1. CMV in KT recipients : D+/R- group
신장내과 이은빈

2. cytomegalovirus CMV is widely distributed in the general population .
-seroprevalence range : 30%-97%
After primary infection ,CMV establishes a life-long latency.
Following SOT, CMV can be a major cause of morbidity.
-Without some form of prevention, CMV reactivation /infection occurs in the first 3months following transplantat.
-Without prevention, up to75% of all patients undergoing SOT experience
new infection or reactivation of latent CMV.

3. Impact of CMV on overall mortality
Prospective
single center study
N=500
f/u 66 months
weekly CMV pp65 antigenemia for 100 days
2.9
2.5
Segedal S et al.Kidney Int 2004; 66:329.

4. CMV infection risk :a balance between viral and host factors

5. CMV serology status and outcomes
31.8%
15.9%
9.3%
5.7%
5.7%
Schnitzler MA et al.Am J Transplant 2003; 3:445

6. D+/R- without prevention 70 – 90% → "primary" CMV infection
50- 80% → CMV disease
30 % → CMV pneumonitis(a major contributor to morbidity and mortality)
15%→ death
Some centers had previously avoided the placement of CMV-positive kidneys into CMV-negative recipients.
Advent of effective prophylactic and rescue therapies

7. Preventive strategies Vs standard treatment
Previously, treatment was only administered once CMV disease occurred.
overall incidence of CMV disease : 20 – 60%
preventive strategies lowered the incidence of CMV disease : 5%
Prophylactic strategy and preemptive strategy

8. A prophylactic strategy Vs A preemptive strategy :definition

9. Suggest algorithm for Pre-Emptive Theraphy
IgG or IgM has no role in transplant recipients
KDOQI US comentary on the 2009 KDIGO clinical practice guideline
Margaret Bia et al.AJKD vol56,No2,2010:189
A.Humar ET AL. American Journal of Transplantation 2009; 9 (Suppl 4): S78–S86

10. A prophylactic strategy Vs A preemptive strategy :outcomes
It is unclear which preventive strategy is preferred
All symptomatc CMV diseaes acute rejection all-cause mortality
:no significant differance
Strippoli GF et al. Transplantation 2006; 81:139.
Kalil AC et al. Ann Intern Med 2005; 143:870.
Hodson EM et al. Lancet 2005; 365:2105.

11. A prophylactic strategy Vs A preemptive strategy :outcomes
10 trials (476 solid organ recipients)
Favours pre-emptive Tx
Favours prophylactic Tx
Strippoli GF et al. Transplantation 2006; 81:139.

12. A prophylactic strategy Vs A preemptive strategy :outcomes
Favours prophylactic Tx
Favours pre-emptive Tx
Strippoli GF et al. Transplantation 2006; 81:139.

13. A prophylactic strategy Vs A preemptive strategy
RCT
N=148
KT recipients
preemptive Tx arm
(N=74)
positive : (≥ 400 copies/mL)
5 mg/kg IV q12hrs
Until DNA <100 copies/mL
(at least 10 days)
+PO 1000mg TID 14d
Prophylaxis arm
(N=74)
ganciclovir mg TID
initial∼ for 90 days
F/U for 4yrs
Kliem V et al. Am J Transplant 2008; 8:

14. A prophylactic strategy Vs A preemptive strategy :outcomes
92.2%
78.3%
p =
80.2%
41.5%
Kliem V et al. Am J Transplant 2008; 8:

15. A prophylactic strategy Vs A preemptive strategy
International consensus guidelines on the management of CMV in solid organ transplantation Kotton CN et al.Transplantation 2010; 89:779.

16. International concensus guidelines on the CMV in SOT
Use of Prophylaxis Versus Preemptive Therapy
• Both universal prophylaxis and preemptive strategies are viable
approaches for prevention of CMV disease (I).
• For the highest risk patients (D+/R-), prophylaxis may have some
advantages over preemptive therapy (II).
Prophylaxis Strategy
• The duration of prophylaxis in (D+/R-)patients should be generally
between 3 and 6 months (I).
The decision to use 3 vs 6 months may depend on degree of
immunosuppression, including the using of antilymphocyte ab for
induction.
• Pharmacologic agents
- valganciclovir, IV or oral ganciclovir, or valacyclovir in KT (I).
International consensus guidelines on the management of CMV in solid organ transplantation Kotton CN et al.Transplantation 2010; 89:779.

17. Ganciclovir
Adverse effect
hematologic : neutropenia, anemia, thrombocytopenia
Gastrointestinal : nausea, vomitting, diarrhea, abdominal pain
Neurologic : headache, confusion, hallucination, seizures
Other : pain and phlebitis in injection site(due to high ph),
sweating, iching, rash, increased serum cr
Toxicity
Human carcinogen, teratogen and mutagen
Inhibits spermatogenesis
Dosing (renal dose reduction)
IV : induction-5mg/kg q12hrs
maintenance-5mg/kg qd
PO :1gm TID
Pharmacokinetics
Poor oral absorption : 5% in fasting, 8% with food

18. valganciclovir Adverse effect Similar to ganciclovir
Myelosuppression-main side effect that may limit prolonged use
Dosing
PO: 900mg(two 450mg tablets) once daily
Pharmacokinetics:
Oral bioavilability : 60%
Fatty foods significantly increase the bioavailability

19. Oral ganciclovir VS valganciclovir
RCT
N=364
(D+/R-)
28.0%
30.5%
Paya C et al. Am J Transplant 2004; 4:611.

20. Late-onset CMV disease
Definition
CMV disease after completion of prophylaxis
-Seen almost exclusively in patient who receive prophylaxis vs
preemptive therapy
Potential options
Careful clinical F/U with treatment as soon as symptoms occur.
Virologic monitering following prophylaxis
Prolonged prophylaxis from 3 to 6 months in D+/R- patients.
A.Humar ET AL. American Journal of Transplantation 2009; 9 (Suppl 4): S78–S86

21. 1st option : HYBRID therapy

22. 2nd option : Prolonged CMV prophylaxis 24 vs 12 weeks
prospective cohort study
KT recipients
N=70 (D+/R-)
93%
71%
Doyle AM et al. Transplantation 2006; 81:1106.

23. Prolonged CMV prophylaxis : IMPACT trial
multicentre, double-blind, randomized controlled trial
N= kidney allograft recipients (D+/R-)
Endpoints: CMV disease
at 12 and 24 months
Humar A et al. Am J Transplant 2010; 10:1228.

24. * Adverse events occurred at similar rates between the groups
IMPACT trial
(CMV disease)
16.1%
38.5%
* Adverse events occurred at similar rates between the groups
Humar A et al. Am J Transplant 2010; 10:1228.

25. Treatment of Established CMV Disease
Ganciclovir IV has been the ‘gold standard “ for CMV disease treatment for many years.
-In those with non-severe CMV disease, (oral) valganciclovir 900mg twice daily is alternative to IV ganciclovir.(VICTOR study)
-IV ganciclovir or oral valganciclovir treatment should be continued for at least 2weeks and, with weekly monitering of viral loads, until 2consecutive negative samples are obtained.
International consensus guidelines on the management of CMV in solid organ transplantation Kotton CN et al.Transplantation 2010; 89:779.

26. VICTOR study:(oral) valganciclovir Vs IV ganciclovir
Multicenter randomized Non-inferiority trial
N=321
SOT recipients with CMV disease(74%:KT)
Asberg A, et al. Am J Transplantation.2007;7(9):

27. VICTOR study:oral valganciclovir Vs IV ganciclovir
: similarly effective in suppressing viremia
Valganciclovir 900mg twice daily is alternative to IV ganciclovir.
Asberg A, et al. Am J Transplantation.2007;7(9):

28. In case of life- threatening or severe CMV disease.
IV therapy
In case of life- threatening or severe CMV disease.
In situation where there is the potential for problems with oral drug absorption.
-severe diarrhea or CMV enteritis
In cases of suspected ganciclovir resistant CMV.
International consensus guidelines on the management of CMV in solid organ transplantation Kotton CN et al.Transplantation 2010; 89:779.

29. Management of immunosuppression in CMV Viremia /Disease
Clear data to guide management is lacking -Always lower immunosuppression for severe/life-threatening CMV disease (II-2) -Always lower immunosuppression for suspected ganciclovir resistace (III) Based on the VICTOR study data: -Dual, as compared to triple immunosuppressive therapy showed on odds ratio of 2.55(p=0.002) for early (day21) CMV clearance. -Low concentration of CNI were associated higher odds ratio of 5.53(p=0.045) for early CMV clearance(day21).
International consensus guidelines on the management of CMV in solid organ transplantation. Kotton CN et al.Transplantation 2010; 89:779.

30. CMV antiviral resistance
Suspected when increasing or high-level CMV viremia or progressive clincal disease is observed during prolonged antiviral therapy.
1-2% with 3months prophylaxis
Risk factors
-prolonged low-dose prophylaxis
-increased intensity of immunosuppression
-lack of prior CMV immunity(D+/R-)
International consensus guidelines on the management of CMV in solid organ transplantation Kotton CN et al.Transplantation 2010; 89:779.

31. CMV antiviral resistance :proposed treatment alorithm
A. Humar et al. American Journal of Transplantation 2009; 9 (Suppl 4): S78–S86