Inhibitory Quotient of Boosted Protease Inhibitors & Viral Load
Inhibitory Quotient of Boosted Protease Inhibitors & Viral Load
Objective: The normalized inhibitory quotient (NIQ) has been proposed as a measure for refining the precision of HIV resistance testing when selecting antiretroviral therapy (ART). We undertook an assessment of NIQ and 48-week virological outcome in patients commencing ritonavir-boosted protease inhibitor (PI) regimens.
Design: A cohort of 87 HIV-infected individuals who all had extensive prior exposure to ART were assigned a new boosted PI regimen following resistance testing. PI therapy consisted of lopinavir, indinavir, saquinavir and amprenavir at 50, 32, 11 and 6%, respectively. Fold change (FC) for each PI was determined from the resistance test at baseline. Trough drug concentration (Cmin) was determined at week 4.
Methods: NIQ was derived individually by taking the logarithm of the ratio of Cmin/FC divided by the fixed ratio of population mean trough drug concentration/clinical cut off. Associations between viral load (VL) response over 48 weeks with baseline VL, FC, Cmin, NIQ and selected PI were assessed.
Results: Mean change from baseline VL reduced by 0.83 log at week 48. In multivariate analyses, baseline VL and NIQ were the parameters most associated with change from baseline VL at week 48 (P = 0.012 and 0.003, respectively). FC, Cmin and selected PI were not significantly associated with VL changes.
Conclusion: In this cohort of highly treatment-experienced individuals treated with boosted PI regimens, baseline VL and NIQ were significantly predictive of virological response over 48 weeks whereas FC and Cmin were not. These results support the use of a NIQ at week 4, as a tool for predicting response to therapy in this setting.
The development of HIV-1 resistance and subsequent virological failure occur in a substantial proportion of HIV-infected individuals receiving highly active antiretroviral therapy (HAART). Resistance represents an increase in the concentration of an antimicrobial agent required to inhibit a given level of microbial infection. This implies overcoming drug resistance by increasing drug exposure may be possible.
Inherent variability in the plasma concentration of the HIV protease inhibitors (PI) have been demonstrated in controlled pharmacokinetic studies in individuals who are HIV infected. In these studies, coefficients of variation for the area under concentration time curves range between 37 and 91% among all the available protease inhibitors. Using ritonavir as a pharmacokinetic enhancer may reduce, but not eliminate, this variability.
The use of HIV drug resistance testing has been shown to provide virological benefit in randomized controlled trials. A significant relationship between plasma drug concentrations and virological response has been described for several agents. The ratio of drug concentration at trough (Cmin) to a measure of susceptibility to a drug, the inhibitory quotient (IQ), was first suggested as a means to assess the response to antibiotics over 20 years ago. More recently IQs have been proposed as a predictive measure of virological response to HIV protease inhibitors. To date limited clinical data have shown correlations between IQs for individual PIs and virological response.
A lack of standardization in measuring IQ has prevented direct comparisons of different antiretroviral agents. Several methods to calculate IQ have been proposed including the use of genotypic resistance testing and virtual phenotypic resistance testing (virtual IQ; VIQ). Recently the use of normalized IQ (NIQ) has been suggested; namely the normalizing of IQ values using population average Cmin and fold changes in sensitivity. This method overcomes differences in protein binding and Cmin between different PIs. In a recent study of 55 treatment-experienced individuals, NIQ was significantly associated with virological response to lopinavir-ritonavir.
The aim of this study was to describe the relationship between a range of covariates, including NIQ, and 48-week virological response within a cohort of highly treatment-experienced individuals treated with a range of boosted single-PI-containing regimens.
Objective: The normalized inhibitory quotient (NIQ) has been proposed as a measure for refining the precision of HIV resistance testing when selecting antiretroviral therapy (ART). We undertook an assessment of NIQ and 48-week virological outcome in patients commencing ritonavir-boosted protease inhibitor (PI) regimens.
Design: A cohort of 87 HIV-infected individuals who all had extensive prior exposure to ART were assigned a new boosted PI regimen following resistance testing. PI therapy consisted of lopinavir, indinavir, saquinavir and amprenavir at 50, 32, 11 and 6%, respectively. Fold change (FC) for each PI was determined from the resistance test at baseline. Trough drug concentration (Cmin) was determined at week 4.
Methods: NIQ was derived individually by taking the logarithm of the ratio of Cmin/FC divided by the fixed ratio of population mean trough drug concentration/clinical cut off. Associations between viral load (VL) response over 48 weeks with baseline VL, FC, Cmin, NIQ and selected PI were assessed.
Results: Mean change from baseline VL reduced by 0.83 log at week 48. In multivariate analyses, baseline VL and NIQ were the parameters most associated with change from baseline VL at week 48 (P = 0.012 and 0.003, respectively). FC, Cmin and selected PI were not significantly associated with VL changes.
Conclusion: In this cohort of highly treatment-experienced individuals treated with boosted PI regimens, baseline VL and NIQ were significantly predictive of virological response over 48 weeks whereas FC and Cmin were not. These results support the use of a NIQ at week 4, as a tool for predicting response to therapy in this setting.
The development of HIV-1 resistance and subsequent virological failure occur in a substantial proportion of HIV-infected individuals receiving highly active antiretroviral therapy (HAART). Resistance represents an increase in the concentration of an antimicrobial agent required to inhibit a given level of microbial infection. This implies overcoming drug resistance by increasing drug exposure may be possible.
Inherent variability in the plasma concentration of the HIV protease inhibitors (PI) have been demonstrated in controlled pharmacokinetic studies in individuals who are HIV infected. In these studies, coefficients of variation for the area under concentration time curves range between 37 and 91% among all the available protease inhibitors. Using ritonavir as a pharmacokinetic enhancer may reduce, but not eliminate, this variability.
The use of HIV drug resistance testing has been shown to provide virological benefit in randomized controlled trials. A significant relationship between plasma drug concentrations and virological response has been described for several agents. The ratio of drug concentration at trough (Cmin) to a measure of susceptibility to a drug, the inhibitory quotient (IQ), was first suggested as a means to assess the response to antibiotics over 20 years ago. More recently IQs have been proposed as a predictive measure of virological response to HIV protease inhibitors. To date limited clinical data have shown correlations between IQs for individual PIs and virological response.
A lack of standardization in measuring IQ has prevented direct comparisons of different antiretroviral agents. Several methods to calculate IQ have been proposed including the use of genotypic resistance testing and virtual phenotypic resistance testing (virtual IQ; VIQ). Recently the use of normalized IQ (NIQ) has been suggested; namely the normalizing of IQ values using population average Cmin and fold changes in sensitivity. This method overcomes differences in protein binding and Cmin between different PIs. In a recent study of 55 treatment-experienced individuals, NIQ was significantly associated with virological response to lopinavir-ritonavir.
The aim of this study was to describe the relationship between a range of covariates, including NIQ, and 48-week virological response within a cohort of highly treatment-experienced individuals treated with a range of boosted single-PI-containing regimens.