HCV and the kidney Stanislas Pol, MD, PhD Liver Department, Hôpital Cochin Paris, PHC, 11 January 2016 Inserm UMS 20 & U-818, Instjtut Pasteur Université Paris Descartes, Paris, France stanislas.pol@aphp.fr
Disclosures Consultant: BMS, Boehringer Ingelheim, Janssen, Gilead, Roche, MSD, Abbvie Speaker: GSK, BMS, Boehringer Ingelheim, Janssen, Vertex, Novartjs, Sanof, Gilead, Roche, MSD, Abbvie Grants: BMS, Gilead, Roche, MSD
Prevalence of HCV in dialysis and kidney transplantation Poordad F et al. Semin Liver Dis 2004 Fabrizi F et al. J Viral Hepat 2014 0.85% % in the general populatjon HCV infectjon is more frequent in patjents with CKD
Prevalence of HCV in dialysis and kidney transplantation Poordad F et al. Semin Liver Dis 2004 Fabrizi F et al. J Viral Hepat 2014 7.6% in 2010, 3.72% in 2013 HCV infectjon is more frequent in patjents with CKD but the prevalence is decreasing overtjme
HCV and the kidney - Impact of chronic HCV on kidney function Impact of chronic HCV on survival - - Impact of kidney dysfunction on HCV therapy - How to treat my CKD patients in 2016
HCV and the kidney - Impact of chronic HCV on kidney function Impact of chronic HCV on survival - - Impact of kidney dysfunction on HCV therapy - How to treat my CKD patients in 2016
Chronic HCV infection impairs renal function Increased risk of CKD in HCV+ (23%) vs. HCV-: risk ratjo = 1.23; 95% CI : 1.12-1.34 Molnar MZ et al. Hepatology 2015;61:1495 Park H et al. J Viral Hepat 2015
HCV infection may be associated with any kidney disease • Glomerulus : ● Type II Cryoglobulinemia (MPGN) ● GN with mesangial IgA deposits ● Membranous GN ● Hyalinosis ● Fibrillar GN ● Immunotactoïd GN • Interstjtjum ● Sjogren Syndrom ● B Lymphoproliferatjon • Vascular : thrombotjc microangiopathy • Rejectjon nephropathy
Reduction in CKD incidence in treated patients - Cumulated incidence of ESRD at 8 years in teated vs. untreated patjents : 0.15% vs 1.32% (p<0.001) - Reduction in CKD incidence in treated patients (HR 0.15; 95% CI 0.07– 0.31; p<0.001) Hsu Y-C, et al. Gut 2015;64:495–503
Chronic HCV infection increases ESRD- related mortality ➜ Cumulatve risk of death related to renal disease according to HCV status 0,045 4.3 % Antj-HCV negatjve (n = 16 629) 0,040 Undetectable HCV RNA (n = 330) 0,035 Low HCV RNA (n = 371) 0,030 High HCV RNA (n = 124) 2.6 % 0,025 0,020 p < 0.001 0,015 0,010 0,005 0.5 % 0,000 0.3 % 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Follow up (years) Reveal HCV Longitudinal taïwanese study in 23 785 patents HCV infecton is associated with an increased risk of renal disease, ESRD and renal-related mortality Lai TS et al., AASLD 2014 abstr. 172
HCV increases the risk of extra-hepatic mortality Hazard ratjo [95% CI] for nephritjs or nephrotjc syndrome: 2.77 [1.49-5.15] Mei-Hsuan Lee, et al. Chronic Hepatjtjs C Virus Infectjon Increases Mortality From Hepatjc and Extrahepatjc Diseases: A Community-Based Long-Term Prospectjve Study. J Infect Dis. (2012) 206 (4): 469-477
HCV and the kidney - Impact of chronic HCV on kidney function Impact of chronic HCV on survival - - Impact of kidney dysfunction on HCV therapy - How to treat my CKD patients in 2016
Harmful impact of HCV in hemodialysis patients 77% (n = 1194) p<0.001 (n = 276) 67% Causes of death HCV+ HCV - HCC 5.5 % 0 % p<0.001 Cirrhosis 8.8 % 0.4 % p<0.001 Nakayama E, et al. J Am Soc Nephrol 2000
Harmful impact of HCV in kidney recipients Pol et al. Lancet 1991; Legendre C et al. Transplantation 1997; Mathurin P et al. Hepatology 1999; Bruchfeld A, et al. Transplantation 2004 Adjusted RR death : 1.79 [1.57-2.03] Adjusted RR grafu loss : 1.56 [1.35-1.8) Fabrizi F et al. Am J Transplant 2005;5:1452-61
HCV and the kidney - Impact of chronic HCV on kidney function Impact of chronic HCV on survival - - Impact of kidney dysfunction on HCV therapy - How to treat my CKD patients in 2016
GFR may be afgected by DAAs • 219 patjents with sofosbuvir-including regimen and 217 patjents treated by boceprevir or telaprevir • Renal impairement defned as an increase of creatjnine ≥ 0.3 mg/dl or ≥ 50 % vs. baseline Evoluton of GFR under therapy (ClCr > 60 ml/min at beginning) 0,2 0.18 mg/dl 17 % 0,18 SOF 0,16 BOC/TVR 0,14 11% 0,12 0,1 7 % 0,08 0,06 4 % 0.04 mg/dl 0,04 23 36 8 16 0,02 218 217 218 217 0 Mean max Delta creat. 0.3 mg/dl creat. 50 % creat. mg/dl p = 0.066 p = 0.09 p = 0.01 Almarzooqi S et al. , AASLD 2015, Abs. 1099
GFR may be afgected by DAAs • 219 patjents with sofosbuvir-including regimen and 217 patjents treated by boceprevir or telaprevir • Renal impairement defned as an increase of creatjnine ≥ 0.3 mg/dl or ≥ 50 % vs. baseline No urine analysis: renal dysfuncton or variatons of reabsorpton of creatnine? 0,2 0.18 mg/dl 17 % 0,18 SOF 0,16 BOC/TVR 0,14 11% 0,12 0,1 7 % 0,08 0,06 4 % 0.04 mg/dl 0,04 23 36 8 16 0,02 218 217 218 217 0 Mean max Delta creat. 0.3 mg/dl creat. 50 % creat. mg/dl p = 0.066 p = 0.09 p = 0.01 Evoluton of GFR under therapy (ClCr > 60 ml/min at beginning) Almarzooqi S et al. , AASLD 2015, Abs. 1099
Pharmacokinetics of sofosbuvir and kidney dysfunction Normal Renal Functon Severe Renal Impairment eGFR > 80 mL/min/1.73 m2 eGFR < 30 mL/min/1.73 m2 Mean Mean %GMR PK Parameter (%CV) (%CV) (90% CI) (n=6) (n=6) (n=6) 12,700 92,600 551 GS-331007 AUCinf, ng•h/mL (19.1) (85.9) (313, 968) 1360 1740 134 GS-331007 Cmax, ng/mL (42.3) (23.0) (98.6, 183) SOF AUCinf, 590 1580 271 (29.9) (28.1) (183, 402) ng•h/mL AUCinf=area under the curve; CI=confdence interval; Cmax=maximum observed plasma concentratjon of drug; CV=coefcient of variatjon, GMR=geometric mean ratjo, PK=pharmacokinetjc. Cornpropst M, et al. EASL 2012. Barcelona, Spain. #1101
Pharmacokinetics of sofosbuvir and kidney dysfunction Normal Renal ESRD: Period 1 ESRD: Period 2 Functon eGFR (Dose Pre-Dialysis) (Dose Post-Dialysis) >80 mL/min /1.73 m2 Mean Mean Mean %GMR %GMR PK Parameter (%CV) (%CV) (%CV) (90% CI) (90% CI) (n=6) (n=3 to 5) (n=3 to 5) 1380 2170 GS-331007 12,700 226,000 358,000 AUCinf, (693, (1090, (19.1) (78.6) (70.7) ng•h/mL 2760) 4330) 180 GS-331007 1360 1470 110 2420 Cmax, (132, (42.3) (39.5) (81.0, 150) (35.0) ng/mL 246) 128 160 SOF 590 785 948 AUCinf, (84.5, (106, (29.9) (42.7) (32.9) ng•h/mL 193) 242) AUCinf=area under the curve; CI=confdence interval; Cmax=maximum observed plasma concentratjon of drug; CV=coefcient of variatjon, GMR=geometric mean ratjo, PK=pharmacokinetjc. Cornpropst M, et al. EASL 2012. Barcelona, Spain. #1101
Pharmacokinetics of protease inhibitors and kidney dysfunction Linear mean plasma concentratjon–tjme profles of SMV comparing severely renal impaired and matched healthy subjects 20000 Subjects with severe renal impairment (n=8) 9000 Matched healthy subjects (n=8) SMV plasma concentratjon 8000 10000 7000 GZR AUC, nM*hr 5000 6000 (ng/mL) 5000 2000 4000 3000 1000 2000 500 1000 0 PHASE 3 (All Trials C-SURFER: C-SURFER: 0 4 8 12 16 20 24 0 1 2 except CKD) no dialysis dialysis Time (h) Bars represent SD • GZR AUC compared between subjects in C-SURFER (with CKD) and other Phase 3 trials (C-EDGE; includes cirrhotjc subjects) Overall, GZR AUC is ~ 22% higher in patents with SMV, simeprevir • CKD compared to AUC in the other Phase 3 Simion et al. HCV Clin Pharm Workshop 2013 studies
Pharmacokinetic of NS5A inhibitors (Elbasvir) and kidney dysfunction 10000 10000 5000 5000 EBR AUC, nM*hr EBR AUC, nM*hr 2000 2000 1000 1000 0 1 PHASE 3 (All Trials C-SURFER: 0 1 2 PHASE 3 (All Trials C-SURFER: C-SURFER: except CKD) Dedicated CKD Study except CKD) no dialysis dialysis • EBR AUC compared between subjects in C-SURFER GM AUC Ratio vs N (uM*hr) no CKD (with CKD) and other Phase 3 studies (C-EDGE; no CKD (P060, includes cirrhotjc subjects) 061, 068) 950 2.38 -- • Overall, EBR AUC is ~ 24% higher in patents with CKD (P052) 116 2.96 1.24 CKD compared to AUC in the other Phase 3 CKD, no dialysis 30 3.31 1.39 studies CKD, dialysis 86 2.84 1.19 GM = geometric mean
ABT-450/r, ombitasvir +/- dasabuvir and kidney dysfunction • Étude de Phase I study in 24 non infected subjects répartjs en 4 groupes de 6 : fonctjon rénale normale (clairance de la créatjnine ≥ 90 ml/mn, ou avec une insufsance rénale minime (de 60 à 89), modérée (30 à 59) ou sévère (15 à 29) Moderate renal Minim renal Severe renal By comparison with normal renal impairement impairement impairement functjon (GFR= 30-59) (GFR= 60-89) (GFR= 15-29) Unchanged AUC ombitasvir Unchanged Unchanged AUC ABT-450 and dasabuvir 20 % 37 % 50 % AUC ritonavir 42 % 80 % 114 % • No clinically relevant PK modifcatjon Khatri A et al., AASLD 2014 abstr. 238
Asunaprevir/Daclatasvir/beclabuvir and kidney dysfunction Adapted from: Adamczyk R. ILC 2015, #PO790
HCV DAAs and kidney function Summary • Polymerase inhibitors: Sofosbuvir - no dose adjustement for GFR> 30 mL/mn - For GFR< 30 mL/mn: ? 400 mg, 200mg/d or 400mg/2d • NS5A inhibitors: - no dose adjustement - no adjustement of calcineurin inhibitors • Protease inhibitors: - no dose adjustement - DDI with anticalcineurin drugs
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