HIV in the CSF: Total and unbound concentrations of efavirenz in cerebrospinal fluid and in plasma

In this study L Moberg and colleagues from the Karolinska Institute in Sweden looked at efavirenz in CSF. Efavirenz exerts central nervous system side-effects and has been reported to enter the cerebrospinal fluid (CSF). It is, however, unknown what the pharmacologically active unbound concentrations of efavirenz are in CSF and in plasma. It is suggested that the amount of unbound drug is important to antiviral activity.

Twelve HIV-infected patients on combination therapy including efavirenz since at least one month were subject to lumbar puncture and plasma collection taken between 8 and 23 hours from the last drug intake. Unbound concentrations were measured by ultrafiltration. Efavirenz was analysed by high performance liquid chromatography with UV-detection after liquid-liquid extraction.

The mean total efavirenz concentration in plasma was 7.7 uM. The unbound fraction in plasma was 0.4% (sd 0.18) of total plasma and the total CSF was 1.6% (0.96) of total plasma. The unbound CSF was 41% of unbound plasma concentration. Finally, CSF HIV-RNA was below 500 copies/mL in 9/12 patient which is significantly more frequent than the 14/36 observed in an untreated reference population. Moberg concluded that efavirenz reaches the CSF in concentrations likely to contribute to an antiretroviral effect.

Increased stavudine concentrations in plasma and cerebrospinal fluid: A possible interaction with ritonavir and/or indinavir?

M Reijers, S Danner, J Lange, R Hoetelsmans and colleagues from Amsterdam reported findings suggesting ritonavir and/or indinavir increases d4T concentrations in plasma, and ritonavir increases d4T concentrations in CSF.

The metabolism of stavudine (d4T), a frequently used nucleoside analogue RT inhibitor (NRTI), is partly unknown. Except for an interaction with zidovudine on the level of phosphorylation, no clinically important in vivo pharmacokinetic interactions have been reported.

For this study D4T concentrations were assessed in paired samples of blood and cerebrospinal fluid (CSF) of patients participating in the 050, ADAM, Prometheus, or ERA study.

All of the 39 patients available for this analysis used 40 mg d4T bid for at least 12 weeks. Patients in the 050 study (n = 11) used d4T and lamivudine (3TC). In the ADAM study (n = 10), d4T, 3TC, nelfinavir (NFV) and saquinavir (SQV) were used, while Prometheus patients (n = 8) used ritonavir (RTV), SQV and d4T. ERA patients (n = 10) used d4T, 3TC, nevirapine, abacavir, and a PI (indinavir (IDV), IDV/RTV, RTV/SQV, or NFV). Baseline characteristics of the patients were comparable. Patients in the 050 and ADAM study had 3 to 6 fold lower d4T concentrations in plasma and CSF as compared to patients in the Prometheus and ERA study (p = 0.0001 and p = 0.0001, resp.). CSF/plasma concentration ratios were however comparable (p = 0.6). The association was studied between stavudine concentrations and the age, the body mass index (BMI), the CD4+- and CD8+ cell count and the HIV-1 RNA concentration in plasma at baseline and at time of sampling, the cell- and protein concentration in CSF, the use of a protease inhibitor, time of sampling and the treatment duration. In a multivariate linear regression analysis, only the use of RTV and/or IDV and the BMI were significantly associated with the d4T concentrations in plasma (p = 0.0001 and p = 0.04 resp.). The concentration of d4T in CSF was associated with the use of RTV, and the CD4+ cell count at time of sampling (p = 0.0001and p = 0.004 resp.).

The authors concluded that this unexpected finding might suggest that d4T metabolism is at least in part, inhibited by ritonavir and/or indinavir.