Dose–response curve slope is a missing dimension in the analysis of HIV-1 drug resistance

Abstract

HIV-1 drug resistance is a major clinical problem. Resistance is evaluated using in vitro assays measuring the fold change in IC 50 caused by resistance mutations. Antiretroviral drugs are used at concentrations above IC 50 , however, and inhibition at clinical concentrations can only be predicted from IC 50 if the shape of the dose-response curve is also known. Curve shape is influenced by cooperative interactions and is described mathematically by the slope parameter or Hill coefficient (m). Implicit in current analysis of resistance is the assumption that mutations shift dose-response curves to the right without affecting the slope. We show here that m is altered by resistance mutations. For reverse transcriptase and fusion inhibitors, single resistance mutations affect both slope and IC 50 . For protease inhibitors, single mutations primarily affect slope. For integrase inhibitors, only IC 50 is affected. Thus, there are fundamental pharmacodynamic differences in resistance to different drug classes. Instantaneous inhibitory potential (IIP), the log inhibition of single-round infectivity at clinical concentrations, takes into account both slope and IC 50 , and thus provides a direct measure of the reduction in susceptibility produced by mutations and the residual activity of drugs against resistant viruses. The standard measure, fold change in IC 50 , does not correlate well with changes in IIP when mutations alter slope. These results challenge a fundamental assumption underlying current analysis of HIV-1 drug resistance and suggest that a more complete understanding of how resistance mutations reduce antiviral activity requires consideration of a previously ignored parameter, the dose-response curve slope.HIV/AIDS | pharmacology | virology | highly active antiretroviral therapy | evolution

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

“…1B, Methods, and SI Appendix). The antiviral activity of a drug can be expressed as the instantaneous inhibitory potential (IIP) (13)(14)(15)(16)(17)(18):…”

“…This system supports efficient replication of genotype 1 HCV, and thus enables one to measure the intrinsic antiviral effects of any drug combination and at any concentration of the component drugs in a highly sensitive manner and with high throughput. The experimental data were analyzed by calculating the IIP, which is the log reduction in HCV replication caused by drugs singly and in combination at a particular concentration (13)(14)(15)(16)(17)(18). From the calculated IIP of 15 anti-HCV drugs, we found that IFN-α and the NI SOF had the largest potential to inhibit viral replication events.…”

A Mathematical Model to Predict HIV Virological Failure and Elucidate the Role of Lymph Node Drug Penetration

“…As this can significantly vary between individuals due to immunity and quasispecies differences, the attributed R 0 is sampled from random distributions, which are reported for patients in the acute (primary infection, higher viral growth rate) and chronic (a few months after primary infection) phases 11, 12. For the resistant strain, growth is hampered by a nonzero fitness cost ( s ), which value depends on the considered mutation, and is reported for multiple strains in Sampah et al 13. A newly infected cell starts producing new virions after an eclipse period of 1 day ( τ ) and for a median period of 1 day ( d y ) 14, 15.…”

“…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.…”

“…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. If multiple drug treatment are considered, an algorithm for the combined effect is used 21.…”