15th International HIV Drug Resistance Workshop 13-17 June 2006, Sitges, Spain

NATURAL VARIATION IN SUSCEPTIBILITY OF PATIENT-DERIVED HIV-1 TO AN INTEGRASE STRAND TRANSFER INHIBITOR

Antivir Ther. 2006, 11:S27 (abstract no. 22)

S Fransen, S Gupta, E Paxinos, W Huang, C Chappey, C Petropoulos and Neil Parkin
Monogram Biosciences, South San Francisco, CA, USA

BACKGROUND: Integrase inhibitors (INIs) are currently in phase II and III clinical trials. Genotypic and phenotypic assays are required to characterize resistance to this new class of compounds. In this study we evaluated the susceptibility of patient-derived HIV-1 to the naphthyridine carboxamide integrase strand transfer inhibitor (InSTI), L-870,810.

METHODS: The susceptibility of 130 INI-naïve patient samples to 870,810 (Merck) was measured using an adaptation of the PhenoSense HIV assay. Patient-derived test vectors contained the 3'end of RT (amino acids 317-440), RNaseH and integrase. Differences in IC₅₀ fold-change (FC) among groups of samples were evaluated using the Mann Whitney nonparametric test.

RESULTS: 100 subtype B and 30 non-subtype B patient samples (including subtype A, C, D, CRF01_AE, G) were tested. The variation in 870,810 FC was approximately 8.5 fold (range 0.31-2.64), although 95% of samples fell within a 3.4-fold range (0.4-1.3). Sequence analysis revealed an additional 4 amino acids at the C-terminus of integrase in 5 out of 12 subtype C samples, without apparent effect on InSTI susceptibility. Comparison of phenotypic and genotypic results identified 2 integrase substitutions correlating with changes in drug susceptibility. Isolates with T97A had ~2.5-fold reduced susceptibility to 870,810. The role of T97A was confirmed using site directed mutants. Samples with K156N had ~2-fold increased susceptibility to 870,810. Clones from one patient that contained or lacked K156N displayed statistically significant differences in FC (mean FC 1.2 for 156K compared to 0.65 for 156N, P=0.008). T97A was found in 2.3% of samples while K156N was present in 11.5%. These mutation prevalence data are consistent with those from GenBank (n=1200; T97A, 2.5%; K156N, 3.1%).

CONCLUSIONS: The variation in InSTI susceptibility among untreated patients is relatively narrow and similar to that of most nucleoside reverse transcriptase inhibitors. Naturally occurring polymorphisms such as T97A and K156N in integrase can modulate InSTI susceptibility and may impact the magnitude of resistance in viruses from treated patients.

2006-06-13
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