1

RESIST Trials - Grade 3 or 4 AST, ALT or Total Bilirubin:Actions and Outcomes

Action Taken:TPV/rN=748

CPI/rN=737

Total Number of Grade 3 or 4 ALT, AST, or Bilirubin

74 (9.9) 26 (3.5)

Continued treatment 57 (7.6%) 26 (3.5%)

No interruption 47 (6.3%) 23 (3.1%)

Interrupted 10 (1.3%) 3 (0.4%)

Discontinued treatment 17 (22.7%) 0 (0%)

With Grade 3 7 (0.9%)

With Grade 4 10 (1.3%)

2

Lipid Lowering Agent Use Among RESIST Participants

Note: agents included are statins, fibrates, and omega-3 fatty acids

n=108 n=102 n=130 n=79 n=238 n=181

14.417.4

31.8

13.810.7

24.6

0.05.0

10.015.020.025.030.035.0

Enrolled on LLD Needed to Start LLD Total on LLD

TPV/r CPI/r

Use of Lipid Lowering Drugs in RESIST

Per

cen

tag

e

3

Effect of LLD on triglycerides: RESIST

0

100

200

300

400

500

CPI Before CPI After TPV Before TPV After

390 (259, 581)

355 (230, 538)

445 (298, 634)

367 (286, 568)

N 63 63 118 118

# deter 3 4 6 3

4

Risk Confirmed (3 times) Triglycerides Above 500 mg/dl for RESIST Patients

17.26

8.20

0

2

4

6

810

12

14

16

18

0 4 8 12 16 20 24 28 32 36 40 44 48

Exposure (weeks)TPV/r CPI/r

Pro

bab

ility

of

even

t (%

)

Note: Included are RESIST participants who had baseline triglycerides <500 and developed at least 3 determinations above 500 mg/dL

5

RTV-boosted drug interaction assessments

Substrate Drug TPV/r result

Norvir® result

Kaletra® result

Zidovudine 43% AUC 56% Cmax

25% AUC 27% Cmax

NR

Didanosine 10% AUC 20% Cmax

13% AUC 16% Cmax

NR

Tenofovir , except 38%

Cmax

NR NR

Rifabutin 3 x, metabolite 21 x

4 x, metabolite 35 x

3 x, metabolite 47 x

Atorvastatin 9.4 x metabolite >90%

NR 5.9 x metabolite NR

Ethinyl Estradiol 45-50% 40% 42% Methadone 50% 36-38% 45-53% Loperamide 50% NR NR NR = not reported in Norvir® or Kaletra® prescribing information

6

Reduced GSS as Key Mutations Increase

0

10

20

30

40

50

60

70

0 1 2 3 4

Number of key mutations% b

asel

ine

ba

ckg

rou

nd

RT

I su

scep

tib

ilit

y sc

ore

s <

2

7

Hypertriglyceridemia:Relative Contribution of TPV and RTV

Median baseline and maximal increase in serum triglycerides accordingto dose among Trial 1182.52 participants

Dose nMedian (Q25, Q75) baseline

(mg/dL)

Median (Q25, Q75) maximum increase

(mg/dL)

500/100 73 263 (168, 430) 161 (58, 403)

500/200 72 221 (172, 332) 271 (99, 558)

750/200 71 223 (173, 416) 196 (72, 421)

8

Analysis of Treatment Response at Week 48

n = Number of respondersN = Number of evaluable patientsTreatment difference and confidence interval weighted for the size of enfuvirtide and PI strata

RESIST-1 RESIST-2

Treatment Group

TPV/r CPI/r TPV/r CPI/r

n (%) N n (%) N n (%) N n (%) N

Key analysis

FAS (week 24) (NCF, as randomised)

130

(41.8)

311 74 (23.9)

309 177

(40.7)

435 76 (17.8)

428

FAS (week 48) (NCF, as randomised)

103

(33.1)

311 49 (15.9)

309 148

(34.0)

435 64 (15.0)

428

Sensitivity analysis

PPS (week 48) (NCF, as randomised)

66 (35.7)

185 38 (19.7)

193 102

(37.4)

273 41 (16.1)

254

9

K-M Probabilities for Grade 3 or 4 ALT and/or ASTThrough 120 Weeks in 8 HIV+ Integrated Trials*

0

3

6

9

12

15

0 10 20 30 40 50 60 70 80 90 100 110 120Study drug exposure (weeks)

Pro

bab

ilit

y (

%)

of

an

even

t

29 25 6 2 1 0

1870 1445 1019 417 148 133# At Risk-

Events-

* Includes TPV/r patients from 1182.2, 1182.4, 1182.6, 1182.17, 1182.51, 1182.52, and CPI/r patients who switched to TPV/r 500/200 from RESIST trials 1182.12 and 1182.48

RESIST StudiesCox Regression Model for Risk of Grade 3 or 4 ALT/AST

Baseline risk factors for Grade 34 ALT/AST are similar in TPV/r and CPI/r

Independent variables: age, gender, race, ΔCD4, baseline triglycerides, NRTI, NNRTI, viral load, CDC HIV stage, duration of HIV infection

Factor/Comparison Risk Ratio 95% CI

Treatment Group:TPV/r vs CPI/r 2.4 1.5 – 3.8

Baseline ALT,AST Total Bilirubin:(Grade > 1 vs Grade < 1) 2.5 1.3 – 4.8

CD4+ Cell Count at Baseline: >200 vs ≤200 cells/mm3 2.0 1.3 – 2.5

HBV or HCV Co-infection:Co-infected vs not co-infected 2.3 1.4 – 3.7

10

11

Predictors of TPV/r Antiviral Response Multiple Regression Model

P ValueEstimate

<0.010.17TPV Score

(per mutation)

<0.01-0.24Per Available Drug

in OBR

<0.01-0.91Enfuvirtide Use

<0.01-1.25Tipranavir/r

24 Weeks

Parameter

12

Tipranavir trough concentrations with proton pump inhibitors

0

20

40

60

80

100

120

140

160

180

200

Geo

met

ric M

ean

Tip

rana

vir

Cp

10-1

4h (M

)

No PPI

33.4 M

n = 506

39.3 M

n = 44

13

Trial 1182.52Impact of IQ on 14-Day Viral Load Response

Cha

nge

from

bas

elin

e at

2 w

eeks

(lo

g 10)

Inhibitory quotient

Observed data Fold Change = 30 1 log10 decline

30

-3

-2

-1

0

1

0.1 1 10 100 1000 10,000

14

1182.52Impact of IQ on 14-Day Viral Load Response

0.05

-0.13

-1.03-1.16

-0.98

-1.25-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

≤5 >5–30 >30–50 >50–100 >100–150 >150

Inhibitory quotient

HIV

RN

A lo

g 10

chan

ge f

rom

bas

elin

e

7

27 14 34 25 58

0.2

15

RESIST Trials24 Week VL Change according to IQ in Patients not using Enfuvirtide

-5

-4

-3

-2

-1

0

1

2

1 10 100 1000 10000

Log Inhibitory Quotient

Lo

g C

han

ge

fro

m b

asel

ine

HIV

RN

A

16

RESIST Trials24 Week VL Change according to IQ in Patients using Enfuvirtide

-5

-4

-3

-2

-1

0

1

2

1 10 100 1000 10000

Log Inhibitory Quotient

Lo

g C

han

ge

fro

m b

asel

ine

HIV

RN

A

17

0

20

40

60

80

100

120

140

160

Antiviral activity of tipranavir (ViroLogic)Non-clade B isolates

Mea

n EC

50 (n

M)

10274

11638

124Ref. NL4-3 (B virus)

EC50 = 62 nM

EC50 values measured at ViroLogic Inc (South San Francisco) using the PhenoSense assay

No evidence that other HIV-1 clades and circulating recombinant formshave lower susceptibility to TPV than HIV-1 clade B

Clade B biological cutoff value for TPV not yet determined

(1.6X LPV or 99nM)*

* Parkin et al, AAC, 2004, 48, 437-443

(three isolates each except two for clade H)

18

VIRCO / ViroLogic in Tipranavir Phenotype

19

Mutations Which Increase Susceptibility to TPV

Amino acid

Median FC IC50

NParameter Estimate

P-valueWild type Mutated

18L 1.00 0.50 5 -0.55 0.035

30N 1.20 0.50 26 -0.54 <0.001

50V 1.10 0.70 19 -0.31 0.021

54L 1.10 0.70 21 -0.31 0.018

77I 1.20 1.00 102 -0.18 0.011

88D 1.10 0.60 26 -0.38 0.001