key study results in pi monotherapy

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%


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%.


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


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)



11



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

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


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.

key study results in pi monotherapy

Documents

intensification or2

intensification orfailure

copiesml includedokn

copiesml itt

speaker fees

pi monotherapydr

baseline nucleosides

major pi mutations2