XIX International AIDS Conference

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TUPE050 - Poster Exhibition


Low rates of integrase resistance for elvitegravir and raltegravir through week 96 in the phase 3 clinical study GS-US-183-0145

N.A. Margot1, M. Rhee2, J. Szwarcberg2, M.D. Miller1, GS-US-183-0145 Study Team

1Gilead Sciences, Inc., Clinical Virology, Foster City, United States, 2Gilead Sciences, Inc., Clinical Research, Foster City, United States

Background: Elvitegravir (EVG) is a once-daily HIV-1 integrase (IN) strand transfer inhibitor (INSTI). Previous in vitro and clinical trial data defined key EVG-associated IN resistance mutations at IN positions T66, E92, Q148, and N155.
Methods: GS-US-183-0145 was a double-blind, randomized phase 3 study in treatment-experienced patients comparing once-daily EVG to twice-daily raltegravir (RAL), both with a background regimen of a fully active PI/r plus a 2nd antiretroviral agent. Patients were analyzed for resistance development if they had >400 copies/mL at week 48 or week 96, early discontinuation, or upon virologic rebound.
Results: Among 702 patients (ITT population), baseline resistance to NRTI, NNRTI, and PI was present in 70%, 61%, and 32% of patients, respectively; only 17% had no known resistance mutations. At the end of the double blind phase, treatment efficacy was comparable in both arms with 48% vs. 45% for EVG and RAL, respectively, maintaining < 50 c/mL at week 96 (TLOVR). The resistance analysis population (RAP) consisted of 180 patients with a minority developing INSTI resistance (Table 1). Population sequencing showed the presence of mixtures of IN mutations in many cases. However, clonal sequencing analyses showed mostly single mutations per genome with the exception of the RAL-associated Q148H mutation which was consistently observed with a secondary G140S mutation. IN phenotypic analyses showed resistance to both EVG and RAL in 55% and 87% of patients with INSTI resistance mutations in EVG- and RAL-treated, respectively. The highest cross-resistance was associated with RAL-treatment and Q148H+G140S; lowest cross-resistance with EVG-associated T66I/A. Analyzed patients without INSTI resistance had a higher incidence of documented non-adherence and wild-type virus at baseline. Resistance to the background regimen developed minimally and was generally additive to pre-existing mutations.


Mutation CategoryEVG (% ITT [351]; % RAP with data [86])RAL (% ITT [351]; % RAP with data [92])All Subjects (% ITT [702]; % RAP with data [178])
INSTI-R23 (6.6%; 26.7%)26 (7.4%; 28.3%)49 (7%; 27.5%)
T66I/A8 (2.3%; 9.3%)08 (1.1%; 4.5%)
E92Q/G7 (2%; 8.1%)3 (0.9%; 3.3%)10 (1.4%; 5.6%)
T97A4 (1.1%; 4.7%)4 (1.1%; 4.3%)8 (1.1%; 4.5%)
Y143R/H/C01 (0.3%; 1.1%)1 (0.1%; 0.6%)
S147G4 (1.1%; 4.7%)04 (0.6%; 2.2%)
Q148R4 (1.1%; 4.7%)04 (0.6%; 2.2%)
Q148H07 (2%; 7.6%)7 (1%; 3.9%)
N155H5 (1.4%; 5.8%)16 (4.6%; 17.4%)21 (3%; 11.8%)
[Table 1]




Mutation CategoryEVG (% ITT [351]; % RAP with data [82])RAL (% ITT [351]; % RAP with data [90])All Subjects (% ITT [702]; % RAP with data [172])
PI-R5 (1.4%; 6.1%)5 (1.4%; 5.6%)10 (1.4%; 5.8%)
NNRTI-R12 (3.4%; 14.6%)8 (2.3%; 8.9%)20 (2.8%; 11.6%)
NRTI-R9 (2.6%; 11%)12 (3.4%; 13.3%)21 (3%; 12.2%)
[Table 2]


Conclusions: Through week 96, development of integrase resistance was uncommon (~7%) and was observed similarly with both EVG and RAL treatment.


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