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Population-based Sequencing of the V3-loop is Comparable to the Enhanced Sensitivity Trofile Assay (ESTA) in Predicting Virologic Response to Maraviroc of Treatment-naïve Patients in the MERIT Trial
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Reported by jules Levin
17th CROI 2010 Feb 16-19 SF
RA McGovern, W Dong, X Zhong, T Mo, D Knapp, A Thielen, D Chapman, M Lewis, I James, J Heera H Valdez, PR Harrigan
1BC Ctr for Excellence in HIV/AIDS, Vancouver, Canada; 2Max Planck Inst for Informatics, Saarbrücken, Germany; 3Pfizer Inc, New York, NY, US; and 4Pfizer Global R&D, Sandwich, UK
ABSTRACT
Background: A previous reanalysis of MERIT, a randomized trial comparing efavirenz (EFV) vs maraviroc BID (MVC) in drug-naïve patients, suggested that CXCR4-using virus undetected by the original Trofile screening assay was responsible for the failure of MVC to meet non-inferiority. We retrospectively examined virologic responses in patients in whom tropism was determined using population-based V3-loop sequencing.
Methods: Blinded to clinical data, the HIV V3-loop of screening plasma samples of patients entering MERIT was amplified in triplicate and sequenced using an ABI 3730 and automated base-calling software. Tropism was inferred from the resultant V3 sequences using the geno2pheno co-receptor (g2P) algorithm with the optimized 5.75% false-positive cut-off. Results were compared to both original and ESTA assays where all results were available (N=705).
Results: Approximately 8% of patients who screened as R5 by the original Trofile assay were classed as X4 by V3-loop sequencing. These patients were significantly less likely to have sustained virologic response (<50 c/mL) at week 48 in the MVC arm, but not in the EFV arm. Week 48 virologic response was similar among those classified as R5 by genotype for MVC vs EFV arms (66% vs 69%; see Table). A total of 193/283 (68%) classified as R5 by both ESTA and genotype assays had week 48 virologic response (<50 copies/mL) on MVC, compared with only 1/9 (11%) patients classified as non-R5 by both assays. Where results were discordant, the performance of ESTA and genotype assays were intermediate in terms of median viral load suppression over the course of the trial. 12 of 20 (60%) patients called non-R5 by genotype but R5 by ESTA had a week 48 viral load <50 copies/mL, compared with 20 of 40 (50%) of those classified as R5 by genotype and non-R5 by ESTA. Similar results were observed in the arm where maraviroc was given once daily.
Conclusions: The exclusion of ∼8% of patients with CXCR4-using virus by population-based genotype, who tended to be very early treatment failures, would likely have resulted in comparable responses in the EFV and MVC arms. Population-based V3 sequencing performed similarly to the ESTA assay in terms of predicting MVC response.
Maraviroc BID; LOCF
*Missing = Failure
*Missing = Failure Bars= 95% CI
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