The MONET trial: darunavir/ritonavir monotherapy shows non-inferior efficacy to standard HAART, for patients with HIV RNA Publish Susan Walton, Modified 6 years ago

The MONET trial: darunavir/ritonavir The MONET trial: darunavir/ritonavir monotherapy shows non-inferior efficacy to monotherapy shows non-inferior efficacy to standard HAART, for patients with HIV RNA standard HAART, for patients with HIV RNA

<50 copies/mL at baseline<50 copies/mL at baselineJR Arribas, A Horban, J Gerstoft, G FJR Arribas, A Horban, J Gerstoft, G Fätkenheuer, M Nelson, N Clumeck, F Pulido, A Hill, tkenheuer, M Nelson, N Clumeck, F Pulido, A Hill, Y van Delft, C Moecklinghoff, T Stark for the MONET Study GroupY van Delft, C Moecklinghoff, T Stark for the MONET Study Group

Oral Late-Breaker presentation at 5th IAS ConferenceOral Late-Breaker presentation at 5th IAS ConferenceCape Town, South Africa, July 2009Cape Town, South Africa, July 2009 #TUAB106-LB#TUAB106-LB

MONET - Trial DesignMONET - 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

4, 12, 24, 36, 48 weeks96 wks

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).

Follow-upphase 96 weeks

256 subjects

DRV/r 800/100 mg OD+ 2 NRTI (re-optimised at baseline)

n = 129

DRV/r 800/100 mg ODn = 127

Follow-upphase 96 weeks

No run-in period

SC

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

30 days BL


MONET: Study Design and ObjectivesMONET: 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)

57912%

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 (%)

43 (24-72)83%90%

43 (25-67)78%92%

Age, years (median, range) Male (%) Caucasian (%)

DRV/r + 2NRTI (n=129)

DRV/r (n=127)

0

10

20

30

40

50

60

70

80

90

100

DRV/r + 2NRTI (PP) DRV/r mono (PP) DRV/r + 2NRTI (ITT) DRV/r mono (ITT)

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

Table EFF 4-5

HIV RNA<50 byWeek 48(%)

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

N=123 N=123 N=129 N=127

87.8% 86.2% 85.3% 84.3%

-1.6%; lower limit 95%CI: -10.1% -1%; lower limit 95%CI: -9.9%



MONET trial: sensitivity analysesMONET trial: sensitivity analyses

PP, HIV RNA <200, TLOVR, switch equals failure

0%

Difference in 48 week HIV RNA response rate between DRV/r mono and DRV/r + 2NRTI arms (95% confidence intervals)

DRV/r + 2NRTI better

-7.0% -1.8% +3.5%

-12% Analysis

ITT, HIV RNA <50, TLOVR, switch included (S F)

-1.6% +4.2%

Observed HIV RNA <50

Observed HIV RNA <200-0.8% +2.6%-4.2%

-9.5% -3.2% +3.1%

94.8% vs 96.6%

93.5% vs 95.1%

91.3% vs 94.6%

97.6% vs 98.4%

-7.4%


DRV/r + 2NRTI: n=129

HIV RNA<50: 110

Baseline

Treatment

period

Last visit

HIV RNA>50

x2: n=7 (TLOVR)

d/c or changed

treatment, n=9

HIV RNA<50: 6

HIV RNA>50: 1

HIV RNA<50: 8

no data: 1

Missing data

n=3

HIV RNA<50: 2

RNA <50 wk36: 1

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

HIV RNA<50: 97.7% 126/129


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

DRV/r monotherapy: n=127

HIV RNA<50: 107

Baseline

Treatment

period

Last visit

HIV RNA>50

x2: n=11 (TLOVR)

d/c or changed

treatment, n=9

HIV RNA<50: 10

HIV RNA>50: 1

HIV RNA<50: 7

HIV RNA>50: 2

Missing data

n=0

HIV RNA<50: 97.6% 124/127

MONET: Drug resistanceMONET: Drug resistance

1 0DRV mutations

11 Primary IAS-USA PI mutations

01M184V

21/22 (96%) 12/13 (92%)No primary PI, DRV or NRTI mutations

2213 Patients with at least 1 successful genotype

DRV/r mono

N=127

DRV/r + 2NRTI

N=129Genotypic results

1 patient per arm had any evidence of genotypic resistanceNo patients had phenotypic resistance to DRV


Median CD4 count:cells/uL

Time - weeks

DRV/r + 2NRTI (n=129)

DRV/r mono (n=127)

MONET: Median CD4 Cell Count (Observed) – ITTMONET: Median CD4 Cell Count (Observed) – ITT

2 (1.6%)

0 (0%)

6 (4.7%)

7 (5.5%)

(N=127)

DRV/r mono

5 (3.9%) GI (all AEs)

2 (1.6%)Diarrhea

(N=129)

2 (1.6%)Rash (all types)

1 (0.8%))Nausea

DRV/r + 2NRTI

Gr 2–4 AEs† ≥2% incidence, n (%)

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

MONET: Grade 2–4 drug related MONET: Grade 2–4 drug related clinical adverse eventsclinical adverse events


6 (4.8%)2 (1.6%)Total cholesterol >7.77 mmol/l, sustained

6* (4.0%) 1 (0.8%)AST >5 x ULN

4 (3.2%)3 (2.3%)Lipase >3 x ULN

6* (4.8%)2* (1.6%)ALT >5 x ULN

n = 126n = 129

DRV/r monoDRV/r + 2NRTI

> 2 % Incidence, n (%)*

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

MONET: Grade 3 / 4 Laboratory abnormalities MONET: Grade 3 / 4 Laboratory abnormalities (Worst values)(Worst values)


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).


Efficacy of darunavir/ritonavir as single-drug Efficacy of darunavir/ritonavir as single-drug maintenance therapy in patients with HIV-1 maintenance therapy in patients with HIV-1 viral suppression: a randomized open-label viral suppression: a randomized open-label

non-inferiority trial, MONOI-ANRS 136non-inferiority trial, MONOI-ANRS 136

C. Katlama et al #WELBB102C. Katlama et al #WELBB102

WEDNESDAY. LATE BREAKERS TRACK B. WEDNESDAY. LATE BREAKERS TRACK B. Session Room 1. 13:10Session Room 1. 13:10



Country and Race

Israel3.1%

Hungary4.3%

Germany10.9%

Denmark10.9%

Belgium9.4%

Austria6.3%

UK8.2%

Switzerland0.8%

Spain18.8%

Russia4.3%

Portugal5.5%

Poland11.3% Italy

6.3%

MONET: AcknowledgementsMONET: Acknowledgements

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


MONET: AcknowledgementsMONET: Acknowledgements

Participating centers:Austria: A. Rieger, N. VetterBelgium: N. Clumeck, E. FlorenceSwitzerland: P. VernazzaGermany: G. Fätkenheuer, A. Stoehr, W. Schmidt, M, Stoll, C. StephanDenmark: J. Gerstoft, C. Pedersen, L. MathiesenSpain: B. Clotet, F. Pulido, J. Arribas, J. Gatell, J. Iribarren, R. Rubio, J. PasquauUnited Kingdom: M. Johnson, B. Peters, M. Nelson, A. Winston, Hungary: D. BanhegyiIsrael: S. MaayanItaly: A. Lazzarin, A. Antinori, F. Suter, A. D‘Arminio Monforte, G. CarosiPoland: A. HorbanPortugal: F. Antunes, R. MarquesRussia: 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.

Documents

The MONET trial: darunavir/ritonavir monotherapy shows non-inferior efficacy to standard HAART, for patients with HIV RNA Publish Susan Walton, Modified 6 years ago