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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

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Introduction

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  1. 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

  2. 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

  3. Screening 6 weeks Follow-up 4 weeks 600 patients target per trial DUET Study Design • 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 48-week treatment period with optional 48-week extension 24-week primary analysis 48-week analysis TMC125 + BR* Placebo + BR* *All patients received a background regimen (BR)of DRV/r with optimised NRTIs and optional enfuvirtide 2From extended list of NNRTI RAMs (Tambuyzer L, et al. EHDRW 2007. Abstract 67); DRV/r = darunavir with low-dose ritonavir

  4. ETR + BR (n=599) Placebo + BR (n=604) Pooled DUET-1 and DUET-2: Week 48 Results Patients with VL <50 copies/mL at Week 48 (ITT-TLOVR) 100 90 80 70 60 50 40 30 20 10 0 61% Responders (%) ± 95% CI 40% p<0.0001* 0 2 4 8 12 16 20 24 32 40 48 Time (weeks) *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

  5. ETR + BR (n=599) Placebo + BR (n=604) Pooled DUET-1 and DUET-2: Week 48 Results Patients with VL <50 copies/mL at Week 48 (ITT-TLOVR) 100 90 80 70 60 50 40 30 20 10 0 <50 HIV-1 copies at Week 24 61% Responders (%) ± 95% CI 40% p<0.0001* 0 2 4 8 12 16 20 24 32 40 48 Time (weeks) *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

  6. 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

  7. 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

  8. 100 93 100 82 90 67 75 80 73 71 78 70 57 56 60 60 78 63 67 50 50 40 45 40 29 35 30 30 0 27 27 17 20 10 0 DRV RAMs 0 0 DRV RAMs 1 DRV RAMs 2 DRV RAMs 3 DRV RAMs >3 ETR RAMs 2 ETR RAMs 3 ETR RAMs 0 ETR RAMs 1 ETR RAMs >3 Combined effect of ETR and DRV RAMs on virologic response (<50 copies/mL)

  9. Number of patients per subgroup DRV 0 9 12 3 3 1 1 44 38 14 7 5 2 41 24 16 7 6 3 40 24 20 5 10 100 >3 27 23 11 11 5 93 100 ETR 0 1 2 3 >3 82 90 67 75 80 73 71 78 70 57 56 60 60 78 63 67 50 50 40 45 40 29 35 30 30 0 27 27 17 20 10 0 DRV RAMs 0 0 DRV RAMs 1 DRV RAMs 2 DRV RAMs 3 DRV RAMs >3 ETR RAMs 2 ETR RAMs 3 ETR RAMs 0 ETR RAMs 1 ETR RAMs >3 Combined effect of ETR and DRV RAMs on virologic response (<50 copies/mL)

  10. 100 93 100 82 90 67 75 80 73 71 78 70 57 56 60 60 78 63 67 50 50 40 45 40 29 35 30 30 0 27 27 17 20 10 0 DRV RAMs 0 0 DRV RAMs 1 DRV RAMs 2 DRV RAMs 3 DRV RAMs >3 ETR RAMs 2 ETR RAMs 3 ETR RAMs 0 ETR RAMs 1 ETR RAMs >3 Combined effect of ETR and DRV RAMs on virologic response (<50 copies/mL)

  11. Combined effect of ETR and DRV RAMs on virologic response (<50 copies/mL) 100 78 82 90 67 71 80 70 60 50 40 30 20 10 DRV RAMs 0 0 DRV RAMs 1 DRV RAMs 2 DRV RAMs 3 DRV RAMs >3 ETR RAMs 2 ETR RAMs 3 ETR RAMs 0 ETR RAMs 1 ETR RAMs >3

  12. Combined effect of ETR and DRV RAMs on virologic response (<50 copies/mL) 100 93 100 78 82 90 75 67 80 73 71 70 56 60 78 67 50 40 30 20 10 DRV RAMs 0 0 DRV RAMs 1 DRV RAMs 2 DRV RAMs 3 DRV RAMs >3 ETR RAMs 2 ETR RAMs 3 ETR RAMs 0 ETR RAMs 1 ETR RAMs >3

  13. 100 93 100 82 90 67 75 80 73 71 78 70 57 56 60 60 78 63 67 50 50 40 45 40 29 35 30 30 0 27 27 17 20 10 0 DRV RAMs 0 0 DRV RAMs 1 DRV RAMs 2 DRV RAMs 3 DRV RAMs >3 ETR RAMs 2 ETR RAMs 3 ETR RAMs 0 ETR RAMs 1 ETR RAMs >3 Combined effect of ETR and DRV RAMs on virologic response (<50 copies/mL)

  14. Combined effect of ETR and DRV RAMs on virologic response (<50 copies/mL) 100 90 80 78 70 60 60 50 50 45 40 30 30 20 10 DRV RAMs 0 0 DRV RAMs 1 DRV RAMs 2 DRV RAMs 3 DRV RAMs >3 ETR RAMs 2 ETR RAMs 3 ETR RAMs 0 ETR RAMs 1 ETR RAMs >3

  15. Combined effect of ETR and DRV RAMs on virologic response (<50 copies/mL) 100 90 80 78 70 60 60 63 50 50 45 40 35 30 30 27 27 20 10 0 DRV RAMs 0 0 DRV RAMs 1 DRV RAMs 2 DRV RAMs 3 DRV RAMs >3 ETR RAMs 2 ETR RAMs 3 ETR RAMs 0 ETR RAMs 1 ETR RAMs >3

  16. Combined effect of ETR and DRV RAMs on virologic response (<50 copies/mL) Virologic response: 40-61% > 61% < 40% DRV RAMs ETR RAMs 0 1 2 3 4 5 0 7/9 (77.8%) 8/12 (66.7%) 3/3 (100%) 2/3 (66.7%) 0/1 (0.0%) 1 36/44 (81.8%) 27/38 (71.1%) 13/14 (92.9%) 4/7 (57.1%) 1/3 (33.3%) 1/2 (50.0%) 2 30/41 (73.2%) 18/24 (75.0%) 9/16 (56.3%) 2/7 (28.6%) 1/3 (33.3%) 0/3 (0.0%) 3 31/40 (77.5%) 12/24 (50.0%) 9/20 (45.0%) 3/5 (60.0%) 3/8 (37.5%) 0/2 (0.0%) 4 11/18 (61.1%) 4/10 (40.0%) 3/5 (60.0%) 1/6 (16.7%) 5 4/7 (57.1%) 4/11 (36.4%) 0/4 (0.0%) 1/3 (33.3%) 0/4 (0.0%) 6 1/1 (100%) 0/2 (0.0%) 0/2 (0.0%) 1/2 (50.0%) 7 1/1 (100%) 0/1 (0.0%)

  17. Combined effect of ETR and DRV RAMs on virologic response (<50 copies/mL) Virologic response: > 61% < 40% 40-61%

  18. In vitro susceptibility to DRV in subgroups by DRV and ETR RAMs FC > 40 FC 10 - 40 FC  10 Median DRV FC:

  19. In vitro susceptibility to ETR in subgroups by DRV and ETR RAMs FC > 13 FC 3 - 13 FC  3 Median ETR FC:

  20. 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%

  21. 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

  22. Acknowledgements • The patients and DUET investigators • The study center staff • Tibotec clinical trial staff, clinical virology, and biometrics • Virco

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