Maria S Di Yacovo1, José Moltó2, Elena Ferrer1, Adrian Curran3, Laura Else4, Magnus Gisslén5, Bonaventura Clotet6, Juan M Tiraboschi1, Jordi Niubò1, Antonia Vila1, H Zetterberg7, David Back4, Daniel Podzamczer8. 1. Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain. 2. Fundació Lluita Contra la Sida, Hospital Universitari Germans Trias i Pujol, Badalona, Spain Universitat Autònoma de Barcelona, Barcelona, Spain. 3. Hospital Vall d'Hebrón, Barcelona, Spain. 4. Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK. 5. Department of Infectious Diseases, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. 6. Fundació Lluita Contra la Sida, Hospital Universitari Germans Trias i Pujol, Badalona, Spain Universitat Autònoma de Barcelona, Barcelona, Spain Fundació IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Badalona, Spain Universitat de Vic, Vic, Spain. 7. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. 8. Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain dpodzamczer@bellvitgehospital.cat.
Abstract
OBJECTIVES: The objective of this study was to assess whether a lower dose than the currently used one of darunavir/ritonavir might achieve good CSF concentrations and contribute to inhibition of CNS viral replication. PATIENTS AND METHODS: This was a substudy of a randomized, open, multicentre study (eudraCT 2011-006272-39), comparing the efficacy and safety of 800/100 mg of darunavir/ritonavir (darunavir 800) versus 600/100 mg of darunavir/ritonavir (darunavir 600) once daily plus tenofovir/emtricitabine or abacavir/lamivudine in 100 virologically suppressed patients. Paired blood and CSF samples were obtained. Total plasma darunavir concentrations were determined by HPLC, and CSF concentrations by liquid chromatography-tandem MS. Viral load (VL) was determined in plasma and CSF (limit of detection = 40 copies/mL) by PCR. RESULTS:Sixteen patients were enrolled. The median (range) of darunavir CSF concentrations in darunavir 600 (n = 8) and darunavir 800 (n = 8) patients was 17.08 (5.79-30.19) and 13.23 (3.47-32.98) ng/mL, respectively (P = 0.916). The median (range) darunavir CSF:plasma ratio was 0.010 (0.005-0.022) in darunavir 600 patients and 0.008 (0.004-0.017) in the darunavir 800 arm (P = 0.370). All 16 patients had a VL < 40 copies/mL in plasma and 14 had a VL < 40 copies/mL in CSF. Of the two patients with detectable CSF VL (280 copies/mL and 159 copies/mL), one was receiving darunavir 600 and the other darunavir 800 plus tenofovir/emtricitabine. Of note, these patients had the lowest CSF darunavir concentrations in their respective groups: 5.79 ng/mL (802 ng/mL in plasma) and 3.47 ng/mL (958 ng/mL in plasma). CONCLUSIONS:Darunavir CSF and plasma concentrations were comparable between the two arms. However, one patient from each group (with the lowest CSF darunavir concentrations in their respective groups) had detectable CSF VL despite undetectable plasma VL.
RCT Entities:
OBJECTIVES: The objective of this study was to assess whether a lower dose than the currently used one of darunavir/ritonavir might achieve good CSF concentrations and contribute to inhibition of CNS viral replication. PATIENTS AND METHODS: This was a substudy of a randomized, open, multicentre study (eudraCT 2011-006272-39), comparing the efficacy and safety of 800/100 mg of darunavir/ritonavir (darunavir 800) versus 600/100 mg of darunavir/ritonavir (darunavir 600) once daily plus tenofovir/emtricitabine or abacavir/lamivudine in 100 virologically suppressed patients. Paired blood and CSF samples were obtained. Total plasma darunavir concentrations were determined by HPLC, and CSF concentrations by liquid chromatography-tandem MS. Viral load (VL) was determined in plasma and CSF (limit of detection = 40 copies/mL) by PCR. RESULTS: Sixteen patients were enrolled. The median (range) of darunavirCSF concentrations in darunavir 600 (n = 8) and darunavir 800 (n = 8) patients was 17.08 (5.79-30.19) and 13.23 (3.47-32.98) ng/mL, respectively (P = 0.916). The median (range) darunavirCSF:plasma ratio was 0.010 (0.005-0.022) in darunavir 600patients and 0.008 (0.004-0.017) in the darunavir 800 arm (P = 0.370). All 16 patients had a VL < 40 copies/mL in plasma and 14 had a VL < 40 copies/mL in CSF. Of the two patients with detectable CSF VL (280 copies/mL and 159 copies/mL), one was receiving darunavir 600 and the other darunavir 800 plus tenofovir/emtricitabine. Of note, these patients had the lowest CSFdarunavir concentrations in their respective groups: 5.79 ng/mL (802 ng/mL in plasma) and 3.47 ng/mL (958 ng/mL in plasma). CONCLUSIONS:DarunavirCSF and plasma concentrations were comparable between the two arms. However, one patient from each group (with the lowest CSFdarunavir concentrations in their respective groups) had detectable CSF VL despite undetectable plasma VL.