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Reduced
Susceptibility to Protease Inhibitors (PI) in the Absence of Primary
PI Resistance-associated Mutations
N
Parkin, C Chappey, E Lam, and C Petropoulos. ViroLogic, Inc, South
San Francisco, CA
The
majority of clinical samples submitted for phenotypic
and genotypic resistance testing that demonstrate reduced
protease
inhibitor (PI) susceptibility also have one or more
“primary” PI-selected resistance-associated mutations (RAMs). However,
occasionally samples are observed with unexplained PI resistance.
Primary
PI RAMs were defined as any change vs. wild-type at positions 23,
24, 30, 32, 46, 47, 48, 50, 54, 82, 84, 88, 90, with the following
exceptions: I54V and N88D (not reported to occur without other primary
mutations) and V82I (known polymorphism in PI-naïve patients).
PI
susceptibility (fold-change [FC] in IC50), gag (positions 418-500)
and PR genotype were determined with the PhenoSense and GeneSeq
assay, respectively (ViroLogic, Inc.).
Fisher’s
exact test was used to determine genotypic changes in gag or PR
associated with reduced PI susceptibility; mixtures were counted
as mutant, and variables with p<0.005 were considered significant.
Results
·
A
small group of samples with no primary PI RAMs but at least one
PI with FC > 5 was identified (n=125; 0.5% of samples lacking
PI RAMs); 28 had at least one PI with FC > 10.
·
The median/maximum FC to amprenavir
(Agenerase), indinavir
(Crixivan), nelfinavir
(Viracept), ritonavir (Norvir),
saquinavir
(Fortovase; Invirase), lopinavir
(Kaletra), and atazanavir
(Reyataz) were 2.4/25, 3.1/15, 9.6/65, 5.2/75, 2.7/52,
2.4/28, and 3.6/41, respectively.
·
The number of samples with FC > 5 to 1, 2, 3, or
≥4 PIs was 89 (mostly nelfinavir), 17 (mostly nelfinavir and
ritonavir), 11, and 8, respectively.
·
Compared to 3956 samples with no PI RAMs and all PIs
FC < 5, PR mutations over-represented in samples with at least
one PI FC > 5 included: L10IV, I13V, L19V, K20IMT, A22V, M36IV,
N37D, I54V, H69R, A71ITV, G73S, T74KS, V82I, N83D, N88D and I93L.
·
In
gag, several changes including K418ER, A431V, I437V, L449IP, P453L,
and E482G were associated with PI FC >5.
The
authors conclude, “Although rare, reduced susceptibility to PIs
in excess of 5-fold in the absence of primary mutations in PR can
be observed in clinical samples.”
“Accumulation
of secondary mutations and/or polymorphisms in PR, as well as changes
in the C-terminal region of gag, are potential contributors to reduced
PI susceptibility and may modulate response to PI treatment.”
06/15/05
Reference
N
Parkin and others. Reduced Susceptibility to Protease Inhibitors
(PI) in the Absence of Primary PI Resistance-Associated Mutations.
Abstract 108 (poster). XIV International HIV Drug Resistance
Workshop: Basic Principles and Clinical Implications. June
7-11, 2005. Québec City, Québec, Canada.
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