GSK Presentation Guidelines

1
Kaletra BID vs LEXIVA BID, Both with EPIVIR and
Abacavir QD, in ART-Naïve Patients The KLEAN
Study

Joseph J. Eron, Jr., MD Professor of Medicine,
University of North Carolina Chapel Hill, NC
2
Acknowledgements
Investigators
Austria A Rieger H M Schalk Belgium N Clumeck J
C Legrand J C Schmit D Vogelaers E Van
Wijngaerden Canada J G Baril H Dion J Gill K
Gough D Kilby K Logue A Rachlis S
Walmsley France J F Bergmann J F Delfraissy C
Katlama M A Khuong Josses J M Livrozet J M
Ragnaud D Salmon Ceron D Sereni C Trepo G P Yeni
Germany W Becker B Kuhlmann A Plettenberg K
Schewe L Schneider D Schuermann S Staszewski
Spain C Barros B Clotet D Dalmau P Domingo V
Estrada M J Galindo F Gutierrez H Knobel L López
Cortes M Marquez A Ocampo J M Pena M J Perez
Elias D Podzanczer F Pulido M Riera R Rubio
Study Participants Study Coordinators GlaxoSmith
Kline A Cameron S Gooding M Shaefer D
Sutherland-Phillips P Tabona C Vavro P
Wannamaker L Yau V Garay S Chriscoe J Yeo MB
Wire C Garris L Patel
D Berger M Bochan J Brand R Brennan S Brown A
Burnside M Byers W Causey J Collins P Cook T
Cooley R Corales E DeJesus J Duggan J Eron M
Fischl J Flamm G Frechette J Gathe E Godofsky M
Goldman S Green R Greenberg P Kumar A LaMarca P
Lackey C Lucasti C McDonald P McLeroth J Mobley K
Mounzer
R Myers J Nadler R Nahass J Narro D Norris D
Parks R Poblete B Rashbaum J Rodriguez G Simon L
Slater L Sloan R Spitzer R Steigbigel D Stein K
Tashima N Thielman M Thompson L Thornton G
Townsend J Uy W Weinberg M Weinert B Yangco B
Young
Italy A Capetti G Di Perri A Lazzarin M Moroni P
Ortolani G Rizzardini L Sighinolfi
Latvia B Rozentale
Switzerland E Bernasconi M Opravil R Piso P
Vernazza
Poland A Boron-Kaczmarska A Gladysz W Halota
Portugal J Vera
United States B Akil D Alvarez C Aneziokoro R
Barnes J Barrett N Bellos
Romania D Duiculescu L J Prisecariu S Rugina A
Streinu-Cercel
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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.
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Study Design
Phase IIIb, randomized (11), open-label, 48 week
study conducted at 131 sites in the US, Europe,
and Canada
FPV/r 700mg/100mg BID ABC/3TC (600mg/300mg) FDC
QD n434
ART-naïve subjects
LPV/r 400mg/100mg BID ABC/3TC (600mg/300mg) FDC
QD n444

• Entry criteria
• HIV-1 RNA ?1000 c/mL
• No CD4 cell count restrictions
• Stratified by entry HIV-1 RNA lt100,000 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

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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 lt400 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 lt400 c/mL, or who
  discontinues the randomized PI for any reason
• Protocol-Defined Virologic Failure
• Reduction of plasma HIV-1 RNA lt400 c/mL with a
  subsequent increase to 400 c/mL on 2 consecutive
  occasions
• Failure to achieve plasma HIV-1 RNA lt400 c/mL by
  Week 24

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Geographic Distribution N878
Europe Spain 12 France 9 Germany
6 Other 13
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Baseline Demographics

• FPV/r LPV/r Total
• (N434) (N444) (N878)
• Median age, years 38 37 38
• Female 22 22 22
• Racial Distribution
• Caucasian 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)
• Hepatitis
• Hep B Positive 17 ( 4) 14 (3) 31 ( 4)
• Hep C Positive 50 (12) 40 (9) 90 (10)
• Hep B C Positive 3 (lt1) 2 (lt1) 5
  (lt1)

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Baseline Characteristics

• FPV/r LPV/r Total
• n () (N434) (N444) (N878)
• Median HIV-1 RNA, log10 c/mL 5.08 5.06
  5.07
• HIV-1 RNA lt100,000 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
• lt50 cells/mm3 67 (15) 80 (18) 147 (17)
• 50 - lt200 cells/mm3 163 (38) 152 (34) 315
  (36)
• ?200 cells/mm3 204 (47) 212 (48) 416 (47)

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Study Outcomes
TLOVR (HIV-1 RNA lt400 c/mL) FPV/r (N434) LPV/r (N444)
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 (lt1) 2 (lt1)
Death 3 (lt1) 1 (lt1)
Protocol violation 2 (lt1) 2 (lt1)
Insufficient viral load response 0 1 (lt1)
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Virologic Response HIV-1 RNA lt400
c/mL
73
71
n (obs) FPV/r 434
399 387 375
358 340
328 LPV/r 444 408
396 389
371 359 341
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HIV-1 RNA lt400 c/mL at Week 48
Proportion of Subjects
Stratified 95 CI (-4.84, 7.05)
TLOVR
FPV/r n 434 LPV/r
n 444
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HIV-1 RNA lt400 c/mL at Week 48
Proportion of Subjects
TLOVR
CD4 lt50 cells/mm3
HIV-1 RNA lt100,000 c/mL
HIV-1 RNA 100,000 c/mL
CD4 50-199 cells/mm3
CD4 200 cells/mm3
FPV/r n 434 197
237 67
163 204 LPV/r n
444 209
235 80
152 212
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HIV-1 RNA lt50 c/mL at Week 48
Proportion of Subjects
TLOVR
CD4 lt50 cells/mm3
HIV-1 RNA lt100,000 c/mL
HIV-1 RNA 100,000 c/mL
CD4 50-199 cells/mm3
CD4 200 cells/mm3
FPV/r n 434 197
237 67
163 204 LPV/r n
444 209
235 80
152 212
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Change from Baseline in CD4 Cell Count (ITT-E,
Obs)
IQR
191
176
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
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Resistance Through 48 Weeks

• FPV/r LPV/r
• Confirmed virologic failures 16 24
• Unable to sequence 2 3
• No treatment-emergent mutations 9 14

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
No treatment-emergent reduced phenotypic
susceptibility to FPV/r or LPV/r per IAS-USA
resistance guidelines, Oct 2005
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Clinical Treatment-Related Grade 2-4 AEs 2

FPV/r LPV/r Total
(Grade 3/4) (N436)
(N443) (N879) Diarrhea 13 (2)
11 (lt1) 12 (1) Nausea 6 (lt1) 5
(lt1) 6 (lt1) Suspected HSR to ABC
6 (2) 4 (2) 5 (2) Headache 3
(lt1) 1 (0) 2 (lt1) Rash 3
(0) lt1 (lt1) 2 (lt1) Vomiting 2 (0)
2 (lt1) 2 (lt1) Fatigue 2 (lt1) 1
(lt1) 2 (lt1) 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
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AEs Leading to Discontinuation of Any
Study Drug

FPV/r LPV/r Total n
()
(N436) (N443)
(N879) Subjects with any event 53 (12)
43 (10) 96 (11) Suspected HSR to ABC
32 ( 7) 20 ( 5) 52 ( 6)
Diarrhea 5 ( 1) 7 ( 2) 12 (
1) Vomiting 3 (lt1) 4 (lt1)
7 (lt1) Nausea 2 (lt1) 3 (lt1)
5 (lt1) Abdominal Pain 1 (lt1)
2 (lt1) 3 (lt1) Transaminases
increased 2 (lt1) 1 (lt1) 3
(lt1) Hypercholesterolemia 1 (lt1)
2 (lt1) 3 (lt1) Rash 2 (lt1)
1 (lt1) 3 (lt1) Other 5 ( 1)
3 ( 1) 8 ( 1)
One additional case of ABC HSR was
reported Subjects may have experienced more than
one AE which led to discontinuation of study drug
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Median Fasting Lipids (mg/dL) at Baseline and
Week 48
Cholesterol
Triglycerides
mg/dL
Baseline n 363
377 363
377 Week 48 n 287
294
287 294
Use of lipid-lowering medications was similar in
the FPV/r and LPV/r groups (11)
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Median Fasting Lipids (mg/dL) at Baseline and
Week 48
LDL
HDL
mg/dL
Baseline n 345
362 358
371 Week 48 n 257
260
285 290
Use of lipid-lowering medications was similar in
the FPV/r and LPV/r groups (11)
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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)