Kaletra BID vs LEXIVA BID, Both with EPIVIR and Abacavir QD, in

ART-Naïve Patients: The KLEAN Study

Joseph J. Eron, Jr., MDProfessor of Medicine, University of North Carolina

Chapel Hill, NC

AcknowledgementsAustriaA RiegerH M Schalk

BelgiumN ClumeckJ C LegrandJ C SchmitD VogelaersE Van Wijngaerden

CanadaJ G BarilH DionJ GillK GoughD KilbyK LogueA RachlisS Walmsley

FranceJ F BergmannJ F DelfraissyC KatlamaM A Khuong JossesJ M LivrozetJ M RagnaudD Salmon CeronD SereniC TrepoG P Yeni

Investigators:

GermanyW BeckerB KuhlmannA PlettenbergK ScheweL SchneiderD SchuermannS Staszewski

ItalyA CapettiG Di PerriA LazzarinM MoroniP OrtolaniG RizzardiniL Sighinolfi

LatviaB Rozentale

PolandA Boron-KaczmarskaA GladyszW Halota

PortugalJ Vera

RomaniaD DuiculescuL J PrisecariuS RuginaA Streinu-Cercel

SpainC BarrosB ClotetD DalmauP DomingoV EstradaM J GalindoF GutierrezH KnobelL López CortesM MarquezA OcampoJ M PeňaM J Perez EliasD PodzanczerF Pulido

M RieraR Rubio

SwitzerlandE BernasconiM OpravilR PisoP Vernazza

United StatesB AkilD AlvarezC AneziokoroR BarnesJ BarrettN Bellos

Study Participants

StudyCoordinators

GlaxoSmithKlineA CameronS GoodingM ShaeferD Sutherland-PhillipsP TabonaC VavroP WannamakerL YauV GarayS ChriscoeJ YeoMB WireC GarrisL Patel

D BergerM BochanJ BrandR BrennanS BrownA BurnsideM ByersW CauseyJ CollinsP CookT CooleyR CoralesE DeJesusJ DugganJ EronM FischlJ FlammG Frechette

J GatheE GodofskyM GoldmanS GreenR GreenbergP KumarA LaMarcaP LackeyC LucastiC McDonaldP McLerothJ MobleyK Mounzer

R MyersJ NadlerR NahassJ NarroD NorrisD ParksR PobleteB RashbaumJ RodriguezG SimonL SlaterL SloanR SpitzerR SteigbigelD SteinK TashimaN ThielmanM ThompsonL ThorntonG TownsendJ UyW WeinbergM WeinertB YangcoB Young

Background

Current DHHS guidelines recommend LPV/r (Kaletra) in combination with 3TC or FTC and ZDV as a first-line regimen for ART-naïve subjects1

FPV/r (LEXIVA, TELZIR) has also been shown to be a potent, well-tolerated and convenient regimen in ART-naïve subjects

ABC/3TC FDC (EPZICOM, KIVEXA) provides for a simplified QD dosing regimen that may enhance adherence

1DHHS Guidelines, May 2006.

Study DesignPhase IIIb, randomized (1:1), open-label, 48 week study conducted at 131 sites in the US, Europe, and Canada

•Entry criteria: HIV-1 RNA 1000 c/mL No CD4 cell count restrictions

•Stratified by entry HIV-1 RNA <100,000 c/mL or 100,000 c/mL

•KLEAN had 90% power to detect non-inferiority of FPV/r to LPV/r within a 12% difference

ART-naïve subjects

FPV/r 700mg/100mg BID + ABC/3TC

(600mg/300mg) FDC QD n=434

LPV/r 400mg/100mg BID + ABC/3TC

(600mg/300mg) FDC QD n=444

Loss of Virologic Response

TLOVR- FDA Algorithm – Includes all data for subjects while still on randomized PI

– Responders are those with confirmed plasma HIV-1 RNA <400 c/mL who are not yet treatment failures

– A treatment failure is a subject whose plasma HIV-1 RNA never goes below 400 c/mL, or who has confirmed rebound from <400 c/mL, or who discontinues the randomized PI for any reason

Protocol-Defined Virologic Failure– Reduction of plasma HIV-1 RNA <400 c/mL with a subsequent

increase to ≥400 c/mL on 2 consecutive occasions– Failure to achieve plasma HIV-1 RNA <400 c/mL by Week 24

55%39%

6%

US

Europe

Canada

Geographic Distribution N=878

EuropeSpain 12% France 9%Germany 6%Other 13%

Baseline Demographics FPV/r LPV/r Total(N=434) (N=444) (N=878)

Median age, years 38 37 38

Female 22% 22% 22%

Racial DistributionCaucasian 61% 56% 58%Black 29% 33% 31%American Hispanic 7% 9% 8%

Other 3% 2% 3%

CDC Class C 42 (10%) 53 (12%) 95 (11%)

HepatitisHep B Positive 17 ( 4%) 14 (3%) 31 ( 4%)Hep C Positive 50 (12%) 40 (9%) 90 (10%)Hep B & C Positive 3 (<1%) 2 (<1%) 5 (<1%)

Baseline Characteristics

FPV/r LPV/r Totaln (%) (N=434) (N=444) (N=878)

Median HIV-1 RNA, log10 c/mL 5.08 5.06 5.07

HIV-1 RNA <100,000 c/mL 197 (45%) 209 (47%) 406 (46%)

HIV-1 RNA 100,000 c/mL 237 (55%) 235 (53%) 472 (54%)

Median CD4 count, cells/mm3 188 194 192

<50 cells/mm3 67 (15%) 80 (18%) 147 (17%)

50 - <200 cells/mm3 163 (38%) 152 (34%) 315 (36%)

200 cells/mm3 204 (47%) 212 (48%) 416 (47%)

Study Outcomes

TLOVR (HIV-1 RNA <400 c/mL) FPV/r

(N=434) LPV/r

(N=444)

Responder through Week 48 315 (73%) 317 (71%)

Virologic Non-responders 26 ( 6%) 30 ( 7%)

Discontinuations 93 (21%) 97 (22%) Lost to follow-up 20 ( 5%) 31 ( 7%)

Adverse event 23 ( 5%) 24 ( 5%)

Subject decision 16 ( 4%) 8 ( 2%)

Non-compliance 13 ( 3%) 8 ( 2%)

No data at week 48 or beyond 6 ( 1%) 12 ( 3%)

Other 6 ( 1%) 8 ( 2%)

Pregnancy 4 (<1%) 2 (<1%)

Death 3 (<1%) 1 (<1%)

Protocol violation 2 (<1%) 2 (<1%)

Insufficient viral load response 0 1 (<1%)

0

20

40

60

80

100

0 8 16 24 32 40 48

Study Week

Pro

po

rtio

n o

f S

ub

ject

s

FPV/r, TLOVRLPV/r, TLOVRFPV/r, ObservedLPV/r, Observed

9697

7371

Virologic Response HIV-1 RNA <400 c/mL

n (obs)

FPV/r = 434 399 387 375 358 340 328

LPV/r = 444 408 396 389 371 359 341

HIV-1 RNA <400 c/mL at Week 48

73 71

0

20

40

60

80

100

FPV/r BID LPV/r BID

TLOVR

Pro

po

rtio

n o

f S

ub

ject

s

Stratified 95% CI: (-4.84, 7.05)

FPV/r n = 434

LPV/r n = 444

HIV-1 RNA <400 c/mL at Week 48

73 71 70 6975 73

7074 74

7073 72

0

20

40

60

80

100

FPV/r BID LPV/r BID

TLOVR HIV-1 RNA <100,000 c/mL

HIV-1 RNA ≥100,000 c/mL

CD4+ <50 cells/mm3

CD4+ 50-199 cells/mm3

CD4+ ≥200 cells/mm3

Pro

po

rtio

n o

f S

ub

ject

s

FPV/r n = 434 197 237 67 163 204

LPV/r n = 444 209 235 80 152 212

HIV-1 RNA <50 c/mL at Week 48

66 65 67 64 65 6663

7066

6367 64

0

20

40

60

80

100

FPV/r BID LPV/r BID

TLOVR HIV-1 RNA <100,000 c/mL

HIV-1 RNA ≥100,000 c/mL

CD4+ <50 cells/mm3

CD4+ 50-199 cells/mm3

CD4+ ≥200 cells/mm3

Pro

po

rtio

n o

f S

ub

ject

s

FPV/r n = 434 197 237 67 163 204

LPV/r n = 444 209 235 80 152 212

0

50

100

150

200

250

300

0 8 16 24 32 40 48

Study Week

Med

ian

Ch

ang

e fr

om

Bas

elin

e,

cell

s/m

m3

FPV/r LPV/r

176191

Change from Baseline in CD4+ Cell Count (ITT-E, Obs)

Median CD4+, 188 375 cells/mm3 194 397

n (obs) FPV/r = 434 395 381 371 357 337 323 LPV/r = 444 401 394 388 368 355 336

IQR

Resistance Through 48 Weeks FPV/r LPV/r

Confirmed virologic failures 16 24

Unable to sequence 2 3

No treatment-emergent mutations 9 14

No treatment-emergent reduced phenotypic susceptibility to FPV/r or LPV/r* per IAS-USA resistance guidelines, Oct 2005

Treatment-emergent mutations (n)*

TAM-associated mutations (M41M/L)

3TC-associated mutations (M184I, M184V, M184M/V)

NNRTI –associated mutations (V106V/A)

PI-associated mutations- all minor (I54I/L, I93I/L, K20K/R, I62I/V)

0 1

3 4

0 2

3 2

Clinical Treatment-Related Grade 2-4 AEs ≥2%

FPV/r LPV/r Total% (%Grade 3/4) (N=436) (N=443) (N=879)

Diarrhea 13% (2%) 11% (<1%) 12% (1%)

Nausea 6% (<1%) 5% (<1%) 6% (<1%)

Suspected HSR to ABC 6% (2%) 4% (2%) 5% (2%)

Headache 3% (<1%) 1% (0) 2% (<1%)

Rash 3% (0) <1% (<1%) 2% (<1%)

Vomiting 2% (0) 2% (<1%) 2% (<1%)

Fatigue 2% (<1%) 1% (<1%) 2% (<1%)

All Grades ABC HSR 7% 5% 6%

The safety population consisted of all subjects randomized who received at least one dose of study drug and were analyzed by treatment actually received

AEs Leading to Discontinuation of Any Study Drug

FPV/r LPV/r TotalFPV/r LPV/r Totaln (%) (N=436) (N=443) (N=879)n (%) (N=436) (N=443) (N=879)

Subjects with any eventSubjects with any event 53 (12%) 53 (12%) 43 (10%) 43 (10%) 96 (11%) 96 (11%)

Suspected HSR to ABC*Suspected HSR to ABC* 32 ( 7%) 32 ( 7%) 20 ( 5%) 20 ( 5%) 52 ( 6%) 52 ( 6%)

DiarrheaDiarrhea 5 ( 1%) 5 ( 1%) 7 ( 2%) 7 ( 2%) 12 ( 1%) 12 ( 1%)

VomitingVomiting 3 (<1%) 3 (<1%) 4 (<1%) 4 (<1%) 7 (<1%) 7 (<1%)

NauseaNausea 2 (<1%) 2 (<1%) 3 (<1%) 3 (<1%) 5 (<1%) 5 (<1%)

Abdominal PainAbdominal Pain 1 (<1%) 1 (<1%) 2 (<1%) 2 (<1%) 3 (<1%) 3 (<1%)

Transaminases increasedTransaminases increased 2 (<1%) 2 (<1%) 1 (<1%) 1 (<1%) 3 (<1%) 3 (<1%)

HypercholesterolemiaHypercholesterolemia 1 (<1%) 1 (<1%) 2 (<1%) 2 (<1%) 3 (<1%) 3 (<1%)

RashRash 2 (<1%) 2 (<1%) 1 (<1%) 1 (<1%) 3 (<1%) 3 (<1%)

OtherOther 5 ( 1%) 3 ( 1%) 8 ( 1%) 5 ( 1%) 3 ( 1%) 8 ( 1%)

*One additional case of ABC HSR was reported*One additional case of ABC HSR was reported

Subjects may have experienced more than one AE which led to discontinuation of study drugSubjects may have experienced more than one AE which led to discontinuation of study drug

0

50

100

150

200

250

FPV/r LPV/r FPV/r LPV/r

Baseline

Week 48

Cholesterol Triglycerides

Baseline n= 363 377 363 377

Week 48 n= 287 294 287 294

Median Fasting Lipids (mg/dL) at Baseline and Week 48

Use of lipid-lowering medications was similar in the FPV/r and LPV/r groups (11%)

mg

/dL

0

50

100

150

FPV/r LPV/r FPV/r LPV/r

Baseline

Week 48

LDL HDL

Baseline n= 345 362 358 371

Week 48 n= 257 260 285 290

Median Fasting Lipids (mg/dL) at Baseline and Week 48

Use of lipid-lowering medications was similar in the FPV/r and LPV/r groups (11%)

mg

/dL

Conclusions

FPV/r BID had comparable efficacy to LPV/r BID in this study using an ABC/3TC FDC QD backbone

Few subjects had protocol-defined virologic failure– No major PI-associated mutations (IAS-USA) or reduced

phenotypic susceptibility emerged to either PI.

Both regimens were well-tolerated with few study discontinuations due to AEs

FPV/r and ABC/3TC FDC are now recommended components for initial antiretroviral therapy in the IAS-USA Adult Treatment Guidelines (JAMA Aug. 16, 2006)