Welcome and. Introductions

Transcription

1 1 Welcome and Introductions 2 2

2 Levels of Evidence Quality of evidence on which recommendations are based: Grade I II-1 II-2 Definition Evidence from at least one properly randomized, controlled trial Controlled trials without randomization Cohort or case-control analytic studies II-3 Multiple time series or dramatic uncontrolled experiments (including data on new therapies that were not collected in a randomized fashion) III Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees Adapted from CDC 1 Each rating is applied to a single reference in the lecture, not to the entire body of evidence on a topic. 1. MMWR Recomm Rep. 1999;48(RR-10):1-59, Updates on Prophylaxis Camille Nelson Kotton, MD, FIDSA Harvard Medical School Massachusetts General Hospital 4 4

3 Disclosures Consultant for clinical trial design: Cellestis, T2 Biosystems She discusses non FDA-approved or investigational use of prolonged use of valganciclovir and off-label use of diagnostics 5 Outline Risk factors for CMV Approaches to prevention Chemoprophylaxis with antivirals Updates on: Guidelines Data on duration of therapy New pediatric uses and formulations 6

4 Audience Question A 50-year year-old woman is s/p renal transplant, CMV D+/R-; ; receives basiliximab induction, tacrolimus, prednisone, mycophenolate mofetil. What would you do at your center to prevent CMV? A. Monitor weekly CMV PCR/antigenemia and treat if tests turn positive B. Give valganciclovir for 3 months C. Give valganciclovir for 6 months D. Nothing; treat if she develops disease 7 Audience Response A. Monitor weekly CMV PCR/antigenemia and treat if tests turn positive 8.8% B. Give valganciclovir for 3 months 33.4% C. Give valganciclovir for 6 months 53.6% D. Nothing; treat if she develops disease 4.1% Percentage 8

5 CMV Spectrum CMV Infection CMV Syndrome CMV Disease Asymptomatic Fevers, Neutropenia Organ Disease All represent replicating CMV virus 9 Who Is at Risk? Donor/Recipient Factors CMV serology status of donor/recipient (D+/R-) Organ transplanted Lung/small bowel > pancreas, heart > liver, kidney Patient factors (age, comorbidities) Exogenous immunosuppression induction, induction, routine, rejection High-volume transfusion of blood products CD4+, CD8+ T-cell T (general and specific), NK cell, B-cellB Polymorphisms of Toll-like like receptor-2 2 and Toll-like like receptor-4 Deficiencies of complement proteins and mannose-binding lectin Viral Factors Replication dynamics Co-infection with other viruses (EBV, HHV-6, HHV-7) Immunologic evasion Viral heterogeneity Humar A et al. Am J Transplant. 2009;9(suppl 4):S78-S86. 10

6 Paradigms for Prevention Universal (chemo)prophylaxis Administration of antiviral medication to all at-risk patients (or a specified subset) starting < 10 days after transplant for a defined duration Preemptive therapy Patients monitored regularly and treatment dose antiviral medications begun if positive, optimally before symptoms 11 AJT

7 Chemoprophylaxis Recommendations (AST/TTS) The duration of prophylaxis in D+/R- should be generally between months (I) Decision may depend on degree of immunosuppression 6 months (minimum) is recommended for lung (II-2) and small intestine (III) SOTs Some centers add CMV immunoglobulin (CMV Ig) for heart, lung, and bowel transplants (III) AST: Humar A et al. Am J Transplant. 2009;9(suppl 4):S78-S86. TTS: Kotton CN et al. Transplantation. 2010;89: Chemoprophylaxis Recommendations Kidney: valganciclovir, IV or oral ganciclovir, or valacyclovir (I) Pancreas (including kidney/pancreas): valganciclovir and IV or oral o ganciclovir (II) Liver: IV or oral ganciclovir (I) or valganciclovir (III) In a subgroup analysis, valganciclovir was associated with a higher her rate of tissue-invasive invasive disease after liver transplant In one survey, it was most commonly used drug for CMV prevention after liver transplant The FDA has a caution against the use of valganciclovir in liver transplant recipients, but many experts still recommend its use in this setting Heart: valganciclovir, IV or oral ganciclovir (II), ± CMV Ig (III) Lung: valganciclovir or IV ganciclovir (II), ± CMV Ig (III) Intestinal: valganciclovir, IV or oral ganciclovir, ± CMV Ig (III) Kotton CN et al. Transplantation. 2010;89:

8 Late CMV Disease occurring after the discontinuation of prophylaxis Found in all studies evaluating chemoprophylaxis PV16000 study 1 : occurred in 18+% at 12 months In other recent trials in D+R- kidney transplant recipients, late-onset disease occurred in 29% 2 and 37% 3 Determinants of late-onset CMV disease: D+/R- Ongoing significant immunosuppression Allograft rejection Lack of development of significant CMV-specific, cell-mediated immunity Immunologic/genetic factors 1. Paya C et al. Am J Transplant. 2004;4: Arthurs SK et al. Clin Infect Dis. 2008;46: Humar A et al. Am J Transplant Mar 26 [epub ahead of print]. 15 CMV Prophylaxis Recommendations for Kidney Transplant Recipients (except for D-/RD /R- patients) Chemoprophylaxis with oral ganciclovir or valganciclovir For at least 3 months after transplantation (1B) For 6 weeks after treatment with a T-cellT cell depleting antibody (1C) KDIGO Levels of Evidence 1=Recommend A=High quality of evidence 2=Suggest B=Moderate quality of evidence C=Low quality of evidence D=Very low quality of evidence KDIGO Transplant Work Group. Am J Transplant ;9(suppl 3):S1-S157. S

9 The IMPACT Trial: Improved Protection Against Cytomegalovirus in Transplantation 17 IMPACT Randomization (n=326) Allocated 200 day valganciclovir prophylaxis (n=160) Received treatment and had post- randomization safety assessment (safety population; n=156) Received treatment and D+/R- (ITT population; n=155) Allocated 100 day valganciclovir prophylaxis (n=166) Received treatment and had post- randomization safety assessment (safety population; n=164) Received treatment and D+/R- (ITT population; n=163) Withdrew from treatment (n=33) Adverse events (n=17) Insufficient treatment response (n=4) Refused treatment (n=7) Other (n=5) Withdrew from study (n=25) Withdrew from treatment (n=70) Adverse events (n=10) Insufficient treatment response (n=47) Refused treatment (n=4) Other (n=9) Withdrew from study (n=26) Humar A, Lebranchu Y, Vincenti F, Blumberg EA, Punch JD, Limaye AP, Abramowicz D, Jardine AG, Voulgari AT, Ives J, Hauser IA, Peeters P. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant. 2010;10: Figure 1. Included with permission of John Wiley & Sons, Ltd. 18

10 IMPACT (Cont d) Time to CMV disease days days Time to CMV viremia Serum creatinine Humar A, Lebranchu Y, Vincenti F, Blumberg EA, Punch JD, Limaye AP, Abramowicz D, Jardine AG, Voulgari AT, Ives J, Hauser IA, Peeters P. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant. 2010;10: Figures 2, 3, and 5. Included with permission of John Wiley & Sons, Ltd. 19 IMPACT: Conclusions Extending valganciclovir prophylaxis (900 mg once daily, renally dosed) to 200 days in high- risk kidney allograft recipients significantly reduces the incidence of CMV disease and viremia compared with 100 days Higher rates of leukopenia (38% vs 26%) The number needed to treat to avoid one additional patient with CMV disease up to 12 months posttransplant is ~ 5 Humar A et al. Am J Transplant. 2010;10:

11 Recommended Regimens for CMV Prevention in Children Risk Categories Recommended Regimen(s)* Alternative Regimen(s)* Lower (R+ renal transplants) Intermediate (R+ liver 2 and heart transplants) Higher (All D+/Rtransplants and R+ lung and small bowel 3 transplants) IV ganciclovir 2 wk followed by PO valganciclovir 1 10 wk IV ganciclovir 12 wk IV ganciclovir 12 wk IV ganciclovir 12 wk Some centers use 2-4 wk of prophylaxis IV ganciclovir 2 wk followed by PO valganciclovir 1 10 wk Some centers use 2-4 wk of prophylaxis Some centers use 2-4 wk of prophylaxis, and some centers extend prophylaxis to 6 mo Some experts recommend CMV immunoglobulin for intermediate and higher h risk recipients, but there are no randomized studies indicating that CMV immunoglobulin is any better than ganciclovir r or valganciclovir alone. When used, it is more consistently given to DR small-bowel, lung, and heart transplant recipients. The regimens above do not imply an exclusive course of action. CMV DR patients are excluded given the low risk (5%) of CMV disease. 1. Assumes the child is able to take oral medication; otherwise the default option is IV ganciclovir. 2. Some experts place R liver recipients in the lowest risk group. 3. Some experts place R small-bowel recipients in the intermediate risk group. *See text of reference for doses Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Snydman DR, Allen U, Humar A, on behalf of The Transplantation Society International CMV Consensus Group. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation. 2010;89: Table 4. Included with permission from Wolters Kluwer Health. 21 Evaluated pharmacokinetics and safety of valganciclovir solution or tablets in 63 pediatric SOTs, up to 100 days No clear relationship to body size, renal f(x) Treatment was well tolerated; safety profile similar to that in adults 22

12 Pediatric Prophylaxis 2009 FDA approval of valganciclovir solution (50 mg/ml) for those 4 months 16 years after kidney and heart transplant 1 Pediatric dose (mg) = 7 x BSA x CrCl (calculated using a modified Schwartz formula) 1,2 Doses may be higher than expected in a child with an adult kidney 1. Valcyte [package insert]. South San Francisco, CA: Genentech; Vaudry W et al. Am J Transplant. 2009;9: Updates on Preemptive Therapy Atul Humar, MD University of Alberta, Canada 24 24

13 Disclosures Advisory board for scientific information: Roche Laboratories, ViroPharma, Inc Consultant for clinical trial design: ViroPharma, Inc Grant recipient/research support: Dr Humar is the principal investigator on grants from Astellas and Roche, and funds are paid to the University of Alberta He discusses non FDA-approved or investigational use of alternative treatments for CMV, including foscarnet, cidofovir, and maribavir PREEMPTIVE THERAPY CMV disease TEST _ weeks Could have initiated preemptive therapy 26

14 Advantages: Preemptive Therapy Minimizes drug exposure This may potentially decrease toxicity and costs Theoretically lowers risk of resistance Less late-onset disease: may allow development of cell-mediated immune response Humar A et al. Am J Transplant. 2009;9(suppl 4):S78-S86. Kotton CN et al. Transplantation. 2010;89: CELL-MEDIATED IMMUNITY DEVELOPMENT PROPHYLAXIS VS PREEMPTIVE THERAPY Interferon γ (IU/mL) Time (days) Prophylaxis Kumar D et al. Am J Transplant. 2009;9: Interferon γ (IU/mL) CMV Viremia = preemptive Valganciclovir ganciclovir Preemptive Monitoring Time (days) 28

15 Preemptive Therapy: Disadvantages Disadvantages: Logistically more difficult to coordinate May be unsuccessful in preventing progression to active disease in high-risk patients due to rapid doubling time May not eliminate the indirect effects of CMV Humar A et al. Am J Transplant. 2009;9(suppl 4):S78-S86. Kotton CN et al. Transplantation. 2010;89: Preemptive Therapy: Treatment Logistics What drug, how long, what dose? IV ganciclovir definitely works for treating CMV viremia BUT a real Pain! Oral ganciclovir not an option RESISTANCE, FAILURE Can I use oral valganciclovir in my preemptive strategy? YES! 30

16 Study Design: VICTOR Induction Day 0 to 20 Maintenance Day 21 to 49 Follow-up Phase Month 3 to 12 CMV disease Oral valganciclovir 900 mg BID Oral valganciclovir 900 mg QD No study medication IV ganciclovir 5 mg/kg BID Multicenter noninferiority study 42 centers: 25 in Europe, 9 in Latin America, 4 in India, 2 in Canada, 2 in Australia and New Zealand Asberg A et al. Am J Transplant. 2007;7: Cytomegalovirus Clearance Kinetics CMV load (copies/ml) Oral valganciclovir IV ganciclovir Treatment phase 10 Days Valganciclovir (N) IV Ganciclovir (N) Asberg A, Humar A, Rollag H, Jardine AG, Mouas H, Pescovitz MD, Sgarabotto D, Tuncer M, Noronha IL, Hartmann A, on behalf of the VICTOR Study Group. Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2007;7: Figure 2. Included with permission of John Wiley & Sons, Ltd. 32

17 Suggested Algorithm for Preemptive Therapy Validate appropriate threshold for site-specific assay (NAT or Ag [II-2]) Select appropriate population to employ preemptive therapy (I) Test patients weekly at weeks 1-12 posttransplant (II-2) Assay positive at threshold Start valganciclovir or IV ganciclovir at treatment dose (I) No positive assay or threshold not reached. Stop testing at week 12 (II-2) Treat until negative threshold achieved (II-2) Resume weekly monitoring until week 12 (II-2) Humar A, Snydman D, and the AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009;9(suppl 4):S78-S86. Figure 1. Included with permission of John Wiley & Sons, Ltd. 33 Preemptive Therapy: Meta-Analyses Study Author Strippoli GF et al. Cochrane Database Syst Rev Jan 25;(1):CD Kalil et al. Ann Intern Med ;143: Small et al. Clin Infect Dis. 2006;43: CMV Disease Relative Risk (95% CI) 0.29 ( ) 0.28 ( ) 0.30 ( ) All Cause Mortality Relative Risk (95% CI) 1.23 ( ) 0.94 ( ) 0.94 ( ) 34

18 CMV Replication: Rapid Viral Doubling Time in Some Patients Viral Load y = y 0 e ax Doubling time = ln2/a Average DT= 1-2 days For a preemptive strategy to work, weekly monitoring with a sensitive assay is required in D+/Rpatients who exhibit a rapid doubling time Detection threshold Time (days) Emery V et al. Lancet. 2000;355: Preemptive Therapy vs Prophylaxis There are very few comparative randomized trials comparing preemptive therapy vs prophylaxis In 2 separate trials, Khoury et al (n=98 kidney transplant) and Reischig et al (n=70 kidney transplant) randomized to preemptive therapy vs prophylaxis Equally effective in preventing CMV disease Kliem et al: randomized 148 renal transplant patients to preemptive therapy (IV ganciclovir) vs prophylaxis (3 months oral ganciclovir) Long-term graft survival at 4-years 4 posttransplant was significantly improved in the prophylaxis group Khoury JA et al. Am J Transplant. 2006;6: Kliem V et al. Am J Transplant. 2008;8: Reischig T et al. Am J Transplant. 2008;8:

19 Preemptive Therapy vs Prophylaxis: Long-Term Outcome 100 Freedom from Graft Loss (Uncensored for Death) [%] N=130 Graft Loss (Failure Rates) ITT D+/R- D+/R+ D-/R+ O-GP [%] IV-PT [%] O-GP IV-PT P Value (Log rank test) Years After Transplantation ITT=Intent-to-treat IV-PT=Intravenous preemptive therapy O-GP=Oral ganciclovir prophylaxis Kliem V, Fricke L, Wollbrink T, Burg M, Radermacher J, Rohde F. Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: results of a randomized clinical trial. Am J Transplant. 2008;8: Figure 2B. Included with permission of John Wiley & Sons, Ltd. 37 HYBRID APPROACHES CMV disease TEST _ _ + + _ months Prophylaxis Could have initiated preemptive therapy THIS STRATEGY REQUIRES MONITORING AT VERY FREQUENT INTERVALS AFTER STOPPING PROPHYLAXIS Humar A et al. Am J Transplant. 2004;4:

20 Prophylaxis vs Preemptive Therapy Prophylaxis Preemptive Evidence of efficacy Indirect effects/mortality ++ + Other viruses + for some? Late-onset disease ++ - Resistance Low Low Adapted from Kotton CN et al. Transplantation. 2010;89: GUIDELINES Kidney, Liver, Pancreas, and Heart Ease ++ +/- D+/R- Universal prophylaxis preferred (II/III) Valganciclovir (FDA caution in livers but some experts still use), oral ganciclovir, IV ganciclovir, or valacyclovir (kidney) (I, except II-2 2 for pancreas) Start by day 10 until months (I) Humar A et al. Am J Transplant. 2009;9(suppl 4):S78-S86. Kotton CN et al. Transplantation. 2010;89:

21 GUIDELINES Kidney, Liver, Pancreas, and Heart (Cont d) R+ Patients: Prophylaxis: ganciclovir, valganciclovir (FDA caution in livers), valacyclovir (kidneys) (I/II) or Preemptive therapy pp65 antigen test or molecular diagnostic test (II-2); IV ganciclovir or valganciclovir for positive test (I) Humar A et al. Am J Transplant. 2009;9(suppl 4):S78-S86. Kotton CN et al. Transplantation. 2010;89: Audience Question A 50-year year-old woman is s/p renal transplant, CMV D+/R-; ; receives basiliximab induction, tacrolimus, prednisone, mycophenolate mofetil. What would you do now to prevent CMV? A. Monitor weekly CMV PCR/antigenemia and treat if tests turn positive B. Give valganciclovir for 3 months C. Give valganciclovir for 6 months D. Nothing; treat if she develops disease 42

22 Audience Response A. Monitor weekly CMV PCR/antigenemia and treat if tests turn positive 8.4% B. Give valganciclovir for 3 months 23.6% C. Give valganciclovir for 6 months 65% D. Nothing; treat if she develops disease 3% Percentage Interactive Case Study: Pediatric Transplant Recipient Michael Green, MD, MPH Division of Infectious Diseases Children s Hospital of Pittsburgh 44 44

23 Disclosures Advisory board for scientific information: Bristol-Myers Squibb He discusses non FDA-approved or investigational use of CMV loads in pediatric organ transplants CMV Prevention and Pediatric SOT: What Does the 2nd Edition of the AST ID Guidelines Say? 7-year-old heart-lung transplant recipient Thymoglobulin induction CMV D+/R- What should you do? 1. Treat this child with multiple doses of CMV-IVIG 2. Monitor the child s s CMV load in the blood and start antiviral therapy if and when the CMV load becomes elevated 3. Start the child on IV ganciclovir and continue for months 4. Start the child on oral valganciclovir and continue for months 5. A combination of the above 46

24 Audience Response 1. Treat this child with multiple doses of CMV-IVIG 1.4% 2. Monitor the child s CMV load in the blood and start antiviral therapy if and when the CMV load becomes elevated 3.7% 3. Start the child on IV ganciclovir and continue for 3-6 months 19.7% 4. Start the child on oral valganciclovir and continue for 3-6 months 44.1% 5. A combination of the above Percentage 31.2% Prophylaxis vs Preemptive Therapy Feature Prophylaxis Preemptive Therapy Efficacy Ease Late-onset disease Yes: large randomized trials Relatively easy to coordinate A potential problem Yes: smaller trials; fewer D+/R- More difficult to coordinate; test thresholds not standardized Much less commonly seen Cost Higher drug costs Higher laboratory costs Toxicity Potential for greater drug toxicity (myelosuppression) Potential for less drug toxicity with shorter courses of antivirals Indirect effects (graft loss, mortality and opportunistic infections) Consistent and positive impact based on metaanalyses and limited comparative trials Very limited data that preemptive therapy affects indirect effects Humar A, Snydman D, and the AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009;9(suppl 4):S78-S86. Table 1. Included with permission of John Wiley & Sons, Ltd. 48

25 Lung and Heart-lung Transplant Recipients Limited randomized clinical trial data for lung transplant recipients Considered to be at the highest risk for CMV disease Options for D+/R- lung transplant recipients Prophylaxis with IV ganciclovir (5 mg/kg/day) or oral valganciclovir (900 mg/day) for 6 months (II-2) Humar A et al. Am J Transplant. 2009;9(suppl 4):S78-S Prevention and Treatment (Pediatrics) Recommendations for the use of prophylaxis and preemptive therapy y in adult transplant recipients can be applied to pediatric organ transplant nt recipients with the following exceptions: 1) There are limited data on the efficacy of preemptive therapy in pediatric organ transplant recipients 2) Treatment and prevention strategies mainly consist of IV ganciclovir especially in younger children. Data on the dosing and efficacy of oral ganciclovir and oral valganciclovir in children are currently lacking 3) The risk of catheter-associated associated bloodstream infections can influence the duration of IV ganciclovir in some settings. Length of prophylaxis is also affected by factors that vary among transplant centers (I) 4) There is no single standard of care for the duration of prophylaxis in this context. Most transplant centers administer IV ganciclovir prophylaxis for a minimum of 14 days to 3 months (II-2) Humar A et al. Am J Transplant. 2009;9(suppl 4):S78-S86. 50

26 The Story Continues The transplant team was unaware of the recommendations in the AST ID Guidelines and made a decision to monitor our patient s s CMV viral load using a quantitative CMV PCR assay to inform preemptive therapy. Results and clinical decisions are shown in the next slide. 51 CMV Loads and Preemptive Treatment Days Post-Tx CMV Load Treatment 7 ND 14 < IV Ganciclovir IV Ganciclovir IV Ganciclovir IV Ganciclovir IV Ganciclovir Oral Valganciclovir Oral Valganciclovir ??? 52

27 Although the CMV load has climbed, the patient remains clinically asymptomatic. What would you do now? 1. Increase the dose of oral valganciclovir 2. Switch back to IV ganciclovir 3. Add a dose of CMV-IVIG 4. Switch to IV foscarnet 5. Order CMV resistance testing 6. A combination of the above choices 53 Audience Response 1. Increase the dose of oral valganciclovir 7.5% 2. Switch back to IV ganciclovir 20.2% 3. Add a dose of CMV-IVIG 8.5% 4. Switch to IV foscarnet 3.6% 5. Order CMV resistance testing 15% 6. A combination of the above choices 45.3% Percentage 54

28 Our Story Continues The child was switched back to IV ganciclovir and given a dose of CMV-IVIG. He remained clinically asymptomatic. His immunosuppression was reviewed and was mildly reduced. Resistance testing was ordered at this time. 55 CMV Loads and Preemptive Treatment (Cont d) Days Post-Tx CMV Load Treatment IV Ganciclovir + CMV-IVIG Resistance Testing Sent IV Ganciclovir IV Ganciclovir IV Ganciclovir IV Ganciclovir IV Ganciclovir IV Ganciclovir Resistance Results Available Resistance Testing Results: A594V Mutation 56

29 CMV Resistance: A Complicated Story Chou S. J Infect Dis. 2002;185: Chou S. Cytomegalovirus UL97 mutations in the era of ganciclovir and maribavir. Rev Med Virol. 2008;18: Figure 3. Included with permission of John Wiley & Sons, Ltd. 57 A Happy Ending Based on the finding of the A594V mutation, our patient was taken off IV ganciclovir and started on IV foscarnet and given an additional dose of CMV-IVIG The CMV load fell from 3800 to undetectable levels over the next month The patient remained asymptomatic and was taken off of foscarnet after two serial undetectable results 58

30 Lessons Learned Current recommendations support the use of chemoprophylaxis for prevention of CMV in high-risk D+/R- children undergoing organ transplantation (III) Persistence and/or increase in viral load despite ongoing use of ganciclovir should raise the question of antiviral resistance (III) Our understanding of antiviral resistance in CMV is evolving and increasingly complex Consultation with an infectious disease specialist can help to optimally determine the best therapeutic approach for patients with potential resistance Humar A et al. Am J Transplant. 2009;9(suppl 4):S78-S86. Kotton CN et al. Transplantation. 2010;89: Interactive Case Study: Adult Transplant Recipient Atul Humar, MD University of Alberta, Canada 60 60

31 CASE 32-year year-old female kidney transplant recipient, diabetes mellitus. CMV D+/R-; tacrolimus, prednisone, mycophenolate mofetil. Creatinine 1.2 mg/dl Receives 3 months of prophylaxis with valganciclovir Presents at 4 months post-transplant transplant with increased malaise, myalgias/arthralgias, and occasional loose stools. Creatinine 1.4 mg/dl, WBC 3.4 CMV viral load 32,000 copies/ml (Cobas Amplicor) You diagnose this patient with CMV viral syndrome 61 What Would You Do? 1. Initially treat with IV ganciclovir followed by oral valganciclovir 2. Treat for the full course with IV ganciclovir therapy 3. Treat with oral valganciclovir 4. Oral or IV therapy + CMV immunoglobulin 62

32 Audience Response 1. Initially treat with IV ganciclovir followed by oral valganciclovir 37.9% 2. Treat for the full course with IV ganciclovir therapy 16.3% 3. Treat with oral valganciclovir 26.8% 4. Oral or IV therapy + CMV immunoglobulin 19% Percentage 63 CMV Treatment Treat with full dose IV ganciclovir or oral valganciclovir (I) Monitor CMV viral load or antigenemia once weekly while on therapy (II-1) Generally, continue treatment until undetectable (II-1) The additional benefit of CMV Ig in this setting unknown (III) Kotton CN et al. Transplantation. 2010;89:

33 CMV DISEASE When to not use oral therapy Life-threatening or severe CMV disease (III) Potential problems with absorption significant diarrhea, CMV enteritis (III) Suspected ganciclovir-resistant resistant CMV (III) Caution with children (III) Kotton CN et al. Transplantation. 2010;89: This Patient Is Treated With Oral Valganciclovir 900 mg po BID for CrCl > 60 ml/min CMV Load During Treatment Viral Load (copies/ml) Time (weeks) 66

34 HOW LONG TO TREAT? Asberg A, Humar A, Rollag H, Jardine AG, Mouas H, Pescovitz MD, Sgarabotto D, Tuncer M, Noronha IL, Hartmann A, on behalf of the VICTOR Study Group. Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2007;7: Figure 3. Included with permission of John Wiley & Sons, Ltd. 67 What Would You Do With the Immunosuppression in This Patient? Tacrolimus level ng/ml; prednisone 5 mg; mycophenolate mofetil 750 mg BID 1. No change in immunosuppression 2. Lower mycophenolate mofetil dose 3. Discontinue mycophenolate mofetil 4. Lower tacrolimus 5. Combination of choices 2 and 4 68

35 Audience Response 1. No change in immunosuppression 14.2% 2. Lower mycophenolate mofetil dose 34.9% 3. Discontinue mycophenolate mofetil 13.4% 4. Lower tacrolimus 12.2% 5. Combination of choices 2 and % Percentage 69 WHAT TO DO WITH IMMUNOSUPPRESSION??? Lack of clear data to guide us Always lower immunosuppression for severe / life-threatening CMV disease (II-2) 1,2 Always lower immunosuppression for suspected ganciclovir resistance (III) 1,2 Based on the VICTOR study data: Dual, as compared to triple, immunosuppressive therapy showed an OR of 2.55 (P=0.002) for early CMV clearance (Day 21). Also low blood concentrations of calcineurin inhibitors were associated with w higher OR of 5.53 (P=0.045) for early clearance 3 BUT No effect of immunosuppression load was seen on ultimate rates of viral eradication or recurrence 3 1. Humar A et al. Am J Transplant. 2009;9(suppl 4):S78-S Kotton CN et al. Transplantation. 2010;89: Asberg A et al. Am J Transplant. In press. 70

36 CMV Recurrence After a course of treatment watch for recurrence 1 Clinical recurrence: ie, symptoms: 15.1% Virological recurrence: ie, viremia +/- symptoms: 30% After treatment can consider 2-3 Close clinical follow-up Virologic monitoring (III) Secondary prophylaxis for months (II-3) 1. Asberg A et al. Am J Transplant. 2009;9: Humar A et al. Am J Transplant. 2009;9(suppl 4):S78-S Kotton CN et al. Transplantation. 2010;89: Questions and Answers Panel Discussion 72 72