boosted pi therapy: theoretical basis

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