a two-year randomised controlled clinical trial in antiretroviral-naïve subjects using...

A two-year randomised controlled clinical trial in antiretroviral-naïve subjects using lopinavir/ritonavir monotherapy after initial

induction treatment compared to an efavirenz 3-drug regimen.

96 week results, Study M03-613 DW Cameron1, BA da Silva2, JR Arribas3, R Myers4, NC Bellos5,

N Gilmore6, KR Niemi2, KJ Wikstrom2, MS King2, GJ Hanna2, SC Brun2

1University of Ottawa at The Ottawa Hospital, Ottawa, Ontario, Canada 2Abbott Laboratories, Abbott Park, IL, USA 3Hospital La Paz, Madrid, Spain 4Body Positive, Inc., Phoenix, AZ, USA 5Southwest Infectious Disease Associates, Dallas, TX, USA 6Montréal Chest Institute, Montréal, Québec, Canada

Oral Presentation #THLB0201

AIDS2006 – 17 August 2006 2

Study design and methods

Screening

LPV/r SGC 400/100 mg BID

+ ZDV/3TC(n=104)

EFV 600 mg QD+ ZDV/3TC (n=51)

96 weeks

LPV/r 400/100 mg BID

LPV/r 400/100 mg BID+ ZDV/3TC

2:1 randomisation, open trial

VL monitored monthly for 18 months, then every 2 months through month 24

In the LPV/r group, subjects with VL < 50 / mL for 3 consecutive months from month 3 to 11 discontinued ZDV/3TC at the next visit (earliest month 6), and remained on LPV/r monotherapy. Subjects not meeting these criteria remained on LPV/r + ZDV/3TC

Primary outcome: HIV-1 viral load < 50 c/mL at week 96 (24 months)Primary analysis: intention-to-treat, prior failure (> 50 c/mL x 2) = failure

Rx naïveHIV-1 RNA >1000Any CD4 countNo evidence of resistance to study drugs

AIDS2006 – 17 August 2006 3

Demographics

Gender maleAge* (years) mean (range)

HIV-1 VL** (log10 / mL) mean (range) >100,000/mLCD4 (cells/L) mean (range)

Race/ethnicity*** Caucasian Black Hispanic Other

LPV/r(n=104)

EFV(n=51)

84 (81%)

40 (18 – 73)

5.0 (3.4 - 6.5)44 (42%)

227 (6 - 773)

68 (65%)29 (28%)6 (6%)7 (7%)

39 (77%)

35 (18 - 56)

4.8 (3.5 - 6.2)16 (31%)

250 (3 - 756)

32 (63%)17 (33%)8 (16%)2 (4%)

* p=0.003** p=0.04*** some state more than one category

AIDS2006 – 17 August 2006 4

Disposition

51 subjects EFV + ZDV/3TC

104 subjects LPV/r + ZDV/3TC

2 switched to EFV, subsequently d/c

71 completed study on LPV/r alone

Median(range) weeks on monotherapy:68 (56-72) weeks

34 completed study on EFV + NRTIs

155 subjects randomised and dosed

8 completed study on LPV/r + NRTIs

(2 never deintensified, 6 restarted NRTIs)

4 switched to LPV/r, remain on LPV/r

3 switched to LPV/r, subsequently d/c

10 discontinued study from EFV

8 d/c study prior to deintensification

15 d/c study after deintensification

AIDS2006 – 17 August 2006 5

Discontinuations

Subjects enrolledPremature discontinuationsReasons for discontinuation1

Death2

Adverse Event3

Lost to follow-up

Noncompliance

Withdrew Consent

Virologic failure

Other reasons4

LPV/r EFV

2 (2%)

3 (3%)

5 (5%)

3 (3%)

6 (6%)

2 (2%)

10 (10%)

10425 (24%)

5113 (25%)

1 (2%)

1 (2%)

4 (8%)

3 (6%)

4 (8%)

0

5 (10%)1 Investigator may have indicated more than one reason for discontinuation

2 Both LPV/r deaths were considered unrelated to LPV/r (Burkitts Lymphoma and ethylene glycol ingestion)

3 Includes subject who died due to Burkitts Lymphoma

4 Primarily site closure (n=6) or subject moving out of area (n=5)

AIDS2006 – 17 August 2006 6

Primary outcome analysis: HIV-1 viral load < 50 c/mL (ITT, prior failure = failure)

WeekSample SizeLPV/r ArmEFV Arm

10451

0%

20%

40%

60%

80%

100%

0 16 32 48 64 80 96

Pe

rce

nt

LPV/r Arm

EFV Arm

61%

50%

p=0.23*

* Week 96 comparison

WeekSample SizeLPV/r ArmEFV Arm

10451

Sample SizeLPV/r ArmEFV Arm

10451

0%

20%

40%

60%

80%

100%

0 16 32 48 64 80 96

Pe

rce

nt

LPV/r Arm

EFV Arm

61%

50%

p=0.23*

* Week 96 comparison0%

20%

40%

60%

80%

100%

0 16 32 48 64 80 96

Pe

rce

nt

LPV/r Arm

EFV Arm

61%

50%

p=0.23*


AIDS2006 – 17 August 2006 7

Secondary outcome analysis: HIV-1 viral load < 50 c/mL (ITT, non-completer = failure)

0%

20%

40%

60%

80%

100%

0 16 32 48 64 80 96

Pe

rce

nt

LPV/r Arm

EFV Arm

Week

63%63%


p>0.99*


10451

0%

20%

40%

60%

80%

100%

0 16 32 48 64 80 96

Pe

rce

nt

LPV/r Arm

EFV Arm

Week

63%63%


p>0.99*


10451


10451

AIDS2006 – 17 August 2006 8

0%

20%

40%

60%

80%

100%

0 16 32 48 64 80 96

Pe

rce

nt

LPV/r Arm

EFV Arm

Week

65%

72%


p=0.36*


10451

0%

20%

40%

60%

80%

100%

0 16 32 48 64 80 96

Pe

rce

nt

LPV/r Arm

EFV Arm

Week

65%

72%


p=0.36*


10451


10451

Secondary outcome analysis: HIV-1 viral load < 500 c/mL (ITT, non-completer = failure)

AIDS2006 – 17 August 2006 9

92 67 4843 36 31

No. at riskLPV/r Arm EFV Arm

Time from LPV/r monotherapy to 1st of 2 VL > 50 c/mLLPV/r maintenance versus corresponding EFV subjects

0%

20%

40%

60%

80%

100%

0 8 16 24 32 40 48 56 64 72

% M

ain

tain

ing

Re

sp

on

se

LPV/r ArmEFV Arm

Weeks since switch to maintenance (LPV/r arm) or 3rd consecutive HIV-1 RNA value <50 copies/mL (EFV arm)

90%

62%

P<0.001 (log-rank test)

0%

20%

40%

60%

80%

100%

0 8 16 24 32 40 48 56 64 72

% M

ain

tain

ing

Re

sp

on

se

LPV/r ArmEFV Arm


90%

62%



90%

62%


AIDS2006 – 17 August 2006 10

92 83 6343 36 31

No. at riskLPV/r Arm EFV Arm

Time from LPV/r monotherapy to 1st of 2 VL > 500 c/mL LPV/r maintenance versus corresponding EFV subjects

0%

20%

40%

60%

80%

100%

0 8 16 24 32 40 48 56 64 72

% M

ain

tain

ing

Re

sp

on

se

LPV/r ArmEFV Arm


95%84%

p=0.18 (log-rank test)

0%

20%

40%

60%

80%

100%

0 8 16 24 32 40 48 56 64 72

% M

ain

tain

ing

Re

sp

on

se

LPV/r ArmEFV Arm


95%84%

p=0.18 (log-rank test)

AIDS2006 – 17 August 2006 11

Point prevalence of disposition and HIV-1 viral loads

0%

20%

40%

60%

80%

100%

0 16 32 48 64 80 96

Discon-tinued

On study,HIV RNA>500 c/mL

On study,HIV RNA 50-500 c/mL

On study,HIV RNA <50c/mL

0 16 32 48 64 80 96

Week Week

LPV/r

0%

20%

40%

60%

80%

100%

0 16 32 48 64 80 96

Discon-tinued

On study,HIV RNA>500 c/mL

On study,HIV RNA 50-500 c/mL

On study,HIV RNA <50c/mL

0 16 32 48 64 80 96

Week Week

EFV + NRTIsLPV/r

AIDS2006 – 17 August 2006 12

Outcome of HIV-1 viral load breakthrough on LPV/r monotherapy

VL Breakthrough > 500 c/mL

(n=8)

> 50 & not > 500 c/mL

(n=17)

Re-suppression* in those with subsequent data available

5 / 7 (71%) 13 / 16 (81%)

* Re-suppression means at least one subsequent VL measure < 50 c/mL

AIDS2006 – 17 August 2006 13

CD4 count response(observed data, mean change from baseline)

0

50

100

150

200

250

300

350

0 16 32 48 64 80 96

Ce

lls/µ

L

LPV/r Arm

EFV Arm

WeekSample SizeLPV/r Arm EFV Arm

104 91 7651 38 31

+289

+240

p=0.12*


AIDS2006 – 17 August 2006 14

Detection of genotypic resistance mutations

LPV/r

Genotype results available 15

PI mutation 3 / 15 (20%)*

M184V 2 / 15 (13%)

* 2 subjects on monotherapy, and 1 subject on combination therapy

EFV

Genotype results available 5

NNRTI mutation 1 / 5 (20%)

M184V 1 / 5 (20%)

AIDS2006 – 17 August 2006 15

Summary and conclusions• With successful LPV/r + ZDV / 3TC treatment, subsequent

LPV/r monotherapy continuously maintained VL suppression in a large proportion of patients

• Patients receiving LPV/r monotherapy experienced more VL breakthrough of 50 - 500 c/mL versus EFV + ZDV / 3TC

• LPV/r monotherapy VL breakthrough was usually 50 - 500 c/mL

• VL breakthrough generally re-suppressed to < 50 c/mL• Detection of drug resistance mutations did not differ in

proportion for LPV/r versus EFV

• LPV/r monotherapy may provide an alternative treatment option for selected patients

AIDS2006 – 17 August 2006 16

Acknowledgements

CanadaDr. Anita Rachlis, TorontoDr. Stephen Shafron, EdmontonDr. Sharon Walmsley, Toronto

FranceDr. Laurent Cotte, LyonDr. Veronique Joly, Paris

SpainDr. Bonaventure Clotet, BarcelonaDr. Pere Domingo, BarcelonaDr. Fernando Dronda, MadridDr. Frederico Pulido, MadridDr. Rafael Rubio, Madrid

United KingdomDr. Philippa Easterbrook, LondonProf. Brian Gazzard, LondonDr. Clifford Leen, EdinburghDr. Ed Wilkins, Manchester

United StatesDr. Rafael Campo, Miami, FLDr. Paul Cimoch, Fountain Valley, CADr. Calvin Cohen, Boston, MADr. Charles Farthing, Los Angeles, CADr. Joseph Gathe Jr., Houston, TXDr. Charles Hicks, Durham, NCDr. Harold Katner, Macon, GADr. Harold Kessler, Chicago, ILDr. George McKinley, New York, NYDr. David Parenti, Washington DCDr. Gerald Pierone, Vero Beach, FLDr. Robert Redfield, Baltimore, MDDr. Patricia Salvato, Houston, TX

Abbott Study 613 study team Marion DeHaan, Karmin Robinson, Mary Woulfe, Florence McMillan

In addition to the authors, we would like to thank the rest of the M03-613 investigators, all study coordinators, and all study participants

a two-year randomised controlled clinical trial in antiretroviral-naïve subjects using...

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