|
17th International HIV Drug Resistance Workshop10-14 June 2008, Sitges, Spain |
PRE-EXISTING MUTATIONS IN THE U5 VIRAL DNA END OF THE HIV-1 LTR DO NOT AFFECT RESPONSE TO THE INTEGRASE INHIBITOR ELVITEGRAVIR: DATA FROM STUDY GS-US-183-0105
Antivir Ther. 2008; 13(Suppl. 3):A16 (abstract no. 14)
ES Svarovskaia1, RM Hluhanich2, D Goodman1, NA Margot2, DJ McColl2, MD Miller2 and K Borroto-Esoda1
1Gilead Sciences, Inc., Durham, NC, USA; 2Gilead Sciences, Inc., Foster City, CA, USA
BACKGROUND: Integration of HIV-1 requires interaction between the viral DNA ends and the integrase. Sequence variation in the viral DNA termini could potentially affect antiviral activity of integrase inhibitors (INI). Deviations from the consensus sequence of the U5 end of the viral cDNA were defined in HIV-1-infected patients entering a Phase II study (GS-US-183-0105) of the INI elvitegravir (EVG, GS-9137) and their effect on INI susceptibility analyzed.
METHODS: Highly treatment-experienced patients were randomized to 20, 50 or 125 mg once-daily doses of ritonavir-boosted EVG, or a comparator protease inhibitor, plus optimized nucleoside reverse transcriptase inhibitors ± T20. Mean plasma HIV-1 RNA at baseline ranged from 4.47–4.71 log10 copies/ml. A 250 base pair fragment of the U5-psi junction was reverse transcriptase-PCR amplified and sequenced from plasma viral RNA. A site-directed mutant of U5 was constructed in the upstream LTR of HXB2. Mutant viruses were phenotyped using a luciferase-based cell-viability assay.
RESULTS: The U5-psi junction was PCR amplified and sequenced from baseline samples of 50 randomly selected patients. The consensus of the U5 terminal 16 nucleotides was GAAAATCTCTAGCAGT-3′. No mutations were detected in the four highly-conserved terminal bases (CAGT). An ‘A’ insertion, designated ‘5A’, at positions 12–16 (AAAA to AAAAA) was observed in 5/50 patients (10%), four of whom received EVG-containing therapy for >24 weeks. All four patients showed a strong viral load decrease with <400 copies/ml by week 16. A 5A site-directed mutant virus showed minimal changes (<twofold) in EC50 for both EVG and raltegravir, compared with >10-fold changes associated with known INI resistance mutations in integrase. The U5-psi junction was also sequenced from 23 randomly selected patients at virological failure, 12 of these had matching baseline data. No changes in the U5 viral ends were observed in response to EVG therapy.
CONCLUSIONS: Among this highly treatment-experienced population, ~10% of patients examined had sequence variation within the first 16 nucleotides of the U5 viral ends prior to treatment with EVG. The observed polymorphic changes did not appear to affect susceptibility or clinical response to EVG. Additionally, patients did not develop detectable changes in the U5 viral ends in cases of virological failure.
2008-06-10
14
Copyright © 2008 - International Medical Press Ltd.. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the International Medical Press Ltd. 2-4 Idol Lane, London EC3R 5DD UK.