614   The CSF Concentration/ IC₅₀Ratio: A Predictor of CNS Antiretroviral (ARV) Efficacy.

S. Letendre*, R. Ellis, I. Grant, A. McCutchan, and the HNRC Group.
Univ. of California San Diego, La Jolla.

Background:ARVs differ in their penetration of the CSF. Better penetrating drugs generally control HIV replication better but viral response can be inconsistent. The ratio between pharmacokinetic parameters, such as the plasma minimum concentration (conc) (C_min) and the 50% inhibitory conc (IC₅₀) provides a measure of ARV systemic antiviral efficacy. The ratio of CSF concs to IC₅₀may provide a better estimate of CNS efficacy than CSF conc alone.

Methods:The CSF concs of FDA-licensed ARVs were obtained from published studies, conference abstracts, and package inserts. IC₅₀ranges were obtained from the ViroLogic PhenoSense assay, which is performed under standardized conditions.

Results:The table shows the highly variable CSF conc/IC₅₀ratios for the nucleoside reverse transcriptase inhibitors (NRTIs). These ratios support clinical observations that zidovudine has the best CNS efficacy among the NRTIs and that ddI has nearly the worst even though their CSF concs are similar. Among the NNRTIs and protease inhibitors (data not shown), nevirapine and indinavir demonstrate the best CSF/IC₅₀ratios.

Conclusions:The CSF conc/IC₅₀ratio may provide a more accurate estimate of CNS efficacy than CSF ARV concs alone. In addition, measuring the IC₅₀of HIV in the CSF of individual patients may be clinically useful in predicting CSF viral response.