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Resistance and Cross-Resistance to First Generation Integrase Inhibitors: Insights from a Phase 2 Study of Elvitegravir (GS-9137)
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Reported by Jules Levin
16th Intl HIV Drug resistance Workshop, June 12-15, 2007, Bridgetown, Barbados, Abstract 9
D. J. McColl1, S. Fransen2, S. Gupta2, N. Parkin2, N. Margot1, R Ledford1, J. Chen1, S. Chuck1, A. K. Cheng1 and M. D. Miller1
Gilead Sciences, Inc., Foster City, CA, USA
Monogram Biosciences, Inc., South San Francisco, CA, USA
AUTHOR CONCLUSIONS:
In highly treatment-experienced patients, treatment with 125 mg EVG/r and at least one additional active NRTI or T-20 resulted in a sustained >2 log10 reduction in HIV-1 RNA through 24 weeks
Common IN mutation patterns at failure included:
-- E92Q + other mutations
-- N155H + other mutations
-- Q148R/H/K + other mutations
These patterns overlap with the two major resistance patterns reported in raltegravir clinical trials (N155H + others; Q148K/R/H + others)
Development of IN mutations was associated with reduced susceptibility to both EVG and RAL
-- Clinical cutoffs for both drugs remain to be established
-- Potential for drug sequencing within the class is unknown
Development of IN mutations was associated with significant reductions in viral replication capacity
-- Clinical significance of IN RC reduction is unknown
Elvitegravir (EVG, GS-9137 / JTK-303) Background
-- Dihydroquinoline carboxylic acid strand transfer inhibitor of
-- HIV integrase (both HIV-1 and HIV-2)
-- Serum-free antiviral IC50 = 0.2 nM; IC90 = 1.2 nM in PBMCs
-- Active against NRTI-, NNRTI-, and PI-resistant isolates
Secondary IN mutations observed
-- With E92Q: H51Y, S147G, E157Q
-- With T66I: F121Y, S153Y, R263K
-- Further reduce EVG susceptibility
-- F121Y also reduces RAL susceptibility
Study GS-183-0105: Active Control, Dose Ranging Phase 2 Study of EVG/r
278 patients
HIV RNA ≥1000 copies/mL
Any CD4 cell count
≥1 protease resistance mutation
OBT = NRTIs +/- T-20
NNRTIs not allowed in OBT
Stratified by T-20 use in OBT
PIs not allowed in EVG arms*
(* Darunavir and tipranavir permitted after week 8 in EVG/r arms)
RANDOMIZED TO:
--Comparator PI/r (n=63)
--EVG/r 20mg QD (n=71)
--EVG/r 50mg (n=71)
--EVG/r 125 mg (n=73)
EVG/r 125 mg Virologic Failure (VF) Patients Analyzed for INI Resistance by Week 24
Patients in EVG/r 125 mg arm with protocol-defined VF by Week 24 were analyzed, n=30
--Baseline and confirmed VF sample
--IN genotype and INI phenotypes (blinded)
--Median time > 400 c/mL before analysis: about 14 weeks
--Median HIV-1 RNA log10 c/mL at analysis: 4.8 (3.2 - 5.8)
Baseline and VF IN genotype / INI phenotype, n=28
--NL4-3 reference for GeneSeq and PhenoSense INI Assays
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