Background:  The multi-drug resistance gene (MDR-1) encodes P-glycoprotein (P-gp). P-gp is expressed on many cells and effluxes its substrates across apical-luminal surfaces, limiting their penetration into certain cells and tissues. P-gp is heavily expressed at the blood-brain and blood-cerebrospinal fluid (CSF) barriers. Many ART, including indinavir (IDV), are substrates for P-gp. MDR-1 knockout mice show substantially higher levels of IDV in brain tissue than do mice with intact MDR-1 genes. This is the first study to evaluate the relationship between IDV concentration in CSF and MDR-1 genotype in humans.

Methods:  IDV concentrations were measured by HPLC in plasma and by LC-MS in CSF collected from 37 HIV⁺ subjects. Genomic DNA was extracted by the Flexigene DNA kit and the region containing the –3435 single nucleotide polymorphism was amplified via polymerase chain reaction (PCR) for use with the NanoChipâ instrument. Subjects possessing at least one wild type allele were grouped. Plasma IDV concentration was adjusted to reflect the amount of drug that was unbound but CSF IDV was not because protein levels in CSF are low. IDV concentrations and viral loads were log transformed to improve their distribution. Non-parametric analyses were used when analyzing VL because their distribution was highly skewed even after log transformation.

Results:  Of the total, 9 subjects (24%) were homozygous mutants (T/T), 12 (33%) were homozygous wild type (C/C), and 16 (43%) were heterozygous (T/C). The median duration of IDV use was 44.3 weeks. Plasma and CSF IDV levels were higher in homozygous mutants than the wild-type group (mean [sd] plasma: 3.5 [0.54] vs 2.5 [1.2], p = 0.04; CSF: 2.3 [0.3] vs 1.9 [0.6], p = 0.02). Higher levels of IDV correlated with lower levels of viral load in both plasma and CSF (plasma Spearman  r = –0.45, p = 0.01; CSF Spearman r= –0.36, p = 0.03). Homozygous mutants had somewhat lower plasma and CSF viral load, but this relationship did not reach statistical significance (plasma p = 0.10; CSF p = 0.29).

Conclusions:  The MDR-1 C3435T polymorphism was associated with higher IDV levels in plasma and CSF, and the latter was, in turn, associated with improved virologic suppression. Higher levels of IDV are associated with lower viral loads for plasma and CSF. In this sample, MDR genotype was not related to viral load however in a larger sample this relationship may be present. MDR-1 genotype may affect the neurotherapeutic potential of ART regimens.