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Determination of phenotypic clinical cut-offs for etravirine (ETR): pooled Week 24 results of the DUET-1 and DUET-2 trials
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Reported by Jules Levin
17th HIV Drug Resistance Workshop
June 10-14, 2008
Sitges, Spain
M Peeters1, S Nijs1, J Vingerhoets1, L Tambuyzer1, B Woodfall1, M-P de Bethune1, G Picchio2
1Tibotec BVBA, Mechelen, Belgium; 2Tibotec Inc.,Yardley, PA, USA
AUTHOR RESULTS
Baseline etravirine fold change in EC50 (FC) was a significant predictor of response (HIV-1 RNA<50 copies/mL) at 24 weeks
Baseline FC and responses to etravirine were characterised by a continuum rather than a bimodal distribution.
Inverse prediction of the ANCOVA model, with covariates baseline viral load, baseline CD4 and baseline darunavir FC, NRTI sensitivity and etravirine FC, resulted in an initial CCO of 13, based on a 1 log greater response at Week 24 versus placebo.
Since response in patients with baseline FC>13 was still substantial (37%), this value was considered an intermediate CCO.
A FC value above which etravirine provided no or little additional efficacy benefit (high CCO) could not reliably be established.
AUTHOR CONCLUSIONS
ETR is the first NNRTI for which phenotypic CCOs could be determined
These CCOs provide phenotypic guidance for use of etravirine in treatment-experienced HIV-1-infected patients.
Based on the analysis of the Week 24 DUET virologic response data, two CCOs were determined for ETR
Response in the etravirine arms of the DUET trials decreased with increasing baseline etravirine FC.
The highest response rate was observed in the group of patients with etravirine FC3 (lower CCO).
A lower CCO of 3 and an intermediate CCO of 13 were identified for ETR
-- the 'highest' response rate (71% VL <50 copies/mL) was observed in patients with baseline ETR FC ≤3
-- an 'intermediate' response rate (50% VL <50 copies/mL) was observed in patients with baseline ETR FC between 3 and 13
-- an upper CCO above which patients would no longer benefit from ETR could not yet be determined in this dataset, due to the small number of patients with FC >13 and the substantial virologic response rate in this subset of patients (37% VL <50 copies/mL)
The majority of patients in DUET had an ETR baseline FC ≤3: 66% (779/1190)
METHODS: In pooled DUET, 599 patients received etravirine. Phenotypic CCOs for Antivirogram were determined using ANCOVA models and data-mining techniques in patients not using for the first-time (de novo) enfuvirtide and excluding those who discontinued before 24 weeks for reasons other than virological failure (n=403).
61% of patients in the ETR group achieved confirmed undetectable VL (<50 copies/mL) compared with 40% in the placebo group at Week 48
ITT = intent-to-treat; TLOVR = time to loss of virologic response;
CI = confidence interval; *Logistic regression model
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