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The IMPACT Study Extended slide deck

The IMPACT Study Extended slide deck. CMV background. Exposure to maternal blood (in utero ), vaginocervical secretions, breast milk. Close contact among children in day care centres. Sexual transmission, close contact. Blood transfusion. Organ transplantation. CMV epidemiology.

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The IMPACT Study Extended slide deck

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  1. The IMPACT Study Extended slide deck

  2. CMV background

  3. Exposure to maternal blood (in utero), vaginocervicalsecretions, breast milk Close contact amongchildren in day care centres Sexual transmission,close contact Blood transfusion Organ transplantation CMV epidemiology • Cytomegalovirus is a member of the herpes virus family • CMV is an ubiquitous virus: 50-80% of adult population are seropositive • > 90% of HIV-positive patients are infected with CMV • > 75% of SOT allograft recipients show CMV replication after Tx Griffiths PD et al. Clinical Virology 1997; 445-70. Bloom JN, Palastine AG. Ann Intern Med 1988; 109:963-9. Hay JE. Mayo clinic gastroenterology and hepatology board review 2005; 367-76. Fishman JA et al. Clinical Transplantation 2007; 149-58.

  4. CMV in solid organ transplantation (SOT) Threemechanismsofinfection Primary infection • D+/R- or D-/R- • Where D-/R- isthelowestriskgroupand D+/R- thehighest Reactivation (endogenous latent virus) • D+/R+ or D-/R+ • Reactivationofownvirus Superinfection • D+/R+ • Reinfectionwithdonorvirus Rubin RH. Transpl Infect Dis 1999; 1:3-7.

  5. Direct and indirect effects of CMV after transplantation CMVinfection Directeffects Indirecteffects CMV syndrome Organ-specificeffects Opportunisticinfections Acute/chronicrejection Cardiovascular complications Lymphoma Diabetes Adapted from Fishman JA et al. Clin Transplant 2007; 21:149-58.

  6. Direct and indirect effects of CMV Direct effects • Signs and symptoms of CMV disease • CMV syndrome = fever, malaise, diaphoresis • Tissue-invasive disease • Pneumonitis, GI disease, hepatitis, retinitis, nephritis • In most cases, CMV is detected in peripheral blood or upon organ biopsy and is associated with high viral loads Indirect effects • Are associated with asymptomatic CMV infection • Indirect effects include graft rejection, opportunistic infections, cardiovascular complications, diabetes, etc. Fishman JA et al. Clin Transplant 2007; 21:149-58.

  7. Persistent CMV infection is associated with reduced kidney function p = 0.007 p = 0.007 1 year 2 years Non-persistent or no CMV Persistent CMV Helanterä I et al. Transplant Int 2006; 19:893-900.

  8. CMV disease and CMV infection are both risk factors for kidney graft loss No CMV infection No CMV infection 1.0 1.0 0.8 0.8 0.6 0.6 CMV disease during first 100 days Uncensored graft survival Asymptomatic CMV infection first 100 days 0.4 0.4 0.2 0.2 Log-rank p = 0.001 Log-rank p = 0.001 0 0 0 1000 2000 3000 0 1000 2000 3000 Time post-transplant (days) n = 477 Sagedal S et al. KidneyInt 2004; 66:329-37.

  9. Risk factors for cardiac complications after kidney transplantation Humar A et al. Transplantation 2000; 70: 310–3.

  10. *p < 0.05 Survival (%) CMV(-) Age ≥ 45 n = 31 CMV(+) Age ≥ 45 n = 157* Time post-transplant (months) Effect of CMV serum status on cardiovascular death Kalil RS et al. Am J Transplant 2003; 3:79-81.

  11. CMV background - conclusions • CMV is associated with direct and indirect effects after transplantation • CMV infection is a risk factor for reduced graft function, graft loss and cardiovascular complications after transplantation • High viral load may not be necessary for indirect effects

  12. Strategies for CMV Management

  13. Strategies to prevent CMV infection Preemptive therapy • Highly sensitive, quantitative assays (e.g. molecular diagnostic test or antigenaemia assay) utilised to monitor patients at predefined intervals to detect infection before symptoms arise Universal prophylaxis • Antiviral therapy provided to all at-risk patients for a defined time period Fishman JA et al. Clin Transplant 2007; 21:149–58.

  14. Universal antiviral prophylaxis vs preemptive therapy • Both universal antiviral prophylaxis and preemptive antiviral therapy reduce the incidence of invasive CMV infection • Preemptive therapy incurs extra costs for monitoring and coordination of outpatient care, but avoids the costs of universal prophylactic antiviral therapy Fishman JA et al. Clin Transplant 2007; 21:149–58.

  15. What do current guidelines recommend? • "We recommend that KTRs (except D-/R-) receive chemoprophylaxis for CMV infection with oral ganciclovir or valganciclovir for at least 3 months after transplantation, and for 6 weeks after treatment with a T-cell–depleting antibody“ • "[…] while many experts have previously felt that both strategies (universal chemoprophylaxis or viral load monitoring to inform preemptive antiviral therapy) were acceptable for the prevention of CMV disease in this population, if confirmed, the newer data may provide evidence that all KTRs at risk for the development of CMV should receive chemoprophylaxis and not a preemptive therapy approach. KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients. Am J Transplant 2009; 9 (Suppl 3): S46-8.

  16. Anti-CMV prophylaxis is associated with improved survival post-transplant 1 0.8 p < 0.02 p = 0.00004 0.6 p < 0.00001 Relative risk 0.4 p = 0.02 0.2 0.26 0.63 0.61 0.42 0 CMV infection CMV disease Mortality from CMV All-cause mortality Placebo/ No treatment Hodson EM et al. Cochrane Database Syst Rev 2008: Issue 2. Art. No: CD003774.

  17. Effects of anti-CMV prophylaxis on concomitant infections 1 0.8 p = 0.03 0.6 Relative risk 0.4 p = 0.05 p < 0.00001 0.65 0.2 0.31 0.27 0 Placebo/ No reatment HSV/VZV Bacterial infections Protozoal infections Meta-analysis of 34 trials in 3850 transplant patients Hodson et al. Cochrane Database Syst Rev 2008: Issue 2. Art. No: CD003774.

  18. Ganciclovir prophylaxis reduces the incidence of acute rejection 1.0 0.8 0.6 Cumulative proportion free of acute rejection p = 0.002 0.4 0.2 Aciclovir or no prophylaxis (n = 122) Ganciclovir (n = 83) 0.0 900 90 180 270 360 450 540 630 720 810 990 1080 1170 0 Time post-transplant (days) Kidney/pancreas transplant recipients Ricart MJ et al. Nephrol Dial Transplant 2005 20 (Suppl 2):ii25–ii32.

  19. Anti-CMV prophylaxis associated with improved kidney allograft survival 100 90 Prophylaxis (n = 5426) 80 Grafts surviving (%) No prophylaxis (n = 2908) 70 60 50 0 0 1 2 3 Time (years) CTS Registry data. D+/R- kidney transplant recipients Opelz G et al. Am J Transplant 2004; 4:928-36.

  20. Anti-CMV prophylaxis is associated with significant improvement in graft survival 100 Oral ganciclovir prophylaxis (n = 73) 90 80 IV preemptive therapy (n = 65) 70 Freedom from graft loss (uncensored for death; %) 60 50 p value (Log rank test) = 0.0425 0 1 2 3 4 0 Time after transplantation (years) D+/R- kidney transplant recipients Kliem V et al. Am J Transplant 2008; 8:975-83.

  21. CMV management- conclusions • Preemptive therapy and universal prophylaxis are both effective at preventing CMV disease • Prophylaxis may also have an impact on indirect effects of CMV • Prophylaxis significantly reduces the incidence of • Concomitant infections • Acute rejections • Graft loss • All-cause mortality • Current guidelines recommend prophylaxis for all all kidney transplant recipients (except D-/R-) for at least 3 months

  22. EFFicacy of Valcyte

  23. Time to CMV disease is comparable between Valcyte and ganciclovir 100 900 mg Valcyte (n = 239) 80 1000 mg ganciclovir (n = 125) 60 Patients with no CMV disease (%) 40 20 Prophylaxis period 0 50 100 150 200 250 300 350 0 Time (days) D+/R- transplant recipients Paya C et al. Am J Transplant 2004; 4:611-20.

  24. Time to first viraemia is comparable between Valcyte and ganciclovir 100 80 900 mg Valcyte (n = 239) 60 Patients with no CMV viral load> BLQ (%) 40 1000 mg ganciclovir (n = 125) 20 Prophylaxis period 0 50 100 150 200 250 300 350 0 Time (days) BLQ = below level of quantitation ( ≥ 400 copies/mm3) D+/R- transplant recipients Paya C et al. Am J Transplant 2004; 4:611-20.

  25. The cost of Valcyte is the same as for ganciclovir Average costs of prophylaxis ($) Valcyte** Ganciclovir* * IV ganciclovir 10 mg/kg daily for 14 days, oral ganciclovir 1 g t.i.d. for 3 months ** Valcyte 900 mg q.d. for 100 days Oppenheimer F et al. Clin Transplant 2007; 21:441-8.

  26. Efficacy of Valcyte - conclusions • 900 mg Valcyte is as effective as oral ganciclovir in preventing CMV disease up to 6 and 12 months post-transplant • A simple dosing regimen (2 tablets daily – 900 mg) facilitates routine prophylaxis

  27. Valcyte dosing

  28. Reduced systemic exposure to ganciclovir increases the risk of CMV viraemia 40 Mean ganciclovir exposure with 900 mg Valcyte 46 ± 15 µg*h/ml Reduced ganciclovir exposure = Increased risk for CMV viraemia 30 Patients (%) developing CMV viraemia(>400 copies/ml) 20 10 0 <20 21-26 26-30 31-35 36-40 41-45 46-50 51-55 >56 Systemic exposure to ganciclovir(µg*h/ml) Adapted from Wiltshire H et al. Transplantation 2005; 79:1477–83. .

  29. Dosing of Valcyte for prophylaxis Paya C et al. Am J Transplant 2004; 4:611-20. Valcyte. SummaryofProductCharacteristics (April 2007 andJanuary 2008).

  30. Valcyte Powder for Oral Solution delivers equivalent systemic exposure 7 Valcyte tablet 6 Valcyte Powder for Oral Solution 5 4 Ganciclovir (g/ml) 3 2 1 0 0 4 8 12 16 20 24 Nominal time after dosing (h) Pescovitz MD et al. Transplant Proc 2007; 39:3111-6.

  31. Valcyte dosing - conclusions • Valcyte dosed at 900 mg daily, in patients with normal renal function, provides the best protection from CMV disease with the lowest risk of resistance • Valcyte Powder for Oral Solution allows for tailored dosing in patients requiring lower doses, such as patients with impaired renal function, or patients with swallowing difficulties

  32. Length of prophylaxis

  33. CMV prophylaxis • CMV prophylaxis prevents the indirect effects of CMV infection, leading to significantly improved graft and patient survival1-3 • CMV prophylaxis was traditionally given for 100 days4-7 • - At the time, 100 days was considered to the correct length of therapy for oral prophylaxis • Current immunosuppressive regimens may provide greater immunosuppression for a longer period post-transplant • CMV viraemia develops in many patients shortly after cessation of 100 days prophylaxis7 1. Hodson EM et al. Cochrane Database Syst Rev 2008: Issue 2. Art. No: CD00377. 2. Opelz G et al. Am J Transplant 2004; 4:928-36. 3. Kliem V et al. Am J Transplant 2008; 8:975-83. 4. Balfour HH et al. N Engl J Med 1989; 320:1381-88. 5. Winston DJ et al. Lancet 1995; 346:69-74. 6. Gane E et al. Lancet 1997; 350:1729-33. 7. Paya C et al. Am J Transplant 2004; 4:611-20.

  34. 100 80 60 40 20 Viraemia occurs after the cessation of prophylaxis Viraemia on treatmentGanciclovir 10.4% Valcyte 2.9% p < 0.01 900 mg Valcyte (n = 239) Patients with no CMV viral load> BLQ (%) 1000 mg Ganciclovir (n = 125) 6 months 12 months Prophylaxis period 0 0 20 60 100 200 300 400 Time (days) BLQ = below level of quantitationSet at ≥ 400 copies/mm3 D+/R- transplant recipients Paya C et al. Am J Transplant 2004; 4:611-20.

  35. Late CMV infection occurs after cessation of prophylaxis • CMV antigenaemia developed in 51% of patients, but only after cessation of prophylaxis 1.0 0.8 D+/R+ (n = 15) Fraction antigenemia-free 0.6 Period of oral ganciclovir prophylaxis D+/R- (n = 26) 0.4 0.2 0 100 150 0 200 50 Time post-transplant (days) Murray BM, Subramaniam S. Transplant Infect Dis 2004; 6:3-9.

  36. Extended prophylaxisreducestheincidenceof CMV infection p ≤ 0.01 - 77% Patients with CMV infection (%) 12 weeks 24 weeks Length of prophylaxis Doyle AM et al. Transplantation 2006; 81:1106-11.

  37. Impact on varying duration of prophylaxis on CMV infection and disease in lung transplantation 100 365 days 80 270 days 180 days 60 Patients free from CMV infection and disease (%) 100-179 days 40 <100 days 20 30 120 90 180 60 150 Valcyte cessation Time (days) p< 0.02 for 180, 270 or 365 days vs either < 100 days or 100-179 days group p = NS for 180 vs 270 vs 365 days Valcyte is currently approved for 100 days prophylaxis in lung transplant recipients Zamora MR et al. Am J Transplant 2004; 4:1635-42.

  38. Retrospective, single-centre study Late CMV reduced by extended Valcyte prophylaxis in lung transplantation Lung transplantation i.v. ganciclovir *4 doses of CMV IVIg Valcyte Valcyte * * * * Days: 0 1 7 14 21 3 12 Months: 0 Group A: 3 months prophylaxis with Valcyte 900 mg/day Group B: 12 months prophylaxis with Valcyte 900 mg/day Valcyte is currently approved for 100 days prophylaxis in lung transplant recipients Jaksch MD et al. J Heart Lung Transplant 2009; 28:670-5.

  39. 12 months prophylaxis significantly reduces the incidence of CMV disease 12 months Valcyte (n = 17) 100 Valcyte cessation 80 p < 0.05 Valcyte cessation 60 3 months Valcyte (n = 15) Patients (%) 40 20 0 0 90 180 270 360 450 540 630 720 Time (days) Valcyte is currently approved for 100 days prophylaxis in lung transplant recipients Jaksch MD et al. J Heart Lung Transplant 2009; 28:670-5.

  40. Reduced incidence of CMV viraemia with 12 months prophylaxis 100 12 months Valcyte (n = 17) Valcyte cessation 80 60 Patients (%) p < 0.05 Valcyte cessation 40 3 months Valcyte (n = 15) 20 0 0 90 180 270 360 450 540 630 720 Time (days) Valcyte is currently approved for 100 days prophylaxis in lung transplant recipients Jaksch MD et al. J Heart Lung Transplant 2009; 28:670-5.

  41. Length of prophylaxis - conclusions • Despite effective prophylaxis for 100 days, many patients develop CMV infection after cessation of therapy • Numerous studies have suggested that extended prophylaxis may be beneficial • The IMPACT study shows that prophylaxis for 200 days with 900 mg Valcyte significantly reduces the incidence of CMV disease and CMV viraemia compared to 100 days in kidney transplant patients

  42. The impact study

  43. IMPACT – Study design and endpoints • Study of efficacy and safety of 100 days vs 200 days prophylaxis with 900 mg Valcyte in CMV D+/R- kidney transplant recipients • Primary endpoint • CMV syndrome or disease within the first 12 months post-transplantation • Main secondary endpoints • Time to CMV disease • Incidence of viraemia • Acute rejection • Graft loss • Adverse events Humar A et al. Manuscript in preparation.

  44. IMPACT – Study design Valcyte – 100 days Placebo Valcyte 900 mg qd* Valcyte – 200 days Valcyte 900 mg qd* Valcyte 900 mg qd* Randomisation 100 days 12 24 200 days months post-transplant n = 326 randomised * qd = once daily; dose adjusted for renal function Humar A et al. Manuscript in preparation.

  45. IMPACT – CMV definition • CMV disease = CMV syndrome and/or tissue invasive CMV • CMV syndrome was defined as CMV viraemia identified by quantitative PCR and at least one of the following: • A fever ≥ 38°C • Severe malaise • Leukopenia on two successive measurements separated by at least 24 hours • Atypical lymphocytosis of ≥ 5% • Thrombocytopenia • Elevation of hepatic transanimases to ≥ 2 x ULN Humar A et al. Manuscript in preparation.

  46. IMPACT – Baseline demographics Humar A et al. Manuscript in preparation.

  47. IMPACT – 200 days prophylaxis reduces the incidence of CMV disease p < 0.001 - 56% Patients with confirmed CMV disease at 12 months (%) (n = 163) (n = 155) Humar A et al. Manuscript in preparation.

  48. IMPACT – 200 days Valcyte prophylaxisprolongs time to CMV disease 1.0 Valcyte - 200 days 0.8 p < 0.001 0.6 Valcyte - 100 days Event-free probability 0.4 0.2 0 Study day 0 60 120 180 240 300 360 Humar A et al. Manuscript in preparation.

  49. IMPACT – The number needed to treat (NNT) to prevent one case of CMV disease is low • 200 days Valcyte is associated with a reduced risk of CMV disease • Relative risk reduction = 56.3% • Absolute risk reduction = 20.7% • To avoid one additional patient contracting CMV disease • Only approximately 5 patients need to be treated with extended prophylaxis • NNT = 4.83 Humar A et al. Manuscript in preparation.

  50. Comparison of CMV disease in IMPACT and PV16000 • IMPACT and PV16000 were conducted 5 years apart with a different medical practice • In IMPACT, monoclonal antibodies and antithymocyte immunoglobulins were more frequently used • The CMV definition used in the two studies was different • PV16000: 2 CMV-positive events 24 hours apart with fever • IMPACT: 1 CMV-positive event and 1 clinical symptom Paya C et al. Am J Transplant 2004; 4:611-20; Humar A et al. Manuscript in preparation.

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