#O-16: Darunavir and Ritonavir Total and Unbound Plasmatic Concentrations in HIV-HCV Coinfected Patients with Hepatic Cirrhosis Adrian Curran 1, Ramon Marti 2, Rosa Maria Lopez 3, Mercè Perez 1, Eva van den Eynde 1, Manel Crespo 1, Maria Jesús Melià 2, Joaquin Burgos 1, Vicenç Falcó 1 and Esteve Ribera 1 1. Hospital Universitari Vall d Hebron, Barcelona, Spain. 2. Institut de Recerca Vall d Hebron, Barcelona, Spain. 3. Hospital Clinic, Barcelona, Spain.
Introduction (I) High HIV-HCV co-infection prevalence in Spain Advanced liver disease has important morbidity and mortality in HIV-HCV co-infected patients Hepatic cirrhosis can impair liver function: Impair CYP Decrease plasmatic proteins Unbound rather than total plasmatic ARV concentrations may be more reliable in cirrhotic patients.
Introduction (II) Dose modifications suggested for some PI/r in patients with cirrhosis, eg. Fosamprenavir Scarce data on DRV use in hepatic impairment and on DRV unbound concentrations In a PK study in HIV-negative patients with hepatic impairment, no dose adjustment necessary with Child A or B. 1 1. Sekar et al. Clin Pharmacokinet 2010; 49:343-50.
Objectives Primary: to measure total and unbound DRV and RTV concentrations in plasma in HIV-HCV patients with hepatic cirrhosis Secondary: Correlate concentrations with Child-Pough score Correlate concentrations with side effects Correlate concentrations with other co-variables (gender, co-medication, laboratory parameters)
Methods (I) Inclusion criteria: HIV-HCV co-infected patients with cirrhosis, defined by one of the following: Biopsy Prior clinical decompensation (ascites, encephalopathy, variceal bleeding) FibroScan >14 kpa Compatible image tests and/or varices in gastroscopy HIV treated with DRV/r 800/100 mg qd or 600/100 mg bid ± NRTIs as appropriate (steady state). Exclusion criteria: Currently decompensated hepatic cirrhosis Pregnancy Use of other medications known to significantly interact with CYP
Methods (II) Proceedings: Blood tests: including WBC, coagulation, total protein, albumin, AAG, liver function (AST, ALT, AP, GGT, BLR), CD4, viral load Adherence assessment with SMAQ FibroScan (Echosens, France) Complete 12-hour PK study: pre-dose (fasting), 1, 2, 3, 4, 6, 8 and 12 hours post-dose (drugs given with standard breakfast)
Methods (III) Complete 12 hour PK study: -Total extracts obtained through liquid-liquid organic extraction; unbound fraction obtained by ultrafiltration with 30 kda membrane (Centrifree) at 37ºC. -Determination of total and unbound concentrations with Liquid Chromatographytandem Mass Spectrometry (LC-MS/MS) -Lower limits of quantification: 5 ng/ml for total DRV and RTV; 0.5 ng/ml for unbound DRV and RTV. -Precision (between series variability): 4.8% (total DRV; 3,000 ng/ml); 27.0% (total RTV; 60 ng/ml); 7.9% (unbound DRV; 200 ng/ml); and 17.7 % (unbound RTV; 0.8 ng/ml) -Extrapolation C 24 = C 0 for QD dosing. AUC and oral clearance calculated with non-compartmental method using lineal/log trapezoidal rule with WinNonlin. -Statistical analyses: Descriptive values expressed as medians (IQR). Mann- Whitney U test to compare concentrations between groups. Spearman test for studying correlations (SPSS).
Results (I) N=19. Baseline characteristics: Characteristic Value* DRV qd 15 (79%) Gender, male 13 (68%) Age, years 48 (43-49) BMI, Kg/m 2 23.4 (20.2-26.6) CD4, cel/mm 3 350 (249-677) Backbone ARV TDF+FTC ABC+3TC RAL ETR Monotherapy 5 1 4 5 7 Characteristic HCV genotype 1 3 Prior clinical decompensation * Results are expressed as n (%) or median (interquartile range) Value* 15 (79%) 4 (21%) 8 (42%) Meld 9 (8-12) Child-Pugh A B C 14 (74%) 2 (10%) 3 (16%) FibroScan, kpa 22 (13-35)
Results (II): DRV/r 800/100 mg qd Darunavir Ritonavir Total Unbound Total Unbound C min, ng/ml 1299 (915-4920) 153 (113-317) 82 (54-168) 1 (0.4-1.5) C max, ng/ml 6445 (5631-11863) 1131 (985-1382) 533 (489-1057) 7 (6-14) T max, hours 4 (2-4) 2 (2-4) 3 (1-6) 3 (1-6) AUC 0-24, ng h/ml 63732 (56045-153704) 12753 (8472-16002) 5357 (4357-9193) 70 (44-101) CL/F, L/h 10.1 (4.5-14.1) 62.7 (49.9-94.9) 18.0 (10.7-22.3) 1422.3 (772.0-2285.7) DRV Unbound Fraction: C min 11.8%, C max 17.5%
Results (II): DRV/r 800/100 mg qd 800/100 QD Total DRV Unb DRV 10000 C min 1299 153 C max 6445 1131 Darunavir concentration, ng/ml 8000 6000 4000 2000 AUC 0-24 63732 12753 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Total Darunavir QD (800/100) Unbound Darunavir QD (800/100) Time, hours
Results (III): DRV/r 600/100 mg bid Darunavir Ritonavir Total Unbound Total Unbound C min, ng/ml 2566 (1290-4260) 260 (108-363) 222 (95-707) 3.4 (1.3-5.8) C max, ng/ml 6775 (4545-7135) 944 (429-1308) 915 (267-1366) 9.5 (4.4-24.9) T max, hours 4 (2-4) 3 (2-4) 4 (2-6) 3 (2-5) AUC 0-12, ng h/ml 65727 (36064-88043) 7616 (3112-12239) 7973 (2580-12444) 80.3 (36.2-161.49) CL/F, L/h 9.2 (8.5-26.7) 87.8 (60.5-216.5) 13.9 (8.1-50.4) 1320.7 (663.2-3099.8) DRV Unbound Fraction: C min 10.1%, C max 13.9%
Results (III): DRV/r 600/100 mg bid 600/100 bid Total DRV Unb DRV 8000 C min 2566 260 C max 6775 944 Darunavir concentration, ng/ml 6000 4000 2000 AUC 0-24 65727 7616 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Total Darunavir BID (600/100) Unbound Darunavir BID (600/100) Time, hours
Results (IV) 1400 Darunavir concentration, ng/ml 1200 1000 800 600 400 200 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Unbound Darunavir QD (800/100) Unbound Darunavir BID (600/100) Time, hours
Results (V) Patients were followed for 24 weeks. There were no grade 2-4 side effects. There were no differences in PK parameters depending on: -Child-Pough score -FibroScan score -Gender -Concomitant medications (including raltegravir, methadone, PPI, BZD)
Results (V) There were significant correlations between: total DRV C max and AAG (rho=0.53, p=0.03) unbound DRV C max and albumin (rho=-0.48, p=0.03) unbound DRV AUC and albumin (rho=-0.58, p=0.01) unbound DRV CL/F and albumin (rho=0.60, p= 0.007)
Limitations No HIV mono-infected control group (currently performing PK in this group) Small sample size Patients already taking DRV: bias regarding tolerability
Conclusions In HIV-HCV patients with compensated cirrhosis, DRV/r total and unbound concentrations are well above the EC 50 for wild-type HIV. DRV total concentrations are similar to those observed in prior studies in non-cirrhotic patients. There were no grade 2-4 side effects with DRV/r DRV dose adjustments do not seem necessary.
Acknowledgements We would like to thank: All the patients who participated in the study All the staff personnel at the hospital and the outpatient clinic. This work has been funded by a grant from the Spanish Ministry of Health (FIS PI09/2123)