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Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
Samuel virus  lt du 2012
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Samuel virus lt du 2012

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  • 1. LIVER TRANSPLANTATION IN VIRAL HEPATITISNatural Course, Overview Didier SAMUEL, M.D. Professor of Hepatology CENTRE HEPATOBILIAIRE INSERM PARIS XI UNIT 785 HOPITAL PAUL BROUSSE VILLEJUIF, FRANCE C.H.B.
  • 2. Evolution of Liver Transplantation For Viral Cirrhosis without HCC in Europe 700 600 500 400 300 200 100 0 6 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 8 19 19 19 19 19 19 19 19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 re Virus Delta Virus B Virus C ELTR foBe
  • 3. Evolution of Liver Transplantation For Viral Cirrhosis with HCC in Europe 500 450 400 350 300 250 200 150 100 50 0 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 19 19 19 19 19 19 19 19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 re Virus Delta + HCC Virus B + HCC Virus C + HCC fo ELTRBe
  • 4. LIVER TRANSPLANTATION IN VIRAL HEPATITIS BNatural Course, Overview C.H.B.
  • 5. Liver Transplantation for Viral B Cirrhosis in USAKim WR Gastro 09
  • 6. Prophylaxis of HBV Infection PosttranplantationMajor improvements have been made in prevention ofHBV infection in past 15 yrsBefore transplantation– Lamivudine or adefovir– Nucleos(t)ide analoguesAfter transplantation– Anti-hepatitis B immunoglobulins (HBIG)– Lamivudine or Adefovir, or ETV monoprophylaxis– Combination HBIG + lamivudine/adefovir– Combination HBIG + nucleos(t)ide analogue
  • 7. Prophylaxis afterLiver Transplantation C.H.B.
  • 8. HBV Recurrence and Survival According to ProphylaxisD. Samuel et al. NEJM 1993;329:1842-7 C.H.B.
  • 9. Long-Term Use of IV HBIG AimHigh doses during anhepatic phase, then duringfirst wk– Aim Make serum HBsAg negative Obtain protective anti-HBs titer– Maintain protective anti-HBs titer Effective in FHF, HDV-C Less effective in nonreplicative HBV-C - Possible low replication detected by PCR Insufficient in replicative HBV-C
  • 10. Actuarial HBV Recurrence Rate in Relation to Initial Liver Disease Hôpital Paul Brousse: 19862000 100 284 Patients Risk of Recurrence (%) 80 60 56.5 54.4 49.4 49.4 HBV-C 41.8 37.5 40 FHD 25.0 25.0 25.0 25.0 20 13.5 13.5 15.3 15.3 5.8 HDV-C 0 FHB 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (yr)HBV-C = HBV cirrhosis; FHD = fulminant hepatitis B-Delta; HDV-C = HDV cirrhosis;FHB = fulminant hepatitis BRoche B et al. Hepatology. 2003;38:86
  • 11. Lamivudine MonoprophylaxisPatients remained HBsAg positive after liver transplantProgressive decline of HBsAg1Rate of HBV reinfection– Related to HBV DNA level before liver transplant– Related to treatment duration– Increased with time posttransplantHBV reinfection due to YMDD HBV mutantQuestion of long-term compliance and risk of reinfection1. Grellier L et al. Lancet. 1996;348:1212 [published correction in Lancet. 1997;349:364]
  • 12. HBV Recurrence with Lam Monoprophylaxis A Great FailureJiang WJG 2009
  • 13. ETV Monoprophylaxis after LT 80 Patients Mean follow up Rate of HBsAg loss 86% and 91% at 1-2 years 10 patients had HBsAg reappearance At end of FU : – 18 Patients (22%) were HBsAg positive, one was HBV DNA positiveFung Gastro 2011 in Press
  • 14. HBsAg Clearance after LT on ETV MonoprophylaxisFung Gastro 2011 in Press
  • 15. HBsAg Relapse after LT on ETV MonoprophylaxisFung Gastro 2011 in Press
  • 16. Virology HBV DNA and HBsAg Used 2 Distinct Pathways Brunetto J Hepatol 2010Nguyen J Hepatol 2010 Antiviral alone not able to block HBsAg
  • 17. Posttransplant Combination HBIG + Nucs: RationaleLower rate of escape mutation due to pressure on 2different regions in HBV genome– PreS/S region for HBIG– YMDD region of polymerase gene for lNucsPossible to reduce HBIG amount and overall cost
  • 18. HBV Recurrence HBIG Monoprophylaxis vs Combined HBIG + Nucleos(t)ide Paul Brousse 1995-2005 Factors independently associated with HBV recurrence: • HBV DNA at LT> 105 copies/ml • HCC at LT • HBIG monoprophylaxisFaria Gastroenterology 2008
  • 19. Low-Dose HBIG + Lamivudine• 147 patients• Pretransplant • LAM if HBV DNA (+) (80% pts) 0.5 - Proportion of Patients With• Posttransplant • LAM + HBIG IM 400–800 IU daily  7 0.4 - HBV Recurrence days 0.3 - • LAM + HBIG IM 400/800 IU monthly• HBV recurrence: 4% at 5 yr 0.2 -• 5 pts with HBV recurrence • All YMDD HBV 0.1 - • ADV in all, 1 death from liver failure• Factor independently associated with 0.0 - I I I I HBV recurrence 2 4 6 8 • HBV DNA prior LAM Time Posttransplant (yr) Number 147 124 89 56 14 at risk Gane EJ et al. Gastroenterology. 2007;132:931
  • 20. HBV Recurrence In Patients with and without HCC Paul Brousse 1995-2005Faria L. Gastroenterology 2008
  • 21. HBV Recurrence Is Associated with HCC Recurrence Paul Brousse 1995-2005Faria L. Gastroenterology 2008
  • 22. HBV Recurrence Is Associated with HBV DNA at LT USADegertekin AJT 2010
  • 23. Prophylaxis Protocol Place of HBIG in Combination? HBIG at start is essential – Immediately makes HBsAg negative – Protects graft from immediate reinfection High doses of HBIG – Important at start – Dose related to HBV DNA level at liver transplant3 – Lower doses can be used at medium term1. Gane EJ et al. Gastroenterology. 2007;132:931; 2. Han SH et al. Liver Transpl. 2003;9:182; 3.Dickson RC et al. Liver Transpl. 2006;12:124
  • 24. Absence or Discontinuation of HBIG? Cost?Highly variable– Depending countries, preparations ( ratio 1 to 4)– High doses needed only at the start to control HBs Ag– Medium term Low doses in combination protocols Decreased cost Cost to be compared to combination new generation Nucs
  • 25. Discontinuation of HBIG? Few cases of HBV reinfection after 1-2 year Yes but: – Only if HBIG prophylaxis given – On Lam, HBV reinfection cases increase with time – Cases of long-term recurrence after discontinuation – Residual HBV DNA in > 50% -70% of patients at 10 yr1,2 – Difficult to identify patients who have cleared virusRoche Hepatology 2003, Hussain Liver Transplant 2007
  • 26. Discontinuation of HBIG? HBV Reinfection no more severe, Nucs alone will give the same results?HBV Reinfection no more severe?– True if well monitored, but will be reinfected anyway– Untrue if monitoring inaccurate, severe HBV reactivationNucs alone will give the same results?– At best, it will be a non-inferiority comparison– Will always be less good than combination HBIG +Nucs
  • 27. Discontinuation of HBIG Replacement by Lamivudine21 pts stopped HBIG (Wong SN et al. Liver Transplant. 2007)All on lamivudine2 recurrence (actuarial rate of 3 year HBV recurrence 9% afterHBIG withdrawal), both recurrence YMDD, 3 additional patientswith transient HBV DNA20 Pts stopped HBIG replaced by Lam: HBV reinfection 3/20 at 5years (Buti Transplantation 2007) HBV recurrence Increase with Follow-up
  • 28. Discontinuation of HBIG after 12 Months HBIG + Lam and Replacement by ADV/Lam Positive HBsAg Detectable HBV DNAADV/Lam 1/15 (6%) 0/18 (0%)HBIG/Lam 0/15 (0%) 0/18 (0%)13 718 $ VS 8 289 $ Angus Hepatology 2008
  • 29. Vaccine After TransplantationGreat discordance in results– Good Results dependent of the adjuvant or Pre S vaccine ( none commercialised)– Durability of response?– Tolerance and reproducibility of results– Response probably more frequent in FHB patients (spontaneous seroconversion boosted by vaccine?)How to identify patients susceptible to respond to vaccine? NOT READY TO REPLACE HBIG
  • 30. Discontinuation of all Prophylaxis after LT: End of a Dogma ? • Inclusion criteria: • > 5 years post-LT treated with HBIG ±Nuc • Serum HBV DNA negative • HBV DNA and cccDNA negative in liver biopsy 1Lenci I. J Hepatol 2011
  • 31. Results 1 patient 30 patients stop HBIg HBs+ 4 week after HBIg discontinuation cccDNA 2nd biopsy négative 29 patients 29 patients stop NUC25 patients no HBV reactivation 4 patients became HBsAg + after 24 months after 8-32 wks discontinuation NUCs 3 patients HBV DNA neg 1 patient HBV DNA > 50 in 4 weeks seroconversion HBs cccDNA pos on third biopsy after 18 week. (16-24) Lenci I. J Hepatol 2011
  • 32. Discontinuation of HBV Prophylaxis after LT : Patients with HBV recurrenceLenci I. J Hepatol 2011
  • 33. Strategies for Prevention of HBV Recurrence 40% 36 36Recurrence Rate 30% 33 33 Overall HBV 20% 18 18 10% 66 0% Lamivudine Low-Dose High-Dose Lamivudine (mono) HBIG HBIG + HBIG Seehofer D, Berg T. Transplantation. 2005;80(1 suppl):S120
  • 34. ConclusionHBIG + Nuc the Best combination at the startAt mid-term– HBIG can be stopped in patients with low risk recurrence Spontaneous HBV DNA negative patients at LT FHF Patients If Nuc are maintained– In high risk Patients: HBV DNA +ve at LT, HCC, HIV coinfection Low dose HBIg + Nuc remain the best combination
  • 35. HCV AND LIVER TRANSPLANTATION C.H.B.
  • 36. PATTERN OF HCV RECURRENCE POST OLTx NO HEPATITIS CHRONIC HEPATITIS 20% 6 MTH ? 1 MTH ACUTE HEPATITIS OLT 70% 6 MTH CHRONIC HEPATITIS CIRRHOSIS 1 MTH 1 MTH  CHOLESTATIC VIRAL HEPATITISRECURRENCE < 10 % DEATH Adapted From McCaughan 50%
  • 37. CHOLESTATIC HEPATITIS C McCaughan J Hepatol 2011
  • 38. Pathobiology of Chronic HCV Post LTImmunosuppression - The immune response + HCV load - Inflammation + IFN- related genes IFN- response Stimulation of the IMMUNE RESPONSE by more HCV WINS Proliferation Acute Rejection Apoptosis Inflammation Fibrosis Stress Response McCaughan and Zekry J.Hepatol 2004, Samuel Easl Hepatol 2006
  • 39. HCV Entry in HepatocyteT Pietschmann Nature 2009
  • 40. Streoids Increase HCV Entry in Liver TransplantationGc: GlucocorticoidsGr: Glucocorticoid Receptor Ciesek Gastro 2010, Fafi Kremer J Hepatol 2010
  • 41. Additive Effect of Anticlaudin, AntiE2 and HCVIg on HCV Entry and InfectionFofana Gastro 2010
  • 42. EVALUATION OF THE SEVERITY OF HCV RECURRENCE• Liver Biopsy Gold Standard, Bring additional information than fibrosis stage. HPVG Invasive, can be done with liver biopsy Not routine for many Centres. Non invasive tests Biochemical Elastometry (fibroscan). Time post-LT as an adding variable C.H.B.
  • 43. HPVG, Fibrosis at 1 Year Post-Transplant and OutcomeBlasco Hepatology 2006; 43: 492-499
  • 44. Fibrosis Stage at 12 months at Liver Biopsy and SurvivalGallegos-Orozco Liver Transplant 2009
  • 45. Non Invasive Test (3-M-ALG) and HPVG at 6 and 12 Months in Control and HCV Reinfected PatientsCarrion Gastro 2010
  • 46. Non Invasive 3-MALG Test and Decompensation and Survival Post-TransplantCarrion Gastro 2010
  • 47. Liver Stiffness and Severity of HCV RecurrenceCarrion Hepatology 2010
  • 48. Donor and Host Factors of HCV Recurrence C.H.B.
  • 49. EFFECT OF DONOR AGE ON THE DEVELOPMENT OF HCV GRAFT FIBROSIS AND CIRRHOSIS Cirrhosis and donor age Fibrosis and donor age Wali et al. Gut 2002; 51: 248-252 C.H.B.Berenguer Hepatology 2002; 36: 202-210
  • 50. Fibrosis on the Graft In HCV+ve Liver Transplant Patients According to Donor Age and GenderRisk of Fibrosis: Stable over years, Higher in women receiving old donors Belli Liver Transplant 2007; 13: 733-740
  • 51. STEROIDS AND HCV• Controversial role – Increase viral load (Fong Gastro 1994, Gane Gastro 1996) – Increase viral hepatocyte entry (Gastro 2010) – Boluses of steroids deleterious (Berenguer J Hepatol 2000) – Rapid withdrawal deleterious (Berenguer Hepatology 2003, McCaughan J Hepatol 2004, Vivarelli J Hepatol 2007) » Immune rebound? – Immunosuppression without steroids: not yet proven beneficial (Klintmaln Liver Transplant 2007) C.H.B.
  • 52. Rapid Steroid Withdrawal Deleterious for Hep C Recurrence Group A: Rapid Steroid Withdrawal D91 Group B: Slow Decrease in steroids, Stop at M25 % patients without severe Fibrosis Vivarelli J Hepatol 2007
  • 53. HCV Recurrence , Cyclosporine vs Tacrolimus• There is currently no proof of superiority of one vs another – Antiviral effect of Cyclosporine only in vitro – Better efficacy of IFN in Ciclosporine patients not confirmed – Randomized studies showed earlier reinfection with Tac but no difference in survival and fibrosis stage C.H.B.
  • 54. Overall Role of IS 80 70 54 60 48 50 40 33 23 29 30 20 7 10 0 1999-2000 (n=52) 2001-2003 (n=90) F3,4,FCH FCH AH 1999-2000 2001-2003 PDuration Pred (d) 249 350 <.0001Bolus MP 21 4.5 .002 Berenguer> Is double (%) 25 10 .001 J Hepatol 2006IFN preTH (%) 9 30 .006Donor age (yr) 51 57 .07
  • 55. ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION – Difficult to manage in decompensated cirrhotic patients – Risk of deterioration of liver function – Risk of sepsis, severe neutropenia, and anemia – Poor antiviral effect at this stage – However, some patients candidates to LT: » Have preserved liver function (those with HCC) » Have a long expected waiting time for LT » Have never been treated or are ”false” non responders C.H.B.
  • 56. ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION » 124 patients • 56 Child A, 45 Child B, 23 Child C • 86 Genotype 1, 16 Genotype 2, 17 Genotype 3 » SVR: • 50% in genotype non-1, • 13% in genotype 1 » 22 complications in 15 patients ( 21 in Child B and C), 4 died » No HCV recurrence in sustained responders.Everson Hepatology 2005 C.H.B.
  • 57. ANTIVIRAL TREATMENT PRE-LTAuthors Patients Child Treatment Virologic SVR Tolerance Response EOT Post-LTForns 30 A 50% INF 3M/d 9 (30%) 6/30 Decrease INF(2003) (Time pre- B 43% +RBV (20%) 60%, RBV LT 4 800mg 23% C 7% Factors for mths) Mean response : viral Stop 20% G1:83% Duration : laod pre-LT, Sepsis: 2 12 wks Decrease viral Liver Failure: (2-33 wks) load≥ 2 log Wk 4 4Carrion 51 Meld Peg 2a 15 (29%) 10/51 infectious(2008) G1:80% 11 180 g/wk (20%) risk +RBV increased by Factors response: Trt (NS) 51 0,8-1g/d G non 1, controls Mean RVR Wk4 duration: 15 Wks Forns J Hepatol 2003, Carrion J Hepatol 2008 C.H.B
  • 58. Antiviral Treatment Before TransplantationRoche, Samuel Liver Transplant 2010
  • 59. Antiviral Treatment Immediately after TransplantationRoche, Samuel Liver Transplant 2010
  • 60. PegIFN+RBV for Established Infection after Transplantation • SVR: 25-45% – Genotype 1: 30-35% – Genotype 2-3: 60-70% • Variables associated with SVR: – Non-1 Genotype – EVR, RVR – Adherence to therapy – Low pretreatment viral loadBerenguer J Hepatol 2008, Roche Liver Transplant 2010 C.H.B.
  • 61. Treatment with PEG IFN + RBV After LT SVR Dependent of Fibrosis stage• 27 Pts mild Hepatitis C (F1-F2): SVR 48%• 27 Pts severe hepatitis C (F3-F4), Cholestatic Hepatitis: SVR 18% • F3-4: 4/15 • Cholestatic hepatitis, 1/12 ( Carrion Gastro 2007)• 20% F3-F4 vs 1% F1 Patients died or were retransplanted ( RocheLiver transplant 2008) C.H.B.
  • 62. SVR and Snp near IL28 gene in Donor, Recipient, Combined in Genotype 1 Transplant PatientsFukuhara Gastro 2010 In Press C.H.B.
  • 63. SVR and IL28 mRNA expression in Transplant Liver in Genotype 1 Transplant PatientsFukuhara Gastro 2010 In Press C.H.B.
  • 64. Tolerance to Treatment• The tolerance is poor• 40-80% rate of doses reduction• 40-50% discontinuation rate• Anaemia++ is the first cause of discontinuation• EPO is required in many cases ( > 30%)• Risk of rejection and alloimmune hepatitis ( 2-15%) C.H.B.
  • 65. Auto(Allo)immune Hepatitis and IFNSharma Liver Transplant 2007
  • 66. Histological Outcome in Relation withVirological Response to PEGIFN+ Ribavirine Variables associated with Histological improvement: EVR, BR, SVRCarrion Gastroenterology 2007 C.H.B.
  • 67. Role of SVR After LT in HCV + PatientsPiciotto J Hepatol 2007; 46:459-465
  • 68. Telaprevir In Naive HCV Non-Transplant PatientsMcHutchison NEJM 09
  • 69. Direct Antiviral Agents Before LT A New Challenge• Data In cirrhotic patients are lacking• Therapies with IFN will remain poorly tolerated• Increase possibility to achieve SVR or on treatment virologic response• Increase risk of virologic breakthrough• Duration, safety issues to be analysed• Therapies without IFN awaited C.H.B.
  • 70. Direct Antiviral Agents After LT A New Challenge• Increase possibility to achieve SVR or on treatment virologic response• Interaction between anti NS3 protease and calcineurin inhibitors• Duration, safety issues to be analysed• Therapies without IFN awaited C.H.B.
  • 71. Interaction Telaprevir-Cyscloporine, Telaprevir-Tacrolimus Dose normalised AUC X 4.5 Dose-normalised AUC X 70 Garg Hepatology 2011
  • 72. Patient Survival after Liver Transplantation For Viral Cirrhosis in Europe From 13/11/1973 to 30/06/2009 Without HCC With HCC 1 92% 1 88% 87% 85% 82% 77%Survie Cum. ,8 ,8 84% 71% Survie Cum. 73% 81% 67% 82% 68% ,6 60% ,6 67% 59% ,4 55% ,4 Virus D (n=1148) 46% Virus D (n=288) Virus B (n=3398) Virus B (n=1810) ,2 ,2 Virus C (n=8545) Virus C (n=4882) 0 0 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Years Years
  • 73. Evolution of Patient Survival after LTFor Viral Cirrhosis without HCC in Europe From 13/11/1973 to 30/06/2009 After 2005 1 2000 to 2005 1995 to 2000 ,8 1990 to 1995 Before 1990Survie Cum. ,6 ,4 ,2 0 0 1 2 3 4 5 6 7 8 9 10 Years
  • 74. Evolution of Patient Survival after LTFor Virus C Cirrhosis without HCC in Europe From 13/11/1973 to 30/06/2009 2005 After 2000 to 2005 1 1995 to 2000 1990 to 1995 ,8 Before 1990 Survie Cum. ,6 ,4 ,2 0 0 1 2 3 4 5 6 7 8 9 10 Years
  • 75. Patient survival according to the year of LT HBV Cirrhosis ELTR update of December 2007 >= 2005 : 419 2000 to 2005 : 973 95 to 2000 : 831 100 91% 90% 90 to 95 : 653 85 to 90 : 175 80 <1985 : 12 60% Survival 40 20 0 0 1 2 3 4 5 6 7 8 9 10 Years
  • 76. CONCLUSION• Survival still affected by HCV recurrence• Monitoring combining liver biopsy and non invasive methods• Treatment before Transplantation poorly effective – SVR before LT , no recurrence post-LT – HCVRNA negativity at LT, Risk of post transplant recurrence reduced by 70%• Treatment after transplantation : – Effective at time of Chronic hepatitis before the F3 stage » 30-40% SVR in G1 Patients » 70% SVR in G2-G3 Patients C.H.B.
  • 77. CONCLUSION• Advent of Direct antiviral agents will open a new era• Before LT: Presence of IFN in the treatment arm will remain a limitating factor• After LT: new strategies will arise• Viral breakthrough, tolerance, interaction with calcineurin inhibitors, treatment duration: – Open questions for the close future C.H.B.

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