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Phenotypic and genotypic determinants of resistance to TMC114: pooled analysis of POWER 1, 2 and 3
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Reported by Jules Levin
15th Intl HIV Drug Resistance Workshop
June 13-17, 2006, Sitges, Spain
S De Meyer 1, T Vangeneugden1, E Lefebvre 2, H Azijn1, I De Baere1, B Van Baelen1 and M-P de Bethune1
1Tibotec BVBA, Mechelen, Belgium
2Tibotec Inc., Yardley, PA, USA
AUTHOR CONCLUSIONS
- Resistance analyses of the results of POWER 1, 2 and 3 have provided tools to interpret resistance testing data
- Baseline phenotypic TMC114 FC was the strongest predictor of virological response compared to other BL parameters
- phenotypic clinical cut-offs of 10 and 40 were generated for TMC114
- mutations associated with a diminished response to TMC114 (V11I, V32I, L33F, I47V, I50V, I54L or M, G73S, L76V, I84V and L89V) were present mostly with a high number of other PI-resistance associated mutations. This set of mutations provided better virological outcome prediction than the IAS PI mutation list
- there was a diminished response to TMC114/ritonavir (>1 log10 decrease in VL [data not shown] or VL <50 copies/mL at Week 24) when three or more of the above mutations were present at BL
- no PI resistance-associated mutation associated with a diminished response to TMC114, either alone or in combination with one to two others, resulted in TMC114 FC >10 in SDM experiments.
- These tools apply to the patient population studied in the POWER trials, and will be subject to change, pending additional data in different patient populations (naive [TMC114-C211 study] and early treatment-experienced [TMC114-214 study]).
ABSTRACT
BACKGROUND: TMC114 (darunavir) with low-dose ritonavir (TMC114/ritonavir) showed significant antiviral efficacy in treatment-experienced patients in POWER 1, 2 and 3: 42% of patients reached HIV RNA <50 copies/ml at Week 24. This analysis provides further insight into the phenotypic and genotypic determinants of resistance to TMC114.
METHODS: In POWER 1, 2 and 3, 458/924 patients initiated treatment with TMC114/ritonavir 600/100mg twice-daily, the recommended dose for treatment-experienced patients. Non-completer = failure analysis was used for change in viral load [VL] and time-to-loss-of virological response analysis was used for the proportion reaching HIV RNA <50 copies/ml at Week 24. Phenotyping was performed by Antivirogram. Sitedirected mutants (SDMs) were constructed using Medigenomix proprietary technology.
RESULTS:
Baseline TMC114 EC50 fold change (FC) was the strongest predictor of Week 24 virological response.
Clinical cut-offs of 10 and 40 were determined by analysis of VL change versus baseline TMC114 FC, using an ANCOVA model and inverse prediction.
At baseline, 70% and 13% of viruses had TMC114 FC ≦10 and >40, respectively.
At Week 24, 50%, 25% and 13% of patients with FC ≦10, 10 < FC≦40 and FC >40, respectively, reached HIV RNA <50 copies/ml.
TMC114 FC increased with the number of PI resistance-associated mutations.
Analysis of baseline isolates of all patients showed median TMC114 FC <10, close to or >10, and >40, for subgroups with <10, 10 or 11, and ≥12 PI resistance- associated mutations, respectively.
Diminished responses observed in the last two subgroups reinforced the correlation between FC, number of mutations and virological outcome.
SDMs were constructed with up to three protease mutations either associated with a lower response to TMC114/ritonavir when present at baseline, or related
to resistance to amprenavir, a structural analogue of TMC114. Whereas amprenavir FC >10 was observed in 8/30 strains with 2-3 mutations, and
4 < FC≦10 for 6/30, only one strain had 4 < FC≦10 for TMC114; none had FC >10.
CONCLUSION: Baseline TMC114 FC was the strongest predictor of virological response. Reduced response at TMC114 FC >10 correlated with =10 PI
resistance-associated mutations. No mutation associated with a diminished response, alone or in combination with 1-2 others, resulted in TMC114 FC >10.
PHENOTYPIC DETERMINATION OF RESPONSE
50% of patients with 40 fold-change to TMC114 at baseline 13% achieved <50 copies/ml at week 24 (VL decline= -0.76). So Tibotec proposed a lower cut-off of 10 and a higher cutoff of 40 for phenotypic testing.
GENOTYPIC DETERMINATION OF RESPONSE
Eleven mutations appear associated with a diminished response: V11I, V32I, L33F, I47V, I50V, I54L or M, G73S, L76V, I84V and L89V. The data presented at Sitges suggests having 3 or more of these mutations resulted in diminished viral response compared to having less than 3 of these mutations. As you can see in the grapg below when there were no mutations 64% of patients achieved <50 copies/ml, when 1 mutation was present 50% of patients achieved <50 copies/ml, and when 2 mutations were present 42% of patients had <50 copies/ml, but when 3 mutations were present only 22% of patients achieved <50 copies/ml, and when 4 or more mutations were present only 10% of patients achieved <50 copies/ml. This suggests that if a patient has 3 or more of these mutations the capacity to achieve <50 copies/ml is diminished.Its important to realize that these phenotypic and genotypic cutoffs are not black and white. There is a continuum meaning that some patients with 4 mutations can achieve <50 copies/ml and some patients with only 2 or 3 mutations might not achieve <50 copies/ml.
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