1. Case Two: When the drugs don’t work Drug resistance in CMV
Educational Workshops 2015
Case Two: When the drugs don’t work Drug resistance in CMV
We are grateful to William Tong, Consultant Virologist,
Barts Health NHS Trust, London for composing this case.

2. Background 35 year old patient with AML Initially diagnosed in 2006
Remission after chemotherapy
Relapse of AML August 2012
Mismatched unrelated donor allograft stem cell transplantation

3. CMV status of donor and recipient
Donor CMV IgG negative, recipient CMV IgG positive

4. What is the significance?

5. What is the significance?
Latent CMV in the recipient
Absence of immunity in the donor stem cells against CMV
High risk of CMV reactivation

6. What management strategies are there?

7. What management strategies are there?
Prophylaxis
X 3-6 months
versus
Pre-emptive therapy
Monitor CMV viral load. Treat on first sign of reactivation (variable definitions used, copies/ml vs IU/ml)
Antiviral agent of choice - Valganciclovir

8. Monitoring of Plasma viral load
Day after transplant
CMV viral load (copies/ml)
Log value 7
Not detected 11 12
750
2.9 16
780 18
720 21
1508
3.2 25
12022
4.1 27
21730
4.3

9. How to interpret the CMV viral load result

10. How to interpret the CMV viral load results
Evidence of CMV reactivation from Day 12
If patient is CMV IgG negative pre-transplant, any detectable CMV viral load post-transplant is significant as this indicates a primary infection
Significant increase in viral load between Day 21 and Day 25
~ 1 log increase in viral load within 4 days
“Interpret any change in viral load using the log value”
Acceptable change within assay = < 0.5 log
Significant increase = > 1.0 log

11. Progress of patient
Treated with 2 courses of VGCV (total duration 8 weeks) until CMV viral load undetectable
Viral load in blood suppressed, but patient developed diarrhoea

12. Could CMV be the cause of the diarrhoea?

13. Could CMV be the cause of the diarrhoea?
Colonoscopy with biopsy confirmed two pathologies:
CMV colitis and Graft Versus Host Disease (GVHD) A B
Typical owl eye inclusion body in colonic biopsy and nuclear staining observed in cytomegalovirus (CMV) colitis. Source:
Colonic biopsy specimen shows acute graft-vs-host disease, grade III, with crypt destruction and apoptotic cells (A, H&E, x100; B, x400) Source: medscape

14. Could CMV be the cause of the diarrhoea?
Colonoscopy with biopsy confirmed CMV colitis and GVHD
Suppressed CMV viral load in plasma does not exclude CMV colitis

15. Re-started VGCV
VGCV re-started but CMV VL continued to increase despite VGCV
What to do next?

16. What to do next? Request CMV resistance test
Genotyping method available
CMV genes
UL97
UL54
Function
Protein kinase – phosphorylation of Ganciclovir
DNA polymerase – Essential for DNA replication
Mutations confer resistance to:
Ganciclovir
Ganciclovir, Foscarnet, Cidofovir
Remain susceptible to:
Foscarnet, Cidofovir
Cross resistance to other agents acting on the same target

17. UL97 mutation map
UL97 mutations conferring GCV resistance

18. UL54 mutation map
UL54 mutations conferring GCV, CDV and foscarnet resistance

19. CMV resistance test result
UL97 sequencing
A594V
UL54
no resistance mutation detected
Interpretation
7-10 fold resistance to GCV
Retains susceptibility to cidofovir and foscarnet

20. What other options are there?

21. What other options are there?
Immunosuppression reduction
Note this patient also has GVHD
Foscarnet
Cidofovir
Newer agents
Maribavir
Brincidofovir
Letermovir

22. Information for the new agents
Maribavir
Target UL97 (protein kinase) - Incompatible with ganciclovir
Potent in vitro
Failed to meet goal in phase III prophylaxis study - no difference cf placebo
Available for compassionate use
Brincidofovir
Prodrug of cidofovir - Conjugated to lipid, released intracellularly
Increase oral bioavailability, reduce toxicity
Broad spectrum of in vitro antiviral effectiveness
Letermovir
Terminase (UL56) inhibitor - affects DNA cleavage and packaging
Novel target
Little toxicity
Successful phase II clinical trial in Hematopoietic-Cell Transplantation
(N Engl J Med 2014; 370: )

23. Progress Maribavir Cidofovir VGCV VGCV VGCV Log CMV viral load
No of days after transplantation

24. Further progress
Readmitted Day 340 after transplant with nausea and diarrhoea
Developed SOB requiring O2

25. Chest X-Ray

26. What is the diagnosis
Differential diagnoses?

27. What is the diagnosis Presumed CMV pneumonitis
Too ill to have bronchoscopy or broncho-aveolar lavage

28. What treatment is available for CMV pneumonitis?

29. What treatment is available for CMV pneumonitis?
Antiviral +
IVIG
Note: UK Clinical guidelines for IVIG
Outcome poor
RIP

30. Department of Health. Clinical guidelines for immunoglobulin use: second edition 2008
Update to second edition (01 Aug 2011)

31. Summary A stem cell transplant recipient developed CMV reactivation
initially controlled by valganciclovir, but then developed resistance
Second line therapies were either intolerant or ineffective
Patient eventually died of CMV pneumonitis.

32. Lessons
CMV is still a major cause of mortality and morbidity after transplantation.
The use of valganciclovir can prevent or control CMV in most cases, but there is a risk of development of resistance.
Current second line therapies against CMV are often suboptimal in effectiveness and can be associated with significant side effects such as renal impairment
New antiviral against CMV are badly needed