key study results in pi monotherapy
DESCRIPTION
Key Study Results in PI Monotherapy. Dr. Jose R Arribas HIV UNIT. OK04 trial design. Visits : Screening , Baseline , Week 4 and 12, then every 12 weeks up to Week 96. Arribas JR. et al ., JAIDS 2009 OK04. Time to HIV-1 RNA > 50 copies/mL (ITT M = F, Reinduction = F)*. 77.6%. - PowerPoint PPT PresentationTRANSCRIPT
Key Study Results in PI Monotherapy
Dr. Jose R ArribasHIV UNIT
clinicaloptions.com/hiv
OK04 trial design
Visits: Screening, Baseline, Week 4 and 12, then every 12 weeks up to Week 96
LPV/r SGC400/100 mg BID
(“OK”)(n=100)
LPV/r SGC 400/100 mg BID
+ 2 NRTIs (“Triple”)(n=100)
HIV-1 RNA < 50 c/mL for > 6 months
No history of virological failure while taking a PI
Receiving LPV/r for + 2 NRTIs > 1 month
LPV/r Tablet (“OK”)
400/100 mg BID
Week 96
Arribas JR. et al., JAIDS 2009 OK04
* Patients in the monotherapy arm who reached and maintained < 50 c/mL after resuming baseline nucleosides are considered as failures (n = 10)
P=0.865; Log rank
Time to HIV-1 RNA > 50 copies/mL (ITT M = F, Reinduction = F)*
%
77%77.6%
Arribas JR. et al., JAIDS 2009 OK04
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 960
102030405060708090
100
OK (n = 100)Triple (n = 98)
Weeks after randomization
Proportion without therapeutic failure at Week 96*
* Patients in the monotherapy arm who reached and maintained < 50 c/mL after resuming baseline nucleosides are not considered as failures (n = 10)
- 9%; upper-limit 95%CI: 1.2%.
Arribas JR. et al., JAIDS 2009 OK04
96 weeks0
10
20
30
40
50
60
70
80
90
100
8778
OKTriple
Perc
ent w
ithou
t fai
lure
*All patients with HIV-1 RNA > 500 copies/mL analyzed (blips > 500 copies/mL included)
OK(n = 100)
Triple(n = 98)
Genotyping Population*
Samples16 (16%)
294 (4%)
9
Patients with isolates with major PI mutations 2 (2%) 2 (2%)
Genotypic testing through Week 96
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
4, 12, 24, 36, 48 weeks 96 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: Baseline Characteristics (ITT)
579 12%
6.4 (4.0)57%
43%48%28%
015 (12%)12 (9%)
571 14%
7.4 (4.2)56%44%35%23%
024 (19%)20 (16%)
Disease characteristics CD4 count (median (range), 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 naïveHep B Surface Antigen, positive, n (%)Hep C Antibody, positive, n (%)History of IV Drug use
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)
Rieger et al. WAC July 2010, Vienna [abstr TBLBB209]
Multivariate analysis at Week 48 showed that HCV co-infection was highly predictive of response in the primary endpoint.
Main efficacy endpoint: TLOVR, switch equals failure analysis
If a patient shows a confirmed elevation in HIV RNA >50 copies/mL at two visits, this is a failure, even if the HIV RNA is then suppressed <50 copies/mL at Week 96. Stoping DRV/r in either arm, or adding NRTIs in the monotherapy arm is also a failure. Missing data is failure.
Secondary endpoint: Switch included analysis
This analysis only includes the HIV RNA levels at Week 96. If HIV RNA is re-suppressed at Week 96 following an earlier elevation, this is counted as success. Changes in treatment are permitted. Missing data is failure.
MONET: statistical methods for HIV RNA analysis
Rieger et al. WAC July 2010, Vienna [abstr TBLBB209]
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: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%
J. Arribas et al, AIDS 2010
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
HIV RNA <50
75,2%69,3%
10,1%16,5%
2,3%7,9%
11,6%6,3%
0,8%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
DRV/r + 2NRTI (ITT) DRV/r mono (ITT)
MONET Week 144 analysis: HIV RNA, TLOVR, ITT Population Switch=failure
Switch NRTI
HIV RNA <50
VF
d/c - AE
d/c - other
Per
cent
age
of p
atie
nts
difference=-5.9%, 95% C.I.-16.9%,
+5.1%).
MONET Week 144 analysis: Major IAS-USA Genotypic mutations when HIV RNA >50 copies/mL
Genotypic resultsDRV/r + 2NRTI
N=129DRV/rN=127
Number of patients with genotypes performed (RNA >50 copies/mL) 40 47
Patients with at least 1 successful genotype 23 31
Patients with genotype(s) showing no primary PI or DRV mutations, M184V or NRTI mutations 22/23 (96%) 30/31 (97%)
NRTI mutations 1 0
M184V 1 0
Primary IAS-USA PI mutations 1 1
DRV mutations 0 1
Only 1 patient per arm had any evidence of genotypic resistance
MONET Week 144 analysis: Outcome of HIV RNA elevations in DRV/r arm (21 patients)
Patient HIV RNA blips Changed ARV / comments Last HIV RNA1 140, 133 None / sinusitis <50 (wk 144)2 59, 214 ZDV/3TC/NVP <50 (wk 144)3 53,160 TDF/FTC/DRV/r <50 (wk 144)4 132, 139 LPV/r mono <50 (wk 144) - local5 539, 862 TDF/FTC/EFV <50 (wk 128) - local6 75, 111 TDF/FTC/RAL <50 (wk 144) - local7 215, 56 None / Poor adherence 50 (wk 144)8 810, 605 TDF/FTC/DRV/r <50 (wk 144)9 40500, 628 None (stopped Rx) <50 (wk 144)10 154, 100 None <50 (wk 144)11 158, 60 ABC/3TC/DRV/r <50 (wk 144)12 134, 79 None / Viral infection <50 (wk128)13 585, 69 None 69 (wk 144)14 151,97 None / Poor adherence <50 (wk 144)15 51, 80 None <50 (wk 96)16 114, 106 TDF/FTC/DRV/r 231 (wk 112)17 722, 157 TDF/FTC/DRV/r <50 (wk 96), 82 (wk 144?)18 398, 288 TDF/FTC/DRV/r / Infection <50 (wk 144)19 156, 6530 None <50 (wk 144)20 779, 267 ABC/3TC/DRV/r / Infection <50 (wk 144)21 164, 114 None <50 (wk 144)
MONET Week 144 analysis: Outcome of HIV RNA elevations in DRV/r arm (21 patients)
Patient HIV RNA blips Changed ARV / comments Last HIV RNA1 140, 133 None / sinusitis <50 (wk 144)2 59, 214 ZDV/3TC/NVP <50 (wk 144)3 53,160 TDF/FTC/DRV/r <50 (wk 144)4 132, 139 LPV/r mono <50 (wk 144) - local5 539, 862 TDF/FTC/EFV <50 (wk 128) - local6 75, 111 TDF/FTC/RAL <50 (wk 144) - local7 215, 56 None / Poor adherence 50 (wk 144)8 810, 605 TDF/FTC/DRV/r <50 (wk 144)9 40500, 628 None (stopped Rx) <50 (wk 144)10 154, 100 None <50 (wk 144)11 158, 60 ABC/3TC/DRV/r <50 (wk 144)12 134, 79 None / Viral infection <50 (wk128)13 585, 69 None 69 (wk 144)14 151,97 None / Poor adherence <50 (wk 144)15 51, 80 None <50 (wk 96)16 114, 106 TDF/FTC/DRV/r 231 (wk 112)17 722, 157 TDF/FTC/DRV/r <50 (wk 96), 82 (wk 144?)18 398, 288 TDF/FTC/DRV/r / Infection <50 (wk 144)19 156, 6530 None <50 (wk 144)20 779, 267 ABC/3TC/DRV/r / Infection <50 (wk 144)21 164, 114 None <50 (wk 144)
11
MONET Week 144 analysis: Outcome of HIV RNA elevations in DRV/r arm (21 patients)
Patient HIV RNA blips Changed ARV / comments Last HIV RNA1 140, 133 None / sinusitis <50 (wk 144)2 59, 214 ZDV/3TC/NVP <50 (wk 144)3 53,160 TDF/FTC/DRV/r <50 (wk 144)4 132, 139 LPV/r mono <50 (wk 144) - local5 539, 862 TDF/FTC/EFV <50 (wk 128) - local6 75, 111 TDF/FTC/RAL <50 (wk 144) - local7 215, 56 None / Poor adherence 50 (wk 144)8 810, 605 TDF/FTC/DRV/r <50 (wk 144)9 40500, 628 None (stopped Rx) <50 (wk 144)10 154, 100 None <50 (wk 144)11 158, 60 ABC/3TC/DRV/r <50 (wk 144)12 134, 79 None / Viral infection <50 (wk128)13 585, 69 None 69 (wk 144)14 151,97 None / Poor adherence <50 (wk 144)15 51, 80 None <50 (wk 96)16 114, 106 TDF/FTC/DRV/r 231 (wk 112)17 722, 157 TDF/FTC/DRV/r <50 (wk 96), 82 (wk 144?)18 398, 288 TDF/FTC/DRV/r / Infection <50 (wk 144)19 156, 6530 None <50 (wk 144)20 779, 267 ABC/3TC/DRV/r / Infection <50 (wk 144)21 164, 114 None <50 (wk 144)
7
3
MONET Week 144 analysis: Outcome of discontinuations in DRV/r arm (18 patients)
Patient Reason for d/c Change in treatment Last HIV RNA (wk)
1 History of VF ABC/3TC/ATV/r <50 (wk 144) - local
2 Adverse Events TDF/3TC/EFV <50 (wk 144) - local
3 Adverse Event ABC/3TC/NVP <50 (wk 144)
4 Acute HCV infection DRV/r <50 (wk 144) - local
5 Adverse events TDF/FTC/EFV <50 (wk 144) - local
6 Adverse events ABC/3TC/NVP <50 (wk 144) - local
7 Adverse events ABC/3TC/ATV/r <50 (wk 144) - local
8 Withdrew consent <50 (wk 128)
9 Pregnancy ZDV/3TC/LPV/r <50 (wk 128) - local
10 Withdrew consent TDF/FTC/EFV <50 (wk 144) - local
11 History of VF TDF/FTC/DRV/r <50 (wk 128)
12 Adverse event ZDV/3TC/LPV/r <50 (wk 60)
13 Adverse events TDF/FTC/RAL <50 (wk 144) - local
14 Long holiday DRV/r <50 (wk 96)
15 Pregnancy DRV/r <50 (wk 144)
16 Adverse event ZDV/3TC/EFV <50 (wk 144) - local
17 Withdrew consent no data <50 (wk 84)
18 In prison DRV/r <50 (wk 128) - local
MONET Week 144 analysis: Outcome of discontinuations in DRV/r arm (18 patients)
Patient Reason for d/c Change in treatment Last HIV RNA (wk)
1 History of VF ABC/3TC/ATV/r <50 (wk 144) - local
2 Adverse Events TDF/3TC/EFV <50 (wk 144) - local
3 Adverse Event ABC/3TC/NVP <50 (wk 144)
4 Acute HCV infection DRV/r <50 (wk 144) - local
5 Adverse events TDF/FTC/EFV <50 (wk 144) - local
6 Adverse events ABC/3TC/NVP <50 (wk 144) - local
7 Adverse events ABC/3TC/ATV/r <50 (wk 144) - local
8 Withdrew consent <50 (wk 128)
9 Pregnancy ZDV/3TC/LPV/r <50 (wk 128) - local
10 Withdrew consent TDF/FTC/EFV <50 (wk 144) - local
11 History of VF TDF/FTC/DRV/r <50 (wk 128)
12 Adverse event ZDV/3TC/LPV/r <50 (wk 60)
13 Adverse events TDF/FTC/RAL <50 (wk 144) - local
14 Long holiday DRV/r <50 (wk 96)
15 Pregnancy DRV/r <50 (wk 144)
16 Adverse event ZDV/3TC/EFV <50 (wk 144) - local
17 Withdrew consent no data <50 (wk 84)
18 In prison DRV/r <50 (wk 128) - local
Resistance when HIV RNA above 50 copies/mL: Week 24: fully sensitive to NRTI, NNRTI and PI Week 26: not amplifiable Week 36: not amplifiable Week 40: fully sensitive to NRTI, NNRTI and PI
DRV plasma PK levels (ng/mL): Week 4: 4430 Week 12: 2140 Week 24: 1570 Week 36: 3470 Week 48: 2800 Week 96: 3370
NRTI intensification: Yes - with ABC/3TC after Week 36
Patient PL0000520Treatment arm: DRV/r
-10 0 10 20 30 40 50 60 70 80 90 100 110 1200
100
200
300
400
500
600
700
800
900
779
267
7951
98
223
116
ARV treatment started: 2002 Prior antiretrovirals taken: ABC/3TC, EFV Nadir CD4 count: 125Hepatitis C: Antibody positiveHCV RNA PCR: no data
Intensified onto ABC/3TC/DRV/r
Double HIV RNA blip
HIV
RN
A (c
opie
s/m
L)
Time in MONET trial - weeks
Week 96Endpoint
FAILURE by TLOVR, switch equals failure analysisNOT FAILURE by Switch included analysis
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
MONET Week 144 analysis: HIV RNA <50 copies/mL, Switch included analysis, and observed failure (OF)
DRV/r + 2NRTI (PP)
DRV/r mono (PP)
DRV/r + 2NRTI (PP)
DRV/r mono (PP)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
84.3%89.3%
86.1% 83.6%
TLOVR HIV RNA<50 by
Week 144(%)
Switch included analysis (PP) Observed Failure analysis (PP)
n=121 n=122 n=121 n=122
MONET Week 144 analysis: delta and 95% c.i.*(full multivariate analysis)
-20 -15 -10 -5 0 5 10 15
-3.7%
-4.0%
+1.54%
-4.8%
PP, HIV RNA <50, TLOVR, switch=failure
ITT, HIV RNA <50, TLOVR, switch=failure
PP, HIV RNA <50Switch included
Observed failure TLOVR HIV RNA <50
Difference between arms Lower and upper 95% C.I.
-14.6% +7.3%
-15.1% +7.1%
-7.19% +10.28%
-12.9% +3.4%
DRV/r + 2NRTI better DRV/r mono better
+
74.5% vs 78.2%
71.3% vs 75.3%
86.72% vs 85.18%
85.5% vs 90.3%
HIV RNA <50 at Wk 144DRV/r vs DRV/r +2NRTI Analysis
++
* Multivariate logistic regression, adjusting for previous PI use and factors from exploratory multivariate analysis
Which is more clinically relevant?
MONET 144 weeks: laboratory abnormalities
Arribas JR, et al. IAS 2011. Abstract MOPE216.
Differences in lipid parameters likely reflect the fact that some patients in the DRV/r + 2 NRTIs arm were taking TDF, which may have a direct lipid-lowering effect
*Of the 16 patients with elevated total cholesterol in the DRV/r arm, 10 were at a single visit
Elevated triglycerides
Elevated total cholesterol
Elevated LDL-cholesterol
Elevated AST
Elevated ALT
0 2 4 6 8 10 12 14 16
3.2
12.9
13.6
4.8
6.4
1.6
3.9
9.4
2.4
2.4
DRV/r + 2 NRTIs (n=129)DRV/r monotherapy (n=127)
Patients with laboratory abnormality, %
MONET: DRV/r MT does not increase IL-6 or hs-CRP levels
• Levels of the inflammatory markers, interleukin-6 (IL-6) and C-reactive protein (CRP), are elevated in HIV-infection.
• High levels of IL-6 (>3 pg/mL) and CRP (>5 mg/L) have been associated with more rapid progression to AIDS and death1
1. Rodger A, et al. JID 2009, 200: 973-983.
• There was no difference between the treatment arms in IL-6 or hs-CRP levels at the Week 144 visit
MarkerDRV/r + 2 NRTIs
DRV/r monotherapy
IL-6 >3 pg/mL 20/65 (31%) 15/64 (23%)
hs-CRP > 5 mg/L 8/80 (10%) 9/75 (12%)
p=n.s. for both comparisons, chi-square test
Arribas JR, et al .EACS, Belgrade, Serbia, October 2011. Abstract PS 10/2.
MONOI Design
Valantin MA et al. Poster 534 CROI
MONOI: Predictors of Response
Marcelin AG, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 534.
A PI/r switching strategy is suggested as an option in the EACS guidelines
‘PI/r monotherapy with bid LPV/r or qd DRV/r might represent an option in patients with intolerance to NRTI or for treatment simplification. Such a strategy only applies to patients without history of failure on prior PI-based therapy and who have had
viral loads <50 copies/mL in at least the past 6 months’
European AIDS Clinical Society (EACS) guidelines, 2011. Available at: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/eacsguidelines-6.pdf.