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Efficacy and safety of NRTI´s switch to tenofovir plus emtricitabine (Truvada®) vs. abacavir plus lamivudine (Kivexa®) in patients with virologic suppression receiving a lamivudine containing

HAART: The BICOMBO study

Martinez E.1, Arranz J.A.2, Podzamczer D.3, Ribera E.4, Knobel H.5, Roca V. † 6, Gutierrez F.7, Llibre J.M.8, Sans J. 2, Barragan P.3, Clotet B.9, Dalmau D.10,

Segura F.13, Arribas J.R.14, Cosin J15., Force L.16, Palleras A.17, de los Santos I.18, Peraire J.19, Galo F.20, Pich J.11, de Lazzari E.12, Gatell J.M.1 , for the

BICOMBO study group1Hospital Clinic Universitari, Infectious Diseases, Barcelona, Spain, 2Principe Asturias, Medicina, Oviedo, Spain, 3Bellvitge, Infectious Diseases, Barcelona,

Spain, 4Vall d´Hebron, Infectious Diseases, Barcelona, Spain, 5Hospital del Mar, Infectious Diseases, Barcelona, Spain, 6Clinico San Carlos, Medicina, Madrid,

Spain, 7Hospital de Elche, Medicina, Elche, Spain, 8Hospital Calella, Medicina, Calella, Spain, 9Fundacio IrsiCaixa, HIV, Barcelona, Spain, 10Mutua de Tarrasa,

Medicina, Tarrasa, Spain, 11Hospital Clinic Universitari, Pharmacology, Barcelona, Spain, 12Hospital Clinic Universitari, Biostatistics, Barcelona, Spain, 13

Hospital Parc Tauli. Sabadell, 14 Hospital La Paz, Madrid, 15 Hospital Gregoria Marañon, Madrid, 16 Hospital de Mataro, 17 Hospital Son Llatzer, Baleares, 18

Hospital de la Princesa, Madrid, 19 Hospital Joan XXIII, Tarragona, 20 Hospital Sierrallana

IAS meetingSydney, Australia, July 22-26, 2007

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Background

Tenofovir (TDF) plus emtricitabine (Truvada®) and abacavir (ABC) plus lamivudine (Kivexa®) are fixed dose combinations and the most commonly recommended and used nucleoside analogs backbone for initial antiretroviral therapy

Kivexa® has favourably compared with zidovudine plus lamivudine (Combivir®) while Truvada® has demonstrated superiority.

However, no head to head comparison has been performed so far between Truvada® and Kivexa®.

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Objective

To compare the efficacy and safety of Truvada® vs. Kivexa® in patients with virologic suppression and receiving a lamivudine containing regimen.

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Switch to Kivexa® † Switch to Truvada ® *

* Tenofovir 300 mg plus emtricitabine 200 mg + unchanged NNRTI or PI.† Abacavir 600 mg plus lamivudine 300 mg + unchanged NNRTI or PI.

Study Population (N = 335) Stable lamivudine based Regimen for > 6 months (VL < 200)

No contraindications for abacavir or tenofovir based regimens

No HLA screening

The study was conducted in Spain

Primary Analysis, Week 48

1:1 Randomization

Study Design

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Primary end-point

– The proportion of patients with treatment failure for any reason through Week 48• Includes virologic rebound (> 200 cp/mL),

discontinuation of study therapy or lost to follow-up, progression to a new CDC category C event or death.

• Non-inferiority study of Kivexa® vs Truvada®. Upper limit of 95% CI of estimated difference < 12.5%.

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Secondary end-points

– The proportion of patients with virologic failure at or prior to week 48• Confirmed on-study HIV RNA ≥ 200 copies/mL or

last on-study HIV RNA ≥ 200 copies/mL followed by discontinuation

– Time to treatment failure and to virologic failure

– CD4 changes– Safety– Changes of fasting plasma lipids, body fat,

bone mineral density and renal function

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KIVEXA ® TRUVADA ®

N = 167 N = 166

Median Age, y 43 43

Gender, N (%)

Male 130 (78) 127 (77)

Risk group, N (%)

Heterosexual trans. 55 (35) 55 (35)

MSM 55 (35) 51 (32)

IDUs 47 (30) 53 (33)

AIDS, N (%) 63 (38) 65 (39)

Glomerular filtration rate (CG) ml/mit 102 97

Creatinine, mg/dL 1 0.9

CD4 < 200, cells/ mm3 13 (9) 15 (10)

Median CD4, cells/mm3 520 508

Baseline Characteristics

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KIVEXA ® TRUVADA ®

N = 167 N = 166

TG > 500 mg/dL, N (%)1 (1 %) 3 (2 %)

Cholesterol > 240 mg/dL, N (%)22 (14%) 25 (16%)

LDL > 130 mg/dL, N (%)51 (38%) 49 (37%)

HDL < 40 mg/dL, N (%)26 (18%) 29 (20%)

ALT > 40 iu/ml, N (%) 23 (16 %) 36 (25 %)

AST > 40 iu/ml, N (%) 48 (31 %) 54 (35 %)

ALT or AST > 40 iu/ml, N (%) 49 (32%) 62 (40 %)

Baseline Characteristics

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KIVEXA ® TRUVADA ®

N = 167 N = 166

ARV exposure, yr. 4.2 3.7

1st. ARV regimen, N (%) 48 (29) 29 (17)*

Efavirenz 94 (56) 88 (53)

Nevirapine, N (%) 56 (34) 62 (37)

PI, N (%) 17 (10) 16 (10)

Previous NRTI

ZDV+3TC, N (%) 59 (35) 48 (29)

d4T +3TC, N (%) 21 (13) 27 (16)

ddI +3TC, N (%) 31 (19) 23 (14)

TDF +3TC, N (%) 44 (26) 56 (34)

ABC +3TC, N (%) 12 (7) 18 (11)

Baseline Therapy

* P=0.01

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Patient Disposition at week 48

Patients enrolled(n=335)

Assigned to KIVEXA ®

(n=167)Assigned to TRUVADA ®

(n=166)#

Continuing assigned therapy 138† (83%)Discontinued 29 (17%)

Adverse events 17 * Death 0Virological failure 2Lost to follow-up 5Patient decision 4Other 1

Continuing assigned therapy 144 (87%)Discontinued 22 (13%)

Adverse events 9Death 1**Virological failure 0Lost to follow-up 8Patient decision 2Other 2

† 2 subjects with virological failure and

1 with a new CDC event (cervix carcinoma)* 3 subjects lost to follow-up and 1 new CDC event

(Cryptosporidiosis)

# 2 additional were not eligible ** Cerebral hemorrage

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Primary EndpointTreatment Failure through Week 48

-2 0 Treatment Failure KVX% – TVD%

12.5

95% CI for difference

-2.0 14.05.9

-2 0 Treatment Failure 12.5

95% CI for difference

-2.0 14.05.9

KIVEXA TRUVADA

0

5

10

15

20

25

30

19%

13%

32/167 22/166

Per

cen

tag

eo

fp

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wit

htr

eatm

ent

fail

ure

KIVEXA TRUVADAKIVEXA ® TRUVADA ®

0

5

10

15

20

25

30

19%

13%

32/167 22/166

Per

cen

tag

eo

fp

atie

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wit

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eatm

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fail

ure

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Secondary EndpointVirologic Failure (≥ 200 c/mL) through Week 48

0 KVX% – TVD%

12.5

95% CI for difference

6.0

0 Virologic Failure 12.5

95% CI for difference

0.05 2.4

KIVEXA TRUVADA ®KIVEXAKIVEXA ®

Pe

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of

pa

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wit

h v

iro

log

ic f

ail

ure

2.4%

0%0

2

4

6

8

10

4/167 0/166

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Secondary EndpointVirologic Failure (≥ 200 c/mL) through Week 48

4 patients developed VF in the Kivexa arm

4 / 4 no resistance tests before any ART regimen4 / 4 two or more previous ART regimens for 1-5 years. Never exposed to ABC 1 / 4 previous virologic failure. Wild type virus

VF developed between months 4-8 of the study

4 / 4 were receiving Kivexa + Nevirapine or Efavirenz2 / 4 genotypic test available at failure 75I, 184V, 219E, 101E, 181E 74V, 100I, 103 ,63S4 / 4 VL became undetectable with same (n=1) or different ART (n=3)

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CD4 Changes

Median changes in CD4 cell count were: +44 cells/mm3 (KIVEXA ®) and – 2.7 cells/mm3 (TRUVADA ®) through Week 48 (p=0.032)

Me

dia

n C

ha

ng

e i

n C

D4

1,000

500

0

-500

-1,000

Weeks 4 16 32 48KVX TVD KVX TVD KVX TVD KVX TVD

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Adverse Events

KIVEXA ® TRUVADA ®

N = 167N (%)

N = 166N (%)

Death 0 (0) 1 (1) &

Any AE 109 (65) 89 (54)*

AE leading to discontinuation: Total 17 (10) 9 (5) **

Suspected ABC hypersensitivity 9 (5) 0 (0)

Cefalea, fever, asthenia, diarrhoea 4 (2) 0 (0)

CNS 1 (1) 3 (2)

GI 1 (1) 2 (1)Rash 0 (0) 1 (1)

Kidney 0 (0) 2† (1)Lipodystrophy 1 (1) 1 (1)Liver 1# (1) 0 (0)

& Cerebrovascular accident; * P=0.02 ** P=0.004; † highest creatinine 1.1 and 6.1; # highest ALT/AST 42/ 59;

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LAB Abnormalities

Liver Function Abnormalities (ALT/AST > 200)N (%)

KIVEXAN = 167

TRUVADA N = 166

ALT 1 (1%) 0 (0%)

AST 1 (1%) 1 (1%)

ALT or AST 1 (1%) 1 (1%)

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0

12

7

0

-16

-9

-4 -4

-20

-15

-10

-5

0

5

10

15

Mg/dL (Month 12 - Month 0)

Change in Median Fasting Plasma Lipids

Triglycerides Cholesterol LDL HDL

P = 0.01 P = 0.001 P < 0.0001 P < 0.0001

KIVEXA TRUVADA

0 0

1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

TC

/HD

L ratio

P =0.015

18

449

13280

164

0

100

200

300

400

500

600

700

800

900

1000

Fat g (Month 12 - Month 0)

Change in Mean Total and Limb Fat and Bone Mineral Density (n=47)

Total Fat Limb Fat

P = ns P = ns

0.0009

-0.0061

-0.04

-0.02

0

0.02

0.04

Bone Mineral Denisty mg/mL

(Month 12 - Month 0)

P = ns

KIVEXA ® TRUVADA ®N=23 N=24

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RENAL FUNCTION. Median Changes From Baseline (mo. 12 – baseline)

KIVEXA ® TRUVADA ®

n Median (IQR) n Median (IQR)

∆ Creatinine , mg/dL

124 -0.03 (-0.1,-0.04)

129 -0.02 (-0.1, 0.03)

∆ GFR (CG), ml/mit

107 1.3 (-5, 7) 129 -0.5 (-5, 9)

Note: Only 1 patient (Truvada arm) developed a plasma creatinine >= 2 mg/dL

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HLA TYPING

N (%)HLA-B05701+ HLA-B05701-

CASES (N=9) * 3 (33%) 6 (67%)

CONTROLS (N=14) 1 (7%) 13 (93%)

* KIVEXA ® interruption due to suspected Abacavir hypersensitivity

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Conclusions

In patients switching from a lamivudine containing regimen:

For treatment efficacy, the Kivexa ® group did not meet the non-inferiority endpoint compared to the Truvada ® group– the difference was mainly driven by Kivexa

discontinuations due to suspected abacavir hypersensitivity

For the virologic efficacy, Kivexa ® met non-inferiority criteria compared to Truvada ®

– however, there were more failures with Kivexa ® than Truvada ® (2.4% vs 0%)

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Conclusions

On switching from a lamivudine nucleoside backbone to either Kivexa ® or Truvada ® :

Retrospective HLA testing showed B5701+ in 3/9 cases of suspected HSR

Safety endpoints showed:

– A more favorable lipid profile (cholesterol, TG and LDL but not HDL) for those switching to Truvada ® vs Kivexa ®

– No differences in renal function or bone mineral density between Truvada ® and Kivexa ® treatment arms

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BICOMBO Study GroupHOSPITAL CLINICE. MartínezJ.M. GatellJ. PichE. de LazzariJ. M. MiróJ. MallolasM. LoncàA. CrucetaH. AgellJ.A. Arnaiz

HOSPITAL BELLVITGEHOSPITALETD. PodzamczerP. Barragán

HOSPITAL VALL D’HEBRÓNBARCELONAE. RiberaA. Currán

HOSPITAL ELCHEF. GutiérrezM. MasiáS. PadillaE. Bernal

HOSPITAL MARBARCELONAH. KnobelA. GonzálezJ. Mercadal

HOSPITAL GREGORIO MARAÑÓN MADRIDJ. BerenguerM. SánchezM. RamírezI. Gutiérrez

HOSPITAL PRINCIPEASTURIAS MADRIDJ.A. ArranzJ. SanzE. CasasJ.M. Prieto HOSPITAL CLÍNICO

SAN CARLOS MADRID

V. Roca †M. Fuster

HOSPITAL JOAN XXIII TARRAGONA

F. VidalJ. PeraireM. Saumoy

HOSPITAL SON LLATZERPALMA MALLORCAA. Palleras

HOSPITAL MATARÓMATARÓLl. ForceP. Barrufet

HOSPITAL CALELLACALELLAJ.M. LlibreS. Valero

HOSPITAL MUTUA TERRASSAD. DalmauM. Cairó

HOSPITAL LA PAZMADRIDJ.R. ArribasM. MontesJ.M. Castro

HOSPITAL LA PRINCESA MADRIDI. de los SantosR. Carrillo

HOSPITAL GERMANS TRIAS I PUJOLBADALONAB. ClotetP. EcheverriaI. Bravo

HOSPITAL PARC TAULÍSABADELLF. SeguraE. Penelo

HOSPITAL SIERRALLANACANTABRIAF.G. Peralta

AND 335 PATIENTS !!!!

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Backup slides

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Time to treatment failure

p=0.609, long rank test

P=0.5P=0.12

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Time to virological failure

p=0.609, long rank test

P=0.5P=0.5

P=0.19

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Range of Possible Outcomesfor Non-inferiority Study Designs

∆ non-inferiority margin

A

B

C

D

E

95% confidence interval of the difference in effect

0

Favours the new drug Favours the active-control drug

Non-Inferior

Superior

Non-Inferiority, but Inferior

New drug is:

Non-Inferiority not demonstrated

Non-Inferiority not demonstrated, but inferior

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LAB Abnormalities

Liver Function Abnormalities (ALT/AST > 200

when ALT/AST were > 40 at baselineN (%)

KIVEXA N = 49

TRUVADAN = 62

ALT 1 (2 %) 0 (0%)

AST 1 (2%) 1 (2%)

ALT or AST 1 (2%) 1 (2%)

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Lipid lowering agents

N (%)KIVEXA N = 167

TRUVADAN = 166

Baseline 11 (7) 18 (11)

At mo. 12 18 (11) 21 (13)

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PLASMA LIPIDS ABOVE/BELOW NCEP RECOMMENDATION FOR TREATMENT

-10

0

10

20

Kivex Truv Kivex Truv Kivex Truv Kivex Truv

TG>500 Cholest>240 LDL>130 HDL< 40

PERCENTAGE (Mo. 12 - Mo. 0)

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Metabicombo

Mitochrondial toxicity

Patients never exposed to abacavir

(n=155) or tenofovir (n=110)

Planned sub-studies / subanalysis

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Virologic Failure (≥ 200 c/mL)Treatment Failure

KIVEXA TRUVADA

0

5

10

15

20

25

30

21%

13%

32/155 14/110

Difference Estimate (95% CI) 8% (–1.4%, 16.8%) 2.6% (-0.08%, 6%)

Treatment Failure and Virologic Failure (≥ 200 c/mL) through Week 48 among patients never exposed to abacavir or tenofovir

0

5

10

15

20

25

30

3%

0%

4/155 0/110

Pro

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