3TC/NRTI mono

30% 60%

<400 copies/ml Week 24 Patients (%)

TORO 1 & 2

LPV/r LPV/r + ENF

46% 64%

<50 copies/ml Week 24 Patients (%)

POWER 1 & 2

TMC114/r TMC114/r + ENF

30% 54%

Patients (%)

RESIST 1 & 2

TPV/r TPV/r + ENF <400 copies/ml Week 24 Haubrich et al. IDSA 2005. Abstract 785; Hill and Moyle. BHIVA 2006. Abstract P1.

7

Patienten <400 Kopien/ml in Woche 16 nach ausgewählten Substanzen im OBT

* Virological failures carried forward

+ : Erstmalig im OBT

• : Kein Einsatz im OBT

Subgruppe n % Patienten

20 40 60 80 100

Raltegravir + OBT Placebo + OBT

79 43 98 87 90 63 90 55 74 29 447 230 44 23 42 24 80 47 191 90

Wirksamkeit nach ART im OBT Enfuvirtid Darunavir + + + +

• Wirksamkeit insgesamt

9

* Protocol-defined randomization strata; Includes all patients who received at least one dose of study medication; LOCF

Mean Change from Baseline in HIV-1 RNA at Week 24 According to Baseline HIV-1-RNA and Enfuvirtide Use in OBT*

• 2.18
• 1.20
• 1.31
• 1.97
• 2.08 -2.08

49 98 107 67 130 127 N=

• 2.10
• 1.45
• 2.02

Screening HIV-1 RNA copies/mL

• 2.18
• 0.94
• 2.02

70 46 135 93 139 95 <100,000 ?100,000 Mean change in HIV-1 RNA from baseline (log10 copies/mL)

• 2.5
• 2.0
• 1.5
• 1.0
• 0.5

N= No Enfuvirtide Enfuvirtide

• 2.5
• 2.0
• 1.5
• 1.0
• 0.5

MOTIVATE 1-Week 24

MVC QD + OBT MVC BID + OBT Placebo + OBT

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Mean Change from Baseline in HIV-1 RNA at Week 24 According to Baseline HIV-1-RNA and Enfuvirtide Use in OBT*

• 2.02
• 1.12
• 2.17
• 2.45
• 0.97
• 2.22
• 2.5
• 2.0
• 1.5
• 1.0
• 0.5

50 113 73 41 67 N= 112 Mean change in HIV-1 RNA from baseline (log10 copies/ml)

• 2.5
• 2.0
• 1.5
• 1.0
• 0.5
• 0.98

53

• 2.13

103

• 2.16

104

• 1.14

38

• 2.26

77

• 2.22

81 <100,000 >=100,000 Screening HIV-1 RNA N=

* Protocol-defined randomization strata; Includes all patients who received at least one dose of study medication; LOCF

MVC QD + OBT MVC BID + OBT Placebo + OBT

No enfuvirtide Enfuvirtide MOTIVATE 2-Week 24

24

Percentage of Patients with HIV-1 RNA < 50 copies/mL at Week 24 by Number of Active Drugs in OBT*

10 20 30 40 50 60 70 80 90 100 35 51 56 44 130 134 59 88 104 64 132 121 3 18 29 9 43 43 19 52 53 55 61 58 1 2 ?3 Number of active drugs in OBT*

* Based on Overall Susceptibility Score Includes all patients who received at least one dose of study medication; LOCF

Patients (%)

N=

MOTIVATE 1 & 2-Week 24

MVC QD + OBT MVC BID + OBT Placebo + OBT

TORO 1 & 2: Positive prognostic factors

Number of active ARVs in OB regimen (≥ 2 active ARVs*) Activity of background regimen Number of prior ARVs (≤ 10) Treatment history Baseline plasma HIV-1 RNA (< 5 log10 copies/ml) Baseline CD4 cell count (≥ 100 cells/mm3) Disease stage

* Based on phenotypic sensitivity score (PSS) at baseline, defined as the total number of drugs in a patient’s assigned OB regimen to which that patient’s pre-study virus sample showed phenotypic sensitivity.

Montaner, et al. XV IAC 2004, Bangkok, Thailand. TuPeB4483

Baseline-Charakteristika

n=44 (40 männl., 4 weibl.)

• Stadium:

– CDC A: 3 (6,8 %) – CDC B: 14 (31,8 %) – CDC C: 27 (61,4 %)

• HIV-Infektion im Mittel 14,3 +/- 4,7 Jahre bekannt
• Mit im Mittel 9,4 -/- 4,0 ARV vorbehandelt
• Umstellung wegen VF (n=40) oder Intoleranz (n=3)
• ENF-unvorbehandelt: 42, vorbehandelt: 2
• CD4-Zellzahl

– Mittelwert 175 +/- 147 Zellen/µL

• HIV-RNA

– Mittelwert 4,7 +/- 1,1 log10 (1,7-7)

• Aktuelles Regime mit ENF + im Mittel 3,7 +/- 1,0 ARVs
• Neue Pis

– TPV: 15 Pat. – DRV: 19 Pat.

• Therapiepause vor ENF: n=2 (2/8 Monate)

TORO 1 & 2 (n=995) + ENF

• ENF

CDD C3 79 % 86 % # ARVs 12 12 CD4 88 97 RNA 5,2 5,1

First interim analysis: RNA

Overall antiviral effect (p=,000001, n=27) vertical bars represent 0.95 CI log BL log W4 log W12 study visit 1,5 2,0 2,5 3,0 3,5 4,0 4,5 5,0 5,5 6,0 HIV RNA (log10)

• 2.13 log

(74% >-1 log10)

N=164 Week 24 N=125 Week 48 N=65 Week 96 <50 copies/mL <400 copies/mL

10 20 30 40 50 60 70 80 90 100

% Patienten

Ja (n = 395) Nein (n = 225)

N=389 Week 24 N=366 Week 48 N=291 Week 96 <50 copies/mL <400 copies/mL

10 20 30 40 50 60 70 80 90 100

% Patienten

Week 12 : decrease from BL of HIV RNA

Raffi et al. CID 2006; 42:870-872

Early = good response to enfuvirtide

clinicaloptions.com/hiv

Strategies for Regaining Control of HIV Replication

Needle-Free Injection System for Administration of Enfuvirtide

Montaner J, et al. IAS 2005. Abstract WeFo0205.

• Use of needle-free gas-powered

injection system – Compared with standard needles and syringes

• No significant differences in ENF

plasma levels

• ISR-related signs and symptoms

significantly reduced

• 24 pts evaluated reported that

needle-free injector was similar or easier to use than needles

Needle Biojection gas-powered device

PBL response to single T20-peptides

0,05 0,1 0,15 0,2 #1 #2 #3 #4 #5 #6

patient #

% of total CD8+ T cells

KN EQ QE LE

ENF induces a specific CD8 response

Cost month year Kaletra 757,85 9220,51 Aptivus/r 1186,18 14431,86 Prezista/r 975,02 11862,48 Truvada 753,69 9169,90 Kivexa 707,53 8608,28 Fuzeon 2032,04 24723,15

Frequency of 3-class failure ("extensive triple class failure", ETCF)

• Analysis of UK CHIC

ART started with ≥3 Medikamenten

• 10.603 patients
• median CD4: 184/µl
• 58% NNRTI
• 10% PI/r

ETCF in 170 subjects; risk of ETCF

• 2% at 5 years; 8% at 10 years
• subjects with CD4>200/µl at BL: 4% at 10 years

Risk factors for ETCF

• low CD4, high age, transmission risk other than MSM

A Phillips et al. CROI 2007 #532

Enfuvirtide: a clinician‘s perspective

• 1. Valuable due to extracellular mode of action without

an intracellular activation step

• 2. Effective in salvage therapy
• 3. In vivo synergy with NRTI, NNRTI, PI
• 4. In vitro synergy with maraviroc, in vivo not shown

(bias ?)

• 5. Clinical use limited by route of administration and

ISR.

• 6. High cost
• 7. Small target population

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