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Treatment Of HCV in CKD Patients - Prof. Hussein El-Fishawy

Treatment Of HCV in CKD Patients Prof. Hussein EL-Fishawy
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Treatment Of HCV in CKD Patients - Prof. Hussein El-Fishawy

  1. 1. 4/22/2011 ICVH Baltimore 2011 Discovery of Hepatitis C
  2. 2. Seroprevalence of Hepatitis C: 170 to 200 Million Worldwide Americas 12-15 M Africa 30-40M Australia .2 M Western Pacific 60 M Western Europe 5 M Eastern Europe 10 M Southeast Asia 30-35 M 1. World Health Organization. Wkly Epidemiol Rec. 2000;75:17-28. 2. Edlin B et al. AASLD; November 11-15; 2005 San Francisco, California. Oral Presentation #44. 3. Fontanet A. Annual Report of Emerging Diseases for Year 2005. Accessed 03/13/06 at http://www.pasteur.fr/recherche/RAR/RAR2005/Epimal-en.html United States 5M Highest Prevalence: Egypt-5M (45% adults >40y) Highest impact in the world Serological prevalence of 13.9–15.5% (14.7%) Positive nucleic acid test in 7.0–12.2% (9.8%) 90% of patients is (GT- 4), difficult to treat
  3. 3. HCV and Renal disease HCV infection may lead to renal disease or be associated with renal disease  Membranoproliferative glomerulonephritis (MPGN)  Mixed cryoglobulinemia (type II cryoglobulins)  Membranous GN  Polyarteritis nodosa NB: Crescentic glomerulonephritis may be superimposed on any of these glomerular lesions Ana Maria Sandri et al., Nephron Clin Pract 2011;119:c121– c130
  4. 4. HCV and Renal disease  Less common  Focal segmental glomerular sclerosis  Poliferative glomerulonephritis  Mesangial proliferative GN  Focal segmental and necrotizing GN  IgA nephropathy  Post infectious GN  Fibrillary glomerulopathies  Immunotactoid glomerulopathies  Amyloidosis  Interstitial nephritis  Thrombotic microangiopathy (Renal transplantation)  Acute and chronic transplant glomerulopathy Ana Maria Sandri et al., Nephron Clin Pract 2011;119:c121– c130
  5. 5. Increased Mortality  Chronic HCV is associated with a 8- to 12-year reduction in overall life expectancy and reduced quality of life1  Chronic HCV patients have significantly higher mortality rate  HR 1.53; (95% CI, 1.13-2.07)2  HR 1.37; (95% CI, 1.31-1.47)3  Death rate 12-fold higher than general population4 1 Ryder SD, et al. J Hepatology, 2007; 3 Butt AA, et al. Hepatology, 2009 2 Uto H, et al. Hepatology, 2009; 4 Mahajan R, et al. Clin Infect Dis 2014
  6. 6. 35 30 25 20 15 10 5 0 Chronic HCV Infection Increases Mortality *P<0.001 for comparison among all 3 groups and P<0.001 for HCV RNA detectable vs. undetectable. †P<0.001 for comparison among all 3 groups and P=0.002 for HCV RNA detectable vs. undetectable Lee MH, et al. J Infect Dis 2012;206:469–77 Follow-up (Years) 20 18 16 14 12 10 2 0 8 6 4 Follow-up (Years) 12 10 8 6 4 2 0 All causes(n=2,394) Liver cancer (n=115) Extrahepatic diseases (n=2,199) Cumulativemortality(%) Follow-up (Years) 30.1%* 12.8% 12.4% 10.4%* 1.6% 0.3% 19.8%† 12.2% 11.0% Anti-HCV+, HCV RNA detectable Anti-HCV+, HCV RNA undetectable Anti-HCV- 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 • 23 820 adults, Taiwan • 1095 anti-HCV positive • 760 (69%) HCV-RNA detectable HCV+, RNA+ HCV+, RNA- HCV-
  7. 7. 35 30 25 20 15 10 5 0 Chronic HCV Infection Increases Mortality from Hepatic Diseases *P<0.001 for comparison among all 3 groups and P<0.001 for HCV RNA detectable vs. undetectable. †P<0.001 for comparison among all 3 groups and P=0.002 for HCV RNA detectable vs. undetectable Lee MH, et al. J Infect Dis 2012;206:469–77 Follow-up (Years) 20 18 16 14 12 10 2 0 8 6 4 Follow-up (Years) 12 10 8 6 4 2 0 All causes (n=2,394) Liver cancer (n=115) Extrahepatic diseases (n=2,199) Follow-up (Years) 30.1%* 12.8% 12.4% 10.4%* 1.6% 0.3% 19.8%† 12.2% 11.0% 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 HCV+, RNA+ HCV+, RNA- HCV- Cumulativemortality(%)
  8. 8. Chronic HCV Infection Increases Mortality from Extra Hepatic Diseases *P<0.001 for comparison among all 3 groups and P<0.001 for HCV RNA detectable vs. undetectable. †P<0.001 for comparison among all 3 groups and P=0.002 for HCV RNA detectable vs. undetectable Lee MH, et al. J Infect Dis 2012;206:469–77 Follow-up (Years) 20 18 16 14 12 10 2 0 8 6 4 Extrahepatic diseases (n=2,199) Cumulativemortality(%) 19.8%† 12.2% 11.0% 0 2 4 6 8 10 12 14 16 18 20 HCV+, RNA+ HCV+, RNA- HCV-
  9. 9. Chronic HCV Infection Increases Mortality from both Hepatic and Extra Hepatic Diseases  Compared with anti-HCV negative individuals, anti-HCV positive individuals had higher mortality  Higher mortality in individuals with detectable HCV RNA vs. those with undetectable HCV RNA CI: confidence interval Lee MH, et al. J Infect Dis 2012;206:469–77 Hazard ratio [95% CI] All causes 1.89 [1.66–2.15] Hepatic diseases Extra hepatic diseases Cardiovascular diseases Nephritis Esophageal cancer Prostate cancer Thyroid cancer 12.48 [9.34–16.66] 1.35 [1.15–1.57] 1.50 [1.10–2.03] 2.77 [1.49–5.15] 4.08 [1.38–12.08] 4.19 [1.18–14.94] 8.22 [1.36–49.66]
  10. 10. Patrice Cacoub et al., annrheumdis-2013-203883
  11. 11. Prevalence of HCV Infection in Dialysis Patients  60 to 100 % in Egypt  8 to 36 % in North America  1 to 54 % in Europe  17 to 51% in Asia  1.2 to 10% in New Zealand and Australia
  12. 12. HCV infecton in ESKD patients  HCV in Hemodialysis patients:  8% (of 400,000 on HD) in USA  5 times greater than general US population  2.6%-23% (mean 13.5%) In industrialized populations  Number of years on dialysis independent risk factor for HCV infection  HCV: Natural History  HCV infection independently associated with increased mortality in hemodialysis patients  Increased rates of cirrhosis and hepatocellular cancer http://kidney.niddk.nih.gov/kudiseases/pubs/kustats/
  13. 13. Impact of HCV on Survival of HD Patients Espinosa et al Nephrol Dial Transplant 2001;16:1669-74.  175 patients  57 anti HCV-positive  Independent predictors of survival  baseline age (RR 1.04)  diabetic aetiology (3.6)  transplantation during f-up (0.66)  HCV-positivity (1.62)  Kaplan-Meier survival  52% at 8 years for HCV-negative  32% at 8years for HCV-positive  Causes of death similar  except 4 HCV-pos died of liver disease (vs 0 HCV-negs) Confirmed in meta-analysis. Fabrizi et al Aliment Pharmacol Ther 2004;20:1271-7.
  14. 14. liver fibrosis score (degree of scarring) 0 6 3 years10 20 30 60 cirrhosis HCV-pos (median time 38 years)cirrhosis
  15. 15. liver fibrosis score (degree of scarring) 0 6 3 years10 20 30 60 cirrhosis ? end-stage renal disease Impact of HCV on Cirrhosis in HD
  16. 16. liver fibrosis score (degree of scarring) 0 6 3 years10 20 30 60 cirrhosis end-stage renal disease ? immune suppression
  17. 17. 20 27 21 20 56 58 68 33 0 20 40 60 80 100 SVR (%) Casanovas Chan Fernandez Pol Degos Izopet Cam pistol Raptopoulou-Gigi Pooled SVR Interferon monotherapy 3 MU TIW 19 IFN In Dialysis Patients: Meta-analysis Russo et al, Am J Gastro July 2003 Studies using IFN 3 MU tiw
  18. 18. SVR and Reduced Risk of All-Cause Mortality US VA Study: Treatment with Pegylated Interferon/Ribavirin Backus L, et al. Clin Gastroenterol Hepatol. 2011 CumulativeMortality 0 1 2 3 4 5 6 0.00 0.05 0.10 0.15 0.20 0.25 0.30 P (log-rank) < 0.0001 No SVR SVR HCV Genotype 1 Years Genotype N SVR Hazard Ratio for Death with SVR P-value 1 12,166 35% 0.70 < 0.0001 2 2904 72% 0.64 0.006 3 1794 62% 0.51 0.0002
  19. 19. “Grading the evidence for hepatitis C therapies: Can we do better than a C”
  20. 20. 2002 IFN RBV 2011 IFN RBV DAA Association of DAA (direct acting agents) Trends in anti-HCV therapies 2014
  21. 21. Simple Regimen Short duration simple, straightforward stopping rules What Are the Key Elements of an Ideal HCV Regimen? Pan-Genotypic Regimen can be used across all genotypes Highly Effective High efficacy in traditionally challenging populations (ie, poor IFN sensitivity, cirrhosis) Safe and Tolerable Few or easily manageable adverse effects All Oral PegIFN/RBV replaced with alternate backbone with low chance of resistance Not Eliminated by the Kidney Easy Dosing Once daily, low pill burden
  22. 22. PEG IFN/RBV/TVR in hemodialysis patients with HCV infection 30 24 weeks 48 weeks PEG 135/TVR/RBV400mg 12 weeks+ 12 weeks PR PEG135 /TVR/RBV200mg 12 weeks+ 36 weeks PR N=18 N=17 SVR 24 weeks 13/18 (72%) SVR 48 weeks 11/17 (65%) Anemia, RBV dose reduction, EPO required Protease inhibitors can be used safely in dialysis patient Basu Journal of Hepatology, Volume 58, Supplement 1, April 2013, Pages S30–S31 #67
  23. 23. From: SaxenaV. ILC 2015, #LP08 The HCV-TARGET cohort
  24. 24. From: SaxenaV. ILC 2015, #LP08
  25. 25. Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function Saxena V, et al. Liver International 2016;Feb.29 Safety outcomes by baseline renal function in RBV-free regimen (SOF/SMV) a Outcome abstracted from HCV TARGET database as reported by investigators; includes test terms of acute kidney failure, acute kidney injury, renal insufficiency, renal failure, azotemia, acute renal failure, acute renal failure, anuric renal failure and impaired renal function. b The patient with eGFR ≤45 who died was a liver transplant recipient with baseline MELD of 26 who died from worsening renal failure and hepatic decompensation. Bold text signifies statistically significant differences. Safety outcome All patients, N = 718 eGFR ≤45, N = 39 eGFR >45, N = 679 P-value arly treatment discontinuation, n (%) 37 (5) 3 (8) 34 (5) 0.45 Early treatment discontinuation because of AE, n (%) 21 (3) 3 (8) 18 (3) 0.10 Common AEs, n (%) Fatigue 76 (25) 9 (23) 167 (25) 1.00 Headache 112 (16) 4 (11) 108 (16) 0.50 Nausea 92 (13) 5 (13) 87 (13) 1.00 Anaemia AE, n (%) 121 (17) 12 (31) 109 (16) 0.03 Required transfusion(s) 9 (1) 3 (8) 6 (1) 0.01 Erythropoietin stimulating drug started on treatment, n (%) 0 (0) 0 (0) 0 (0) 1.00 Worsening renal functiona, n (%) 13 (2) 4 (10) 9 (1) 0.004 Any serious AEs, n (%) 41 (6) 7 (18) 34 (5) 0.005 Cardiac serious AEs, n (%) 2 (<0.5) 0 (0) 2 (<0.5) 0.73 Death, n (%) 6 (1) 1 (3)b 5 (1) 0.28
  26. 26. Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function Saxena V, et al. Liver International 2016;Feb.29 SVR12 rates with 95% confidence intervals by treatment regimen in total cohort and by baseline renal function. eGFR, estimated glomerular filtration rate; PEG, peg-interferon; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response at 12 weeks.
  27. 27. Sofosbuvir-Containing Regimens Have Been Linked to Worsening of Renal Function in HCV-TARGET 1. Saxena V et al. Liver International 2016: ISSN1478-3223
  28. 28. Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function Saxena V, et al. Liver International 2016;Feb.29 On treatment eGFR trend among patients with baseline eGFR ≤45 who experienced worsening renal function. One patient with baseline eGFR <45 and worsening renal failure was excluded from this figure because of lack of longitudinal eGFR submitted.
  29. 29. A small US study
  30. 30. Sofosbuvir • Sofosbuvir extensively metabolized in the liver to form active nucleoside analogue triphosphate GS-461203 • Dephosphorylation results in the formation of inactive nucleoside metabolite GS-331007 • GS-331007 accounts for • >90% of systemic drug exposure • renal elimination
  31. 31. The Austrian experience
  32. 32. RUBY-1
  33. 33. RUBY-1
  34. 34. Pharmacokinetics: DCV-TRIO
  35. 35. Efficacy and safety of daclatasvir and asunaprevir combination therapy in chronic hemodialysis patients with chronic hepatitis C Suda G, et al. J Gastroenterol 2016;Jan 14 Mean changes in hepatitis C virus (HCV) RNA during treatment in all patients, patients with resistance-associated variants (RAVs) in NS5A, or patients with liver cirrhosis 34 HD patients treated for 24 weeks with Daclatasvir 60 mg/d + Asunapevir 100 mg bid Only ONE patient relapsed (he had a NS3 D168E-resistant strain)
  36. 36. Efficacy and safety of daclatasvir and asunaprevir combination therapy in chronic hemodialysis patients with chronic hepatitis C Suda G, et al. J Gastroenterol 2016;Jan 14 Changes in biochemistry, tumor, and fibrosis markers during and after daclatasvir and asunaprevir combination therapy; a alanine transaminase (n = 21), b serum albumin (n = 21), c alpha-fetoprotein (n = 20), d hyaluronic acid (n = 16). EOT, end of treatment ; post. 12 wk, 12 weeks post-treatment completion; ALT, alanine Transaminase ; AFP, alpha-fetoprotein. Paired Mann–Whitney U test, **p0.05, *p0.01
  37. 37. C-SURFER [Grazoprevir + Elbasvir]
  38. 38. HCV Treatment Options Expected in the Near Future
  39. 39. What about NS5a inhibitor? Ledipasvir  Pan-genotypic  Ledipasvir is likely to be approved this year  Excellent safety profile, no anemia  Ledipasvir : Primarily excreted (>98%) unchanged in the feces, with little renal excretion  No data yet in dialysis patients Kirby B, Mathias A, Yang C, et al. Metabolism and excretion of ledipasvir (GS-5885) in humans [abstract O_20]. 8th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 26-27, 2013, Cambridge, MA. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/02/WC500160499.pdf
  40. 40. ASTRAL-1, -2, -3, -4 Trials: Sofosbuvir/ Velpatasvir FDC ± RBV in GT1-6 HCV  Multicenter, randomized phase III trials in Tx-naive and Tx-experienced pts ASTRAL-1[1]: GT 1, 2, 4, 5, or 6 HCV (N = 740) Sofosbuvir/Velpatasvir (n = 624) Placebo QD (n = 116) 12 wks All pts followed for SVR12, primary endpoint ASTRAL-2[2]: GT2 HCV (N = 266) ASTRAL-3[3]: GT3 HCV (N = 552) Sofosbuvir/Velpatasvir (n = 134) Sofosbuvir + RBV (n = 132) Sofosbuvir/Velpatasvir (n = 277) Sofosbuvir + RBV (n = 275) Sofosbuvir/Velpatasvir (n = 90) Sofosbuvir/Velpatasvir + RBV (n = 87) Sofosbuvir/Velpatasvir (n = 90) 24 wks ASTRAL-4[4]: GT1-6 HCV and CTP B cirrhosis (N = 267) 1. Feld JJ, et al. AASLD 2015. Abstract LB-2. 2. Sulkowski MS, et al. AASLD 2015. Abstract 205. 3. Mangia A, et al. AASLD 2015. Abstract 249. 4. Charlton MR, et al. AASLD 2015. Abstract LB-13. Sofosbuvir/velpatasvir 400/100 mg QD
  41. 41. 100 ASTRAL-2 Open-Label Trial: SVR12, Safety With Sofosbuvir/Velpatasvir in GT2 HCV  No impact of BL NS5A RAVs on SVR rates  Safety profile similar to ASTRAL-1 All Pts No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis n/N = P = .018 (superiority) 99 SVR12(%) Treatment Naive Treatment Experienced SOF/VEL 12 wks 80 60 40 20 0 94 133/ 134 124/ 132 99/ 100 92/ 96 15/ 15 14/ 15 15/ 15 13/ 16 4/ 4 4/ 4 10010010099 96 100 93 81 SOF + RBV 12 wks Sulkowski MS, et al. AASLD 2015. Abstract 205. Reproduced with permission. Foster GR, et al. N Engl J Med. 2015;[Epub ahead of print].
  42. 42. 100 ASTRAL-3 Open-Label Trial: SVR12, Safety With Sofosbuvir/Velpatasvir in GT3 HCV Mangia A, et al. AASLD 2015. Abstract 249. Reproduced with permission. Foster GR, et al. N Engl J Med. 2015;[Epub ahead of print]. n/N = SVR12(%) 80 60 40 20 0 264/ 277 221/ 275 191/ 197 163/ 187 73/ 80 55/ 83 200/ 206 176/ 204 64/ 71 45/ 71 95 80 63 909797 87 91 66 86 All Pts No Yes Naive Experienced Cirrhosis P < .001 (superiority) SOF/VEL 12 wks SOF + RBV 24 wks Treatment History
  43. 43. ASTRAL-4: Sofosbuvir/Velpatasvir in Decompensated Cirrhosis  Open-label trial; HCC and liver transplantation excluded  In pts with BL MELD > 15, SVR12, score improved in 84%, worsened in 8%; in pts with BL MELD < 15, SVR12, score improved in 52%, worsened in 27%  AEs consistent with advanced liver disease and RBV toxicity Charlton MR, et al. AASLD 2015. Abstract LB-13. Curry MP, et al. N Engl J Med. 2015;[Epub ahead of print]. All Pts 1 3 HCV Genotype n/N = SVR12(%) SOF/VEL 12 wks SOF/VEL + RBV 12 wks SOF/VEL 24 wks 2, 4, and 6 100 80 60 40 20 0 83 94 86 88 96 92 50 85 50 100 100 86 75/ 90 82/ 87 77/ 90 60/ 68 65/ 68 65/ 71 7/ 14 11/ 13 6/ 12 8/ 8 6/ 6 6/ 7
  44. 44. 3’UTR5’UTR Core E1 E2 NS2 NS4BNS3 NS5A NS5B p7 Telaprevir Boceprevir Simeprevir Asunaprevir Paritaprevir Grazoprevir Daclatasvir Ledipasvir Ombitasvir Elbasvir GS-5816 Sofosbuvir VX-135 IDX21437 ACH-3422 Dasabuvir Beclabuvir NS5B NUC Inhibitors NS3 Protease Inhibitors NS5A Replication Complex Inhibitors Ribavirin NS5B Non-NUC Inhibitors PolymeraseProtease ....previr (PI) ....asvir (NS5A) ....buvir (Pol) How do I know which kind of DAA?
  45. 45. Do we really have to be cornered? BEFORE AFTER To have to treat our patients with all the drawbacks Not be able to treat our patient
  46. 46. Evaluation For Treatment Stage of liver disease Estimated GFR Nature and Severity of Extrahepatic Manifestations Chronic drug administration Previous antiviral treatment with interferon or direct anti-viral agents Nature and stage of CKD Presence of Co-morbid Conditions
  47. 47. Evaluation For Treatment Stage of liver disease Fibrosis stage Compensation of hepatocellular function Fib4 calculation fibroscans Child scores MELD scores
  48. 48. Evaluation For Treatment Nature and stage of CKD Regular HDx KTx Infected wih HCV Waiting For KTx De-novo HCV persisting for over 12 weeks Proteinuria MCGN
  49. 49. Evaluation For Treatment Nature and Severity of Extrahepatic Manifestations Cryoglobulinemic vasculitis with end-organ manifestations (joints, peripheral nerves, skin, kidneys, lungs, , eyes, gut, brain etc.)
  50. 50. Evaluation For Treatment Presence of Co-morbid Conditions Co-infection with HBV, HIV Other co-morbid conditions
  51. 51. Evaluation For Treatment Chronic drug administration Drug compatibility checker for identifying potential drug-drug interactions
  52. 52. Evaluation For Treatment Previous antiviral treatment with interferon or direct anti-viral agents
  53. 53. H. EL-Fishawy, M. Hassaballa, G. Saady, R. Barsoum, et al. 2016
  54. 54. H. EL-Fishawy, M. Hassaballa, G. Saady, R. Barsoum, et al. 2016
  55. 55. Guideline 2 : Treatment of HCV infection in patients with CKD (Kidney International, 2008, 73, Suppl 109)
  56. 56. • 2.1.2 It is suggested that the decision to treat is based on the potential benefits and risks of therapy, including life expectancy, candidacy for kidney transplantation, and comorbidities (weak). • 2.1.6 It is suggested that antiviral therapy be considered for patients with HCV-related GN (weak). Guideline 2.1: Evaluation of HCV-infected CKD patients for antiviral treatment (Kidney International, 2008, 73, Suppl 109)
  57. 57. 83
  58. 58. Guideline All patents with HCV infection should be treated
  59. 59. H. EL-Fishawy, M. Hassaballa, G. Saady, R. Barsoum, et al. 2016
  60. 60. Abstract ERA-EDTA London 2015
  61. 61. Components of Non Invasive Tests
  62. 62. Proceed Change to alternate YES Change DAA regimen NO Adjust dose; proceed with monitoring NO Alternates available? Check for alternates with the help of a specialist if necessary YES Stop co-medication N O Use with caution Contraindicated Is the co-medication absolutely necessary? Proceed NO Selecting the Correct Medications to Avoid DDIs Check for potential interaction with DAA regimen Summary of Product Characteristics www.hep-druginteractions.org Identify all co-medications including physician-prescribed, self- prescribed, herbal, recreational* *including grapefruit, which is a strong inhibitor of CYP3A4

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