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HCV and the kidney. Treatment of HCV in Patients With Renal Impairment 4/30/ PDF

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Treatment of HCV in Patients With Renal Impairment David L. Wyles, MD Associate Professor of Medicine University of California San Diego La Jolla, California FORMATTE: Los Angeles, CA: April 28,
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Treatment of HCV in Patients With Renal Impairment David L. Wyles, MD Associate Professor of Medicine University of California San Diego La Jolla, California FORMATTE: Los Angeles, CA: April 28, 2015 (ADVANCED) HCV and the kidney Slide 2 of 24 Direct injury: MPGN +/- cryoglobulinemia HCV contributes to insulin resistance and DM High prevalence of HCV in those on HD Increased risk for mortality Bi-directional interaction in kidney transplant Accelerated liver disease progression Increased risk of post-transplant DM Many studies show worse graft and pt survival Slide 3 of 24 Treating HCV can prevent kidney disease Hsu Y-C. Hepatology Case 1 Slide 4 of AA male with long-standing HTN, DM and chronic HCV GT1a infection. HCV treatment naïve Viral load 4.2 million F3 estimated by FibroScan ( 10.2 kpa, 11/2014) Remote EtOH, no IDU, smokes MJ Meds: amlodipine, atorvastatin 20mg, lisinopril, clonidine, insulin, erythropoietin Case 1 continued Slide 5 of 24 Labs: ALB 3.8 AST/ALT 47/56, TB 0.6, INR 1.1 Cr 3.47 K+ 4.8 CBC: Hgb 11.2 g/dl, PLT 223 U/A: + 2 protein, no blood or RBCs CrCl: 22 ml/min/ SOF/LDV metabolism and the kidney Slide 7 of 24 Sofosbuvir: 80% of dose excreted in urine (most as 007) 007 t 1/2 is 27 hrs AUC (% increase) compared to GFR 80 Mild Moderate Severe SOF 61% 107% 171% % 85% 451% HD: fold increase in 007 AUC Ledipasvir: Primarily eliminated in feces ( 70%) Limited ( 2.0%) urinary excretion No changes in exposure with GFR 30 Cornpropst M. #1101 EASL Kirby B. #O_22 HCV Clin Pharm Workshop Harvoni package insert. Sovaldi package insert. 2 3D (PrO D) regimen in ESRD Slide 8 of 24 All components: hepatic metabolism 2% excreted in urine Viekira Pak package insert. Ribavirin package insert. Simeprevir and ribavirin Slide 9 of 24 Simeprevir: primary hepatic metabolism and biliary elimination 1% eliminated in urine Highly protein bound (99.9%): not dialyzable Ribavirin: guanosine nucleotide analog Presumed renal elimination Clinical evidence of increased exposure and toxicity with 600mg and 400mg in moderate and severe renal impairment. Slide 11 of 24 What do the package labels say about renal impairment? Drug/Regimen SOF Label language No dose adjustment for mild-moderate renal disease. SOF/LDV SMV 3D + RBV RBV No dose recommendation can be given for egfr 30 ml/min/1.73m 2 or ESRD. Accumulation of SOF metabolite (GS ) up to 20x expected. Safety and efficacy not established. Same as SOF alone. No dose adjustment necessary for mild, moderate, or severe renal impairment. Not studied in patients with GFR 30 or on dialysis. No dose adjustment necessary for mild, moderate, or severe renal impairment. Not studied on dialysis. Moderate (30-50mL/min): 200mg/400mg alternating QOD Severe or HD ( 30mL/min): 200mg QD 3 SVR (%) 4/30/2015 Slide 12 of 24 Can SOF be used effectively and safely in advanced renal disease? Pilot study of SOF/RBV in those with severe renal impairment (egfr 30) or on HD 10 non-cirrhotic GT1 or 3 subjects Gane EJ. #966 AASLD Poor treatment responses? Slide 13 of patients dose reduced or held RBV 1 discontinued RBV 0 SVR4 SVR12 Gane EJ. #966 AASLD SOF and 007 plasma exposures Slide 14 of 24 Gane EJ. #966 AASLD SVR12(%) 4/30/2015 Label be damned- real-world experience with SOF/LDV in ESRD Slide 15 of 24 Miami: 16 pts- GFR 15 or HD 42% naïve, 58% cirrhotic SOF 200mg QD + SMV 150mg QD; no RBV 3 pts: SOF 400mg QOD with SMV Texas: 11pts- GFR 30 or HD 82% naïve, 47% cirrhosis SOF 400mg QD + SMV 150mg QD; no RBV 88% on HD SVR12 1a 1b 11 5 U Miami Texas Czul F. #92 EASL Nazzario HE. #614 EASL Slide 16 of 24 Label be damned- HCV TARGET: SOFcontaining regimens in ESRD Saxena V. EASL Slide 17 of 24 3D + RBV in treatment naïve patients with ESRD RUBY-I Pockros P. EASL Inclusion/Exclusion Criteria Slide 18 of 24 Inclusion HCV GT 1a or 1b Treatment naïve egfr 30 ml/min/1.73m 2 (MDRD method) Stage 4: GFR Stage 5: GFR 15 or HD Exclusion HIV-1 or HBV + History of decompensated liver disease (CPT B or C) Peritoneal Dialysis Key laboratory exclusions ALB 2.8 g/dl Hgb 10.0 g/dl PLT 25,000 Tbili 3.0 mg/dl INR 2.3 Fibrosis stage determination: biopsy, FibroScan, or APRI/FibroSure Pockros P. EASL Slide 19 of 24 3D + RBV in treatment naïve patients with ESRD interim data from EASL 20 pts enrolled; interim SVR4 data on % SVR4 RBV dose reductions/discontinuations 8/13 GT1a with RBV dose interruption RUBY-I Pockros P. EASL Grazoprevir/Elbasvir in ESRD Slide 20 of 24 GZR/EBR: both 1% renal elimination No dose adjustment needed 73% male, 46% AA, 80% naïve, 52% 1a, 6% cirrhosis 81% CKD stage 5 (GFR 15 or HD) C-SURFER Roth D. # EASL Grazoprevir/Elbasvir in ESRD Slide 21 of 24 1 viral relapse 6 discontinuations C-SURFER Roth D. # EASL Slide 22 of 24 Grazoprevir/Elbasvir in ESRD C-SURFER Roth D. # EASL
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