Switch to DRV/r monotherapy

MONOI MONET PROTEA DRV600

Design

Objective– Non inferiority in the proportion of patients with HIV-1 RNA < 50 c/mL at

W48 (per-protocol analysis, switch= failure, TLOVR algorithm) ; lower limit of the 95% CI for the difference= - 12%, 80% power

DRV/r 800/100 mg qd+ 2 NRTIs (optimisation at D0**)

DRV/r 800/100 mg qd

Randomisation*1 : 1

Open-label

Randomisation*1 : 1

Open-label

293 HIV+ adultsOn 2 NRTIs + (PI or NNRTI)

Darunavir-naïveNo history of prior virologic failureHIV-1 RNA < 50 c/mL > 6 months

293 HIV+ adultsOn 2 NRTIs + (PI or NNRTI)

Darunavir-naïveNo history of prior virologic failureHIV-1 RNA < 50 c/mL > 6 months

N = 127

N = 129

W48W48

* Randomisation was stratified on the use of PI or NNRTI(57% patients on PI, 43% on NNRTI)** NRTI used at baseline: TDF + FTC = 46% ; ABC + 3TC: 31% ;ZDV + 3TC = 10% ; TDF + 3TC = 7% ; other combinations: 6%

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy

Arribas J, AIDS 2010;24:223-230MONETMONET

W144W144

DRV/r qd+ 2 NRTIs

DRV/r qdmonotherapy

Mean age, years 44 43

Female 17% 22%

IV drug user 9% 16%

HCV antibody positive 9% 17%

CD4 cell count, mean/mm3 579 571

Duration of ARV treatment, years 5.9 7.4

PI treatment at screening 57% 56%

NNRTI treatment at screening 43% 44%

Protease inhibitor naïve at screening 28% 23%

Protocol defined treatment failure at W48, n (%) 19 (15%) 20 (16%)

Discontinuation for adverse event 0 4

Confirmed HIV RNA elevation 7 11

Baseline characteristics and patient disposition

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy

Arribas J, AIDS 2010;24:223-230MONETMONET

At baseline, 13 patients had HIV-1 RNA levels > 50 c/mL (9 in the monotherapy arm and 4 in the triple therapy arm) despite having results < 50 c/ml at screening

Results: W48 outcome

Arribas J, AIDS 2010;24:223-230MONETMONET

DRV/r + 2 NRTIs DRV/r qd monotherapy

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy

0

25

50

100

75

87.8% 84.3%

123

%

85.3%

123 129 127

86.2%

Per-protocol(primary endpoint) ITT

N=

HIV-1 RNA < 50 c/mL(TLOVR, switch = failure)

95% CI for the difference

= - 10.1 ; 6.8

95% CI for the difference

= - 9.9 ; 8.8

95% CI for the difference

= - 7.4 ; 4.2

93.5%95.1%

ITT, switch-includedanalysis

Non inferiority of DRV/r monotherapy

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy

Patient HIV RNA values(c/mL)

Change inTreatment

Last HIV RNA(c/mL)

DRV/rmonotherapyarm

1 140 ; 133 None < 502 59 ; 214 ZDV/3TC + NVP < 503 132 ; 139 LPV/r monotherapy < 504 539 ; 862 TDF/FTC/EFV < 505 67 ; 810 None 8106 40.500 ; 628 None < 507 158 ; 140 ABC/3TC + DRV/r < 508 51 ; 80 None < 509 106 ; 268 TDF/FTC + DRV/r < 50

10 722 ; 157 TDF/FTC + DRV/r < 5011 779 ; 267 ABC/3TC + DRV/r < 50

Triple therapyarm (DRV/r + 2 NRTIs)

1 294 ; 116 None < 502 54.000 ; 3.400 None < 503 78 ; 50 None < 504 164 ; 67 None < 505 989 ; 59 None < 506 746 ; 2.230 None 2.2307 128 ; 548 None < 50

Outcomes of confirmed HIV RNA elevations

Arribas J, AIDS 2010;24:223-230MONETMONET

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy

Patient

Reasonfor discontinuation

Change inTreatment

Last HIV RNA(c/mL)

DRV/rmonotherapy arm

12 History of virologic failure ABC/3TC + ATV/r < 50

13 Adverse event TDF + 3TC + EFV < 50

14 Investigator decision TDF/FTC + LPV/r < 50

15 Adverse event ABC/3TC + NVP < 50

16 Adverse event ABC/3TC + ATV/r < 50

17 Withdrew consent ZDV/3TC + EFV < 50

18 History of virologic failure None < 50

19 Adverse event Off all ARVs > 75 000

20 In prison None < 50

8 Withdrew consent TDF/FTC + NVP < 50

9 Withdrew consent ZDV/3TC + NVP < 50

Triple therapy arm (DRV/r + 2 NRTIs)

10 Pregnancy ZDV/3TC + NVP < 50

11 Investigator decision NZDV/3TC + NVP < 50

12 Private reasons TDF + ZDV + 3TC < 50

13 Pregnancy ZDV/3TC + LPV/r < 50

14 History of virologic failure None < 50

15 RNA > 50 c/mL at SCR + BL None No data

16 Switched to DRV/r DRV/r monotherapy < 50

Outcomes of discontinuations from the trial

Arribas J, AIDS 2010;24:223-230MONETMONET

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy

In multivariate analysis, hepatitis C co-infection was a significant predictor of confirmed HIV RNA elevations (p < 0.01)

Resistance data: Genotype was available for 35/61 patients with HIV RNA > 50 c/mL (22 in the monotherapy group and 13 in the triple therapy group)– Resistance mutations to PI in 1 one patient in each arm, with no phenotypic

resistance to DRV. HIV-1 RNA returned to < 50 c/mL without changing therapy in both patients

Most common grade 2 to 4 adverse events (AE) were gastrointestinal Serious AE were seen in 9 patients in each group Discontinuation for AE by W48 occurred in 8 patients in the monotherapy

group and 3 in the triple therapy group Grade 1 to 4 nervous system AE were seen in 16% of patients in each

group, and Grade 1 to 4 psychiatric AE in 9% of patients in each group There were more haematological abnormalities in the triple therapy arm,

related to zidovudine

Arribas J, AIDS 2010;24:223-230MONETMONET

Other endpoints

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy

Conclusions from W48 data– In patients with virologic suppression on standard triple therapy

(2 NRTIs + 1 NNRTI or 1 PI), once-daily DRV/r monotherapy has shown non inferior HIV RNA suppression at week 48 compared with a standard therapy of 2 NRTIs + once-daily DRV/r

– A switch to once-daily DRV/r monotherapy can be considered in patients who have HIV RNA < 50 c/mL for more than 6 months on other treatments and no history of virologic failure, but wish to avoid toxicities related to other ARVs

Arribas J, AIDS 2010;24:223-230MONETMONET

Monotherapy is not noninferior with switch = failure analysis at W96

– Δ -5.8% (95% CI: -16.0% to +4.4%)

If resuppression with intensification included as success, then monotherapy is noninferior at W96– Δ +1.4% (95% CI: -5.5% to +8.3%)

Rieger A, et al. AIDS 2010. Abs. THLBB209

HIV-1 RNA < 50 c/mL at W96, ITT, TLOVR (%)

40

0

100

20

80

60

DRV/r monotherapy (N = 127)

DRV/r + 2 NRTIs (N = 129)

80.674.8

Switch = failure

92.1 90.7

Switch allowed

MONETMONET

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy

Results: W96 outcome

HIV-1 RNA < 50 c/mL at W144 (ITT-TLOVR) 2 consecutive HIV-1 RNA > 50

c/mL:– DRV/r monotherapy, N = 21– DRV/r + 2 NRTI, N = 13– 18/21 and 10/13 had HIV-1

RNA < 50 c/mL at W144

Level of HIV-1 RNA at baseline and HCV co-infection were significantly associated with transient viremia during the 144 weeks (p < 0.05)

Resistance emergence to PI (IAS-USA): 1 in each arm, both before W24

Switch* = failure Switch* included

- 16.9 % - 8.7 %

Lower margin of the 95 % CI of the

Non inferiority of DRV/r monotherapy only in the « switch-included » analysis * Change in ARV

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy

0

25

50

100

7575 %

84 %

DRV/r + 2 NRTI

%

83.5 %

DRV/r mono

DRV/r + 2 NRTI

DRV/r mono

69 %

MONETMONET Arribas JR, HIV Medicine 2012;13:398-405