Inhibitory quotient useful as indicator of effective protease inhibitor therapy

Clinicians and patients are well aware that the development of resistance is a significant problem in achieving long-term success with highly active antiretroviral therapy (HAART). It must be recognised, however, that resistance is not an all or none phenomena, but instead comes in gradations.

These gradations are defined by the increase in the inhibitory concentration of a particular drug to a level higher than that of wild-type viruses. Thus, in some cases viral resistance can be overcome by simply increasing drug exposure, something that is routinely done when ritonavir is used in protease inhibitor (PI)-experienced patients to boost other protease inhibitor concentrations to levels sufficient to suppress the mutated virus.

In several recent trials, the use of the Ctrough/IC50 ratio (Inhibitory quotient or “IQ”) has been found to be a useful marker of antiretroviral efficacy. In a study published in AIDS, the clinical usefulness of the IQ as a predictor of virological response was evaluated in two different dual PI regimens.

The study enrolled 52 patients who were on HAART consisting of two nucleoside analogues with either ritonavir/indinavir or nelfinavir/saquinavir and, at baseline, had a median CD4 cell count and viral load of 232 cells/mm3 and 4.2 log10 copies/mL. The enrolled patients had extensive previous antiretroviral (median time 56 months) and PI (median time, 27 months) exposure.

At baseline, the fold increase in the protease inhibitor IC50 values correlated with the patient’s previous PI exposure and was a median of 25.4-fold in indinavir, 108.5-fold in ritonavir, 14.5-fold in nelfinavir, and 2.5-fold in saquinavir.

After at least 15 days on the PI therapy (mean 21 days), pharmacokinetic values used to calculate the PI IQ were obtained. The investigators found a linear relationship between increasing IQ values and a higher HIV-RNA level decrease.

For patients treated with indinavir, the mean HIV decrease was -0.83 and -1.2 log10 copies/ml with an IQ below or above 1, respectively (P = 0.09). Similar results were obtained for ritonavir-treated patients, with a mean decrease of -1.2 log10 copies/ml with an IQ greater than 1. For nelfinavir, the mean HIV-RNA level decrease was -.51 log10 copies/ml with an IQ less than 1 and -1.68 log10 copies/ml with an IQ greater than 1 (P = 0.04). In saquinavir-treated patients, the rate of decrease was -0.92 and -1.1 log10 copies/ml (P = 0.03).

The authors conclude: “This study suggests that it is possible to improve the rate of response by reaching higher drug levels than the IC50. In other words, it demonstrated that the use of available phenotypic testing and the knowledge of the Ctrough reached in every patient may be a useful tool in salvage regimens.

“However, the difficulties with this lie in the uncertainty as to what levels of drugs, relative to in-vitro inhibitory values, are required to achieve optimal efficacy, the lack of standardisation of pharmacokinetic data in PI, and the variability of drug levels among patients. Therefore, we can not establish an ideal IQ to be reached in a dual PI combination.”

J Casado et al. Individualizing salvage regimens: the inhibitory quotient (Ctrough/IC50) as predictor of virological response. AIDS 2003;17:262-264.

Reproduction of articles for personal or educational use is encouraged and does not require permission from the publisher. Permission to re-print copyrighted articles is almost always granted, but does require written permission from the publisher (email publisher@HIVandHepatitis.com)