1. A classic case of loosing options… Hans H Hirsch Transplantation & Clinical Virology Department Biomedicine (Haus Petersplatz) Division Infection Diagnostics Department Biomedicine (Haus Petersplatz) University of Basel Infectious Diseases & Hospital Epidemiology University Hospital Basel Switzerland Cases in TID Cancun, Mexico 13.10.2015

2. Case 1 2 Male, 50-years-old, follicular lymphoma in 2002, CMV IgG + Matched unrelated HSCT in 2011 Donor CMV IgG – GvHD prophylaxis standard low-dose CsA – MTX - MPred Asymptomatic CMV replication 561 IU/mL in weekly surveillance at 3 weeks posttransplant, coincident with engraftment Would your treat with antivirals ?

3. Case 1 (cont’d 2) 3 Male, 50yrs, follicular lymphoma in 2002, CMV IgG + 1.HSCT Matched unrelated HSCT in 2011 Donor CMV IgG – GvHD prophylaxis standard low-dose CsA – Methotrexate Asymptomatic CMV replication 561 IU/mL in weekly surveillance at 3 weeks posttransplant, coincident with engraftment –Valganciclovir 900mg bd (GFR corrected), for 3 weeks –CMV <137 IU/mL after 2 weeks Day 52: Symptomatic CMV replication 73’00 IU/mL Valganciclovir 900mg bd (GFR corrected), for 6 weeks –CMV <137 IU/mL after 4 weeks Day 152: Recurrence CMV 85’000 IU/mL Valganciclovir 900mg bd (GFR corrected), for 6 weeks –CMV remains detectable after 4 weeks, re-increasing

4. Some Questions 4 Why is this so difficult ? –Is this a patient problem? –Is this a donor problem? –Is this a drug problem? Ganciclovir resistance testing –UL97 phopshotransferase mutation

5. Case 1 (cont’d 3) 5 Male, 50yrs, follicular lymphoma 2002, CMV IgG + 1. HSCT 2011 (MUD CMV IgG –), cGvHD; recurrent CMV Month 8: CMV 1.400’000 IU/mL, Foscarvir 60 mg/kg x12h

6. Case 1 (cont’d 4) 6 Male, 50yrs, follicular lymphoma in 2002, CMV IgG + 1.HSCT 2011 (MUD CMV IgG –), cGvHD; recurrent CMV –clinical FOS failure, Cidofovir 5 mg/kg/wk+probenicid

7. Case 1 (cont’d 5) 7 Male, 50yrs, follicular lymphoma in 2002, CMV IgG + 1.HSCT 2011 (MUD CMV IgG –), cGvHD; recurrent CMV –clinical FOS failure, Cidofovir response, CMV rebound

8. Case 1 (cont’d 6) 8 Male, 50yrs, follicular lymphoma in 2002, CMV IgG + 1.HSCT 2011 (MUD CMV IgG –), cGvHD; recurrent CMV –GCV UL97®, FOS failure?, Cidofovir response, CMV rebound –FOS UL54®, Leflunomide failure, lymphopenia

9. Case 1 (cont’d 7) 9 Male, 50yrs, follicular lymphoma 2002, CMV IgG + 1. HSCT 2011 (MUD CMV IgG –), cGvHD; recurrent CMV –GCV UL97®, FOS UL54®; LEF failure, graft failure 2. HSCT 2013 (MUD CMV IgG+); Artes tox, Maribavir + pp65+CMV T-cells

10. Case 1 (cont’d 8) 10 Male, 50yrs, follicular lymphoma 2002, CMV IgG + 1. HSCT 2011 (MUD CMV IgG –), cGvHD; recurrent CMV –GCV UL97®, FOS UL54®; LEF failure, graft failure 2. HSCT 2013 (MUD CMV IgG+); Artes tox, Maribavir + pp65+CMV T-cells

11. 11 Key points High-risk for recurrent CMV replication –HSCT CMV D-/R+ –SOT CMV D+/R- High-risk for CMV resistance –Insufficient antiviral drug levels (dosing, adherence, GFR) –Outpatient, oral administration, high viral loads CMV non-response, resistance –Virological, genotypic, clinical –Limited fitness costs in CMV-T-cell deficiency Experimental drugs –Cave dosing, toxicity Adopitve T-cell transfer –Availability timing, immunopathology (CMV retinitis, IRIS)

12. 12 Evidence level: Dramatic results from single cases http://onlinelibrary.wiley.com/doi/10.1111/tid.12435/abstract

13. 13 Risk factors of viral complications posttransplant Insufficient immune control –Naïve (no memory) –Depleted (anti-lymphocyte globulins, -pheresis) –Immunosuppressed (maintenance, anti-rejection) Allogenic constellation between virus-infected cells and the T- cell effectors –Virus with tropism for organ transplant –Allogeneic HSCT Pathology –Virus determinants –Host determinants –Cytopathology –Immunopathology (including IRIS)

14. Some Questions 14 How does your laboratory determine CMV –CMV pp65 Antigenemia ? –Quantitative Nucleic Acid Testing (NAT) e.g. PCR How is your CMV quantification reported ? –Antigenemia per 200’000 Leukocytes ? –CMV loads in copies/mL, Geq/mL, or IU/ml? What is the Lower Limit of Detection (LOD) used at your center ? –2 AG /200’000 cells? –137 IU/mL ? –Other ? What is the threshold of starting antiviral therapy ? –Any CMV detection in blood in 3 months screening posttransplant? –Any confirmed CMV detection –500 IU/mL; 1500 IU/mL; 3000 IU/mL