There are 5 stages of CKD

Transcription

1 There are 5 stages of CKD Stage GFR (ml/min/1.73m2) Description Normal kidney function but evidence of risk: urine findings, structural abnormalities, genetic predisposition 1 > Mildly reduced kidney function 3A 3B Moderately reduced kidney function Severely reduced kidney function 5 <15 or on dialysis Very severe, or end-stage kidney failure KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of CKD.

2 HCV Infection in CKD Patients CKD Prevalence General Population nearly 10% HCV Prevalence among End Stage Renal Disease Patients Developed Countries: nearly 6-8% worldwide Developing Countries: nearly 60-80% worldwide Finelli L et al. Semin Dial. 2005;18: Jadoul M et al. Nephrol Dial Transplant. 2004;19: Chacko E.C. et al. Postgrad Med J. 2010; 86:

3 ? TREAT HCV INFECTION IN END STAGE- RENALDISEASE BEFORE OR AFTER GRAFTING

4 TREAT BEFORE GRAFTING

5 HCV-Target Multicenter cohort with advanced kidney insufficiency (and cirrhosis) N= 73 HCV genotypes 1-6 GFR < 45 ml/min Cirrhosis 64% SOF+RBV; SOF+SIM; SOF+IFN SVR 12 : 88-81% was achieved in 83% of patients with egfr 45 ml/min/1.7 ated with SOF-containing regimens. However, these patients her rates of anaemia, worsening renal dysfunction serious adverse events regardless of use of RBV. Saxena V. Liver Int. 2016

6 SOFOSBUVIR Approximately 80% of Sofosbuvir is excreted by the kidney,15 % is excreted in faeces. The majority of Sofosbuvir recovered in urine is the dephosphorylationderived metabolite GS Sofosbuvir (and Sofosbuvir based therapies) is not recommended for

7 Y-1 ombitasvir,pariteprevir/ ritonavir (+ RBV for HCV Y-2 ombitasvir,pariteprevir /ritonavir,dasabuvir 38 patients, 26: genotype 1 /a, 7 1/b 4: genotype 4 7: CDK stage : stage CKD stage 5 12 :in haemodialysis % SVR 99/100 % eratnce problems in HCV 1/a patients related to RBV Pockros PJ 2016, Gane E 2016

8 MK-5172/MK-8742 (GRAZOPREVIR/ELBASVIR) MK-5172 MK-5172 (grazoprevir) Highly Potent HCV Protease Inhibitor MK-8742 (elbasvir) Highly Potent HCV NS5A Inhibitor MK-5172/MK-8742 Fixed Dose Combination Tablet (100mg/50 mg) Zepatier LB-12 : C- SWIFT Retreatment : 12 weeks of Elbasvir/Grazoprevir + SOF+RBV Fixed-dose combination Elbasvir/Grazoprevir x 8 weekstablet ( G1-G3); naive 90-94% LB-22 : Prevalence and Impact of baseline Efficacious in treatment-naïve andnsa -experienced esistance Variants ( RAVs) onhcv the patients cirrhoticassociated and non-cirrhotic fficacy of Elbasvir/Grazoprevir against G1a Infection

9 razoprevir 100 mg +Elbasvir 50 mg r 12 weeks in CKD patients (C-SURFER ) 235 HCV G1, CKD patients 4: stage 4 / 191: stage (76%) in haemodialysis 80% naive, 6% compensated. cirrhosis SVR 99% Low rate of adverse events Roth D. et, al Lancet 2015

10 (GLECAPREVIR/PIBENTRASVIR) (Glecaprevir) (Pibentrasvir) Highly Potent HCV Protease Inhibitor Highly Potent HCV NS5A Inhibitor G/P Fixed Dose Combination Tablet (300mg/120 mg) Maviret LB-12 : C- SWIFT Retreatment : 12 weeks of Elbasvir/Grazoprevir + SOF+RBV Elbasvir/Grazoprevir x 8 weeks ( G1-G3); naive 90-94% LB-22 : Prevalence and Impact of baseline NSA esistance Associated Variants ( RAVs) on the fficacy of Elbasvir/Grazoprevir against G1a Infection PANGENOTIPIC HCV 1-6, NO RENAL ELIMINATION

11 EXPEDITION-4 : Maviret for 12 weeks, 104 patients,mean age 57 y HCV: G1-6 CKD: stage 4-5 Prior therapy: 42% Cirrhosis: 19% Gane E. et al, N.Eng.J Med 2017

12 EXPEDITION-4 : virologic/clinical features the HCV genotype : 1 in 52%, 2 in 16%, 3 in 11%, 4 in 19%, 5/6 in 2% the renal disease : CKD stage :4 in 13%, 5 in 87%---82% in haemodialyss the liver function : compensated in all, cirrhosis in 19% systemic disorders: hypertension in 86%, anemia in 45%, diabetes in 41% Gane E. et al, N.Eng.J Med 2017

13 EXPEDITION-4, SVR 98% (102/104) Gane E. et al, N.Eng J Med 2017

14 EXPEDITION-4, no virologic failure, no virologic relapse mild adverse events in 72% : pruritus, fatigue,nausea severe cardiovascular events unrelated to therapy in 24 % 4 patients discontinued therapy minimal negative effect on GFR: Mean > 0.4 ml /min at week 36 from baseline Gane E. et al N.Eng.J Med 2017

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16 TREAT AFTER GRAFTING

17 Sofosbuvir based HCV clinical trials in kidney transplant recipients (286b pts) Author Kamar et al.2016 Study design and Regimens Pilot study SOF+ DAC/SIM/LDV Sawinsk Retrospective i et SOF+ al.2016 DAC/SIM/LDV Lubetzk Retrospective y et SOF+LDV al.2017 Fernande z et al.2016 Retrospective SOF+ DCV/SIM/LDV OBV/PTV/r/DSV Colomb Phase II Open Patient Genot SV Comment s ype R s 25 76% % 20 55% 1 45% CNI 10 0% adjustment % % Worsening proteinuria % 1 98 % 55% immunosuppression adjust. 13% SAEs % % SAEs (20% Cirrhosis) (20% Cirrhosis) (35 % cirrhosis) Excellent tolerance. No AE

18 Ledipasvir 90 mg+ Sofosbuvir 400 mg for weeks in kidney transplant recipients 114 patients HCV 1 and 4 median GFR 56 ml/min (range ) 15% compensated cirrhosis serious adverse events in 13 (11%), 3 treatment related SVR 100 % Colombo M,.2016

19 EFFECT OF DAA ON ALLOGRAFT FUNCTION Fernandez 2016 :transient > 25% serum creatinine increase in 16% of the patients ; 65% were cirrhotics Bamidimarri, 2016:frequent renal function decline Sawinsky,2016 :impaired renal function exceptional Lubetzky,2017:no significant change in GFR Colombo,2016 :decrease of GFR in 3 patients Kamar 2016 :no change in GFR

20 USE OF KIDNEYS FROM HCV + DO Kidney from HCV+ donor to HVC+ recipie is acceptable to shorten waiting list tim HCV+ donors are many (20% in US) Kidney from HCV + donor to HCV- recipien HCV 1 positive kidney grafts given to 20 HCV negative recipients treated post-trans with Grazoprevir/Elbasvir ; all HCV-free after THINKER TRIAL,Reeese PR, 2

21 Prophylaxis of HBV reactivation Give HBV antivirals ( lamivudine) if HBsAg is present ( no HBV-DNA) Monitor closely for HBV-DNA if anti-hbc /anti-hbs is present

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24 Key Messages: (1)In patients with an egfr >30, all licensed DAAs regimens can be used. (2) Cure of HCV in CKD stages 4-5, including dialysis patients, and in kidney transplant recipients is now available. (3) The choice of DAA regimen in CKD should be based on HCV genotype, viral load, egfr, concomitant medications, transplant candidacy and comorbidities. (4) The timing of treatment in kidney transplantation candidates (before versus after transplantation) is now an option

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26 100% 90% SOF+RBV SIM+Peg-IFN+RBV SOF+SIM+Peg-IFN IFN+DAAs BOC/TEL 50% SVR % Maviret Vosevi (8 weeks) IFN/IFN+RBV Peg-IFN/ Peg-IFN+RBV YRS Ledipasvir/ SOF+RBV Daclatasvir /SOF +RBV Paritaprevir/RT/ Ombitasvir Dasabuvir/RBV Grazoprevir/Elbasvir Sofosfuvir/Velpatasvir

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28 Kidney Transplant Patients AASLD and IDSA 21 September 2017

29 C-SURFER Study: High SVR Rates in All Treatment Groups % 100 % 100 % 98% 100 % 99% 99% SVR12 (%) Overall (n=116) Cirrhosis (n=6) HCV-1a HCV-1b (n=61) (n=55) Stage Stage Dialysi 4 5 s (n=22) (n=94) (n=87) SVR data from patients in the Immediate Treatment Group and in the PK Treatment Group Roth, et al. Lancet 2015;386:

30 Hepatitis C viral load, genotype, and increased risk of developing end stage renal disease: REVEAL HCV studystage renal disease: REVEAL stage renal disease: REVEAL HCV studyhcv study Cumulative risk of ESRD by serum HCV RNA level at study entry high risk of ESRD (Dialysis or KD traplants) R, % CI ) Tai-Shuan Lai et al, Hepatology, Sept 2017

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32 HCV TARGET: Safety Outcomes With SOF Regimens by Baseline egfr Rates of anemia AEs, worsening renal function, and renal and urinary AEs increased across decreasing egfr strata egfr 30 (n = 17) egfr (n = 56) egfr 4660 (n = 157) egfr > 60 (n = 1559) 6 (35) 16 (29) 37 (24) 246 (16) Transfusions 2 (12) 5 (9) 3 (2) 31 (2) Erythropoietin 1 (6) 8 (14) 14 (9) 50 (3) Reduction in RBV dose 3 (38) 8 (30) 33 (42) 185 (19) RBV discontinuation 0 4 (15) 1 (1) 12 (1) Worsening renal function 5 (29) 6 (11) 4 (3) 14 (1) Renal or urinary system AEs 5 (29) 6 (11) 13 (8) 84 (5) Serious AEs 3 (18) 13 (23) 8 (5) 100 (6) Cardiac AEs 1 (6) 2 (4) 8 (5) 53 (3) Safety Outcome in Pts Who Completed SOF-Containing Therapy, n (%) Anemia AEs Saxena V, et al. EASL Abstract LP08.

33 HCV and Renal Disease HCV infection may lead to renal disease or be associated with renal disease Mixed cryoglobulinemia (type II cryoglobulins, or + RF)[1] Membranoproliferative glomerulonephritis (MPGN)[1] Polyarteritis nodosa[2] Less clearly related to HCV[1] Focal segmental glomerulosclerosis Proliferative glomerulonephritis Membranous glomerulonephritis Fibrillary and immunotactoid glomerulopathies Diabetes (direct link to HCV) and hypertension common in HCV infection[3] 1. Ozkok A, et al. World J Gastroenterol. 2014;20: Saadoun D, et al. Arthritis Care Res (Hoboken). 2011;63: Satapathy SK, et al. J Clin Exp Hepatol. 2014;4:8-13.

34 C-SURFER: Efficacy and Safety Results GZR/EBV for 12 wks SVR12 (%) Death Hb decr from BL 1 grade D/c due to AE 60 n/n = Placebo (n = 113) AE, % Serious AEs Grazoprevir/ Elbasvir (Randomized Tx) (n = 111) 115/ 122 6/ 6 61/ 61 Full Set Cirrhosis GT1a HCV 54/ 55 86/ 87 40/ 41 2 grades 3 grades GT1b HCV On HD Diabetic 4 grades Roth D, et al. EASL Abstract LP02.

35 Grazoprevir (MK-5172) / Elbasvir (MK-8742) HCV treatment with potential to fulfill unmet needs in the CKD population HCV NS3/4A inhibitor 100 mg once-daily, oral Grazoprevir (MK-5172) HCV NS5A inhibitor 50 mg, once-daily, oral Elbasvir (MK-8742)

36 HCV Therapy in CKD patients in Dialysis and Renal Traplants: Update No CKD Trials Genotypes Ribavirin weeks CKD Trials Target Cohort Trio Cohort Pangenotipic RBV-free 12/16/8 weeks Sofosbuvir+/-RBV Simeprevir Daclatasvir Sofosbuvir /Ledipasvir Paritaprevir/R/Ombitasvir/ Dasabuvir Grazoprevir/Elbasvir (Zepatier)* Sovaldi/Velpatasvir (Epclusa)** Glecaprevir /Pibrentasvir ( Maviret)*** Sofosvir/Velpatasvir/Voxilaprevir (Vosevi) **** ruary 2017 ; ** April2 017; ***Maviret 4 ottobre 2017 (AIFA) ; ****Luglio 2017 (

37 Patients with Renal Impairment AASLD and IDSA 21 September 2017

38 Hepatitis C viral load, genotype, and increased risk of developing end stage renal disease: REVEAL HCV studystage renal disease: REVEAL stage renal disease: REVEAL HCV studyhcv study Cumulative risk of ESRD by serum HCV RNA level at study entry high risk of ESRD (Dialysis or KD traplants) R, % CI ) Tai-Shuan Lai et al, Hepatology, Sept 2017

39 Efficacy and tolerability of interferon-free antiviral therapy in kidney transplant recipients with chronic hepatitis C Fernandez I. et al, J Hepatol 2016

40 The prevalence of chronic HCV among patients with CKD on dialysis differs worldwide, ranging from 4% in Canada and Belgium to as high as 52% in Saudi Arabia UK 4.4%1 Canada 4.0%1 US %1,4 Belgium 4.0%1 France 6.9%1 Germany 4.5%1 Japan 11-21%4 Italy 11.4%1 Saudi Arabia 52%1 China %1,3 Brazil %2,5 1. Bieber B, et al. 52nd ERA-EDTA Congress, London, UK, May 28-31, Shimokura G, et al. Infect Control Hosp Epidemiol. 2011; 32: Santos MA, Souto FJ. BMC Public Health. 2007; 7: Vidales-Braz B, et al. Virol J. 2015; 12: Sun J, et al. Ren Fail 2009;31: Liu YB, et al. Eur Rev Med Pharmacol Sci. 2014; 18:

41 Sofosbuvir based HCV clinical trials in kidney transplant recipients (257 pts) Author Kamar et al. Study design and Regimens Pilot study SOF+ DAC/SIM/LDV Sawinsk Retrospective i et al. SOF+ DAC/SIM/LDV Lin et al. Retrospective SOF+ SIM/LDV London o et al. SOF+ DAC/SIM/LDV Colomb Phase II Open Patient Genot SV Comment s ype R s 25 76% % 20 55% 1 45% CNI 10 0% adjustment 24 84% 1 91 % 1 bradycardia 74 85% % 55% immunosuppression adjust. 13% SAEs % % SAEs (20% Cirrhosis) (20% Cirrhosis) (42% F3F4) (51% cirrhosis) Excellent tolerance. No AE

42 HCV-infected patients with CKD are at increased risk of anemia, CKD progression, and mortality compared to CKD patients without HCV Anemia Patients on dialysis who are HCV+ are 16% more likely to have anemia, 43% more likely to require transfusions, and 22% more likely to have a gastrointestinal bleed compared to HCV- patients1 CKD progression In patients with CKD, estimated glomerular filtration rate (egfr) declines more rapidly over time among HCV-infected patients compared to those without HCV2 Among patients with CKD, those with comorbid HCV are 35% more likely to progress to ESRD than uninfected patients3 Mortality A meta-analysis of 7 studies found that all-cause mortality among dialysis patients with HCV is 34% higher than in patients without HCV4 Kidney-related mortality was increased approximately 10-fold in dialysis patients with HCV compared to those without HCV in a study in Taiwan5 Hepatic-related mortality was increased over 6-fold in dialysis patients with HCV compared to uninfected patients in a multinational study6 1. Bieber B, et al. ASN Kidney Week 2015, San Diego, CA, November 3-8, Fabrizi F, et al. J Viral Hepat 2007; 14: Weil C, et al. 52nd ERA-EDTA Congress, London, UK, May 28-31, Lai TS, et al. AASLD Lee JJ, et al. PLoS One 2014;9:e Bieber B, et al. 52nd ERA-EDTA Congress, London, UK, May 28-31, 2015.

43 HCV and CKD Wide spectrum of Glomerular diseases in patients with chronic HCV infection. Cryoglobulinemic (or non-cryoglobulinemic) membranoproliferative glomerulonephritis (MPGN) Membranous nephropathy (MN) IgA nephropathy Mesangial proliferative glomerulonephritis Fibrillary glomerulopathy Focal segmental glomerulosclerosis (FSGS) Renal thrombotic microangiopathy Acute diffuse proliferative glomerulonephritis Rapidly progressive glomerulonephritis Ozkok A, WJG 2014; Johnson RJ, NEJM 1997 Limited data are available on HCV-mediated Tubular damage Hepatitis C virus-associated tubulointerstitial injury Kasuno K et al, American Journal of Kidney Diseases, 2003 Hepatitis C virus RNA and core protein in kidney glomerular and tubular structures isolated with laser capture microdissection Sansonno D, Clin and Experimental Immunology, 2005 Tubular epithelial cells positive for HCV RNA in the perinucleus (arrows).

44 Dosing Considerations for Pts With Renal Impairment OBV/PTV/RTV + DSV: no dose adjustment required with mild, moderate, or severe renal impairment (CrCl: 15 ml/min)[1,2] LDV/SOF and SMV + SOF: no dose adjustment required with mild or moderate renal impairment (CrCl 30 ml/min) [3,4] Safety and efficacy not established in severe renal impairment or hemodialysis TARGET data demonstrate feasibility of SOF-containing regimens but renal and urinary AEs increased across decreasing egfr strata[5] CrCl DCV: no dose adjustment required with any degree of renal impairment (studied in subjects with CrCl: 15 ml/min)[6] RBV: dose adjustment required for CrCl < 50 ml/min[7] RBV Dose ml/min Alternating 200 mg and 400 mg every other day < 30 ml/min 200 mg/day Hemodialysis 200 mg/day 1. OBV/PTV/RTV + DSV [package insert]. 2. Pockros PJ, et al. EASL Abstract L LDV/SOF [package insert]. 4. AASLD/IDSA. HCV Management Saxena V, et al. EASL Abstract LP DCV [European package insert]. 7. RBV [package insert].

45 HCV Infection and ESRD Several forms of kidney injury Risk factors in ESRD ( trasfusions, dialysis) 1-8% in Western countries Up tp 70%& in other part of the world 54% hospitalized patients with cirrhosis had ESRD Prevalence of CKD in HCV + vs HCV (9.6% vs 5.1%) Mortality higher in HCV+ vs HCV -

46 TARGET cohort : treatment of patients with chronic Kidney diseases SVR 12 according to egfr and treatment options % egfr < egfr egfr egfr > 60 SOF + PEG + RBV SOF + RBV SOF + SMV SOF + SMV + RBV Saxena V et al, EASL 2015, Abs. LP08

47 HCV and Renal Disease HCV infection may lead to renal disease or be associated with renal disease Mixed cryoglobulinemia (type II cryoglobulins, or + RF)[1] Membranoproliferative glomerulonephritis (MPGN)[1] Polyarteritis nodosa[2] Less clearly related to HCV[1] Focal segmental glomerulosclerosis Proliferative glomerulonephritis Membranous glomerulonephritis Fibrillary and immunotactoid glomerulopathies Diabetes (direct link to HCV) and hypertension common in HCV infection[3] 1. Ozkok A, et al. World J Gastroenterol. 2014;20: Saadoun D, et al. Arthritis Care Res (Hoboken). 2011;63: Satapathy SK, et al. J Clin Exp Hepatol. 2014;4:8-13.