569-T. The Presence of Nucleoside Analogue Mutations (NAMs)iIs Highly Correlated with Reduced Susceptibility to all NRTIs

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Session 75 Poster Session
Resistance to Antiretroviral Chemotherapeutic Agents
Session Time: 4:30-6:30 pm
Room 4E-F

569-T.

The Presence of Nucleoside Analogue Mutations (NAMs)iIs Highly Correlated with Reduced Susceptibility to all NRTIs
J. M. Whitcomb, E. Paxinos, W. Huang, M. Maranta, K. Limoli, C. Chappey, N. T. Parkin, N. S. Hellmann, and C. J. Petropoulos*
ViroLogic, Inc., South San Francisco, CA

Background: Nucleoside-analog mutations (NAMs) comprise a set of mutations including M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E. These mutations, originally described as zidovudine (ZDV)-resistance mutations, have now been widely recognized as having a role in resistance to stavudine (d4T) and abacavir (ABC). The lamivudine (3TC)-resistance mutation M184V is associated with decreased susceptibility to 3TC, ABC, ddC, and ddI and with increased susceptiblity to ZDV and adefovir (ADV). The effect of NAMs and the M184V mutation on susceptibility to all of the members of the NRTI-class of drugs was evaluated.
Methods: NRTI susceptibilities from 2500 HIV-1 samples with matched phenotypic and genotypic measurements were evaluated. Samples with classical multi-drug resistance mutations (Q151 complex or T69 insertions) were excluded from the analyses. Pair-wise comparisons of NRTI susceptibilities as continuous variables were performed with non-parametric tests (Spearman’s Rank). chi² analyses were used to investigate the associations of NAMs, the M184V mutation, and other substitutions with NRTI cross-resistance.
Results: An increasing number of NAMs was associated with decreased susceptibilities to all NRTIs, however the degree of cross-resistance was influenced by the M184V mutation. 2 NRTI cross-resistance groups were defined based on the effect of M184V: group 1 (ZDV, d4T, ADV) and group 2 (ddI, ddC, ABC, 3TC). Among samples with the same number of NAMs, the M184V mutation generally increased susceptibility to group 1 and decreased susceptibility to group 2 NRTIs. The magnitude of reduced susceptibility caused by NAMs varied: 100-fold reductions in ZDV susceptibility correlated with a 3TC 6.5-fold reduced susceptibility, ABC 5.7-fold, d4T 5.1-fold, ADV 4.7-fold, ddI 2.0-fold, and ddC 1.9-fold. Higher levels of NRTI-cross resistance are associated with additional substitutions in RT at positions 39, 40, 43, 44, 68, 69, 74, 75, 118, 208, and 228.
Conclusions: Broad cross-resistance among all NRTIs is far more common than previously appreciated. NRTI cross-resistance is highly correlated with the number of NAMs and is modulated by M184V. A reduction in susceptibility to any one NRTI likely translates into reductions in susceptibility to all drugs within this class, albeit at different magnitudes. These observations have important implications for the selection of effective regimens following failure of initial NRTI-containing therapy.