Introduction

Combined PI and NNRTI Resistance Analysis of the Pooled DUET Trial:

Towards a Regimen-Based Resistance Interpretation

J. M. Schapiro, J. Vingerhoets, S. Nijs, M. Peeters,

G. De Smedt, B. Woodfall, MP de Béthune and G. Picchio

National Hemophilia Center, Sheba Medical Center Israel,

Tibotec, Mechelen, Belgium; Tibotec, Yardley, USA

Introduction

Resistance determinations are currently performed for each drug component in isolation

Resistance interpretation of drug combinations could lead to improved predictions of virologic response

The DUET trials included the combination of a potent PI and NNRTI (darunavir and etravirine)

This afforded an opportunity to perform analyses on the combined impact of resistance mutations for these two ARV classes on virologic response

24-week primary analysis

DUET-1 and DUET-2 differed only in geographical location; pooled analysis was pre-specified

Major inclusion criteria– plasma viral load >5,000 HIV-1 RNA copies/mL and stable therapy for ≥8 weeks – ≥1 NNRTI RAMs2, at screening or in documented historical genotype– ≥3 primary PI RAMs at screening

Patients recruited from Thailand, Australia, Europe and the Americas

Screening6 weeks

600 patients target per trial

48-week treatment period with optional 48-week extension

*All patients received a background regimen (BR)of DRV/r with optimised NRTIs and optional enfuvirtide

TMC125 + BR*

Placebo + BR*

Follow-up4 weeks

DUET Study Design

2From extended list of NNRTI RAMs (Tambuyzer L, et al. EHDRW 2007. Abstract 67);

DRV/r = darunavir with low-dose ritonavir

48-week analysis

Pooled DUET-1 and DUET-2: Week 48 Results

0 2 4 8 12 16 20 24 32 40 48

61%

40%

p<0.0001*Res

pond

ers

(%)

± 95

% C

I100

90

80

70

60

50

40

30

20

10

0

Time (weeks)

Patients with VL <50 copies/mL at Week 48 (ITT-TLOVR)

ETR + BR (n=599)

Placebo + BR (n=604)

*Logistic regression model; ‡ANCOVA model; VL = viral load; ITT = intention to treat; BR = background regimen TLOVR = time to loss of virologic response; NC=F = noncompleter equals failure; CI = confidence interval; SE = standard error

Pooled DUET-1 and DUET-2: Week 48 Results

0 2 4 8 12 16 20 24 32 40 48

61%

40%

p<0.0001*Res

pond

ers

(%)

± 95

% C

I100

90

80

70

60

50

40

30

20

10

0

Time (weeks)

ETR + BR (n=599)

Placebo + BR (n=604)

*Logistic regression model; ‡ANCOVA model; VL = viral load; ITT = intention to treat; BR = background regimen TLOVR = time to loss of virologic response; NC=F = noncompleter equals failure; CI = confidence interval; SE = standard error

<50 HIV-1 copies

at Week 24

Patients with VL <50 copies/mL at Week 48 (ITT-TLOVR)

Methods

Analyses were performed in the subgroup of patients (n = 406) that excluded patients:

– Using enfuvirtide as a new drug

– Who discontinued for reasons other than virologic failure

Baseline resistance-associated mutations (RAMs) having an effect on the virological response to ETR or DRV have been identified previously

Virological response was defined as a confirmed viral load (VL) <50 HIV-1 RNA copies/mL at Week 24

Genotypes and phenotypes were determined by Virco

Resistance Associated Mutations

ETR:

V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, G190A/S

DRV:

V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, L89V

1Vingerhoets J, et al. Antivir Ther. 2007;12:S34

2De Meyer S, et al. EHDRW 2008. Abstract 54

Combined effect of ETR and DRV RAMs on virologic response (<50 copies/mL)

7867

100

67

0

82

71

93

57

40

73 75

56

29

17

78

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63

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DRV9 12 3 3 1 044 38 14 7 5 141 24 16 7 6 240 24 20 5 10 327 23 11 11 5 >30 1 2 3 >3ETR

Number of patients per subgroup


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78

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71

0

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71

93

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10

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78

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0/1 (0.0%) 1/1 (100%)7

1/2 (50.0%)0/2 (0.0%)0/2 (0.0%)1/1 (100%)6

0/4 (0.0%)1/3 (33.3%)0/4 (0.0%)4/11 (36.4%)4/7 (57.1%)5

1/6 (16.7%)3/5 (60.0%)4/10 (40.0%)11/18 (61.1%)4

0/2 (0.0%)3/8 (37.5%)3/5 (60.0%)9/20 (45.0%)12/24 (50.0%)31/40 (77.5%)3

0/3 (0.0%)1/3 (33.3%)2/7 (28.6%)9/16 (56.3%)18/24 (75.0%)30/41 (73.2%)2

1/2 (50.0%)1/3 (33.3%)4/7 (57.1%)13/14 (92.9%)27/38 (71.1%)36/44 (81.8%)1

0/1 (0.0%) 2/3 (66.7%)3/3 (100%)8/12 (66.7%)7/9 (77.8%)0

543210

DRV RAMs

ETR RAMs

> 61% 40-61% < 40%Virologic response:


DRV RAMs

ETR RAMs

0 1 2 3 >3

0 77.8% (7/9) 66.7% (8/12) 100% (3/3) 66.7% (2/3) 0.0% (0/1)

1 81.8% (36/44) 71.1% (27/38) 92.9% (13/14) 57.1% (4/7) 40.0% (2/5)

2 73.2% (30/41) 75.0% (18/24) 56.3% (9/16) 28.6% (2/7) 16.7% (1/6)

3 77.5% (31/40) 50.0% (12/24) 45.0% (9/20) 60.0% (3/5) 30.0% (3/10)

>3 63.0% (17/27) 34.8% (8/23) 27.3% (3/11) 27.3% (3/11)

0.0% (0/5)

> 61% < 40%Virologic response: 40-61%

In vitro susceptibility to DRV in subgroups by DRV and ETR RAMs

ETR RAMs

DRV RAMs 0 1 2 3 4 5

0 0.7 1.0 1.2 1.3 0.6

1 2.4 2.4 1.9 1.4 2.8 1.6

2 4.7 4.1 6.4 5.3 4.5 12.7

3 10.1 9.7 9.0 5.1 15.6 12.2

4 32.7 23.4 34.5 53.4

5 74.6 24.2 73.3 122.0 80.6

6 68.0 362.0 302.0 92.0

7 655.0 909.0

FC 10 FC 10 - 40 FC > 40Median DRV FC:

In vitro susceptibility to ETR in subgroups by DRV and ETR RAMs

ETR RAMs

DRV RAMs 0 1 2 3 4 5

0 0.5 1.8 0.6 13.4 5.3

1 1.1 3.2 2.1 6.6 13.3 14.9

2 0.8 2.9 1.9 4.9 42.4 4.1

3 1.0 3.9 3.4 5.1 4.4 5.7

4 0.7 1.9 1.4 2.6

5 0.8 3.3 3.0 2.0 10.7

6 0.2 0.9 5.6 11.0

7 0.7 26.2

FC 3 FC 3 - 13 FC > 13Median ETR FC:

Results - Summary

Virological response rates declined with increasing numbers of combined baseline DRV and ETR RAMs:

– 0 total RAMs: 77.8%

– >7 total RAMs: 14.3%

For patients with 0 or 1 RAM to each of the drugs (4 subgroups):

– median DRV FC: 0.7 – 2.4

– median ETR FC: 0.5 – 3.2

– response rates: 66.7% to 81.8%

For patients with 2 or less RAMs to each drug (9 subgroups):

– median DRV FC: 0.7 – 6.4

– median ETR FC: 0.5 – 3.2

– response rates: 56.3% to 100.0%

Conclusions

In this highly treatment experienced population, patients with 1 or less mutations to each drug had virological responses similar to those seen in trials of drug naïve patients

.

Responses below 50% required at least 3 mutations to either drug

DRV continued to contribute to responses ≥50% even in the presence of 3 mutations

Resistance to a drug regimen appears to be a function of the combined genetic barrier to resistance (GBR) of the different drug components

Resistance interpretations considering drug combinations may be more clinically relevant than those addressing only each drug individually

Acknowledgements

The patients and DUET investigators

The study center staff

Tibotec clinical trial staff, clinical virology, and biometrics

Virco

Introduction

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