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Efficacy and safety of switching from boosted Lopinavir (LPV/r) to boosted Atazanavir

(ATV/r) in patients with virologic suppression receiving a LPV/r containing HAART: The

ATAZIP study

Mallolas J.1, Podzamczer D.2, Domingo P.3, Clotet B.4, Ribera E.5, Gutierrez F.6, Knobel H.7, Cosin J.8, Ferrer E.2, Arranz J.A.9, Roca V.10, Vidal F.13,

Murillas J.14, Pedrol E.15, Llibre J.M.16, Dalmau D.17, Garcia I.18, Aranda M.19, Pich J.11, de Lazzari E.12, Gatell J.M.1, for the ATAZIP study group

1Hospital Clinic Universitari, Infectious Diseases, Barcelona, Spain, 2Bellvitge, Infectious Diseases, Barcelona, Spain, 3Hospital Sant Pau, Medicina Interna,

Barcelona, Spain, 4Fundacio IrsiCaixa, HIV, Barcelona, Spain, 5Hospital Vall d´Hebron, Infectious Diseases, Barcelona, Spain, 6Hospital de Elche, Medicine,

Elche, Spain, 7Hospital del Mar, Infectious Diseases, Barcelona, Spain, 8Gregorio Marañon, Medicina, Madrid, Spain, 9Hospital Principe de Asturias, Medicina,

Madrid, Spain, 10Clinico San Carlos, Medicina, Madrid, Spain, 11Hospital Clinic Universitari, Pharmacology, Barcelona, Spain, 12Hospital Clinic Universitari,

Biostatistics, Barcelona, Spain 13 Hospital Joan XXIII, Tarragona 14 Hospital Son Dureta. Palma de Mallorca. 15 Hospital de Granollers. 16 Hospital de Calella.17

Mutua de Tarrasa. 18 Hospital de Hospitalet. 19 Consorci Sanitari de Tarrasa.

4th IAS Conference on HIV Pathogenesis, Treatment and Prevention Sydney, Australia, July 22-26, 2007

WEPEB117LB

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Background ATV is a potent, well-tolerated, once-daily (QD) protease

inhibitor (PI) extensively studied in treatment-naive and -experienced patients

The SWAN study (BMS 097)1 demonstrated that switching from PI ± RTV-containing regimens to an unboosted ATV-containing regimen maintained virologic suppression with improvement in plasma lipids through 48 weeks in patients without previous failures to PI contaning regimens

However, there are limited data available on the utility of switching virologically suppressed patients from LPV/r-based regimens to a different boosted PI such as ATV/r including those with previous failures to PI containing regimens or PI associated mutations

1Gatell et al. Clin Infect Dis 2007

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Objective

To assess the safety and efficacy of ATV/r based HAART in virologically suppressed patients receiving a LPV/r contaning regimen including patients with previous failures (< 3) to PI regimens or history of having PI associated mutations (< 5) prior to starting the LPV/r-based regimen.

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Final Analysis, Week 96

Switch to ATV/r QD†

(N = 121) BaselineContinue LPV/r BID*

(N = 127)

* LPV/r 400/100 mg BID capsules then tablets when available + unchanged NRTI backbone.† ATV/r 300/100 mg QD + unchanged NRTI backbone.

Study Population (N = 265) Stable LPV/r-based Regimen for > 6 months (VL < 200)

< 3 Previous Virologic Failures While on PI-based HAART and < 5 PI-associated mutations

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 event or death.

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

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Secondary end-points

– The proportion of patients with virologic

rebound 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

– Safety

– Evolution of fasting plasma lipids

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GeneralATV/r LPV/r

N = 121 N = 127

Median Age, y 42 43

Gender, N (%)

Male 97 (80) 100 (79)

Risk group, N (%)

Heterosexual trans. 45(37) 40(31)

MSM 27(22) 41 (32)

IDUs 39 (32) 37 (29)

Other 10 (8) 9 (7)

AIDS, N (%) 48 (40) 74 (57)

CD4 < 200, cell/ mm3 9(8) 12 (10)

Median CD4, cells/mm3 472 435

Baseline Characteristics

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Laboratory

ATV/r LPV/r

N = 121 N = 127

Total chol > 240 mg/dl, N (%) 28 (23%) 26 (20%)

TG > 500 mg/dl, N (%) 4 (3%) 13 (10%)*

LDL-c > 130 mg/dl, N (%) 24 (20%) 25 (20%)

HDL-c < 40 mg/dl, N (%) 19 (16%) 27 (21%)

ALT > 40, N (%) 28 (24%) 22 (18%)

AST > 40, N (%) 20 (21%) 24 (23%)

ALT or AST > 40, N (%) 34 (28%) 33 (26%)

Baseline Characteristics

* P=0.023

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ARV TherapyATV/r LPV/r

N = 121 N = 127ARV exposure, yr. 5.1 5.4

1st. ARV regimen, N (%) 17 (14) 19 (15)

1st. ARV regimen with PI, N (%) 36 (30) 42 (33)

Previous mono/bi therapy, N (%) 47 (39) 48 (38)

Current ZDV+3TC, N (%) 12 (10) 20 (16)

Current TDF+3TC, N (%) 24 (20) 22 (17)

Current TDF+ddI, N (%) 21 (17) 12 (9)

Current ddI+3TC, N (%) 8 (7) 9 (7)

Previous PI failures (>=1), N (%) 25 (21) 25 (20)

History of Previous PI mutations

>=1, N (%) 43 (36) 41 (32)

>=1 major, N (%) 17 (14) 13 (10)

None, N (%) 3 (1) 9 (7)

Not tested, N (%) 75 (63) 77 (61)

Baseline Characteristics

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Patient Disposition at month 12

Pacientes enrolled(n=265)

Assigned to continue with LPV/r (n=127) #

Assigned to switch to ATV/r (n=121) #

Continuing assigned therapy 109† (86%)Discontinued 18 (14%)

Adverse events 6Death 1 *Virological failure 1Lost to follow-up 6Patient decission 2Other 2

Continuing assigned therapy 105† (86%)Discontinued 17 (14%)

Adverse events 6Death 0Virological failure 1Lost to follow-up 7Patient decission 0Other 2

† 5 subjects with virological failure † 7 subjects with virological failure

* Hepatic encephalopaty # 11 additional patients not eligible # 6 additional patients not eligible

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Virologic Failure (≥ 200 c/mL)Treatment Failure

ATV/r LPV/r

0

5

10

15

20

25

30

p = NS

17%

20%

21/121 25/127

Difference Estimate (95% CI) -2.3% (–12%, 8%) –1.3% (–7.7%, 4.8%)

Treatment Failure and Virologic Failure (≥ 200 c/mL) through month 12

0

5

10

15

20

25

30

p = NS

5%6%

6/121 8/127

Pro

po

rtio

n o

f p

atie

nts

Pro

po

rtio

n o

f p

atie

nts

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Time to treatment failure

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Time to virological failure

p=0.609, long rank test

P=0.5P=0.5

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ATV/r (n=121) LPV/r (127)

N 6 8

Previous PI failures 2 4Previous PI mutations 6 1Previous PI major mutations 2 1High baseline risk (*) 5 5

Reported lack of adherence 0 4Continue with same cART 5 7Virological response at 12 mo. 3 4

* Previous >= 1 PI failure or >= 3 PI mutations or >= 1 major PI mutation

Virological failures through month 12

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CD4 Changes

Median changes from baseline in CD4 cell count were similar beteween groups: +26 cells/mm3 (ATV/r) and +51 cells/mm3 (LPV/r) at month 12 (p=0.2)

541

435

495

472

400

450

500

550

600

BL m1 m4 m8 m12

CD

4 co

un

t (c

ells

/mL

)

LPV/r

ATV/r

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Adverse Events through month 12.

Adverse Events leading to discontinuation

ATV/r LPV/rN = 121N (%)

N = 127N (%)

Total 6 (5) 6 (5)GI-related 1 (1) 2 (2)

CNS 1 (1) 0 (0)

Liver 1 (1) # 0 (0)

Metabolic-related 1 (1) 4 (4)

Hyperbilirubin/Jaundice 2 (2) 0 (0)

* Hepatic encephalopaty; # ALT 113, AST 90

Death 0 (0) 1 (1) *Any AE 74 (58) 63 (52)

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LAB Abnormalities

Liver Function Abnormalities (ALT/AST > 200; bilirrubin > 5)

ATV/r N = 121

LPV/rN = 127

ALT 2% 1%

AST 2 % 2%

ALT or AST 4% 2%

Total bilirubin 5% 2%

Liver Function Abnormalities (ALT/AST > 200 ) when ALT or AST

were > 40 at baseline

ATV/r N = 34

LPV/rN = 33

ALT 9 % 6%

AST 9 % 6%

ALT or AST 12% 6%

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Fasting LIPIDS. Median values and Changes From Baseline in Lipid Parameters at month 12

Fasting Lipids

ATV/r LPV/rP

valueBL m12Change mg/dL

BL m12Change mg/dL

TG, mg/dL 181 145 -51 (-29%) 191 202 -3 (-1%) <0.0001

Total Chol, mg/dL 202 193 -19 (-9%) 205 207 -4 (-2%) <0.0001

LDL-c, mg/dL 107 111 -8 (-7%) 111 111 -2 (-3%) 0.163

HDL-c, mg/dL 50 46 -3 (-6%) 49 46 -2 (-3%) 0.375

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CHANGE IN MEDIAN FASTING PLASMA LIPIDS

-60

-40

-20

0

20

Lop/r Ata/ r Lop/ r Ata/ r Lop/ r Ata/ r Lop/ r Ata/ r

TG Cholest LDL HDL

P<0.0001 P<0.0001

mg

/dl

(Mo

. 12

- M

o.

0)

21LIPIDS. Percentage above NCEP treatment recommendations at baseline and through month 12.

ATV/rN=121

LPV/rN=127

BL Mo 12 Change BL Mo 12 Change

TG m12 > 500 mg/dL 3% 4% +1% 10% 17% +7%

Total Chol > 240 mg/dL 23% 20% -3% 20% 26% +6%

LDL > 130 mg/dL 20% 25% +5% 20% 30% +10%

HDL < 40 mg/dL 16% 32% +16% 21% 29% +8%

No significant changes were obseved in Lipid Lowering Agents (LLA) usage during the follow-up in both arms.

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Conclusions

Switching to ATV/r in virologically suppressed patients who were receiving a LPV/r containing HAART provided comparable efficacy and safety profile with improved lipid parameters.

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ATAZIP Study GroupHOSPITAL CLINICBARCELONAJ. MallolasJ.M. GatellJ. PichE. de LazzariE. MartínezA. MilinkovicA. CrucetaH. AgellJ.A. Arnaiz

HOSPITAL BELLVITGEHOSPITALETD. PodzamczerE. FerrerG. Leibenger

HOSPITAL SANT PAUBARCELONAP. DomingoM. GutiérrezerrerG. Mateo

HOSPITAL GERMANS TRIAS I PUJOLBADALONAB. ClotetP. EcheverriaC. Alcalde

HOSPITAL VALL D’HEBRÓNBARCELONAE. RiberaS. Villar

HOSPITAL ELCHEALICANTEF. GutiérrezM. MasiáE. Bernal

HOSPITAL MARBARCELONAH. KnobelA. GonzálezG. Mestre

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

HOSPITAL PRINCIPEASTURIAS MADRIDJ.A. ArranzJ. SanzE. Casas

HOSPITAL CLÍNICOSAN CARLOS MADRIDV. RocaJ. VergasM.J. Téllez

HOSPITAL JOAN XXIII TARRAGONA

F. VidalJ. PeraireM. Saumoy

HOSPITAL SON DURETAPALMA MALLORCAM. PeñarandaJ. Murillas

HOSPITAL GRANOLLERS GRANOLLERS

E. PedrolE. Deig

HOSPITAL CALELLACALELLAJ.M. LlibreS. Valero

HOSPITAL MUTUA TERRASSA

TERRASSAD. DalmauM. Cairó

HOSPITAL L’HOSPITALETHOSPITALETI. García

HOSPITAL TERRASSATERRASSAM. Aranda