boosted pi therapy: theoretical basis
DESCRIPTION
Boosted PI therapy: theoretical basis. Drug concentration. treatment-limiting toxicity. Toxicity threshold. Therapeutic window. Efficacy threshold. viral rebound. 0. 0. 24. Time (hours). MaxCmin1 - HIV RNATRANSCRIPT
Time (hours)Time (hours)
Drug Drug concentrationconcentration
Boosted PI therapy: theoretical basisBoosted PI therapy: theoretical basis
viral rebound00
00
Efficacy Efficacy thresholdthreshold
Toxicity Toxicity thresholdthreshold
treatment-limiting toxicity
2424
TherapeuticTherapeuticwindowwindow
0
20
40
60
80
100
indinavir/r (n=158)
saquinavir/r (n=148)
% p
atie
nts
Baseline 24 weeks
MaxCmin1 - HIV RNA <400 c/ml ITT - Exposed
Dragstead UB et al. 8th ECCATH, Athens, 2001. Abst O10
100
1000
10000
100000
1000000
Sept 99
June 00
Oct 00
June 01
Sept 01
400
200
300
100
HIV RNA log10 c/ml
CD4 cells/mm3
Male 30 yr, HIV+ 1994, ARC 1995 CD4=300
Dual nucs
AZT 3TC IDV
D4T ddI
NVP
AZT 3TC EFV ddI
ABC SQV LPV/r
HyperS HyperS stopstopABCABC
switch switch to to
CombComb
CombCombddIddIEFVEFV
LPV/r LPV/r SQVSQVAPVAPV
Switch Switch EFV EFV to to
DLVDLV
PCP
Feb 01
Clinical progression on PI based Tx by CD4 and HIV RNA response (n=2236)
Grabar et al. Ann Int Med 2000;133:401-419
PI Treatment time (months)6 9 12 15 18 21 24 27 30
100
95
90
85
80
75
% w
ith
ou
t n
ew A
IDS
eve
nt
CD4 RNACD4 RNACD4 RNA
CD4 RNA
All patients
Virologic efficacy of HAARTOn-treatment versus intent-to-treat analyses
1. Staszewski et al. N Engl J Med 1999;341:1865-18732.Staszewski et al. JAMA 2001;285:1155-1163
3. Goodgame et al. Antiviral Ther 2000;5:215-225
EfavirenzStudy 0061
IndinavirCNAAB30052
AmprenavirPROAB30013
AbacavirCNAAB30052
% p
atie
nts
<40
0 co
pie
s/m
l at
48
wks
0
20
40
60
80
100
ITT
OT28
35 43 52
Loss in efficacy because of poor tolerability and adherence
Prisoners in 4 clinical trials by DOT or self-administration (SAT)
Directly observed therapy (DOT) and RNA decline
Fischl M et al. 7th CROI 2000. San Francisco: Poster 71
HIV
RN
A<
50 c
op
ies/
ml
0
20
40
60
80
100
wk 4 wk 8 wk 16 wk 24 wk 32 wk 40 wk 48
DOT
SAT
P<0.01
Total6
PI PillsPer Day
Total12
PI PillsPer Day
0
20
40
60
80
100
Indinavir/r (n=159)
Saquinavir/r (n=158)
% p
ati
ents
<
400
co
pie
s/m
l
MaxCmin1 – Pill count and viral load response at week 24 (ITT, nc=f)
Adapted from Dragstead UB et al. 8th ECCATH, Athens, 2001. Abstract O10 and Presentation
54626262
7678
878991
9596
0 20 40 60 80 100
“Relative to my other HIV/AIDS drugs,injections have not limited or altered my ability to...”
Prepare meals
Travel
Privacy of health
Personal appearance
Perform daily activities
Be intimate w/partner
Perform work
Social relationships
Family life
Vigorous activities
Moderate activities
% of patients who agree (somewhat or strongly)
Cohen C et al. 1st IAS Conference on HIV Pathogenesis and Treatment, Buenos Aires, 2001, Poster 708
Inside – investigational drugs 2001
RT inhibitorsNucleosides
DAPD
Emtricitabine (FTC)
d4C
ACH-126,443
BCH-10618
Nucleotides
Tenofovir (PMPA)
NNRTIs
Emivirine
TMC 120 and 125
Calanolide A
DPC 083
DPC 961
DABO compounds
Inside – investigational drugs 2001
Protease inhibitors
Tipranavir
Atazanavir (BMS 232632)
Mozenavir (DMP-450)
DPC 681/684
Tibotec compound (TMC 114)
Fos-amprenavir (GW433908)
Other Inhibitors
Integrase inhibitors: L-drugs, S-1360
RNase H inhibitors
Zinc finger inhibitors
Others
Outside – Investigational drugs 2001
Entry inhibitors
Attachment
PRO 542, Pro 367, FP-21399, sCD4
Co-receptor
CXCR4: ALX40-YC, Met-SDF-1, KRH-120, T-22, AMD 3100
CCR5: SCH-C, SCH-D, PRO 140, TAK 779, RANTES derivatives
Fusion
T-20, T-1249, 5 helix, d-peptides
10 15 20 2510
100
1000
10000
0 5Time (hours)
SQ
V c
on
cen
trat
ion
(n
g/m
l)Atazanavir boosts saquinavir
Saag et al. ICAAC 1999, Abs 330O’Mara et al. 7th CROI 2000, Abs 504
TAZ exposure unaffected by SQV coadministration
1600 SQV/100 RTV qd
1600 SQV/400 TAZ qd
1200 SQV/400 TAZ qd
1200 SQV tid
0
10
20
30
40
50
60
Percent of patients responding
Intent-to-treat(n = 70)
All patients who completed 48 weeks (n = 41)
*Intent-to-treat (ITT) analysis: non-completer = failure
Lalezari et al. 13th International AIDS Conference, Durban, 2000, Abs LbPp116
T-20: efficacy in ARV-experienced patients at 48 weeks
<400 or >1 log10
from baseline
copies/ml56%
33%
T1249 active against T-20 resistant variants
Concentration (g/ml)0.001 0.01 0.1 1 10
% o
f u
ntr
eate
d c
on
tro
l v
iru
s
0
20
40
60
80
100
120
T20 (day 0)
T20 (day 28)
T1249 (day 0)
T1249 (day 28)
TRI003 Patient #13 Lambert D et al. Antiviral Therapy 1999. 4; (Suppl 1);8