The MONET trial: darunavir/ritonavir monotherapy shows non-inferior efficacy to standard HAART, for ...
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The MONET trial: darunavir/ritonavir monotherapy shows non-inferior efficacy to standard HAART, for patients with HIV RNA <50 copies/mL at baseline.

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MONET - Trial Design

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Monet trial design

The MONET trial: darunavir/ritonavir monotherapy shows non-inferior efficacy to standard HAART, for patients with HIV RNA <50 copies/mL at baseline

JR Arribas, A Horban, J Gerstoft, G Fätkenheuer, M Nelson, N Clumeck, F Pulido, A Hill, Y van Delft, C Moecklinghoff, T Stark for the MONET Study Group

Oral Late-Breaker presentation at 5th IAS Conference

Cape Town, South Africa, July 2009

#TUAB106-LB


Monet trial design

DRV/r 800/100 mg OD

+ 2 NRTI (re-optimised at baseline)

n = 129

Follow-up

phase 96 weeks

256 subjects

No run-in period

DRV/r 800/100 mg OD

n = 127

Follow-up

phase 96 weeks

MONET - Trial Design

  • Taking 2 NRTI + either NNRTI or boosted PI at screening (stratified)

  • No prior use of darunavir (DRV)

  • HIV RNA <50 copies/mL for at least 6 months,

  • No history of virological failure

96 wks

BL

SC

30 days

4, 12, 24, 36, 48 weeks

  • Primary Endpoint:HIV RNA< 50 at week 48 (TLOVR). Per Protocol, Switch = Failure

  • 2 consecutive HIV RNA > 50 copies/mL (Roche Amplicor HIV-1 Monitor assay 1.5)

  • Stopping DRV/r

  • Starting NRTIs in the monotherapy arm

  • Stopping NRTIs in the triple therapy arm (switches in NRTIs were permitted at any time).

J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB


Monet study design and objectives

MONET: Study Design and Objectives

Primary objective: to show non-inferior efficacy for DRV/r monotherapy (800/100 mg OD dose) versus standard HAART (DRV/r + 2 NRTI).

Study power: 80% to show non-inferiority for DRV/r vs DRV/r + 2 NRTIs, with a sample size of 125 patients per arm (delta = -12%).

Analysis:

Per protocol (PP): excluded patients with major protocol violations such as a history of virological failure, or patients randomised incorrectly (n = 10).

Time to loss of virolgical response (TLOVR)

Observed: only virological endpoints.

Intent To Treat (ITT) – all randomised patients

Switch = Failure (S = F)

Switch Included (S  F)

All patients were followed up to Week 48


Monet baseline characteristics itt

MONET: Baseline Characteristics (ITT)

Age, years (median, range)

Male (%)

Caucasian (%)

43 (24-72)

83%

90%

43 (25-67)

78%

92%

579

12%

6.4 (4.0)

57%

43%

48%

28%

2 (1.6%)

14 (11.2%)

571

14%

7.4 (4.2)

56%

44%

35%

23%

1 (0.8%)

24 (19.0%)

Disease characteristics

CD4 count (median, cells/uL)

CD4 <350 cells/uL (%)

Duration of prior ARVs, years (mean, sd)

Use of PI at screening (%)

Use of NNRTI at screening (%)

On their first NRTI combination

PI naïve

Hep B Surface Antigen, positive, n (%)

Hep C Antibody, positive, n (%)

DRV/r + 2NRTI (n=129)

DRV/r

(n=127)


Monet primary efficacy analysis hiv rna 50 copies ml at week 48 tlovr s f

MONET: Primary Efficacy Analysis:HIV RNA <50 copies/mL at Week 48, TLOVR, S = F

Per Protocol analysis (PP)Intent to Treat analysis (ITT)

Primary analysis

  • 1.6%; lower limit 95%CI: -10.1%

  • 1%; lower limit 95%CI: -9.9%

100

87.8%

86.2%

85.3%

84.3%

90

80

HIV RNA

<50 by

Week 48

(%)

70

60

50

40

30

20

10

0

DRV/r + 2NRTI (PP)

DRV/r mono (PP)

DRV/r + 2NRTI (ITT)

DRV/r mono (ITT)

N=129

N=123

N=123

N=127

Table EFF 4-5

J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB


Monet trial sensitivity analyses

MONET trial: sensitivity analyses

Difference in 48 week HIV RNA response rate between

DRV/r mono and DRV/r + 2NRTI arms (95% confidence intervals)

Analysis

-12%

0%

-1.8%

-7.0%

+3.5%

PP, HIV RNA <200,

TLOVR, switch equals failure

94.8% vs 96.6%

-1.6%

+4.2%

-7.4%

ITT, HIV RNA <50,

TLOVR, switch included(S  F)

93.5% vs 95.1%

-9.5%

-3.2%

+3.1%

Observed HIV RNA <50

91.3% vs 94.6%

-0.8%

+2.6%

-4.2%

Observed HIV RNA <200

97.6% vs 98.4%

DRV/r + 2NRTI better


Monet trial design

MONET: Patient outcomes in DRV/r + 2 NRTI (ITT)

Baseline

DRV/r + 2NRTI: n=129

d/c or changed

treatment, n=9

Missing data

n=3

HIV RNA>50

x2: n=7 (TLOVR)

Treatment

period

HIV RNA<50: 2

RNA <50 wk36: 1

HIV RNA<50: 110

HIV RNA<50: 6

HIV RNA>50: 1

HIV RNA<50: 8

no data: 1

Last visit

HIV RNA<50: 97.7% 126/129


Monet patient outcomes in drv r monotherapy itt

MONET: Patient outcomes in DRV/r monotherapy (ITT)

Baseline

DRV/r monotherapy: n=127

Missing data

n=0

HIV RNA>50

x2: n=11 (TLOVR)

d/c or changed

treatment, n=9

Treatment

period

HIV RNA<50: 107

HIV RNA<50: 10

HIV RNA>50: 1

HIV RNA<50: 7

HIV RNA>50: 2

Last visit

HIV RNA<50: 97.6% 124/127


Monet drug resistance

MONET: Drug resistance

Genotypic results

DRV/r + 2NRTI

N=129

DRV/r mono

N=127

Patients with at least 1 successful genotype

13

22

No primary PI, DRV or NRTI mutations

21/22 (96%)

12/13 (92%)

M184V

1

0

Primary IAS-USA PI mutations

1

1

DRV mutations

0

1

1 patient per arm had any evidence of genotypic resistance

No patients had phenotypic resistance to DRV

J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB


Monet trial design

MONET: Median CD4 Cell Count (Observed) – ITT

Median

CD4

count:

cells/uL

DRV/r + 2NRTI (n=129)

DRV/r mono (n=127)

Time - weeks


Monet trial design

MONET: Grade 2–4 drug related

clinical adverse events

Gr 2–4 AEs† ≥2% incidence, n (%)

DRV/r mono

DRV/r + 2NRTI

(N=129)

(N=127)

GI (all AEs)

5 (3.9%)

7 (5.5%)

Diarrhea

2 (1.6%)

6 (4.7%)

Nausea

1 (0.8%))

0 (0%)

Rash (all types)

2 (1.6%)

2 (1.6%)

†At least possibly related to study drug, excluding laboratory-related events

J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB


Monet trial design

MONET: Grade 3 / 4 Laboratory abnormalities

(Worst values)

> 2 % Incidence, n (%)*

DRV/r + 2NRTI

DRV/r mono

n = 129

n = 126

ALT >5 x ULN

2* (1.6%)

6* (4.8%)

AST >5 x ULN

1 (0.8%)

6* (4.0%)

Lipase >3 x ULN

3 (2.3%)

4 (3.2%)

Total cholesterol >7.77 mmol/l, sustained

2 (1.6%)

6 (4.8%)

* 7 of the 8 cases of ALT and AST elevations were associated with Hepatitis A or C

co-infection

J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB


Conclusions

Conclusions

  • Darunavir/ritonavir monotherapy showed consistently non-inferior efficacy versus triple antiretroviral drug treatment at Week 48.

  • Most elevations in HIV RNA were low level (50-400 copies/mL), and patients were re-suppressed <50 copies/mL at last visit, either on the original randomised treatment or with intensified treatment.

  • There were no patients with phenotypic resistance to darunavir during the trial – one patient per arm showed at least one genotypic PI mutation.

  • No new or unexpected safety signals were detected (details submitted to EACS and AELD conferences).

J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB


Monet trial design

Efficacy of darunavir/ritonavir as single-drug maintenance therapy in patients with HIV-1 viral suppression: a randomized open-label non-inferiority trial, MONOI-ANRS 136

C. Katlama et al #WELBB102

WEDNESDAY. LATE BREAKERS TRACK B.

Session Room 1. 13:10

J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB


Monet acknowledgements

MONET: Acknowledgements

Thanks to all the 256 patients who participated in the MONET trial, plus the investigators and study monitors


Monet acknowledgements1

MONET: Acknowledgements

Participating centers:

Austria: A. Rieger, N. Vetter

Belgium: N. Clumeck, E. Florence

Switzerland: P. Vernazza

Germany: G. Fätkenheuer, A. Stoehr, W. Schmidt, M, Stoll, C. Stephan

Denmark: J. Gerstoft, C. Pedersen, L. Mathiesen

Spain: B. Clotet, F. Pulido, J. Arribas, J. Gatell, J. Iribarren, R. Rubio, J. Pasquau

United Kingdom: M. Johnson, B. Peters, M. Nelson, A. Winston,

Hungary: D. Banhegyi

Israel: S. Maayan

Italy: A. Lazzarin, A. Antinori, F. Suter, A. D‘Arminio Monforte, G. Carosi

Poland: A. Horban

Portugal: F. Antunes, R. Marques

Russia: N Zakharova, V. Pokrovsky

The authors would like to thank the patients and their families for their participation and support during the study, and the MONET study team and co-investigators for their collaboration.

This study was sponsored by Tibotec, a division of Janssen-Cilag.


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