DART II

Once Daily Regimen for Once Daily Regimen for Treatment-naïve HIV+ Patients with Treatment-naïve HIV+ Patients with

Stavudine XR + Lamivudine + Efavirenz Stavudine XR + Lamivudine + Efavirenz

24 Week Interim Efficacy and Safety Results

DDaily aily AAntintiRRetroviral etroviral TTherapy IIherapy II

D. JayaweeraD. Jayaweera11, S. Becker, S. Becker22, , F. FelizartaF. Felizarta33, M. Sands, M. Sands44, L. Slater, L. Slater55 S. GothelfS. Gothelf66, J. Maa, J. Maa66, C. Dezii, C. Dezii66, S. Hodder, S. Hodder66, J. Tudor, J. Tudor 6 6

11 University of Miami, Miami, FL, USA. University of Miami, Miami, FL, USA.22 Pacific Horizon Medical Group, San Francisco, CA, USA. Pacific Horizon Medical Group, San Francisco, CA, USA.

33 34th Street Community Health Center, Bakersfield, CA, USA. 34th Street Community Health Center, Bakersfield, CA, USA. 44 University of Florida, Jacksonville, FL, USA. University of Florida, Jacksonville, FL, USA.

55 University of Oklahoma, Oklahoma City, OK, USA. University of Oklahoma, Oklahoma City, OK, USA. 66 Bristol-Myers Squibb, Plainsboro, NJ, USA. Bristol-Myers Squibb, Plainsboro, NJ, USA.

DART II

AI455-096 and -099 AI455-096 and -099 Study OutlinesStudy Outlines

ARV-naive patientsRandomized

d4T XR 100mg QD d4T IR 40mg BID

Patients <60 kg: d4T XR 75 mg QD; d4T IR 30 mg BIDNFV substitution permitted if EFV-intolerant

Adapted from: Brett-Smith H et al. 43rd ICAAC, September, 2003. Poster H-843

Study 096 n=74 n=76Study 099 n=392 n=392

(d4T IR placebo BID)3TC 150mg BIDEFV 600mg QD

(d4T XR placebo QD)3TC 150mg BIDEFV 600mg QD

DART II

Selected Adverse Events of Interest for Selected Adverse Events of Interest for Patients on Therapy for Patients on Therapy for 2 Years 2 Years

Any Lipoatrophy (Any Grade) 64 (14%)36 (8%)

Any Lipodystrophy (Any Grade) 73 (16%)52 (11%)

0.004

0.05

Lactic Acidosis Syndrome

Pancreatitis

Peripheral Neurologic Symptoms (Grades 2-4)

1 (<1%)

4 (1%)

38 (8%)

1 (<1%)

1 (<1%)

17 (4%)

Symptomatic Hyperlactatemia 5 (<1%)2 (<1%)

d4T XR armn=466

d4T IR armn= 468

Study 096/099/110*

P-Value

0.005

Adapted from: Brett-Smith H et al. 43rd ICAAC, September, 2003. Poster H-843

*Median follow up is 116 weeks XR and 114 weeks for IR

DART II

d4T XR 100 mg Once Dailyd4T XR 100 mg Once DailyComparable Drug Exposure to d4T IR 40 mg BIDComparable Drug Exposure to d4T IR 40 mg BID

TIME [h]

1

10

100

1000

PL

AS

MA

C

ON

CE

NT

RA

TIO

N

[ng

/mL

]

0 4 8 12 16 20 24

d4T IR d4T XR

Peak (Cmax) for d4T XR is ~50% of the IR formulation

d4T XR formulation has 2-3 times higher trough plasma levels than d4T IR

*Parallel groups for XR and IR formulations in HIV patients

DART II

Prospective, once-daily, open-label, ARV-Naïve patients,

VL > 1000 c/mL, CD4 > 100Planned N= 70

Patients <60 kg: d4T XR 75 mg QD

DART II: Study DesignDART II: Study DesignDART II: Study DesignDART II: Study Design

d4T XR100 mg QD

3TC300 mg QD

EFV600 mg QD

+ +

Epivir® (lamivudine, 3TC) is a registered trademark and manufactured by GlaxoSmithKline

DART II

DART II: OBJECTIVESDART II: OBJECTIVES

• Efficacy of once daily d4T XR + 3TC + EFV as determined by proportion of patients with plasma HIV-RNA <400 copies/mL at 48-weeks

Primary Objective:

Secondary Objective:

• Proportion of patients with plasma HIV-RNA <400 and <50 copies/mL at Weeks 24, 48, 72, and 96

• Patient adherence using pill counts and Antiviral Medication Adherence Form (AMAF)

• Safety and tolerability

DART II

Baseline CharacteristicsBaseline Characteristics

d4T XR QD3TC QD + EFV QD

(N=64)

Median Age, (years)

Male

White

Black

Other

83%

42%

45%

13%

Median HIV RNA (log10 copies/mL) 4.7

100,000 copies/mL 30%

Median CD4 Counts (cells/L) 315

Demography

Clinical

37

DART II

Patient Disposition at Week 24Patient Disposition at Week 24

Evaluable

Total Discontinuations, n (%)

Reasons for Discontinuation

Adverse Event

Serious Adverse Event

Death

10 (16%)

3 (5%)

0

0

Withdrew Consent 4 (6%)

64

Lost to Follow-up 2 (3%)

Virologic Failure 1 (2%)

d4T XR QD3TC QD + EFV QD

DART II

Virologic Response HIV RNA Virologic Response HIV RNA <400 copies/mL : Baseline to Week 24<400 copies/mL : Baseline to Week 24

0

20

40

60

80

100

20 4 8 12 16 20 24Weeks

Per

cen

t o

f P

atie

nts

94.3%

78.1%

As Treated (n=54)

ITT (NC=F) (n=64)

DART II

Virologic Response HIV RNA Virologic Response HIV RNA <50 copies/mL: Baseline to Week 24<50 copies/mL: Baseline to Week 24

0

20

40

60

80

100

20 4 8 12 16 20 24Weeks

Per

cen

t o

f P

atie

nts

94.3%

78.1%

As Treated (n=54)

ITT (NC=F) (n=64)

DART II

Mean Change in HIV RNA Level: Mean Change in HIV RNA Level: Baseline to Week 24Baseline to Week 24

HIV

RN

A C

han

ge

(lo

g10

co

pie

s/m

L)

Weeks

- 2.7

-3

-2.5

-2

-1.5

-1

-0.5

0

20 4 8 12 16 20 24

DART II

CD4 Cell Mean Change:CD4 Cell Mean Change:Baseline to Week 24Baseline to Week 24

CD

4 M

ean

Ch

ang

e (c

ells

/mm

3 )

Weeks

0

20

40

60

80

100

120

140

160

CD4 cell countBaseline: 354Week 24: 488

20 4 8 12 16 20 24

DART II

Grade 2 - 4 Treatment Related Grade 2 - 4 Treatment Related Adverse Events (>2%)Adverse Events (>2%)

d4T XR + 3TC + EFVn=64

Vomiting 2 (3.1%)

Nausea

Diarrhea

Somnolence

4 (6.3%)

2 (3.1%)

2 (3.1%)

Grade 2-4

Hypoaesthesia 3 (4.7%)

Peripheral Neuropathy 2 (3.1%)

DART II

Treatment Related Adverse Events Treatment Related Adverse Events of Interestof Interest

d4T XR + 3TC + EFVn=64

Pancreatitis 0

Peripheral Neuropathy

Lipodystrophy

Symptomatic Hyperlactatemia

Lactic Acidosis Syndrome

2 (3.1%)

0

0

0

All Grades

DART II

Grade 3-4 New Onset Laboratory Grade 3-4 New Onset Laboratory AbnormalitiesAbnormalities

d4T XR + 3TC + EFVn=64

Lipase

Creatine Kinase

ALT

ANC

3 (4.7%)

2 (3.1%)

2 (3.1%)

1 (1.6%)

Grade 3-4

*No report of Grade 3-4 triglyceride levels

DART II

Fasting Lipid Values Fasting Lipid Values Median Change from BaselineMedian Change from Baseline

Baseline

Total Cholesterol (mg/dL) 162

Median Change (%)

+ 27.5 (17%)

LDL Cholesterol (mg/dL) 102 + 11.5 (11%)

Triglycerides (mg/dL) 114 - 1.0 (-0.9%)

HDL Cholesterol (mg/dL) 38 + 9.5 ( 25%)

P-value

0.001

0.003

0.419

0.0001

TC:HDL Ratio 4.76 - 0.39 (- 8%) 0.006

Median Values (N=32)

Overall Results

DART II

Summary of Adherence and Summary of Adherence and Compliance at 24 WeeksCompliance at 24 Weeks

d4T XR + 3TC +EFV

Did not miss any dose during the past 4 days.

82.3% (51/62)

Any time took fewer pills per dose 5.6%(3/54)

Follow specific schedule 80.8%(42/52)

d4T XRn=53

80% Compliance at Week 24 89%

3TCn=53

91%

EFVn=53

89%

Adherence (by AMAF* questionnaire)

Compliance (by pill count)

90% Compliance at Week 24 70% 70% 72%*Antiviral Medication Adherence Form

DART II

Conclusions: 24 WeeksConclusions: 24 Weeks

• Demonstrated a significant reduction in viral load and excellent efficacy:

• 78.1% of patients achieved viral loads <400 copies/mL and <50 copies/mL (ITT: NC=F)

• 94.3% of patients achieved viral loads <400 copies/mL and <50 copies/mL (As Treated analysis)

• Is well tolerated• Minimal discontinuations due to adverse events (n=3)• Increase in HDL cholesterol, and decrease in TC:HDL ratio,

with minimal effects on triglyceride levels

In this treatment-naive population, d4T XR + 3TC + EFV administered once daily:

DART II

TO ALL THE PATIENTS AND STUDY CENTER TO ALL THE PATIENTS AND STUDY CENTER PARTICIPANTSPARTICIPANTS

AcknowledgmentsAcknowledgments

Stephen Becker, MD. San Francisco, CACoordinator: Sunita Lundy

Nicholaos Bellos, MD. Dallas, TXCoordinators: Christopher Hayes

Dawn Chaney

Paul Cook, MD. Greenville, NCCoordinator: Grace Wilkins, RN

Franco Felizarta, MD. Bakersfield, CACoordinator: Jennifer Kuhach

Dushyantha Jayaweera, MD. Miami, FLCoordinator: Rose Lalanne, RN

Gary Richmond, MD. Ft. Lauderdale, FLCoordinator: Vernon Appleby, RN

Michael Sands, MD. Jacksonville, FLCoordinator: Debbie Aragon, RN

Kunthavi Sathasivam, MD. Washington, DCCoordinator: Takada Harris

Leonard Slater, MD. Oklahoma City, OKCoordinator: Brenda Verel, LPN