copyright © 2009 merck & co., inc. whitehouse station, nj, usa all rights reserverd joseph...

Copyright © 2009 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserverd

Switching from Stable Lopinavir/Ritonavir (LPV/r)-Based to Raltegravir (RAL)-Based Combination

Antiretroviral Therapy (ART) Resulted In a Superior Lipid Profile at Week 12 but Did Not Demonstrate

Non-Inferior Virologic Efficacy at Week 24

Joseph Eron*1, Jaime Andrade2, Roberto Zajdenverg3, Cassy Workman4, David A. Cooper5, Benjamin Young6, Xia Xu7,

Bach-Yen Nguyen7, Randi Leavitt7, and Peter Sklar7

1University of North Carolina, Chapel Hill, NC, USA; 2Antinguo Hospital Civil de Guadalajara, Guadalajara, Mexico; 3Hospital Escola Sao Francisco de Assis, Rio

de Janeiro, Brazil; 4AIDS Research Initiative, Darlinghurst, Australia; 5University of New South Wales, Sydney, Australia; 6Denver Infectious Disease Consultants,

Denver, CO, USA; and 7Merck Research Laboratories, West Point, PA, USA


SWITCHMRK 1 and 2 (P032 & 033) Study Design

Identical, multicenter, double-blind, randomized, active-controlled studies

Study population› Well controlled on a stable LPV/r regimen (b.i.d.) in

combination with at least 2 NRTIs (and no other active PI) for ≥ 3 months HIV RNA <50 copies/mL (US PCR) or <75 copies/mL (bDNA)

Patients were not required to be intolerant of LPV/r

Patients with prior virologic failure were not excluded No limit on number of prior ART regimens

› No lipid lowering therapy for at least 12 weeks

Randomized (1:1) to continue LPV/r or switch to RALNRTI = nucleoside reverse transcriptase inhibitorPI = protease inhibitor


SWITCHMRK 1 and 2 (P032 & 033) Study Design (2) Primary endpoints

› Mean % change in lipids at week 12 Total-C, Triglycerides, non-HDL-C, and LDL-C

› Proportion of patients with viral load <50 copies/mL at Week 24 Non-completer = Failure approach (NC=F)

Noninferiority hypothesis with 12% margin

› Safety and tolerability


*In combination with background antiretroviral therapy‡‡Randomized and treated

174174‡‡

Switched to RAL*Switched to RAL*

25 (14.4%)25 (14.4%)DiscontinuedDiscontinued† due to:due to:

3- Lack of efficacy 3- Lack of efficacy 7- Adverse Experience7- Adverse Experience9 - Withdrew consent9 - Withdrew consent4- Physician decision4- Physician decision2 - Other events 2 - Other events 11

174174‡‡

Remained on LPV/r*Remained on LPV/r*

17 (9.8%)17 (9.8%)DiscontinuedDiscontinued† due to: due to:

1 - Lack of efficacy 1 - Lack of efficacy 3 - Adverse Experience3 - Adverse Experience6 - Withdrew consent6 - Withdrew consent2 - Physician decision2 - Physician decision5 - Other events 5 - Other events 22

Protocol 032

1RAL: Deviation from protocol (1), Other (1)2LPV/r: Lost to follow-up (4), Deviation from protocol (1)

176176‡‡

Switched to RAL*Switched to RAL*

10 (5.7%)10 (5.7%)DiscontinuedDiscontinued† due to: due to:

4- Lack of efficacy 4- Lack of efficacy 0- Adverse Experience0- Adverse Experience3 - Withdrew consent3 - Withdrew consent2 - Physician decision2 - Physician decision1 - Other events1 - Other events 33

178178‡‡ Remained on LPV/r*Remained on LPV/r*

6 (3.4%)6 (3.4%)DiscontinuedDiscontinued† due to:due to:

2- Lack of efficacy 2- Lack of efficacy 0 - Adverse Experience0 - Adverse Experience1 - Withdrew consent1 - Withdrew consent1 - Physician decision1 - Physician decision2 - Other events 2 - Other events 44

Protocol 033

3RAL: Deviation from protocol (1)4LPV/r: Lost to follow-up (1), Deviation from protocol (1)

†Reasons for discontinuation were investigator determined

Protocols 032, 033 Patient Disposition


Protocols 032, 033 Patient Baseline Characteristics

Protocol 032 Protocol 033

RAL* LPV/r* RAL* LPV/r*

# Patients Treated N = 174 N = 174 N = 176 N = 178

Age (mean, years) 44.4 43.6 42.0 41.9

% Male 83.9 74.1 77.8 77.5

% Non-White 16.1 19.0 51.7 54.5

Region

EU/Australia† 117 (67.2)

121 (69.5)

20 (11.4)

20 (11.2)

North America 57 (32.8)

53 (30.5)

32 (18.2)

33 (18.5)

Latin America 75 (42.6)

83 (46.6)

Africa 26 (14.8)

20 (11.2)

Southeast Asia 23 (13.1)

22 (12.4)

*In combination with background antiretroviral therapy.†EU in Protocol 032 only


Protocols 032, 033Patient Baseline Characteristics (2)


RAL* LPV/r* RAL* LPV/r*

# Patients Treated N = 174 N = 174 N = 176 N = 178

% with vRNA ≤ 50 copies/mL 94.3 92.5 96.0 95.5

Mean CD4 count (cells/μl) 478 508 471 482

% on LPV/r ≤ 1 yr 16.7 17.8 17.6 18.5

Median yrs of prior ART (min, max)3.3

(0.3, 22.3)3.6

(0.5, 20.2) 3.7

(0.5,19.2)4.6

(0.6,16.3)

Median # of prior ART (min, max)5.0

(4.0, 16.0)5.0

(2.0,15.0)5.5

(3.0,13.0)6.0

(4.0,14.0)

*In combination with background antiretroviral therapy.


PROTOCOL 032

ARTRAL (n)

LPV/r (n)

abacavir 49 58didanosine 38 40emtricitabine 89 83lamivudine 112 112stavudine 38 40tenofovir 115 114zalcitabine 11 9zidovudine 80 84efavirenz 26 26etravirine 2 1nevirapine 19 19amprenavir 2 .atazanavir 5 3fosamprenavir . 3indinavir 19 16lopinavir 174 174nelfinavir 22 23ritonavir 174 174saquinavir 15 19tipranavir . 1enfuvirtide 2 2

PROTOCOL 033

ARTRAL (n)

LPV/r (n)

abacavir 46 46didanosine 58 65emtricitabine 48 39lamivudine 142 154stavudine 65 59tenofovir 85 73zalcitabine 6 7zidovudine 105 128delavirdine . 2efavirenz 30 50emivirine 1 .etravirine 4 6loviride 1 .nevirapine 26 31amprenavir 2 4atazanavir 7 5darunavir . 1fosamprenavir 1 1indinavir 35 42lopinavir 176 178nelfinavir 28 28ritonavir 176 178saquinavir 13 15tipranavir 2 1enfuvirtide . 1

NRTIsNNRTIsPIsFusion Inhibitor

Protocols 032, 033Prior Antiretroviral Therapies


Protocols 032, 033Concurrent ART During Study

ART

Protocol 032 Protocol 033RAL LPV/r RAL LPV/r

(N=176) (N=178) (N=173) (N=171)n (%) n (%) n (%) n (%)

TDF + FTC/3TC 87 (50.3) 80 (46.8) 58 (33.0) 44 (24.7)

ABC + FTC /3TC30 (17.3)

27 (15.8) 23 (13.0) 19 (10.7)

AZT + 3TC25 (14.5)

28 (16.4) 58 (33.0) 60 (33.7)

other combination of 2 ARTs (RTI)

16 (9.3) 20 (11.7) 21 (12.0) 38 (21.3)

1 ART† 1 (0.6) 4 (2.3) 1 (0.6)

3 or more ARTs

14 (8.1)

16 (9.4) 12 (6.8 ) 16 (9.0)

†protocol violators

TDF=tenofovir, FTC=emtricitabine, 3TC=lamivudine, ABC=abacavir, AZT=zidovudineRTI = reverse transcriptase inhibitor


FastingCholesterol

NonHDL-C

FastingTriglycerides*

Fasting LDL-C

FastingHDL-C

217 205 166 158 190 164 116 105 49 47

186 205 138 159 113 172 109 103 47 46

2%1% 2%

-15%

-2%4%

-41%

1%-1%

-13%

P<0.001P<0.001

P<0.001

P=0.704 nps**

RAL + ARTsLPV/r + ARTs

-50

-40

-30

-20

-10

0

10

20

214 211 168 164 210 219 104 104 46 48

183 212 138 166 125 237 103 104 45 46

1%1% 3%

-15%

4%8%

-43%

-3%-1%

-12%

P<0.001P<0.001

P<0.001

P=0.269 nps**

FastingCholesterol

NonHDL-C

FastingTriglycerides*

Fasting LDL-C

FastingHDL-C

*Median Percent Change **Not prespecified for test

Mean mg/dL:

At Baseline

Cha

nge

fro

m b

asel

ine

at w

eek

12,

mea

n%

At Week 12


Protocols 032, 033 Lipids-Mean Percent Change from Baseline at Week 12


In P032, 149 patients on RAL had HIV RNA < 50

copies/mL at Week 12; 134/149 (90%) remained suppressed (< 50 copies/mL) at Week 24.

152 patients on LPV/r had HIV RNA < 50 copies/mL at Week 12; 145/152 (95%) remained suppressed (< 50 copies/mL) at Week 24.

In P033, 157 patients on RAL had HIV RNA < 50

copies/mL at Week 12; 148/157 (94%) remained suppressed (< 50 copies/mL) at Week 24.

167 patients on LPV/r had HIV RNA < 50 copies/mL at Week 12; 161/167 (96%) remained suppressed (< 50 copies/mL) at Week 24.

Protocols 032, 033Percent of Patients (95% CI) With HIV RNA <50 Copies/mL(NC = F)

0 4 8 12 24

Weeks

94%

88%

Protocol 033

(95% CI) : -5.8 (-12.2, 0.2)

Number of Contributing Patients

Perc

ent

of

Pati

ents

wit

hH

IV R

NA

<5

0 C

opie

s/m

L

50

60

70

80

90

100Protocol 032

0 4 8 12 24Weeks

81%

87%

(95% CI) : -6.6 (-14.4, 1.2)

RAL + ARTs

LPV/r + ARTs

176 176 176 176 175178 178 177 177 178

174 166 169 173 172174 171 171 171 174


Protocols 032, 033 Change From Baseline in CD4 Cell Count (DAO*)

*DAO = data as observed

RAL + ARTs

LPV/r + ARTs

-60

-40

-20

0

20

40

60

C

hang

e fr

om B

asel

ine

CD

4 C

ell C

ount

(ce

lls/m

m3 )

176 169 172 168 165178 177 174 173 174

0 4 8 12 24

WeeksNumber of Contributing Patients

Protocol 033

174 159 145 149 148174 165 157 158 155

0 4 8 12 24

Weeks

Protocol 032

55

(95% CI) : -1.5 (-29.5, 26.6) (95% CI) : 6.6 (-19.0, 32.2)

17

7


Protocols 032, 033Confirmed Virologic Failures


RAL† LPV/r† RAL† LPV/r†

>400 copies/mL* 3 2 9 2

>50 copies/mL* 13 10 19 7

Based upon post-hoc data collection:

• 84% (27/32) of patients with confirmed VF (>50 c/mL) in the RAL group reported that their regimen at study entry was not their 1st ART regimen

• 66% (18/27) reported a history of VF on prior regimen(s)

†In combination with background antiretroviral therapy*Virologic failure required confirmed viral rebound at least 1-week apart


PN032 Confirmed Failures

Study Drug

Virologic Failures (>400/ml) Study drug mutations (InSTI or PI*) RTI mutations†

RAL 3

N155H K103N

None V118I, M184V; V179D

None V179E

LPV/r 2L10I/V, G16G/E, L63S, A71A/T, V77I

None

Not done Not done

Protocol 032Resistance Summary at Time of Failure

*Data derived by population sequencing. All amino acid changes from baseline observed in any of multiple independent PCR reactions are listed without regard to linkage.

†RTI mutations do not necessarily reflect concurrent OBT


Protocol 033Resistance Summary at Time of Failure

PN033 Confirmed Failures

Study Drug

Virologic Failures (>400/ml)

Study drug mutations

(InSTI or PI*) RTI mutations†

RAL 9

G140G/S, Q148R, Q148Q/H, N155N/H D67D/G, M184V, T215T/I; Y181C

N155H M184M/V; K103R

N155H, Q148Q/R, Y143Y/C D67D/N, K70K/R, M184V, K219Q

Q148H, G140S M184V; K103N, P225H

G140G/S, Q148R, Q148Q/H, N155N/H, Q148Q/R

None

N155H None

Y143Y/S, Q148Q/R None

None None

Not done Not done

LPV/r 2L10I, K20R, M36I, M46L, I54V, L63P, A71V, V82A, L90M

K65R, D67N, K219E; K103R, Y181C

V11V/I, L63P, V77I None*Data derived by population sequencing. All amino acid changes from baseline observed in any of multiple independent PCR reactions are listed without regard to linkage.†RTI mutations do not necessarily reflect concurrent OBT


Protocols 032, 033 Combined Analyses of the Subgroups (OF) Analysis of efficacy by age, race/ethnicity

demonstrated similar trends as the overall study results Response (% with HIV RNA < 50 copies/mL) Difference in

PercentResponse†

% (95% CI)RAL LPV/r

Subpopulation n/N % (95% CI) n/N % (95% CI)

Total

293/327

89.6 (85.8, 92.7)

319/338

94.4 (91.4, 96.6)

-4.8 (-9.1, -0.7)

Gender Male

233/265

87.9 (83.4, 91.6)

245/258

95.0 (91.5, 97.3)

-7.0 (-12.1, -2.3)

Female

60/62

96.8 (88.8, 99.6)

74/80

92.5 (84.4, 97.2)

4.3 (-4.4, 12.8)

Region EU/Australia

115/126

91.3 (84.9, 95.6)

125/131

95.4 (90.3, 98.3)

-4.2 (-11.0, 2.1)

North America

68/79

86.1 (76.5, 92.8)

77/83

92.8 (84.9, 97.3)

-6.7 (-17.0, 3.0)

Latin America

65/74

87.8 (78.2, 94.3)

76/82

92.7 (84.8, 97.3)

-4.8 (-15.2, 4.7)

Africa

24/25

96.0 (79.6, 99.9)

19/20

95.0 (75.1, 99.9)

1.0 (-15.6, 20.5)

Southeast Asia

21/23

91.3 (72.0, 98.9)

22/22

100.0 (84.6, 100.0)

-8.7 (-27.1, 7.1)

† The 95% CIs were calculated using Miettinen and Nurminen's method.N = Number of patients in each treatment group; n = Number of patients in each subcategory.


Protocols 032, 033 Overall Safety Summary

RAL in combination with background RTI was generally well tolerated compared with LPV/r in combination with background RTI based on statistical comparisons for clinical and laboratory AE categories› No serious drug-related AE or deaths in any

treatment group in either Protocol Grade 3 or 4 laboratory abnormalities

(excluding lipids) were uncommon (<5%) and similar between treatment groups in either protocol


Summary / Conclusions

The patient population enrolled was heterogeneous with regard to prior ART therapy and included patients who previously experienced virologic failure

Raltegravir was superior to LPV/r as measured by % change from baseline in fasting triglycerides, total, and non-HDL cholesterol at Week 12; changes in LDL and HDL from baseline were comparable between the 2 treatment groups

Raltegravir did not demonstrate non-inferiority, as measured by proportion of patients with HIV RNA < 50 copies/mL at Week 24 (NC=F)

Both raltegravir and LPV/r were generally well tolerated

In these studies where virologically suppressed patients on a LPV/r containing regimen were randomized to continue LPV/r or switch to RAL each in combination with background RTIs:


InvestigatorsMerck Research

LaboratoriesK. A. Ibarguren F. Mazzotta P. SklarA. Antinori A. Mills R. LeavittF. Antunes R. A. Myers B.-Y. NguyenK. Arasteh M. Nelson X. XuN. Bellos C. Orkin A. RodgersD. S. Berger G. Pierone M. WalkerT. Branco D. M. Poretz M. ShaughnessyP. L.W. Church A. Rachlis R. IsaacsE. DeJesus R. R. Redfield K. GottesdienerG. Faetkenheuer G. Rieg G. GallagherM. Fisher G. Rizzardini T. FinnJ. Gerstoft P. J. Ruane M. MillerJ. G. García M. S. Saag R. BarnardM. Gottlieb R. Sarmento D. HazudaJ. Hernández-Quero A. Scarsella K. StrohmaierH. Jaeger J. SlimM. A. Johnson G. H. R. SmithR. Lalonde K. E. SquiresA. Lazzarin E. TeófiloR. L. Liporace J. v. LunzenJ. L. Aldeguer S. WalmsleyF. Maltez C. WorkmanR. Marques B. YoungO. L. Mathiesen

Acknowledgements – Protocol 032


Investigators Merck Research Laboratories

C. A. Alvarez A. K. Patel P. Sklar

J. Andrade G. Perez R. Leavitt

S. M. Andrews P. J. Ruane B.-Y. Nguyen

T. Anekthananon S. Santiago X. Xu

A. I. Arango D. G. Saple A. Rodgers

E. Baraldi S. R. Schrader M. Walker

T. B. Campbell K. Y. Smith M. Shaughnessy

D. A. Cooper T. N. L. Souza R. Isaacs

I. Frank S. Sungkanuparph K. Gottesdiener

J. Garcia-Diaz S. Swaminathan G. Gallagher

J. Gathe M. A. Thompson T. Finn

J. Gold I. Torres M. Miller

D. W. Johnson J. D. Velez R. Barnard

P. N. Kumar D. Wohl D. Hazuda

P. E. L. Leiva C. Workman K. Strohmaier

O. M., Leite D. P. Wright

F. C. M. Urbina R. ZajdenvergS. Miller

Acknowledgements – Protocol 033


Switching from Stable Lopinavir/Ritonavir (LPV/r)-Based to Raltegravir (RAL)-Based Combination

Antiretroviral Therapy (ART) Resulted In a Superior Lipid Profile at Week 12 but Did Not Demonstrate

Non-Inferior Virologic Efficacy at Week 24

Joseph Eron*1, Jaime Andrade2, Roberto Zajdenverg3, Cassy Workman4, David A. Cooper5, Benjamin Young6, Xia Xu7,

Bach-Yen Nguyen7, Randi Leavitt7, and Peter Sklar7

1University of North Carolina, Chapel Hill, NC, USA; 2Antinguo Hospital Civil de Guadalajara, Guadalajara, Mexico; 3Hospital Escola Sao Francisco de Assis, Rio de

Janeiro, Brazil; 4AIDS Research Initiative, Darlinghurst, Australia; 5University of New South Wales, Sydney, Australia; 6Denver Infectious Disease Consultants,

Denver, CO, USA; and 7Merck Research Laboratories, West Point, PA, USA

copyright © 2009 merck & co., inc. whitehouse station, nj, usa all rights reserverd joseph...

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