|
12th International HIV Drug Resistance Workshop10–14 June 2003, Cabo del Sol, Los Cabos, Mexico |
BACKGROUND: SPD754 is a heterocyclic cytidine analogue with anti-HIV activity against a range of wild-type viruses and viruses resistant to other nucleoside reverse transcriptase inhibitors (NRTIs). In order to further characterize the resistance profile of SPD754 antiviral activity has been assessed against a panel of 215 clinical isolates of HIV-1 with genotypes associated with resistance to NRTIs.
METHODS: All viruses were selected from the Virologic library of clinical isolates. Groups of viruses were selected with defined mutation patterns at codons 41, 67, 70, 184, 210, 215 and 219 of reverse transcriptase, with at least 10 different viruses per group. Viruses with 69 insertion mutations, Q151M, or mutations at positions 65, 69, 74 or 75 were excluded. The antiviral activity of zidovudine (AZT), lamivudine (3TC), didanosine (ddI), abacavir, tenofovir and SPD754 against these viruses was assessed using the Phenosense™ assay.
RESULTS: Viruses with no resistance-associated RT mutations had median fold-change (FC) to SPD754 of 0.9 (range 0.7–1.1, n=20). Viruses with mutations at codons 67 and 70 of RT remained sensitive to SPD754 (median FC 1.0 vs 5.5 for AZT, n=10). Addition of mutations at codons 219, 215 and 41 progressively decreased the sensitivity of HIV-1 to SPD754, with viruses containing mutations at 41, 67, 70, 215 and 219 having a median FC of 1.3 (range 0.9–1.9, n=15). The same group of viruses showed 108-fold reduced sensitivity to AZT, and 3.2-, 3.0-, 1.3- and 2.5-fold resistance to 3TC, abacavir, ddI and tenofovir, respectively. Mutations at codons 41 and 215 of RT were associated with 1.2-fold reduced sensitivity to SPD754 (range 0.7-1.7 vs 33 for AZT, n=20). Addition of mutations at codons 210, 67 and 219 progressively decreased the sensitivity of HIV-1 to SPD754, with viruses containing mutations at 41, 67, 210, 215 and 219 having median FC of 1.8 (range 1.2–2.6, n=15). The same group of viruses showed 438-fold reduced sensitivity to AZT, and 4.8-, 4.5-, 1.4- and 3.6-fold resistance to 3TC, abacavir, ddI and tenofovir, respectively. Pairwise comparison of separate groups of viruses with different background genotypes (wildtype, 41 and 215, and 67, 70 and 219) with and without mutations at codon 184 showed that in all three cases, the addition 184 was associated with a 1.8-fold reduction in sensitivity to SPD754. Pairwise regression analysis of log-transformed FC values showed a high degree of cross resistance with abacavir and ddI (r2=0.79 and 0.74, respectively), but a substantially lower level of cross resistance with AZT and tenofovir (r2 approximately 0.5).
CONCLUSIONS: The presence of up to five mutations at codons 41, 67, 70, 210, 215 and 219 of RT confers no more than a twofold reduction in median sensitivity to SPD754. Mutation at codon 184 of RT is associated with a 1.8-fold reduction in sensitivity to SPD754.
PRESENTING AUTHOR: RC Bethell
Download PDF of this abstract.
2003-07-08
3
Copyright © 2003 - 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.