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An Open-label, Randomized, 48-Week Study to Assess the Safety, Tolerability and Activity of

Raltegravir when Replacing the Ritonavir-boosted PI Component of HAART in HIV-Infected

Individuals with Viral Load Suppression on a Ritonavir-Boosted PI Containing Regimen.

The SPIRAL Study

Martinez E.1, Larrousse M.1, Llibre J.M.2, Gutierrez F.3, Saumoy M.4, Antela A.5, Knobel H.6, Pich J.1, Perez I.1, J. Murillas7, J. Portilla8, J. Berenguer9,

E. Ribera10 and Gatell J.M.1 , for the SPIRAL study group

1Hospital Clínic, Barcelona, Spain; 2Hospital Germans Trias i Pujol, Badalona, Spain; 3Hospital General Universitario de Elche, Elche, Spain; 4Hospital de Bellvitge, Hospitalet de Llobregat, Spain; 5Hospital de Santiago, Santiago de Compostela, Spain; and 6Hospital del Mar, Barcelona, Spain;7Hospital Son Dureta, Palma de Mallorca, Spain; 8Hospital Univ. de Alicante, Alicante, Spain;9Hospital Gregorio Marañón,

Madrid, Spain; 10Hospital Vall d’Hebrón, Barcelona, Spain .

Martinez E et al . AIDS 2010

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SPIRAL study groupHOSPITAL CLINICBARCELONAE. MartínezM. LarrousseJ. PichI. PérezD. GarcíaN. RamosH. Beleta A. PejenauteJ.A. ArnaizJ.M. Gatell

HOSPITAL BELLVITGEHOSPITALETM. SaumoyD. Podzamczer

HOSPITAL VALL D’HEBRÓN BARCELONAE. RiberaA. Currán

HOSPITAL ELCHEELCHEF. GutiérrezM. MasiáS. PadillaV. Sánchez

HOSPITAL MARBARCELONAH. KnobelA. GonzálezJ. Mercadal

HOSPITAL GREGORIO MARAÑÓN MADRIDJ. BerenguerP. MirallesM. Sánchez-CondeM. RamírezI. Gutiérrez

HOSPITAL CLÍNICOSAN CARLOS MADRIDV. Estrada

HOSPITAL JOAN XXIIITARRAGONAF. VidalJ. Peraire

HOSPITAL RAMÓN Y CAJAL. MADRIDF. DrondaS. Moreno

HOSPITAL MATARÓMATARÓLl. ForceP. Barrufet

HOSPITAL UNIV. ALICANTE. ALICANTEJ. PortillaL. Giner

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

HOSPITAL GERMANS TRIAS I PUJOLBADALONAJ.M. LlibreB. ClotetR. Guerola

HOSPITAL PARC TAULÍSABADELLF. SeguraE. PeneloM.J. Amengual

HOSPITAL GRANOLLERSGRANOLLERSE. Deig

HOSPITAL SANTIAGOSANTIAGO DE COMPOSTELAA. AntelaA. PrietoE. Losada

HOSPITAL SON DURETAPALMA MALLORCAJ. Murillas

HOSPITAL SANT PAUBARCELONAP. Domingo

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Background» PI/r-based cART is an effective therapy for HIV-

infected patients, but it has been associated with a higher risk of cardiovascular disease due at least in part to lipid effects.

» Raltegravir-based cART may show a better lipid profile while being as effective as PI/r-based cART in selected patients.

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Adjusted relative rate/year of PI: 1.15 (1.06, 1.25)Adjusted relative rate/year of NNRTI: 0.94 (0.74, 1.19)

Num

ber o

f MIs

per

100

0 PY

FU (I

C 9

5%)

Years of exposure to PI or NNRTI

0

2

4

6

8

10

>65–62–3 3–4 4–5 0 1–2<1

Friis-Møller, et al. N Engl J Med. 2007;326:1723-1735

D:A:D study

Higher risk of myocardial infarction with longer exposure to protease inhibitors

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Objective» To demonstrate the non-inferiority of raltegravir vs.

PI/r-based cART when administered for 48 weeks to HIV-1 seropositive patients with virologic suppression.

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Switch to Raltegravir†

(N = 143) BaselineContinue with boosted PI

(N = 143)

* Raltegravir 400mg BID (maintaining other antiretrovirals unchanged).

Study Population (N = 286)Patients on current PI/r + at least 2 ARV for > 6 monthsVL<50 cp/mL within 180 days

Analysis, Week 48

1:1 RandomizationStratified by presence or not of lipid lowering agents

Study Design

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Primary end-point

» The proportion of patients free of treatment failure for any reason through Week 48 (ITT, S=F)• Includes virologic rebound (two consecutive > 50

cp/mL), discontinuation of study therapy or lost to follow-up, progression to a new CDC event or death.

• Non-inferiority study of Raltegravir vs. boosted PI. Lower 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 virological failure defined as the first of two consecutive HIV RNA ≥ 50 cp/mL at least 2 weeks apart) (OT).

» Change in CD4+ cells.» Time to treatment and virologic failure.» Safety (adverse events leading to drug

discontinuation and serious adverse events).» Evolution of fasting plasma lipids.

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Characteristics

Raltegravir PI/r

N = 139 N = 134Age, median (IQR); years 44 (41;50) 45 (40;50)Gender, N (%) 26 (19) 37 (28)

FemaleRisk group, N (%)

Heterosexual transmission 42 (30) 46 (34)Male Homosexuality 46 (33) 44 (33)IDUs 39 (28) 32 (24)Other 12 (9) 12 (9)

AIDS, N (%) 44 (32) 45 (34)CD4 cell count, median (IQR); cells/mm3 529 (377;780) 509 (369;726)TG, median (IQR); mg/dL 168 (117;270) 174 (114;236)Total cholesterol, median (IQR); mg/dL 198 (171;226) 198 (171;223)HDL- cholesterol, median (IQR); mg/dL 44 (35;54) 43 (37;51)LDL- cholesterol, median (IQR); mg/dL 121 (97;141) 122 (97;145)

Baseline Characteristics (I)

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Raltegravir PI/r

N = 139 N = 134

ARV exposure, median (IQR); yearsVirological suppression, median (IQR); years

10.4 (5.0;12.9)6 (3.2-8.8)

9.7 (5.6;12.4)6 (3.3-8)

Nº of regimens before study entry, median (IQR); years 5 (2;8) 5 (3;7)History of previous virological failure, N (%)History of resistance mutations in RT gene, N (%)

55 (40)37 (27)

48 (36)34 (25)

Previous suboptimal treatment, N (%) 57 (41) 47 (35)1st. ARV regimen with PI, N (%) 16 (12) 14 (10)PI exposure, median (IQR); months 30.8 (20.2;46.8) 31.0 (18.3;41.9)PI at entry, N (%)

Lopinavir 60 (43) 60 (45)Atazanavir 52 (37) 44 (33)Other 27 (19) 30 (22)

NRTI at entry, N (%)FTC + TDF, N (%) 72 (52) 70 (52)ABC + 3TC, N (%) 27 (19) 27 (20)Other, N (%) 40 (29) 37 (28)

Baseline Characteristics (III)

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In December 2008 when Switchmrk

studies w

ere interrupted the DSMB

examined the Spiral study and

recommended to continue the

Spiral study

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Patient Disposition at week 48

† 2 subjects with virological failure

* 4 subjects with virological failure

Patients assessed for eligibility(n=339)

Continuing assigned therapy 126† (91%)Discontinued 13 (9%)

Adverse events 3 Virological failure 2Lost to follow-up 1Patient decission 5Other 2

Assigned to Raltegravir (n=142) Excluded: 3Valid cases: 139

Continuing assigned therapy 120* (90%)Discontinued 14 (10%)

Adverse events 3Virological failure 2Lost to follow-up 4Patient decission 4Other 1

Assigned to PI/r (n=140) Excluded: 6Valid cases: 134

Patients enrolled(n=282)

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Free of Virologic Failure (≥ 50 cp/mL) (OT)Free of Treatment Failure (ITT, S=F)

RALTEGRAVIR PI/r

Patients free of Treatment Failure and Virologic Failure (≥ 50 cp/mL) through Week 48

Difference Estimate (95% CI) 2.6% (–5.2%, 10.6%)

0

1020

30

40

5060

70

8090

100

1 2124/139 116/134

89% 87%

97% 96%

Difference Estimate (95% CI) 1.8% (–3.5%, 7.5%)

0

10

20

30

40

50

60

70

80

90

100

97% 95%

124/128 116/122

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Time to virological failure

Time to V irologic failure by treatment group

0,5

0,6

0,7

0,8

0,9

1

0 4 8 12 16 20 24 28 32 36 40 44 48Weeks

Even

t- Fr

ee s

urvi

val

Raltegravir

IP/r

IP/rRaltegravir

Patientsat risk

122

1221287

128

Log Rank p=0.4602

119126

119125

116124

0

Time to Therapeutic failure by treatment group

0,5

0,6

0,7

0,8

0,9

1

0 4 8 12 16 20 24 28 32 36 40 44 48Weeks

Even

t- Fr

ee s

urvi

val

Raltegravir

IP/r

Patientsat risk

134 1311397

138

Log Rank p=0.4775

124132

121130

116124

0

RaltegravirIP/r

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RAL

PI/r

SPIRAL: PROPORTION < 50 COPIES/ML AT 48 WEEKS (OT)

0

20

40

60

8080

85

90

95

100

yes no yes no yes noprior virological failure prior virological failure prior resistance mutations or suboptimal therapy

PER

CEN

TAG

E

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Patients with Virological Failure

Raltegravir (n=4) PI/r (n=6)Failure at week 16,16,16,48 16,16,16,48,48,48VL at failure 71,260,1278,10000 97,111,206,870,49000,500000

Prior virological failure 1/4 (25%) 3/6 (50%)Prior suboptimal ART 2/4 (50%) 3/6 (50%)Prior resistance mut. 1/2 (50%) 5/6 (83%)

Resist. test at failure 1 4Major mutations 0/1 (RT gene) 3/4 (protease & RT genes)

Lack of adherence 1 1

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CD4 Changes

» Median changes in CD4 cell count were: +46 cells/mm3 (Raltegracir arm) and +44 cells/mm3 (PI/r arm) through Week 48 (p=0.33)

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Adverse Events (II)

Characteristic

RALTEGRAVIR PI/rN = 142N (%)

N = 140N (%)

Patients with AE leading to study drug discontinuation 3 (2) 3(2) Neuropsychiatric 2 1 Hepatic 0 1 Digestive 0 1 Respiratory 1 0Patients with Serious Adverse Event 6 (4) 5 (4) Neuropsychiatric 3 1 Digestive 2 1 Respiratory 1 1 Genitourinary 0 1 Cardiovascular 1 0 Hepatic 0 1

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LIPIDS. Change in mean Fasting Lipid Parameters through Week 48

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LIPIDS. Percentage above NCEP treatment recommendations at baseline and through 48

Variable

RALTEGRAVIR PI/r

Baseline Week 48 Baseline Week 48

TG > 200 mg/dl 41 15 38 29

Cholesterol > 240 mg/dl 15 4 15 17HDL < 40 mg/dl 38 42 33 34

LDL > 160 mg/dl 12 3 12 8

Lipid lowering agents 19 12 21 24

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Substudies

» Metabolic substudy (n=40+41)» Body fat composition (n=39+34)» Adipose tissue biopsies (n=3+3)» Relation between prior resistance and virologic

failure substudy (n= 113)

» Inflamatory markers substudy (n= 80+80)

22Comparison between pooled analysis of SWITCHMRK studies at 24 weeks and SPIRAL study at 48 weeks

RAL

PI/r

SM SPIRAL

PROPORTION < 50 COPIES/ML AT 24 (SWITCHMRK) or 48 WEEKS (SPIRAL)

0

20

40

60

8080

85

90

95

100

THERAPEUTIC RESPONSE VIROLOGICAL RESPONSE

PER

CEN

TAG

E

23

8883

77

90 91 92 9089

0

20

40

60

80

100

% o

f Pat

ient

s W

ith H

IV R

NA

<5

0 C

opie

s/m

L

RALLPV/r

Efficacy at 24 Weeks: Subgroup Analysis – SWITCHMRK-1 and -2 Combined Data1,a

CI = confidence interval; LPV/r = lopinavir/ritonavir; RAL = raltegravir.aAll patients who did not complete the study were regarded as failures.bCalculated by the method of Miettinen and Nurminen.cPlus existing baseline regimen.1. Eron JJ et al. Lancet. 2010 Jan 13; [Epub ahead of print].

Protocol 032 (SWITCHMRK-1) and Protocol 033 (SWITCHMRK-2)

128 130 219 222 111 123 228 221

Difference (95% CI)b −2.5 (−10.6, 5.4) −8.3 (−14.8, −2.1) −15.3 (−24.9, −6.2) −1.0 (−6.9, 4.9)

LPV/r as First Regimen History of Virologic Failure

LPV/r First Regimen LPV/R Not First Regimen

Prior Virologic Failure

No Prior Virologic Failure

c

c

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Compared with SPIRAL, Switchmrk studies 1 & 2:

- Double blinded & Double dummy- 24 weeks- No need to confirm VL>50 for the main end point- Different backbone of NRTI´s - Substantially shorter median duration of virological suppression before entry- Shorter minimum duration of virological suppression before entry- All Lopinavir/r

Yet, response rate was very haig in both arms in both studies. Probably among the highest ever seen in switching studies

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AIDS, 2007

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Conclusions of SPIRAL study:

» In patients with sustained virological suppression on PI/r-based cART, switching from PI/r to raltegravir demonstrated non-inferior efficacy and resulted in a better lipid profile at 48 weeks than continuing PI/r.

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Back up slides

clinicaloptions.com/hivWeighing the Options: Choosing the Initial Antiretroviral Regimen

D:A:D: Cumulative Antiretroviral Exposure and Risk of MI

Lundgren JD, et al. CROI 2009. Abstract 44LB. Graphics reproduced with permission.

# PYFU: 68,469 56,529 37,136 44,657 61,855 58,946# MI: 298 197 150 221 228 221

IDV NFV LPV/RTV SQV NVP EFV

PI NNRTI1.201.13

1.001.10

0.90

*Expressed as risk/yr. Expected to have more impact the longer the pt is on the drug.

RR

of C

umul

ativ

e Ex

posu

re/Y

r*(9

5% C

I)

Baseline CharacteristicsSPIRAL SWITCHMRK ‡

RaltegravirN = 139

PI/rN = 134

RaltegravirN = 350

LPV/rN = 352

ARV exposure, median (IQR); years 10.4 (5.0;12.9) 9.7 (5.6;12.4) 3.4 (2.0;7.3) 4.1 (2.1;7.4)

No. of regimens before study entry, median (IQR); years 5 (2;8) 5 (3;7) 5 (4;7) 5 (4;7)

History of previous virological failure, N (%) 55 (40) 48 (36) 112 (32) 123 (35)

1st ARV regimen with PI, N (%) 16 (12) 14 (10) 130 (37)* 130 (37)*

PI at entry, N (%) Lopinavir Atazanavir Other

60 (43) 52 (37) 27 (19)

60 (45) 44 (33) 30 (22)

350 (100)0 (0)0 (0)

352 (100)0 (0)0 (0)

NRTI at entry, N (%) TDF + FTC†, N (%)

ABC + 3TC†, N (%) Other, N (%)

72 (52)27 (19)40 (29)

70 (52)27 (20)37 (28)

145 (41)53 (15)

151 (43)

124 (35)46 (13)

179 (51)

*All patients in SWITCHMRK were on LPV/r†In SWITCHMRK, NRTI could be FTC or 3TC

‡1 PT in the RAL Gp and 3 PTs in the LPVr Gp did not report any concurrent ART

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Raltegravir PI/r

N = 139 N = 134TG > 200 mg/dl, N (%)

57 (41) 51 (38)Cholesterol > 240 mg/dl, N (%)

21 (15) 20 (15)LDL > 160 mg/dl, N (%)

17 (12) 16 (12)HDL < 40 mg/dl, N (%)

53 (38) 44 (33)

Baseline Characteristics (II)

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Free of Treatment Failure

RALTEGRAVIR PI/r

Patients free of Treatment Failure through Week 48: sensitivity analysis

Free of Treatment Failure by sensitivity analysis

Difference Estimate (95% CI) 2.6% (–5.2%, 10.6%)

0

1020

30

40

5060

70

8090

100

1 2124/139 116/134

89% 87%

Difference Estimate (95% CI) 2.3% (–5.4%, 10.0%)

0

1020

30

40

5060

70

8090

100

1 2127/142 122/140

89% 87%

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33Comparison between pooled analysis of SWITCHMRK studies at 24 weeks and SPIRAL study at 48 weeks

RAL

PI/r

SM SPIRAL

PROPORTION < 50 COPIES/ML AT 24 (SWITCHMRK) or 48 WEEKS (SPIRAL)

0

20

40

60

8080

85

90

95

100

THERAPEUTIC RESPONSE VIROLOGICAL RESPONSE

PER

CEN

TAG

E

34

PROPORTION < 50 COPIES/ML AT 24 (SWITCHMRK) or 48 WEEKS (SPIRAL)

RAL-SM

RAL-SP

IP/r -SM

IP/r -SP

RAL-SM

RAL-SP

IP/r -SM

IP/r -SP

0

20

40

60

8080

85

90

95

100

THERAPEUTIC RESPONSE VIROLOGICAL RESPONSE

PER

CEN

TAG

E

Comparison between pooled analysis of SWITCHMRK studies at 24 weeks and SPIRAL study at 48 weeks

RAL

PI/r

SM SPIRAL

35

Adverse Events (I)

Characteristic

RALTEGRAVIR PI/rN = 142N (%)

N = 140N (%)

Patients with a least one AE 78 (55) 79 (56)Patients with grade 3 or 4 side effects Any 16 (11) 18 (13) AEs Clinical 7 (5) 7 (5) Description of clinical grade 3 or 4 AE Neuropsychiatric 3 2 Respiratory 1 3 Digestive 2 1 Genitourinary 1 1 Osteomuscular 0 1 Cardiovascular 1 0 Hepatic 0 1 AEs Laboratory 9 (6) 12 (9) Description of lab grade 3 or 4 AE Triglycerides 3 4 Total cholesterol 1 5 Transaminases 5 3

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Lipid lowering agents

RALTEGRAVIR PI/rN = 139N (%)

N = 134N (%)

Baseline 27 (19) 28 (21)

Week 48 16 (12) 32 (24)

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