566-T.
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Evolution of Reverse Transcriptase and Protease Resistance Mutations in HIV-1-Infected Patients on Antiretroviral Therapy
R. Kantor*1, R. Shafer1, D. Katzenstein1, S. Follansbee2, and J. Fessel2
1Stanford Univ., CA and 2Kaiser Permanente, San Francisco, CA
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Background: There are few clinical data to support specific strategies for changing therapy in patients who have failed a highly active antiretroviral treatment (HAART) regimen. In choosing a treatment strategy for these patients, it is important to know if ongoing virus replication during continued therapy with a failing regimen allows evolution of mutations that might limit future treatment options.
Methods: We examined the evolution of drug resistance mutations in patients continuing therapy despite ongoing virus replication. We identified 24 patients who had 2 genotypic resistance tests separated by a median of 7.5 months (range 3-25) without undergoing a change in their HAART regimen. Changes in susceptibility to the different drugs were assessed by a computer program that interprets drug resistance (http://hivdb.stanford.edu/hiv).
Results: The median VL (copies/mL), CD4 (cells/muL) and number of mutations/patient for the first and second time-points were 9586, 246, 10.5, and 8403, 234, 11.5, respectively (p=0.02 for mutations/patient). New resistance mutations developed in 19/24 (79%) patients (15/24 primary and 15/24 secondary mutations). 16/24 patients (67%) developed PI mutations (8/24 primary and 13/24 secondary mutations); 9/24 (38%) developed NRTI mutations (7/24 primary and 4/24 secondary mutations); and 3/5 (60%) developed NNRTI mutations. The most commonly gained mutations were primary PI mutations M46I (4/24) followed by L90M and D30N (2/24 each); secondary PI mutations L10I and I93L (4/24 each) followed by A71V (3/24); NRTI mutation K70R (3/24) followed by D67N, V118I, and L74V (2/24 each); and NNRTI mutation K103N (3/5). Isolates from 10/24 (42%) patients developed resistance to a mean of 4 drugs during the interval between the 2 sequences.
Conclusions: 80% of sequences from patients staying on a failing multi-drug regimen accumulated either RT or PR mutations, and 40% developed a more drug resistant isolate. These observations provide insight into how an uninterrupted regimen affects the natural history of mutation evolution and may limit future drug options. In patients with a median VL of <10000 and a median CD4 count of 250, it may be a disservice not to change drug treatment.
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