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Absence of Protease Resistance with Virologic Rebound by Single Genome Sequencing on Atazanavir/Ritonavir as Simplified Maintenance Therapy: ACTG 5201
John McKinnon*1, T Wilkin2, S Swindells3, G DiRienzo4, C Fletcher5, D Margolis6, G Thal7, B Bastow8, K Droll4, J Mellors1, and the A5201 Study Group
1Univ of Pittsburgh, PA, US; 2Weill Med Coll of Cornell Univ, New York, NY, US; 3Univ of Nebraska Med Ctr, Omaha, US; 4Harvard Sch of Publ Hlth, Boston, MA, US; 5Univ of Colorado Hlth Sci Ctr, Denver, US; 6Univ of North Carolina at Chapel Hill, US; 7Bristol-Myers Squibb, Plainsboro, NJ, US; and 8ACTG Operations Ctr, Silver Spring, MD, US
Background: Ritonavir-boosted atazanavir (ATV/RTV)
without NRTI is attractive for simplified maintenance ART because of once-daily
dosing, excellent tolerability, and absence of resistance with virologic
rebound. However, these resistance analyses have been performed with standard
population genotyping that often fails to detect variants that comprise <25%
of the virus population. We therefore performed single genome sequencing to
detect the emergence of low frequency ATV-resistant variants.
Methods: Subjects were enrolled in AIDS Clinical
Trials Group (ACTG) 5201, a pilot study of ATV/RTV maintenance therapy in 36
patients. Plasma samples from 4 patients with protocol-defined virologic
failures and 1 patient with detectable viremia at end of study were analyzed by
standard genotyping (ViroSeq version 2.6) and single genome sequencing. An
average of ≥45 sequences per sample were obtained to achieve 90% power to
detect a resistant variant present in 5% of the viral pool.
Results: Plasma HIV-1 RNA levels ranged from 508 to 21,652
copies/mL. Standard genotyping did not detect any major protease inhibitor (PI)
resistance mutations or predicted resistance (ViroSeq algorithm) for the 5
samples tested. Minor mutations detected by standard genotyping were I62V in 2
patients; I64V in 1 patient; and A71V and I93L in 1 patient. A total of 236
single genome sequences of protease were analyzed from the 5 samples with an
average of 47 sequences/sample (range 43 to 53). No major protease mutations
(Stanford drug resistance database) were identified in any of the sequences.
Minor ATV resistance mutations detected only by single genome sequence were: I64V
in 2 of 100 combined sequences from 2 patients, and G73S in 2 of 90 combined
sequences from 2 patients. None of the minor mutations detected altered
susceptibility to ATV (Stanford drug-resistance database). Each patient with
virologic failure had re-suppression of HIV-1 RNA to <50 copies/mL with a
RTV-boosted PI regimen.
Conclusions: Low frequency PI-resistant variants
were not identified with virologic rebound in subjects receiving ATV/RTV alone
as simplified maintenance therapy. This finding supports the continued
investigation of simplified maintenance therapy with ritonavir-boosted PI and
provides evidence that future treatment options are not compromised by this
strategy.
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