2008
DOI: 10.1038/nm1777
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Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs

Abstract: Highly active antiretroviral therapy (HAART) can control HIV-1 replication, but suboptimal treatment allows for the evolution of resistance and rebound viremia. A comparative measure of antiviral activity under clinically relevant conditions would guide drug development and the selection of regimens that maximally suppress replication. Here we show that current measures of antiviral activity, including IC(50) and inhibitory quotient, neglect a key dimension, the dose-response curve slope. Using infectivity ass… Show more

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Cited by 301 publications
(447 citation statements)
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“…The shape is influenced by cooperative interactions and is described mathematically by the slope parameter or Hill coefficient (m) (31,32). Certain drugs, notably nonnucleoside RT inhibitors (NNRTIs) and protease inhibitors (PIs), have cooperative dose-response curves with high slopes even though they target enzymes that are univalent with respect to the inhibitor (33). These high slopes may reflect a unique form of intermolecular cooperativity operative when multiple copies of a drug target participate in a given step in the virus life cycle (33).…”
mentioning
confidence: 99%
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“…The shape is influenced by cooperative interactions and is described mathematically by the slope parameter or Hill coefficient (m) (31,32). Certain drugs, notably nonnucleoside RT inhibitors (NNRTIs) and protease inhibitors (PIs), have cooperative dose-response curves with high slopes even though they target enzymes that are univalent with respect to the inhibitor (33). These high slopes may reflect a unique form of intermolecular cooperativity operative when multiple copies of a drug target participate in a given step in the virus life cycle (33).…”
mentioning
confidence: 99%
“…Certain drugs, notably nonnucleoside RT inhibitors (NNRTIs) and protease inhibitors (PIs), have cooperative dose-response curves with high slopes even though they target enzymes that are univalent with respect to the inhibitor (33). These high slopes may reflect a unique form of intermolecular cooperativity operative when multiple copies of a drug target participate in a given step in the virus life cycle (33). High slopes allow for extraordinarily highlevel inhibition at concentrations above IC 50 .…”
mentioning
confidence: 99%
“…Hill functions are shown to reflect the relationship between drug concentration and drug efficacy in vitro 1. The effect of the drug is accounted in the model using the drug concentration inhibiting 50% of the infection growth in vitro in a medium containing no plasma protein content ( IC500) and using the Hill curve coefficient ( m ).…”
Section: Methodsmentioning
confidence: 99%
“…The former is taken from a random distribution since significant quasispecies differences in IC 50 are commonly reported 17. For the treatments investigated herein, these parameters were obtained from the product monographs3, 18, 19, 20 and from results of in vitro experimentations 1, 13. For the resistant strain, the model uses the fold‐change in IC 50 ( ρ ) and the correction factor for the Hill coefficient ( σ ) 4, 13.…”
Section: Methodsmentioning
confidence: 99%
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