Determination of Clinically Relevant Cutoffs for HIV-1 Phenotypic Resistance Estimates Through a Combined Analysis of Clinical Trial and Cohort Data

Abstract

The proposed CCOs were better correlated with virologic response than were biological cutoffs and provide a relevant tool for estimating the resistance to antiretroviral drug combinations used in clinical practice. They can be applied to diverse patient populations and are based on a consistent methodologic approach to interpreting phenotypic drug resistance.

Residual Activity of Two HIV Antiretroviral Regimens Prescribed without Virological Monitoring

“…A key objective in clinical research has been the identification of cut-points for phenotypic resistance assays that signify when the effect of a drug ceases to exert meaningful clinical activity (3,29,30). However, threshold effects often lack biological plausibility, and arbitrary statistical rules underlie selection of cut-points.…”

“…Samples with HIV RNA above the linear dynamic range which met the inclusion criteria for the current analysis (see below) were retested after 2-to 10-fold dilution to achieve uncensored values. Genotypic (VircoTYPE 4.3.01) (29,30) and phenotypic (Antivirogram 2.5.01, Virco BVBA) (16) resistance testing was performed on samples with HIV-1 RNA of Ն1,000 copies/ml at 48/96 weeks and on the corresponding baseline samples. For each drug, phenotypic resistance was expressed as the fold change (FC) in 50% inhibitory concentration (IC 50 ) compared to that of wild-type (HXB2) virus.…”

Point Mutations Associated with HIV-1 Drug Resistance, Evasion of the Immune Response and AIDS Pathogenesis

“…Winters et al, 2008). Similarly; I50L, I84 and N88S mutations are associated with high levels of phenotypic resistance to atazanavir/r (Colonno et al, 2004;Pellegrin et al, 2006;Rhee et al, 2006b;Vermeiren et al, 2007;Vora et al, 2006;B. Winters et al, 2008).…”

“…In particular, L31I, D30N, M46I/L, G48V/M, I84V, N88D/S and L90M mutations are associated with high levels of phenotypic resistance to nelfinavir because they cause inferior virologic response to therapy relative to that obtainable with most other PI (Johnston et al, 2004;Patick et al, 1996;B. Winters et al, 2008).…”

“…G48V/M, 184V and L90M mutations are relative contraindications to the use of saquinavir/r (Marcelin et al, 2004a;Marcelin et al, 2007;Zolopa et al, 1999). V32I, I47V/A, I54L/M and I84V mutations are relative contraindications to the use of fosamprenavir/r (Dandache et al, 2007;Masquelier et al, 2008;Pellegrin et al, 2007;B. Winters et al, 2008).…”