Higher CNS Penetration-Effectiveness of Long-term Combination Antiretroviral Therapy Is Associated With Better HIV-1 Viral Suppression in Cerebrospinal Fluid

Cusini, Alexia; Vernazza, Pietro L.; Yerly, Sabine; Decosterd, Laurent A.; Ledergerber, Bruno; Fux, Christoph A.; Rohrbach, Janine; Widmer, Nicolas; Hirschel, Bernhard; Gaudenz, Roman; Cavassini, Matthias; Klimkait, Thomas; Zenger, Franziska; Gutmann, Chistine; Opravil, Milos; Günthard, Huldyrich F. (2013). Higher CNS Penetration-Effectiveness of Long-term Combination Antiretroviral Therapy Is Associated With Better HIV-1 Viral Suppression in Cerebrospinal Fluid. JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES, 62(1), pp. 28-35. Lippincott Williams & Wilkins 10.1097/QAI.0b013e318274e2b0

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Objectives: To determine HIV-1 RNA in cerebrospinal fluid (CSF) of successfully treated patients and to evaluate if combination antiretroviral treatments with higher central nervous system penetration-effectiveness (CPE) achieve better CSF viral suppression.

Methods: Viral loads (VLs) and drug concentrations of lopinavir, atazanavir, and efavirenz were measured in plasma and CSF. The CPE was calculated using 2 different methods.

Results: The authors analyzed 87 CSF samples of 60 patients. In 4 CSF samples, HIV-1 RNA was detectable with 43–82 copies per milliliter. Median CPE in patients with detectable CSF VL was significantly lower compared with individuals with undetectable VL: CPE of 1.0 (range, 1.0–1.5) versus 2.3 (range, 1.0–3.5) using the method of 2008 (P = 0.011) and CPE of 6 (range, 6–8) versus 8 (range, 5–12) using the method of 2010 (P = 0.022). The extrapolated CSF trough levels for atazanavir (n = 12) were clearly above the 50% inhibitory concentration (IC50) in only 25% of samples; both patients on atazanavir/ritonavir with detectable CSF HIV-1 RNA had trough levels in the range of the presumed IC50. The extrapolated CSF trough level for lopinavir (n = 42) and efavirenz (n = 18) were above the IC50 in 98% and 78%, respectively, of samples, including the patients with detectable CSF HIV-1 RNA.

Conclusions: This study suggests that treatment regimens with high intracerebral efficacy reflected by a high CPE score are essential to achieve CSF HIV-1 RNA suppression. The CPE score including all drug components was a better predictor for treatment failure in the CSF than the sole concentrations of protease inhibitor or nonnucleoside reverse transcriptase inhibitor in plasma or CSF.

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