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CMV and Herpesviruses Michael Boeckh, M.D. Fred Hutchinson Cancer Research Center

CMV and Herpesviruses Michael Boeckh, M.D. Fred Hutchinson Cancer Research Center University of Washington Seattle, WA, USA. Human Cytomegalovirus. Beta herpesvirus Seroprevalence 50-95% Establishes latency Sites of latency Mononuclear cells Polymorphonuclear cells Tissue (e.g. lung ).

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CMV and Herpesviruses Michael Boeckh, M.D. Fred Hutchinson Cancer Research Center

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  1. CMV and Herpesviruses Michael Boeckh, M.D. Fred Hutchinson Cancer Research Center University of Washington Seattle, WA, USA

  2. Human Cytomegalovirus • Beta herpesvirus • Seroprevalence 50-95% • Establishes latency • Sites of latency • Mononuclear cells • Polymorphonuclear cells • Tissue (e.g. lung )

  3. CMV Seroprevalence in the US Staras et al. Clin Inf Dis, 2006

  4. Transmission of CMV • Saliva • Toddlers • Blood products • Transplanted organs • Breast milk • Trans-placental • Sexual contact • Semen • cervical secretion

  5. CMV Clinical Disease in Healthy Subjects • Mononucleosis • Hepatitis • Meningoencephalitis • Myocarditis • Interstitial pneumonia

  6. Impact of CMV in Immunocompromised Hosts Solid Organ Transplant Disease (Syndrome, Hepatitis, Pneumonia etc.) Other Infections Hospitalization Donor Pool Rejection HIV Disease (Retinitis, GI, CNS etc.) Hospitalization Blindness Mortality Quality of Life Stem Cell Transplant Disease (Pneumonia, GI Disease, Graft Failure etc.) Mortality Hospitalization Donor Pool Other infections ? GvHD Treatment- or Prophylaxis-Related Adverse Events

  7. Congenital CMV • Acquisition during pregnancy • 0.2-2.2% of life birth • Appr. 105 symptomatic • High morbidity of disease • Leading cause of CNS maldevelopment in children • Hearing loss • Mental retardation • Jaundice • Microcephaly • Seizure • Long-term sequelae

  8. CMV Pneumonia in HCT Recipients 1970s and early 1980s: CMV disease is the leading infectious cause of death after HCT 85-90% fatality rate

  9. Time to CMV Reactivation and Disease after HCT Any CMV AG/DNA = Reactivation CMV Disease

  10. o o o o o o o -7 0 7 14 21 28 35 42 49 56 63 70 CMV Viral Load Endpoints Preemptive Antiviral Treatment 50 peak 40 pp65 AG/DNA CMV viral load 30 Area Under the Curve (AUC) 20 Initial Load (Any Reactivation) 10 0 Days after Transplantation

  11. CMV Disease • Pneumonia • Gastrointestinal disease • Retinitis • Encephalitis • Hepatitis • Marrow suppression • Immunosuppressive effects • Rejection • GvHD

  12. Late CMV Disease in HCTClinical Manifestations < Day 100 >Day 100 Retinitis Marrow failure Encephalitis Sinusitis Cystitis Boeckh & Marr 2002

  13. CMV: Current IssuesTransplantation Drug toxicity HCT > SOT Survival disadvantage of seropositive patients undergoing URD/TCD Tx Mainly HCT Late Disease HCT = SOT Drug resistance SOT > HCT

  14. Pre-emptive Antigenemia DNA/RNA Prophylaxis -7 0 7 14 21 28 35 42 49 56 63 70 Current Prevention StrategiesCMV 10 Granulocytes 1 0.1 Days after Transplantation

  15. CMV Prevention Strategies Prophylaxis Indirect Effects Preemptive Therapy Direct Effects

  16. CMV Prevention in HCT RecipientsHistory Preemptive Therapy Prophylaxis 1985 1990 1995 2000

  17. Preemptive Therapy Antiviral Drug PCR, pp65 AG Pp67 mRNA Time RTC Ganciclovir + Foscarnet + Cidofovir not tested Valganciclovir pilot study

  18. Start of Ganciclovir • Based on • Threshold correlating with disease • In vivo replication dynamics • Highly immunosuppressed patients have a shorter replication time

  19. Start of Ganciclovir • Antigenemia: low/moderate risk CMV D-/R- Autologous > 1 mg/kg 1/slide Autologous < 1 mg/kg 5/slide

  20. Viral Doubling Time in vivo relative to Degree of Immunosuppression Slow Fast Log10 CMV Weeks Weeks

  21. Viral Doubling Time in vivo relative to Degree of Immunosuppression Slow Fast Log10 CMV Weeks Weeks R+ or D+/R- allograft < 1 mg/kg steroids and no T cell depletion All other allos CD34-s autos Cord blood: very fast

  22. CMV Viral Load Assay Variability • Quantitative DNA assays have lower variability than antigenemia assay • Coefficient of variation of most DNA assays < 0.3 • Viral load increases of > 0.5 log10 likely to indicate true increase

  23. Preemptive TherapyThreshold Levels for Starting Therapy Risk Threshold Very High < day 100: Any level > day 100: 1000 copies/mL High < day 100: 100 copies/mL* > day 100: 1000 copies/mL Low < day 100 500 copies/mL* > day 100 1000 copies/mL * Repeat after 2-3 days if less and treat if next value > 5x baseline

  24. Other Key Points • Stop of preemptive therapy: • One negative test • Valganciclovir • After day 100: ok for induction • Before day 100: generally IV induction

  25. Case • 58 yo women, 9 months after NM PBSCT for ALL in 1st remission • Early posttransplant complications • 2 episodes of CMV reactivation (+ one pre-Tx) • Acute GvHD • RSV URI • Now severe GI GVHD, diagnosed 4 weeks ago • 1 mg/kg steroids, FK506 and beclomethasone dipropionate • Admitted with respiratory failure requiring intubation

  26. Case – continued • CMV reactivation 7 weeks prior to admission: • plasma PCR 1100 treated with valganciclovir, • switched to 450 mg/day after one week, • switched back to acyclovir prophylaxis a 2 days prior to admission • Lab: Crea 0.2, bili 23.4, AST 390 • PCP prophylaxis: • atovaquone 1500 mg/day, • acyclovir 800 mg BID, • fluconazole 400 mg • Other medications • prednisone 2 mg/kg • beclomethasone dipropionate, FK506 for GI GVHD

  27. Case – Questions What would be your differential diagnosis? • PCP • CMV pneumonia • Respiratory virus pneumonia • Bronchiolitis obliterans • All of the above

  28. Case – Questions The patient was started on broadspectrum antibiotics (imipenem, vancomycin, gentamicin, levofloxacin). Which additional agents would you start empirically? • High-dose TMP-SMX • Ganciclovir induction therapy • Voriconazole • Oseltamivir • 1 and 2 • All of the above

  29. Case – Additional Information • Patient received TMP-SMX and ganciclovir empirically Additional diagnostic • IT aspirate: GPC, GPR, GNR (mixed flora), yeast • BAL: • Gram stain: GPC, GNR • Viral DFA; negative for ADV, RSV, FLU, PIV, HMPV • PCP DFA: negative • CMV shell vial: pending • Respiratory 12-virus multiplex PCR: pending • Aspergillus GM: positive (index 2) • Aspergillus PCR: pending • Legionella: negative • CMV PCR (plasma): 2 million copies/mL

  30. Case – Interim Working Diagnosis • Presumed CMV pneumonia • Drug resistance possible if not probable • Pulmonary aspergillosis • Bacterial pneumonia

  31. Utility of Galactomannan Detection in BAL Hematopoietic Cell Transplantation • Becker et al. Br J Haematol 2003 • Musher et al. J Clin Microbiol 2004 • Maertens et al. Clin Infect Dis 2009 Hematologic malignancies • Hsu et al. BMC Inf Dis 2010 • Bergeron et al. Chest 2010 Lung transplantation • Husein et al. Transplantation 2007 • Pascaloto et al. Transplantation 2010

  32. Case – Questions How would you adjust treatment? • Switch to foscarnet • Add foscarnet • Add voriconazole • Add both foscarnet and voriconazole • No change

  33. Foscarnet and voriconazole added

  34. Ganciclovir Resistance against CMVPrevalence 2010 SOT >>> HCT

  35. Ganciclovir Resistance against CMVPrevalence 2010 SOT >>> HCT However…..

  36. Low immune status Drug induced Severe IS (e.g. TCD, HD steroids) D+/R- CD4 count Ganciclovir ResistanceNot one single factor is responsible + Low drug levels Subclinical CMV load + + + Resistance + + Prolonged Adminstration

  37. CMV Drug Resistance High Risk Situation • Ganciclovir-experienced patient (prophylaxis, preemptive therapy, • pre-transplant use), especially with low doses • Increase of viral load > 2 weeks • High risk transplant setting • Lung, K-P transplant (D+/R-) • HCT (severe TCD or immunosuppression, e.g. haplo Tx) Ganciclovir Viral Load Ganciclovir Months after Transplantation

  38. CMV Drug Resistance Low Risk Situation • Ganciclovir-naïve patient • Increase of viral load during the first 2-3 weeks of therapy • Low risk setting (R+, kidney Tx, liver Tx, heart Tx, HCT) Ganciclovir Viral Load Months after Transplantation

  39. CMV Drug Resistance Mutation Map: UL97 and UL54 UL97 UL54 Chou S, Rev Med Virol 2008

  40. CMV Drug ResistanceDiagnosis • Increases of viral load as surrogate marker for resistance • drug-naïve subjects, early during treatment, low risk setting (R+): • drug resistance unlikely • increases most likely due to the underlying immunosuppression • after significant exposure (especially low-dose), high risk setting • More likely • True viral load increase: > 0.5 log10 (> 3x baseline) • Testing: direct genotypic testing if resistance is suspected • UL97 gene: CMV, maribavir • UL 54 gene: foscarnet, cidofovir, ganciclovir (high level)

  41. CMV Drug ResistanceManagement Strategies • Switch to alternative drug • Ganciclovir Foscarnet Cidofovir (some cross-resistance) • Foscarnet Ganciclovir Cidofovir • Reduce immunosuppression (if possible)

  42. CMV Drug ResistanceManagement Strategies In refractory situations (viral load increases, clinical deterioration): • Reduce immunosuppression if feasible • Consider dose increase if possible (West P et al. Transplant Infect Dis 2008) • Consider combination therapy • Continue ganciclovir in addition to foscarnet (Emery et al. PNAS 2008)

  43. CMV Drug ResistanceManagement Strategies In refractory situations – continued : • Consider alternative agents (alone or in combination) CASE REPORTS ONLY – NO CONSISTENT EVIDENCE • Leflunomide (Avery RK et al. BMT 2004; Battiwalla M et al. TID 2007) • Artesunate (Shapira et al., CID, 2008; Effert et al. CID, 2008) – not available everywhere • Consider alternative immunosuppressive agents • Sirolimus (Chou S, Rev Med Virol, 2008)

  44. CMV Drug ResistanceManagement Strategies In refractory situations – continued : • Consider experimental drugs if available: • High dose maribavir • Alone • In combination with foscarnet or cidofovir (not ganciclovir) • CMX-001 (lipid cidofovir)

  45. Summary: CMV Drug Resistance • Increases of viral load as surrogate marker for resistance • drug-naïve subjects, early during treatment, low risk setting: • Drug resistance unlikely, increases most likely due to the underlying immunosuppression • after significant exposure (especially low-dose), high risk setting • More likely, true increase: > 0.3 log10 • Testing: direct genotyping if resistance is suspected • Alternative treatment while awaiting results

  46. Case – Follow-up • Final BAL results: • Aspergillus GM and PCR positive • CMV SV positive, UL97 mutation detected • Pseudomonas aeruginosa (> 104 cfu/ml) • No evidence of • Respiratory virus disease • PCP • Legionellosis • Mycobacterial disease • Patient died of refractory respiratory failure

  47. Ganciclovir-related Neutropenia Not Reduced after Non-myeloablative Conditioning Adj. HR 1.1, P=0.52 Nakamae et al. ASH 2007 abstract

  48. Reduction of GCV or VGCV-related Neutropenia Strategies • Limit use of marrow-toxic drugs • Hold/replace concomitant medications (e.g. TMP-SMX, MMF, Imatinib) • Preemptive use of G-CSF • Studied in HIV-infected patients (Dubreuil-Lemaire et al. Eur J Haematol 2000, Kuritzkes et al. AIDS 1998) • Foscarnet (Reusser et al. Blood 2002) • Equivalent to IV GCV for CMV disease-free survival • Less neutropenia • Cidofovir: no randomized trials

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