CNS Penetration in the Treatment of HAD

Although viral decay in CSF usually parallels that in plasma, occasionally there can be variability and may even be increases of RNA in the CSF despite a decline in plasma levels. These differences in the decay kinetics may be related to the type of cells infected in each compartment CD4 T cells in plasma, which are rapidly destroyed, versus monocytes and macrophages in the brain, which persist longer (Eggers etal., 2003). 

Among the NNRTls, nevirapine has the highest penetration. Protease inhibitors have poor penetration becanse they are highly protein bound in plasma. Despite this fact, protease inhibitors have been successful in the treatment of HAD (Gendelman et al., 1998 Saksena and Smit, 2005). Some investigators believe that control of virus replication in the periphery may be sufficient to reverse HIV-related brain disease. Improvement in immune status from ART may also reconstitute the defective blood-brain barrier, which is seen in later stages of HIV infection (Evers et al., 2004). The importance of CNS penetration in the treatment of HAD is therefore controversial, and drugs which do not have adequate CSF levels may still be effective. 

Zidovudine monotherapy was the only available treatment for HIV disease before the 1990s, and was used until 1992. Zidovudine monotherapy has been proven to be efficacious for both the treatment of HAD as well as for HIV-associated minor cognitive/motor disorder (MCMD) (Arendt et al., 1992 Sidtis et al., 1993 Tozzi et al., 1993). Unfortunately, the beneficial effect of zidovudine was transient and an addition of a second NRTI such as dideoxyinosine (ddl), lamivudine (3TC), or dideoxycytidine (ddC), may not further improve psychomotor performance. Stavudine was shown to improve motor performance even after pretreatment with zidovndine (Arendt et al., 2001). A study in 1998, using abacavir versns placebo showed no nenrologic deterioration in the abacavir group as compared with the placebo group (Lanier et al., 2001). However, there was no benefit when abacavir was added to a stable ART, despite good proven CNS penetration. 

Protease inhibitors are highly protein-bound. The Pis studied in the CSF include saquinavir, indinavir, andnelfmavir. All of them have very low CSF plasma ratios. However, several 

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