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Impact of Baseline NNRTI Mutations on the Virologic Response to TMC125 in the Phase III Clinical Trials DUET-1 and DUET-2 J Vingerhoets, A Buelens, M Peeters, G Picchio, L Tambuyzer, H Van Marck, G De Smedt, B Woodfall and MP de Béthune Tibotec
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Objectives To identify the baseline genotypic determinants of decreased virological response to TMC125, in the Phase III DUET-1 and DUET-2 trials (pooled data) To provide guidance in the interpretation of genotypic resistance information related to TMC125
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DUET-1 and DUET-2: trial design and inclusion criteria
Screening 6 weeks 48-week treatment period with optional 48-week extension Follow-up 4 weeks 24-week primary analysis TMC125 (200 mg b.i.d.) + BR* 600 patients per trial n=300 per trial Placebo + BR* n=300 per trial *BR = DRV/r with optimised NRTIs and optional enfuvirtide Plasma viral load at screening: >5,000 HIV-1 RNA copies/mL Stable antiretroviral therapy for at least 8 weeks at screening, and remain on that treatment until baseline At least three primary protease inhibitor mutations at screening At least one NNRTI resistance-associated mutation (either at screening or in documented historical genotype) BR = background regimen; DRV/r = darunavir with low-dose ritonavir
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DUET-1 and DUET-2: timeline
24 week last patient last visit DUET-1 DUET-2 RESISTANCE PROFILE TMC125 IHDRW Barbados EFFICACY DATA IAS Sydney Analysis 2007 Jan Mar Jun Jul Feb Apr May Aug Database LOCK No efficacy data will be shown. Virologic response data will be shown relative to the response in the subgroup of TMC125 treated subjects without detectable baseline NNRTI mutations.
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Methods Effect of baseline genotype on the virological response to TMC125 at Week 24, was studied in the subgroup of patients not using enfuvirtide as a new drug, and excluding the patients who discontinued for other reasons than virological failure (n=406). Virological response at Week 24 is presented relative to the response achieved by the subgroup of patients without detectable NNRTI RAMs at baseline* (n=52; relative response = 1.0) (*patients had NNRTI mutations from previous genotype) Decreased virological response was defined as a response that was at least 25% lower than that of the subgroup of patients without detectable NNRTI RAMs at baseline, using the primary efficacy endpoint of confirmed viral load <50 HIV-1 RNA copies/mL RT mutations were included in the analysis if they were present at baseline in 5 or more patients
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Which NNRTI RAMs were evaluated ?
L100I K103N V106A V106M V108I Y181C Y181I Y188C Y188H Y188L G190A G190S P225H P236L 14 NNRTI RAMs listed by IAS-USA1 1Johnson et al. Topics in HIV Med 2006; 14(3):
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Which NNRTI RAMs were evaluated ?
A98G L100I K101E K101P K101Q K103H K103N K103S K103T V106A V106M V108I E138G E138K E138Q V179D V179E V179F V179G V179I Y181C Y181I Y181V Y188C Y188H Y188L G190A G190C G190E G190Q G190S H221Y P225H F227C F227L M230I M230L P236L K238N K238T Y318F L100I K103N V106A V106M V108I Y181C Y181I Y188C Y188H Y188L G190A G190S P225H P236L 14 NNRTI RAMs listed by IAS-USA1 27 additional NNRTI RAMs2 1Johnson et al. Topics in HIV Med 2006; 14(3): 2Tambuyzer et al, EHDRW 2007; Rimsky et al., IHDRW 2007 (poster 63)
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Total list of NNRTI RAMs (n=44)
V90I A98G L100I K101E K101P K101Q K103H K103N K103S K103T V106A V106I V106M V108I E138G E138K E138Q V179D V179E V179F V179G V179I Y181C Y181I Y181V Y188C Y188H Y188L V189I G190A G190C G190E G190Q G190S H221Y P225H F227C F227L M230I M230L P236L K238N K238T Y318F L100I K103N V106A V106M V108I Y181C Y181I Y188C Y188H Y188L G190A G190S P225H P236L A98G L100I K101E K101P K101Q K103H K103N K103S K103T V106A V106M V108I E138G E138K E138Q V179D V179E V179F V179G V179I Y181C Y181I Y181V Y188C Y188H Y188L G190A G190C G190E G190Q G190S H221Y P225H F227C F227L M230I M230L P236L K238N K238T Y318F 14 NNRTI RAMs listed by IAS-USA1 27 additional NNRTI RAMs2 3 additional NNRTI RAMs associated with increased TMC125 FC identified by linear regression analysis of recombinant clinical isolates 44 1Johnson et al. Topics in HIV Med 2006; 14(3): 2Tambuyzer et al, EHDRW 2007; Rimsky et al., IHDRW 2007 (poster 63)
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Identification of the TMC125 resistance-associated mutations
V90I A98G L100I K101E K101P K101Q K103H K103N K103S K103T V106A V106I V106M V108I E138G E138K E138Q V179D V179E V179F V179G V179I Y181C Y181I Y181V Y188C Y188H Y188L V189I G190A G190C G190E G190Q G190S H221Y P225H F227C F227L M230I M230L P236L K238N K238T Y318F 44 NNRTI mutations were studied
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Identification of the TMC125 resistance-associated mutations
V90I A98G L100I K101E K101P K101Q K103H K103N K103S K103T V106A V106I V106M V108I E138G E138K E138Q V179D V179E V179F V179G V179I Y181C Y181I Y181V Y188C Y188H Y188L V189I G190A G190C G190E G190Q G190S H221Y P225H F227C F227L M230I M230L P236L K238N K238T Y318F V90I A98G L100I K101E K101P K101Q K103H K103N K103S K103T V106A V106I V106M V108I E138G E138K E138Q V179D V179E V179F V179G V179I Y181C Y181I Y181V Y188C Y188H Y188L V189I G190A G190C G190E G190Q G190S H221Y P225H F227C F227L M230I M230L P236L K238N K238T Y318F 44 NNRTI mutations were studied 26 NNRTI mutations were present in 5 patients
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Identification of the TMC125 resistance-associated mutations
V90I A98G L100I K101E K101P K101Q K103H K103N K103S K103T V106A V106I V106M V108I E138G E138K E138Q V179D V179E V179F V179G V179I Y181C Y181I Y181V Y188C Y188H Y188L V189I G190A G190C G190E G190Q G190S H221Y P225H F227C F227L M230I M230L P236L K238N K238T Y318F 44 NNRTI mutations were studied 26 NNRTI mutations were present in 5 patients 13 TMC125 RAMs were identified at baseline to have a significant impact on virological response
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The effect of baseline TMC125 RAMs on virological response
1.1 1.0 0.9 0.8 0.7 0.6 Response relative to the subgroup with no NNRTI RAMs 0.5 0.4 0.3 0.2 0.1 No mut. (ref)* L100I G190A Y181I V90I A98G Y181C K101E K101P V179D V106I Y181V G190S V179F† K103N‡ Patients (n) 52 117 2 2–3 No. of NNRTI RAMs (median) No. of NNRTI RAMs (IQR) IQR = interquartile range; *no detectable baseline NNRTI RAMs from the list of 44 †V179F was always observed in the presence of Y181C; ‡K103N included as a reference for a commonly occurring NNRTI RAM; The 13 TMC125 RAMs are represented by red bars
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The effect of baseline TMC125 RAMs on virological response
1.1 1.0 0.9 0.8 0.7 0.6 Response relative to the subgroup with no NNRTI RAMs 0.5 0.4 0.3 0.2 0.1 No mut. (ref)* L100I G190A Y181I V90I A98G Y181C K101E K101P V179D V106I Y181V G190S V179F† K103N‡ Patients (n) 52 34 115 8 22 59 110 53 9 5 24 6 14 7 117 No. of NNRTI RAMs (median) 2 4 4 3 4 4 4 3 3 5 3 3 5 2 No. of NNRTI RAMs (IQR) 2–3 3–5 3–5 2–4 2–5 3–5 3–6 2–3 2–4 4–6 2–3 2–4 4–6 2–3 IQR = interquartile range; *no detectable baseline NNRTI RAMs from the list of 44 †V179F was always observed in the presence of Y181C; ‡K103N included as a reference for a commonly occurring NNRTI RAM; The 13 TMC125 RAMs are represented by red bars
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The number of baseline TMC125 RAMs correlated with the virological response to TMC125
1.1 1.0 0.9 0.8 0.7 0.6 Response relative to the subgroup with no NNRTI RAMs 0.5 0.4 0.3 0.2 0.1 No mutation (reference)* 1 2 3 4 5 Number of TMC125 RAMs (13) Patients (n) 52 161 121 64 32 19 9 Patients† (%) 40 85% 30 16 8 5 2 *no detectable baseline NNRTI RAMs from the list of 44; †n=406 (100%)
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Response relative to the subgroup with no NNRTI RAMs
Decreased virological response is only observed with multiple concomitant TMC125 RAMs Response relative to the subgroup with no NNRTI RAMs No mut (ref)*. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Y181C + 0 TMC125 RAMs Y181C + 1 Y181C + 2 Y181C + 3 Y181C + 4 52 23 36 26 17 8 Patients (n) Y181C No mut (ref)* G190A + 0 TMC125 RAMs G190A + 1 G190A + 2 G190A + 3 G190A + 4 52 18 46 25 17 9 G190A 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 *no detectable baseline NNRTI RAMs from the list of 44
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CONCLUSIONS Using the pooled data from DUET-1 and DUET-2, thirteen baseline RT mutations were associated with resistance to TMC125: V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, G190A/S 85% of the subjects had 0, 1 or 2 TMC125 RAMs, only 15% had 3 or more TMC125 RAMs the TMC125 RAMs occurred mainly in the presence of other NNRTI RAMs The number of baseline TMC125 RAMs was associated with a decreased virologic response to TMC125: The largest impact on virologic response was observed in the subgroup of patients with 3 or more TMC125 RAMs These data provide guidance in the interpretation of genotype resistance data related to TMC125
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Acknowledgements Thanks to the patients and their families
the investigators the study center staff Tibotec clinical trial staff Tibotec Clinical Virology, Biometrics
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