CMV in KT recipients : D+/R- group 2012.1.18 신장내과 이은빈

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.

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.

CMV infection risk :a balance between viral and host factors

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

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

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

A prophylactic strategy Vs A preemptive strategy :definition

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

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.

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.

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

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 1000 mg TID initial∼ for 90 days F/U for 4yrs Kliem V et al. Am J Transplant 2008; 8: 975-983.

A prophylactic strategy Vs A preemptive strategy :outcomes 92.2% 78.3% p = 0.0425 80.2% 41.5% Kliem V et al. Am J Transplant 2008; 8: 975-983.

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.

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.

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

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

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

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

1st option : HYBRID therapy

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.

Prolonged CMV prophylaxis : IMPACT trial multicentre, double-blind, randomized controlled trial N= 326 kidney allograft recipients (D+/R-) Endpoints: CMV disease at 12 and 24 months Humar A et al. Am J Transplant 2010; 10:1228.

* 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.

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.

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):2106-2113

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):2106-2113

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.

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.

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.

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