Cerebrospinal fluid HIV RNA and drug levels with combination ritonavir andsaquinavir

Combination antiretroviral therapy with ritonavir and saquinavir has establ ished potent and durable activity on plasma viremia. CNS HIV infection may be sequestered from drug therapy that does not penetrate the blood-brain ba rrier. Penetration of these protease inhibitors into the cerebrospinal flui d (CSF) and CSF HIV RNA levels on such therapy has not been well described. Design/Methods: In a cross-sectional study, 28 HIV-l-infected study subject s were evaluated either before initiation of or before maximal response to ritonavir-saquinavir therapy, during maximal plasma virologic response, and after virologic failure. Simultaneous samples of plasma and cerebrospinal fluid were obtained from 24 study subjects to measure HIV RNA and protease inhibitor levels. Results: Across the treatment groups, a strong correlation was found betwee n plasma and CSF HIV RNA levels (r = 0.870; p < .001). In each study subjec t with plasma HIV RNA levels below assay limit (80 copies/ml), the CSF HIV RNA level was also below the Limit of quantitation. Low levels of saquinavi r (<2 ng/ml) and ritonavir (<25 ng/ml) in the CSF were observed, with a CSF :plasma drug concentration ratio of less than or equal to 0.005 (0.5%) in a ll study subjects evaluated (n = 11). The plasma:CSF HIV RNA ratio was high before or early in treatment (median, 38; interquartile range [IQR], 13, 9 7), but low (median, 0.29; IQR, 0.17, 7.5) in those failing therapy (group C, p < .001). Conclusions: CSF ritonavir and saquinavir levels are consistent with the es timated known fraction of unbound drug in plasma (<2%). Across these treatm ent response groups, suppression of plasma viremia can predict low CSF HIV RNA levels. This correlation may represent HIV RNA transport and equilibriu m between CSF and plasma, or it may represent CNS anti-HIV activity of prot ease inhibitors. The low drug levels and inverted ratio of HIV RNA in the C SF compared with plasma early in plasma virologic breakthrough suggests CSF virologic failure may contribute to failure of plasma virologic response.