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HCV Treatment in CKD population: past, present and future

This study reviews the impact of HCV infection on all-cause mortality and graft loss after renal transplant in patients with chronic kidney disease. It discusses the detrimental role of HCV on patient and graft survival and explores the potential treatments for HCV in the CKD population.

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HCV Treatment in CKD population: past, present and future

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  1. HCV Treatment in CKD population: past, present and future January 27, 2017 Alcàzar de San Juan, Spain Dr. F. Fabrizi Divisione of Nephrology, Maggiore Hospital IRCCS Foundation, Milano

  2. The aim of this study was to conduct a systematic review of the published medical literature concerning the impact of HCV infection on all-cause mortality and graft loss after Renal Transplant  Fabrizi F, Messa P. Meta-analysis of observational studies: Hepatitis C and survival after renal transplant J Viral Hepat 2014

  3. Systematic review and meta-analysis of observational studies (n=18; 133,530 unique RT recipients) Fabrizi F, Messa P. Meta-analysis of observational studies: Hepatitis C and survival after renal transplant J Viral Hepat 2014

  4. Mathurin P, et al. Impact of Hepatitis B and C Virus on Kidney Transplantation Outcome. Hepatology 1999

  5. The detrimental role of HCV upon patient and graft survival was confirmed by multivariate analysis in order to exclude the role of confounding factors (i.e., age, diabetes, time on dialysis, time after RT, etc) Mathurin P, et al. Impact of Hepatitis B and C Virus on Kidney Transplantation Outcome. Hepatology 1999

  6. Summary estimate for adjusted Relative Risk of all-cause mortality after RT: 1.85 (95% CI, 1.49; 2.31) Fabrizi F, Messa P.Meta-analysis of observational studies: Hepatitis C and survival after renal transplant. J Viral Hepat 2014

  7. Summary estimate for adjusted Relative Risk of all-cause graft loss after RT: 1.76 (95% CI, 1.46; 2.11) Fabrizi F, Messa P.Meta-analysis of observational studies: Hepatitis C and survival after renal transplant. J Viral Hepat 2014

  8. Greater all-cause patient/graft loss in RT-recipients with HCV related to (in addition to chronic liver disease): -Higher rate of post-transplant diabetes (PTDM) -de novo or recurrent HCV-GN -chronic allograft nephropathy -exposure to calcineurin inhibitors Fabrizi F, Messa P.Meta-analysis of observational studies: Hepatitis C and survival after renal transplant. J Viral Hepat 2014

  9. Interferon-based regimens have been the standard of care for HCV in adult general population and chronic kidney disease until a few years ago 2) Interferon and ribavirin play antiviral activity by immunomodulation Fabrizi F, et al. New treatments for hepatitis C in chronic kidney disease, dialysis, and transplant. Kidney Int 2016; 89: 988-994

  10. According to a recent survey from the Dialysis Outcomes and Practice Patterns Study (DOPPS) the current number of dialysis patients who are currently receiving antiviral therapy for HCV is very low (<5%) Goodkin D, et al. Hepatitis C infection is very rarely treated among haemodialysis patients. Am J Nephrol 2013; 38: 405-412

  11. Pegylated interferon-α2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 1 receiving hemodialysis: a randomized trial To compare the efficacy and safety of combination therapy with pegylated interferon plus low-dose ribavirin and pegylated interferon monotherapy for treatment-naive patients with HCV-1 receiving hemodialysis Liu C, et al.Ann Intern Med 2013; 159: 729-38

  12. DESIGN: Open-label, randomized, controlled trial SETTING: 8 centers in Taiwan PATIENTS: 205 treatment-naive patients with HCV-1 receiving hemodialysis INTERVENTION: 48 weeks of pegylated interferon-α2a, 135 µg weekly, plus ribavirin, 200 mg daily (n = 103), or pegylated interferon-α2a, 135 µg weekly (n = 102) RESULTS: Compared with monotherapy, combination therapy had a greater sustained virologic response rate (64% vs. 33%; relative risk, 1.92 [95% CI, 1.41 to 2.62]; P < 0.001) Liu C, et al.Ann Intern Med 2013; 159: 729-38

  13. DESIGN: Open-label, randomized, controlled trial SETTING: 8 centers in Taiwan PATIENTS: 205 treatment-naive patients with HCV-1 receiving hemodialysis INTERVENTION: 48 weeks of pegylated interferon-α2a, 135 µg weekly, plus ribavirin, 200 mg daily (n = 103), or pegylated interferon-α2a, 135 µg weekly (n = 102) RESULTS: The adverse event-related withdrawal rates were 7% in the combination therapy group and 4% in the monotherapy group (risk difference, 3% [CI, -3% to 9%]) Liu C, et al.Ann Intern Med 2013; 159: 729-38

  14. Peginterferon alfa-2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 2 receiving haemodialysis: a randomised trial To compare the efficacy and safety of combination therapy with peginterferon plus low-dose ribavirin and peginterferon monotherapy in treatment-naive haemodialysis patients with hepatitis C virus genotype 2 (HCV-2) infection are limited Liu C, et al.Gut 2015;64:303-11

  15. 172 patients received 24 weeks of peginterferon alfa-2a 135 μg/week plus ribavirin 200 mg/day (n=86) or peginterferon alfa-2a 135 μg/week (n=86) Compared with monotherapy, combination therapy had a greater SVR rate (74% vs 44%, relative risk (RR): 1.68 [95% CI 1.29 to 2.20]; p<0.001) Liu C, et al.Gut 2015;64:303-11

  16. 172 patients received 24 weeks of peginterferon alfa-2a 135 μg/week plus ribavirin 200 mg/day (n=86) or peginterferon alfa-2a 135 μg/week (n=86) The AE-related withdrawal rates were 6% and 3% in combination therapy and monotherapy groups, respectively (RD: 2% [95% CI -4% to 9%]) Liu C, et al.Gut 2015;64:303-11

  17. 1) The knowledge on the mechanisms of HCV entry and release 2) The discovery of viral proteins in HCV replication led to the development of specific drugs for the antiviral treatment of HCV (DAAs, direct-acting antivirals) Fabrizi F, et al. New treatments for hepatitis C in chronic kidney disease, dialysis, and transplant. Kidney Int 2016; 89: 988-994

  18. Hepatitis C virus (HCV) genome and potential drug discovery targets Asselah T, et al. Liver Int. 2016; 36 (Suppl. S1): 47–57

  19. Grazoprevir (GZR, MK-5172) plus Elbasvir (EBR, MK-8742) in Treatment-naive and Treatment-experienced Patients With Hepatitis C Virus Genotype 1 Infection and Stage 4–5 Chronic Kidney Disease (the C-SURFER study): a Combination Phase 3 Study Roth D, et al. Lancet 2015; 386: 1537–1545

  20. Elbasvir/grazoprevir is once-daily, fixed-dose combination therapy containing elbasvir (HCV NS5A replication complex inhibitor) and grazoprevir (HCV NS3/4A protease inhibitor) (12 weeks) Roth D, et al. Lancet 2015; 386: 1537–1545

  21. 224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population 179 (76%) were HD-dependent, 122 (52%) had HCV genotype 1a, 189 (80%) were HCV treatment-naive, 80 (36%) were diabetics, 14 (6%) were cirrhotics, and 108 (46%) were African American Roth D, et al. Lancet 2015; 386: 1537–1545

  22. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population: 99% (95% CI 95·3–100·0; 115/116), with one relapse 12 weeks after end of treatment Roth D, et al. Lancet 2015; 386: 1537–1545

  23. No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs Roth D, et al. Lancet 2015; 386: 1537–1545

  24. ADVERSE EVENTS SUMMARY SAE = serious adverse event. aReported in ≥10% of patients in either treatment group (ASaT). b1 SAE in the DTG (placebo) was considered drug-related (elevated lipase level). C1 SAE in the DTG (EBR/GZR) was considered drug-related (interstitial nephritis). d1 ITG patient died of cardiac arrest and 3 DTG patients died of aortic aneurysm, pneumonia, and unknown cause.

  25. Grazoprevir (GZR)/Elbasvir (EBR) treatment of hepatitis C virus (HCV) infection in patients with chronic kidney disease stage 4/5: Final results of the C-SURFER Phase 3 Study SVR12 in the ‘deferred treatment group’: 95% (97/102) Roth D, et al. Kidney Week 2015, November 5-8, 2015 San Diego, CA

  26. RUBY-I: Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir± Ribavirin in Non-Cirrhotic HCV Genotype 1-Infected Patients with Severe Renal Impairment or End-Stage Renal Disease Pockros P, et al. Efficacy of direct-acting antiviral combination for patients with HCV genotype 1 infection and severe renal impairment or end-stage renal disease. Gastroenterology 2016 Mar 11. [Epub ahead of print]

  27. RUBY-I: Ombitasvir (25 mg/day)/Paritaprevir (150 mg/day) +Ritonavir (100 mg/day)/Dasabuvir (250 mg twice/day) without or with ribavirin (200 mg/day) for 12 weeks Pockros P, et al. Efficacy of direct-acting antiviral combination for patients with HCV genotype 1 infection and severe renal impairment or end-stage renal disease. Gastroenterology 2016 Mar 11. [Epub ahead of print]

  28. RUBY-I: Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir± Ribavirin in Non-Cirrhotic HCV Genotype 1-Infected Patients with Severe Renal Impairment or End-Stage Renal Disease. Gastroenterology 2016

  29. RUBY-I Safety: OBV/PTV/r + DSV ± Ribavirin in Non-cirrhotic HCV Genotype 1-infected Patients With Severe Renal Impairment or ESRD Reported in ≥15% of patients; serious AEs (all unrelated to therapy) included cardiac chest pain (n=1); diskitis and respiratory failure (n=1); partial small intestinal obstruction, pleural effusion, dysphagia, left ventricular systolic dysfunction, and cardiac arrest (n=1, died); loss of consciousness (n=1) • Most AEs were mild or moderate with no study drug discontinuations • 4 patients with serious AEs—none was considered to be treatment related • 4 patients required erythropoietin for anemia; none received blood transfusion • No grade 4 laboratory abnormalities; 1 grade 3, hemoglobin <8 g/dL • No clinically significant changes in markers of liver or kidney function • Pockros P, et al. Gastroenterology 2016

  30. J Viral Hepat 2016 Dec 15. doi: 10.1111/jvh.12664. [Epub ahead of print] Therapy with ombitasvir/paritaprevir/ritonavir plus dasabuvir is effective and safe for the treatment of genotype 1 and 4 hepatitis C virus infection (HCV) in patients with severe renal impairment:a multicenter experience Munoz-Gomez R1, Rincon D2, Ahumada A2, Hernandez E3, Devesa MJ4, Izquierdo S4,  Ortiz M5, Hernandez-Albujar A6, Fernandez-Rodriguez C7, Calvo M8,Gonzalez R9,  Lozano M10, Castellano G1, Fernandez-Vazquez I1 1Department of Gastroenterology, Hospital Universitario 12 de Octubre, Madrid, Spain 2Unit of Hepatology, Hospital Universitario Gregorio Marañón, Madrid, Spain 3Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain 4Department of Gastroenterology, Hospital Universitario Clínico San Carlos, Madrid, Spain 5Department of Gastroenterology, Hospital Universitario Infanta Cristina, Madrid, Spain 6Department of Gastroenterology, Hospital General Universitario de Ciudad Real, Spain 7Department of Gastroenterology, Hospital Universitario Fundación Alcorcón, Madrid, Spain 8Department of Gastroenterology, Complejo Asistencial de Segovia, Segovia, Spain 9Department of Gastroenterology, Hospital Universitario del Sureste, Madrid, Spain 10Department of Gastroenterology, Hospital Universitario Infanta Leonor, Madrid, Spain

  31. Forty-six patients included; 10 (21.7%) had CKD stage 4, 36 (78.2%) CKD stage 5 SVR12 rate in the intention-to-treat population was 95.7%  The effectiveness of OBV/PTV/r±DSV±RBV in patients with CKD 4-5 was similar to that observed in those with normal renal function and was not associated with severe adverse events Therapy with ombitasvir/paritaprevir/ritonavir plus dasabuvir is effective and safe for the treatment of genotype 1 and 4 hepatitis C virus infection (HCV) in patients with severe renal impairment: a multicenter experience. Munoz-Gomez R, et al. J Viral Hepat 2016 Dec 15

  32. HCV-TARGET: Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function HCV-TARGET represents the largest prospective cohort of HCV-treated patients in the United States, and allows an in-depth analysis of ‘real-life’ experience of HCV treatment. • Saxena V, et al. Liver Int. 2016; 36:807-816

  33. Sofosbuvir-Containing Regimens Have Been Linked to Worsening of Renal Function in HCV-TARGET1 1. Saxena V et al. Liver International 2016: ISSN1478-3223

  34. HCV-TARGET: Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function In HCV-infected patients treated with SOF-containing regimens, SVR rates are not significantly influenced by baseline renal dysfunction but more renal safety events occur Association between baseline variables and SVR12 These patients had higher rates of anaemia, worsening renal dysfunction and serious adverse events regardless of use of RBV • Saxena V, et al. Liver Int. 2016; 36:807-816

  35. HCV-TARGET: Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function Safety outcomes of worsening renal function and SAEs were at least 3.5 times more frequent in patients with baseline eGFR ≤45 ml/min/1.73 m2 vs. >45 ml/min/1.73 m2. Predictors of safety outcomes Additional longitudinal studies would help to clarify the riskgroups.

  36. CKD Modifies the Pharmacokinetics of Some New Generation DAAs Percent changes to agent area under the concentration–time curve are shown; Green: no dose adjustment recommended in SmPC (for LDV no dose adjustment is expected due to limited renal elimination of this agent); Amber: caution recommended (due to increased exposure of SMV; safety and appropriate dosing of SOF have not been established in patients with severe renal impairment or ESRD) 1. Viekirax (OBV/PTV/r) SmPC 2015; 2. Exviera (DSV) SmPC 2015; 3. Harvoni (LDV/SOF) SmPC 2015; 4. Olysio (SMV) SmPC 2015 5. Daklinza (DCV) SmPC 2015

  37. Safety, Efficacy and Pharmacokinetics of Daily SOF + Ribavirin for 24 Weeks in Genotype 1 or 3 HCV+ Patients with Severe Renal Impairment Increased exposure of SOF (↑136%) and its inactive metabolite GS-331007 (↑603%) in HCV+ patients with severe renal impairment GS-331007 SOF 100,000 100,000 100,000 10,000 1,000 100,000 10,000 1,000 SOF AUC (ng.h/mL) 10,000 10,000 GS-331007AUC (ng.h/mL) 1000 SVR12 Viral relapse 1000 1000 1000 1000 Historical 400 mg Historical 400 mg Severe RI 400 mg Severe RI 400 mg 10 1000 1000 1,000 *SOF dose indicated in mg; historical values derived from patients with normal renal function Martin P, et al. Hepatol 2015;62:765A

  38. Sofosbuvir (NS5B inhibitor) and simeprevir (NS3/4A inhibitor) gave a SVR12 89% (34/38) (28 pts on HD, 1 on PD, 9 with GFR <30 mL/min) 35 pts treated for 12 wks 3 treated for 24 weeks HCV genotype 1a: n=26 Cirrhosis: n=20 Bhamidimarri K, et al. J Hepatol 2015

  39. Simeprevir 150 mg daily (standard dose) (n=38) Sofosbuvir 200 mg daily (n=11) Sofosbuvir 400 every other day (n=4) Sofosbuvir 400 mg day (n=23) Drop-outs (n=1): anemia and leukopenia Minor adverse events: Insomnia (n=2), fatigue (n=3), headache (n=1) rash/itching (n=2), GI disorders (n=2) Bhamidimarri K, et al. J Hepatol 2015

  40. Sofosbuvir+ Simeprevir (n=9) Sofosbuvir+ Ribavirin (n=3) Sofosbuvir+ Ledipasvir (n=7) Sofosbuvir+ Daclatasvir (n=1) SVR 12: 100% (20/20) Drop-out: 0 Minor adverse events: Anemia (n=2) CNI levels decreased after therapy with DAAs Sawinski D, et al.Successful treatment of HCV after RT with DAAs. Am J Transplant 2016

  41. Sofosbuvir+ Simeprevir (n=6) +RBV (n=1) Sofosbuvir+ Ribavirin (n=3) Sofosbuvir+ Ledipasvir (n=9) +RBV (n=1) Sofosbuvir+ Daclatasvir (n=4) Sofosbuvir+ PegIFN+RBV (n=1) SVR 12: 100% (25/25) Drop-out: 0 No adverse events CNI levels decreased after therapy with DAAs Kamar N, et al.Efficacy and safety of sofosbuvir-based antiviral therapy for HCV after RT.Am J Transplant 2016

  42. Sofosbuvir+ Simeprevir (n=9) +RBV (n=3) Sofosbuvir+ Ribavirin (n=4) Sofosbuvir+ Ledipasvir (n=7) +RBV (n=1) SVR 12: 91% (21/23) Drop-out: 0 No adverse events leading to discontinuation No decrease of CNI levels while on therapy with DAAs Lin M, et al.Efficacy and safety of DAAs in RT recipients with chronic HCV. PLoS One 2016

  43. Adverse Events Reported While on Treatment Lin M, et al. Efficacy and Safety of Direct Acting Antivirals in Kidney Transplant Recipients with Chronic Hepatitis C. PLoS One 2016

  44. Treatment-naive or -experienced kidney transplant recipients with chronic genotype 1 or 4 HCV infection, with or without compensated cirrhosis, and with an estimated glomerular filtration rate (eGFR) of 40 mL/min or greater were randomly assigned 1:1 to receive ledipasvir (90 mg) and sofosbuvir (400 mg) for 12 or 24 weeks Colombo M, et al. Treatment with ledipasvir-sofosbuvir for 12 or 24 weeks in kidney transplant recipients with chronic hepatitis C virus genotype 1 or 4 infection. Ann Intern Med 2017; 166: 109-117

  45. One hundred percent of patients (57 of 57) treated for 12 weeks (95% CI, 94% to 100%) and 100% of those (57 of 57) treated for 24 weeks (CI, 94% to 100%) achieved SVR12 Colombo M, et al. Treatment with ledipasvir-sofosbuvir for 12 or 24 weeks in kidney transplant recipients with chronic hepatitis C virus genotype 1 or 4 infection. Ann Intern Med 2017; 166: 109-117

  46. Serious adverse events were reported in 13 patients (11%) of these, 3 events-syncope, pulmonary embolism, and serum creatinine increase-in 3 patients were determined to be treatment related. One patient permanently discontinued treatment because of an adverse event (syncope). The most frequent adverse events overall were headache (n = 22 [19%]), asthenia (n = 16 [14%]), and fatigue (n = 11 [10%]) Colombo M, et al. Treatment with ledipasvir-sofosbuvir for 12 or 24 weeks in kidney transplant recipients with chronic hepatitis C virus genotype 1 or 4 infection. Ann Intern Med 2017; 166: 109-117

  47. FUTURE The antiviral regimens based on direct-acting antivirals promise to play a pivotal role in the eradication of hepatitis C among CKD patients However, we need to address some issues (costs, drug-drug interactions, pharmacokinetics, etc) concerning DAAs in CKD

  48. Definition of CKD: Kidney Damage ± Impaired Kidney Function for ≥3 Months with Implications for Health • Impaired kidney function defined as GFR <60 mL/min/1.73 m2 • *eGFR: measure of the flow rate of the kidneys, calculated from the creatinine clearance level, as well as the age, sex and race of the individual • †With evidence of kidney damage eGFR* (mL/min/1.73 m2) CKD stage 1† Normal renal function ≥90 6089 Mild renal impairment 2 Moderate renal impairment 3059 3 Severe renal impairment 1529 4 Renal failure <15 or on dialysis 5 • KDIGO Guidelines CKD. KidneyInt 2013;(Suppl 3):5–14

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