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Session 122 Poster Abstracts
Resistance to Specific Drugs and Drug Combinations
Friday, 1:30 - 3:30 pm
Hall A


714    
Cross-resistance of Clinical Samples with K65R, L74V, and M184V Mutations
Mark Underwood*1, M St Clair1, L Ross1, P Gerondelis1, N Parkin2, and R Lanier1
1GlaxoSmithKline, Research Triangle Park, NC, USA and 2ViroLogic, Inc, South San Francisco, CA, USA

Background:  Considerations for initial drug selection in HIV therapy should include the effects resistance will have on subsequent therapy options. Thymidine analog-sparing nucleoside reverse transcriptase inhibitor (NRTI) backbones or all-NRTI regimens do not select for thymidine analog mutations, but may still result in multi-nucleoside resistance patterns, typically involving combinations of K65R, L74V, and M184V. We evaluated phenotypic effects of these mutations in a large database of clinical samples to help define the range of cross-resistance, and potential drug sequencing implications.

Methods:  Phenotypic susceptibilities (mean, median, range, and percentage above cutoff) to NRTI of viruses in the ViroLogic database containing K65R, L74V, M184I, and M184V were determined.  Samples with mixtures at the positions of interest or other nucleotide analog mutations (NAM) (41L, 67N, 69X, 70R, 75X, 115F, 151M, 210W, 215FY, 219X; X = any non-wild type amino acid) were excluded. Data are presented as median fold resistance change vs reference, and as percentage above assay cutoff. Clinical cutoffs for abacavir (ABC) = 4.5, didanosine (ddI) = 1.7, lamivudine (3TC) = 3.5, stavudine (d4T) = 1.7, and tenofovir (TDF) = 1.4; biological cutoffs for dideoxycytidine (ddC) = 1.7 and zidovudine (ZDV) = 1.9.

Results:  For K65R median fold resistance change > above assay cutoff for 3TC, ddI, ddC, and TDF. With L74V median fold resistance change was not reached for any drug, although 23% of samples had ddI fold change > 1.7. For M184I median fold resistance change > above assay cutoff for 3TC and ddC, and for M184V median fold resistance change > above assay cutoff for 3TC. The double mutants K65R/M184V and L74V/M184V are similar, although the L74V/M184V variant is hypersusceptible to TDF.

 

 

Mutations (n)

drug

K65R

(82)

K65R/M184V

(54)

L74V

(22)

L74V/M184V

(74)

M184V

(1720)

M184I

(27)

ZDV

0.5 [2.4]*

0.4 [0]

0.3 [0]

0.3 [0]

0.4 [0.1]

0.2 [0]

3TC

9.3 [98]

200 [100]

1.4 [0]

200 [100]

200 [100]

200 [100]

ddI

1.7 [60]

2.9 [96]

1.2 [23]

2.2 [91]

1.4 [11]

1.4 [26]

ddC

2.3 [91]

3.9 [100]

1.2 [9.1]

2.3 [86]

1.6 [41]

2.0 [70]

d4T

1.3 [12]

1.0 [0]

0.9 [0]

0.8 [0]

0.7 [0.1]

0.8 [0]

ABC

2.5 [1.2]

6.9 [98]

1.6 [0]

5.4 [78]

2.8 [1.6]

1.6 [0]

TDF

1.8 [83]

1.1 [19]

0.5 [0]

0.3 [0]

0.5 [0]

0.4 [0]

* median fold resistance change [% above assay cutoff]; bold indicates median fold-resistance change > assay cutoff

 

Conclusions:  These data suggest the most detrimental single and double mutations are respectively K65R > M184V > L74V and K65R/M184V > L74V/M184V. These in vitro results predict that selection of L74V or M184V alone, vs K65R, or the combinations K65R/M184V or L74V/M184V, will provide for more downstream NRTI therapy options.

Keywords: Resistance; Nucleosides; Phenotype